CN105152827A - Cross coupling reaction of arenesulphonate substrate and organic titanium - Google Patents

Abstract

The invention relates to a cross coupling reaction of an arenesulphonate substrate and organic titanium. The cross coupling reaction comprises steps as follows: A), after palladium acetate and indole phosphine ligands are utilized to generate a catalyst, the arenesulphonate substrate, aryl titanium, potassium phosphate and an organic solvent are added; B), the components react for 12-24 h at the temperature of 110-130 DEG C, and a biaryl compound is obtained. Compared with the Suzuki coupling reaction, the cross coupling reaction of the arenesulphonate substrate and organic titanium has the advantages that with addition of a small amount of alkali, organic titanium can be catalyzed to have the cross coupling reaction, and the reaction cost can be reduced. Besides, organic titanium is adopted as nucleophile for reaction, and compared with a Grignard reagent required to be stored in an organic solvent in the Kumada coupling reaction, solid organic titanium is easier to apply, has high stability, can be massively synthesized and is easy to store. Compared with organic tin in the Stille cross coupling reaction, organic titanium has lower toxicity and assists in improvement of applicability of the reaction.

Description

Cross-Coupling Reaction of Aryl Sulfonate Substrates with Organotitanium

technical field

The invention relates to the cross-coupling reaction of aryl p-toluenesulfonate and organic titanium.

Background technique

In 2002, Hayashi's research group first used organotitanium and aryl bromide and aryl triflate for the bonding reaction to form biaryl compounds. In recent years, Gau's research group and Kwong's research group have used different palladium complexes to catalyze the coupling reaction of aryl chloride and organic titanium to synthesize various biaryl compounds.

Although aryl halides can react with organic titanium to form biaryl compounds, the scope of substrates is small, and the applicability needs to be improved. Aryl sulfonate substrates are complementary substrates of aryl halides, which can effectively complement or replace aryl halides as reaction substrates in the synthetic route. Therefore, if the cross-coupling reaction between aryl sulfonate substrate and organotitanium is successfully carried out, the applicability of this new reaction can be effectively improved. However, the activity of arylsulfonate substrates is very low. As far as we know, there is no example of successfully catalyzing the cross-coupling reaction between arylsulfonate substrates and organotitanium.

Contents of the invention

The present invention relates to the cross-coupling reaction between aryl sulfonate substrates and organic titanium, but the activity of aryl sulfonate substrates is very low, and it is necessary to use palladium metal and indole phosphine ligands to catalyze the reaction with a small amount of alkali Only under these conditions can the reaction form biaryl compounds.

In order to achieve the above-mentioned purpose, the technical scheme adopted in the present invention is: palladium acetate and indole phosphine ligands are used to generate catalysts, and aryl sulfonate substrates, aryl titanium and potassium phosphate are dissolved in 1,4-dioxan In alkanes, react at 110-130°C for 12-24 hours to obtain biaryl compounds.

The molar number and molar ratio of the above catalyst palladium acetate and the phosphine ligand are 0.01mmol-0.025mmol:0.04mmol-0.1mmol, and the molar number and molar ratio of the aryl sulfonate substrate, aryl titanium and potassium phosphate are 0.5 mmol: 1.0mmol-2.5mmol: 0.125mmol. The amount of catalyst used is 2.0-5.0 Pdmol%.

The above-mentioned aryl sulfonate substrates are 4-tert-butylphenyl p-toluenesulfonate, 3,5-xylyl p-toluenesulfonate, 3,4-xylyl p-toluenesulfonate, 3- Methoxyphenyl p-toluenesulfonate, 4-methoxyphenyl p-toluenesulfonate, 4-fluorophenyl p-toluenesulfonate, 2,6-xylyl p-toluenesulfonate, 6-quinoline p-toluenesulfonate, 3,4-methylenedioxybenzene-p-toluenesulfonate, 2-methyl-6-benzothiazolyl-p-toluenesulfonate. The aryl titanium is titanium 4-methylphenisopropoxide, titanium 4-methoxyphenisopropoxide.

The above-mentioned phosphine ligand is 2-[2-(dicyclohexylphosphine) phenyl]-1-methyl-1H-indole, and its structural formula is:

The present invention has the following advantages:

(1) The present invention carries out cross-coupling reaction between aryl sulfonate substrates and organic titanium. Compared with Suzuki coupling reaction, adding a very small amount of alkali can catalyze organic titanium to carry out cross-coupling reaction, which can reduce the reaction cost .

(2) Using organotitanium as a nucleophile for the reaction, compared with the Grizzard reagent that must be stored in an organic solvent in the Kumada coupling reaction, solid-state organotitanium is easier to use and has high stability, and can be synthesized in large quantities and stored easily.

(3) Compared with organotin in the Stille cross-coupling reaction, organotitanium is less toxic and helps to improve the applicability of the reaction.

specific embodiment

The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way.

Embodiment one: the coupling reaction of aryl p-toluenesulfonate and 4-methylphenisopropoxide titanium

In a 20mL Schlenk tube, add palladium acetate (0.025mmol) and phosphine ligand (palladium: phosphine ligand ratio is 5mol%: 20mol%), then add a magnetic stirring bar equipped with a polytetrafluoroethylene coating, and the system is replaced by Under nitrogen protection, 0.1 mL of freshly distilled triethylamine and 1.0 mL of dichloromethane were added, stirred and heated gently to a slight boil, and then sucked dry under reduced pressure to form a palladium complex.

Aryl p-toluenesulfonate (0.5 mmol), titanium 4-methylphenisopropoxide (2.5 mmol) and potassium phosphate (0.125 mmol) were then added under nitrogen. Finally, 1,4-dioxane solution (2.0 mL) was added, and then the Schlenk tube was placed in a preheated oil bath at 110° C. for 18 to 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, about 10 mL of water was added to the system, and about 10 mL of ethyl acetate was added, and the organic layer was analyzed by gas chromatography. Then add about 10 mL of ethyl acetate in three to four times for extraction, combine the organic phases, and concentrate under reduced pressure. The product biaryl compound was obtained by column chromatography, and the isolated yield is shown in Table 1 below.

Table 1: Biaryl compounds generated from aryl p-toluenesulfonate and 4-methylphenyltitanium

Embodiment two: the coupling reaction of aryl p-toluenesulfonate and 4-methoxyphenylisopropoxide titanium

In a 20mL Schlenk tube, add palladium acetate (0.025mmol) and phosphine ligand (palladium: phosphine ligand ratio is 5mol%: 20mol%), then add a magnetic stirring bar equipped with a polytetrafluoroethylene coating, and the system is replaced by Under nitrogen protection, 0.1 mL of freshly distilled triethylamine and 1.0 mL of dichloromethane were added, stirred and heated gently to a slight boil, and then sucked dry under reduced pressure to form a palladium complex.

Aryl p-toluenesulfonate (0.5 mmol), titanium 4-methoxyphenisopropoxide (2.5 mmol) and potassium phosphate (0.125 mmol) were then added under nitrogen. Finally, 1,4-dioxane solution (2.0 mL) was added, and then the Schlenk tube was placed in a preheated oil bath at 110° C. for 18 to 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, about 10 mL of water was added to the system, and about 10 mL of ethyl acetate was added, and the organic layer was analyzed by gas chromatography. Then add about 10 mL of ethyl acetate in three to four times for extraction, combine the organic phases, and concentrate under reduced pressure. The product biaryl compound was obtained by column chromatography, and the isolated yield is shown in Table 2 below.

Table 2: Aryl p-toluenesulfonate and 4-methoxyphenyltitanium generate biaryl compounds

Embodiment three: the coupling reaction of heterocyclic aryl p-toluenesulfonate and organic titanium

In a 20mL Schlenk tube, add palladium acetate (0.025mmol) and phosphine ligand (palladium: phosphine ligand ratio is 5mol%: 20mol%), then add a magnetic stirring bar equipped with a polytetrafluoroethylene coating, and the system is replaced by Under nitrogen protection, 0.1 mL of freshly distilled triethylamine and 1.0 mL of dichloromethane were added, stirred and heated gently to a slight boil, and then sucked dry under reduced pressure to form a palladium complex.

Heterocyclic aryl p-toluenesulfonate (0.5 mmol), organotitanium (2.5 mmol) and potassium phosphate (0.125 mmol) were subsequently added under nitrogen. Finally, 1,4-dioxane solution (2.0 mL) was added, and then the Schlenk tube was placed in a preheated oil bath at 110° C. for 18 to 24 hours. After the reaction was completed, the reaction tube was cooled to room temperature, about 10 mL of water was added to the system, and about 10 mL of ethyl acetate was added, and the organic layer was analyzed by gas chromatography. Then add about 10 mL of ethyl acetate in three to four times for extraction, combine the organic phases, and concentrate under reduced pressure. The product biaryl heterocyclic compound was obtained by column chromatography, and the isolated yield is shown in Table 3 below.

Table 3: Heterocyclic aryl p-toluenesulfonate and organic phenyl titanium generate biaryl heterocyclic compounds

Example 4: Coupling reaction at a temperature of 130°C

In a 20mL Schlenk tube, add palladium acetate (0.025mmol) and phosphine ligand (palladium: phosphine ligand ratio is 5mol%: 20mol%), then add a magnetic stirring bar equipped with a polytetrafluoroethylene coating, and the system is replaced by Under nitrogen protection, 0.1 mL of freshly distilled triethylamine and 1.0 mL of dichloromethane were added, stirred and heated gently to a slight boil, and then sucked dry under reduced pressure to form a palladium complex. Then 4-tert-butylaryl-p-toluenesulfonate (0.5 mmol), titanium 4-methylphenisopropoxide (2.5 mmol) were added under nitrogen. Finally, 1,4-dioxane solution (2.0 mL) was added, and then the Schlenk tube was placed in a preheated 130° C. oil bath for 14 hours to react. After the reaction was completed, the reaction tube was cooled to room temperature, about 10 mL of water was added to the system, and about 10 mL of ethyl acetate was added, and the organic layer was analyzed by gas chromatography. Then add about 10 mL of ethyl acetate in three to four times for extraction, combine the organic phases, and concentrate under reduced pressure. The product biaryl heterocyclic compound was obtained by column chromatography with an isolated yield of 68%.

Embodiment five: the reaction of adding different portions of potassium phosphate

In a 20mL Schlenk tube, add palladium acetate (0.025mmol) and phosphine ligand (palladium: phosphine ligand ratio is 5mol%: 20mol%), then add a magnetic stirring bar equipped with a polytetrafluoroethylene coating, and the system is replaced by Under nitrogen protection, 0.1 mL of freshly distilled triethylamine and 1.0 mL of dichloromethane were added, stirred and heated gently to a slight boil, and then sucked dry under reduced pressure to form a palladium complex. Then 4-tert-butylaryl-p-toluenesulfonate (0.5 mmol), titanium 4-methylphenisopropoxide (2.5 mmol) were added under nitrogen. Finally, tetrahydrofuran solution (2.0 mL) was added, and then the Schlenk tube was placed in a preheated oil bath at 110° C. to react for 11 hours. After the reaction was completed, the reaction tube was cooled to room temperature, about 10 mL of water was added to the system, and about 10 mL of ethyl acetate was added, and the organic layer was analyzed by gas chromatography. Then add about 10 mL of ethyl acetate in three to four times for extraction, combine the organic phases, and concentrate under reduced pressure. The product biaryl heterocyclic compound was obtained by column chromatography, and the isolated yield is shown in Table 4 below.

Table 4: The impact of adding different amounts of potassium phosphate on the reaction

Embodiment six: palladium acetate and ligand ratio are the reaction of 2mol%: 8mol%

In a 20mL Schlenk tube, add palladium acetate (0.01mmol) and phosphine ligand (palladium: phosphine ligand ratio is 2mol%: 8mol%), then add a magnetic stirring bar equipped with a polytetrafluoroethylene coating, and the system is replaced by Under nitrogen protection, 0.1 mL of freshly distilled triethylamine and 1.0 mL of dichloromethane were added, stirred and heated gently to a slight boil, and then sucked dry under reduced pressure to form a palladium complex.

3-Methoxyaryl p-toluenesulfonate (0.5 mmol), titanium 4-methylphenisopropoxide (2.5 mmol) were then added under nitrogen. Finally, 1,4-dioxane solution (2.0 mL) was added, and then the Schlenk tube was placed in a preheated oil bath at 110° C. for 24 hours to react. After the reaction was completed, the reaction tube was cooled to room temperature, about 10 mL of water was added to the system, and about 10 mL of ethyl acetate was added, and the organic layer was analyzed by gas chromatography. Then add about 10 mL of ethyl acetate in three to four times for extraction, combine the organic phases, and concentrate under reduced pressure. The product biaryl heterocyclic compound was obtained by column chromatography with an isolated yield of 80%.

Claims (5)

1. the cross-coupling reaction of tosic acid aryl ester and organic titanium, is characterized in that, comprises step:

A), after acid chloride and indoles Phosphine ligands being generated catalyzer, aromatic yl sulphonate class substrate, aryl titanium, phosphoric acid Potassium and organic solvent is added,

B) in 110-130 DEG C of reaction 12-24 hour, aryl-linking compound is obtained.

2. according to claim 1 the cross-coupling reaction that describes, it is characterized in that: the mole number of described catalyst acetic acid palladium and Phosphine ligands and mol ratio are 0.01mmol-0.025mmol:0.04mmol-0.1mmol, the mole number of aromatic yl sulphonate class substrate, aryl titanium and phosphoric acid Potassium and mol ratio are 0.5mmol:1.0mmol-2.5mmol:0.125mmol.Catalyst levels is 2.0-5.0Pdmol%.

3. according to claim 1 or 2 the cross-coupling reaction that describes, it is characterized in that: described aromatic yl sulphonate class substrate is 4-trimethylphenylmethane base p-toluenesulfonic esters, 3,5-xylyl p-toluenesulfonic esters, 3,4-xylyl p-toluenesulfonic esters, 3-methoxyphenyl p-toluenesulfonic esters, 4-methoxyphenyl p-toluenesulfonic esters, 4-fluorophenyl p-toluenesulfonic esters, 2, one in 6-xylyl p-toluenesulfonic esters, 6-quinoline p-toluenesulfonic esters, 3,4-methylenedioxyphenyl p-toluenesulfonic esters, 2-methyl-6-benzothiazolyl p-toluenesulfonic esters.

4. according to claim 1 or 2 the cross-coupling reaction that describes, it is characterized in that: described aryl titanium is 4-methylbenzene titanium isopropylate, 4-anisole titanium isopropylate.

5. according to claim 1 or 2 the cross-coupling reaction that describes, it is characterized in that: described indoles Phosphine ligands is 2-[2-(dicyclohexylphosphontetrafluoroborate) phenyl]-1-Methyl-1H-indole, and its structural formula is: