JPH09255668A - Production of bisoxazolines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain bisoxazolines from bisamides in a high yield without requiring special equipment. SOLUTION: This bisoxazolines of formula II are obtained by intramolecular condensation of bisamides of formula I (R<1> and R<2> are each an alkyl; (*) is an asymmetric carbon) in the presence of at least one compound selected from among titanium alkoxides (e.g. titanium tetraisopropoxide) and trifluoromethane sulfonates of lanthanoid metals (e.g. ytterbium trifluoromethane sulfonate) in a solvent (e.g. xylene) at 15-200 deg.C. For 1mol of bisamides, 0.001-0.5mol of titanium alkoxide and trifluoromethane sulfonates of lanthanoid metals is used. As a compound of formula II, 2,2'-isopropylidene bis[(4R)-4-t-butyl-2-oxazoline] can be exemplified.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing bisoxazolines.

[0002]

2. Description of the Related Art Bisoxazolines are useful compounds as ligands for obtaining transition metal complexes. For example, their optically active compounds include olefins, diazoacetic acid esters, iron salts and asymmetric ligands. It is known as an asymmetric ligand for producing asymmetric cyclopropanecarboxylic acids by reacting them in the presence of [J. Am. Chem. Soc. , 113 , 726 (1991)]. As a method for producing such bisoxazolines, for example, a method of reacting malonic acid esters and amino alcohols in the presence of dialkyldichlorotins [Tetrahed
Ron Letters, 31,6005 (1990)], a method of intramolecular condensation reaction of bisamides in the presence of thionyl chloride or dialkyldichlorotin (Helv. Chim. Acta., 74 , 232 (199).
1), US Pat. No. 5,298,623] and the like are known, but since dialkyldichlorotin is toxic, special equipment for handling it is required, and the method using thionyl chloride has a low yield. However, it was not an industrially satisfactory method.

[0003]

Therefore, as a result of earnest studies to develop a method for easily producing a bisoxazoline compound in a high yield without using special equipment, the present inventor has found that The present inventors have found that bisoxazolines can be easily produced by carrying out an intramolecular condensation reaction in the presence of at least one selected from titanium alkoxides and lanthanoid metal trifluoromethanesulfonate.

[0004]

That is, the present invention is based on the general formula (2): (In the formula, R ¹ and R ² each represent an alkyl group, and * represents an asymmetric carbon atom.), At least one selected from titanium alkoxides and lanthanoid metal trifluoromethanesulfonate. General formula (1) characterized by carrying out an intramolecular condensation reaction in the presence of (Wherein R ¹ , R ² and * have the same meanings as described above), and a method for producing the bisoxazolines.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION In the bisamides used in the method of the present invention, examples of the alkyl group in the substituents R ¹ and R ² include a methyl group, an ethyl group, a normal propyl group, a normal butyl group and a t-butyl group. And so on.

In the bisamides represented by the general formula (2), there are two asymmetric carbon atoms represented by *, and there are at least two kinds of optically active substances having these as asymmetric centers. The bisamides used in the method of the present invention may be any optically active isomers, racemates thereof, and meso isomers. Examples of such bisamides include dimethylmalonobis [N- (2R) -t-butylethanol] amide, dimethylmalonobis [N- (2R) -methylethanol] amide and (2R) in each of the above compounds is (2S). ,
Examples thereof include compounds corresponding to (2RS) or (2R, 2'S).

Examples of titanium alkoxides include titanium tetraisopropoxide and titanium tetra-t-butoxide.

[0008] Lanthanoid metal Ytterbium and the like are exemplified as the lanthanoid metal in the trifluoromethanesulfonate. Examples of the lanthanoid metal organic acid salt include ytterbium trifluoromethanesulfonate, which may contain water of crystallization.

The titanium alkoxide and the lanthanoid metal trifluoromethanesulfonate are used alone or in admixture of two or more, and the amount thereof is usually 0.001 to 0.5 mol times, preferably the amount of the bisamide. Is in the range of 0.005 to 0.1 molar times.

The reaction may be carried out without solvent, but it is usually carried out in a solvent. The solvent is not particularly limited as long as it is inert to the reaction, for example, hexane, heptane, an aliphatic hydrocarbon solvent such as cyclohexane,
Examples thereof include halogenated hydrocarbon solvents such as 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as toluene and xylene, and among them, high boiling point solvents such as toluene and xylene are preferably used. These solvents are used alone or in combination of two or more, and the amount thereof is usually 1 to 100 with respect to the bisamides.
It is in the range of weight times.

In the reaction, for example, at least one selected from titanium alkoxide and lanthanoid metal trifluoromethanesulfonate and a bisamide may be mixed in a solvent, and the reaction temperature is usually 15 to 200.
C., preferably in the range of 50 to 200.degree. Water is by-produced by such a reaction, which is an ordinary method from the reaction system, for example, a reflux dehydration method of azeotropically distilling with a solvent or distilling out with a solvent and then separating the water into the reaction system. In order to easily carry out such reflux dehydration method, a solvent that can be azeotropically distilled with water or a hydrophobic solvent that can be easily separated from water is preferably used to facilitate the reflux dehydration method.

After the reaction, the reaction mixture obtained is subjected to a conventional method, for example, washing the reaction mixture with water, or using a solvent compatible with water in the previous reaction or using a small amount of the solvent, toluene is used. The target bisoxazolines can be easily obtained by a method of adding a crude aqueous solvent such as xylene, washing with water, and then distilling off the solvent. This may be further purified by a method such as recrystallization or column chromatography.

In the bisoxazolines represented by the general formula (1) thus obtained, the steric configuration centered on the two asymmetric carbon atoms represented by * is the same as in the bisamides used.

Examples of such bisoxazolines include 2,2'-isopropylidene bis [(4R) -4-t
-Butyl-2-oxazoline], 2,2'-isopropylidene bis [(4R) -4-methyl-2-oxazoline] and (4R) in each of the above compounds is (4S),
Examples thereof include compounds corresponding to (4RS) or (4R, 4 ′S).

[0015]

According to the method of the present invention, bisoxazolines can be produced in high yield without using special equipment.

[0016]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.

Reference Example 1 (S) -t-Leucinol 5 in 150 ml of chloroform
g and 8.63 g of triethylamine were dissolved, 3.61 g of dimethylmalonic acid chloride was added dropwise over 40 minutes with stirring at 0 ° C., and then stirring was continued at the same temperature for 8 hours. Next, the obtained reaction mixture was mixed with 200 g of a saturated aqueous ammonium chloride solution, stirred, and then separated to obtain an organic layer and an aqueous layer. Chloroform 1 was added to the obtained aqueous layer.
The extraction operation using 00 ml was performed twice, the obtained organic layer and the above organic layer were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 150 ml of methylene chloride was added, washed twice with 100 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give dimethylmalonobis [N- (2S) -2-t-butyl. Ethanol] amide 4.99 g was obtained.

Example 1 Dimethylmalonobis [N- (2S) was added to 40 ml of xylene.
-2-t-Butylethanol] amide 1 g (3.03 m
g) and titanium tetraisopropoxide 43 mg
(0.15 mmol) was added, and the mixture was heated under reflux with dehydration for 72 hours while stirring. Then, the solvent was distilled off under reduced pressure to obtain 795 mg of a residue. ^When this residue was analyzed by the ¹ H-NMR-IS method, the content of 2,2-isopropylidenebis [(4S) -4-t-butyl-2-oxazoline] was 76% by weight (yield 68 %).

Example 2 The same procedure as in Example 1 was conducted except that the heating time was changed to 24 hours, to obtain 775 mg of a residue. ^When this residue was analyzed by the ¹ H-NMR-IS method, the content of 2,2-isopropylidene bis [(4S) -4-t-butyl-2-oxazoline] was 63% by weight (yield 55 %).

Example 3 Dimethylmalonobis [N- (2S) was added to 40 ml of xylene.
-2-t-Butylethanol] amide 1 g (3.03 m
g) and ytterbium trifluoromethanesulfonate monohydrate (93.8 mg, 0.15 mmol) were added, and the mixture was heated under reflux with stirring for 24 hours. Then, the solvent was distilled off under reduced pressure to obtain 835 mg of a residue. ¹
When this residue was analyzed by the 1 H-NMR-IS method, 2,2-isopropylidene bis [(4S) -4-t
-Butyl-2-oxazoline] content was 65% by weight (yield 61%).

Comparative Example 1 35 g of xylene and 1 g of (S) -t-leucinol
(8.53 mmol), diethyl dimethylmalonate 0.
After 803 g (4.27 mmol) and molecular sieve 4A (100 mg) were added, the mixture was heated with stirring for 4 hours under reflux and dehydration. Thereafter, 65 mg (0.21 mmol) of dichlorodibutyltin was added, and the mixture was further heated with stirring under reflux dehydration for 90 hours. Then, the solid content was removed by filtration and the solvent was distilled off under reduced pressure to obtain 430 mg of a residue. ^An attempt was made to analyze this residue by the ¹ H-NMR-IS method, but there were many by-products, and the content of 2,2-isopropylidene bis [(4S) -4-t-butyl-2-oxazoline] was to be determined. I couldn't.

Comparative Example 2 Dimethylmalonobis [N- (2S) was added to 40 ml of xylene.
-2-t-Butylethanol] amide 1 g (3.03 m
g) was added, and the mixture was heated with stirring under reflux for 4 hours for dehydration. Then, 46 mg of dichlorodibutyltin (0.
15 mmol) was added, and the mixture was further heated with stirring for 48 hours while refluxing and dehydrating. Then, the solid content was removed by filtration and the solvent was distilled off under reduced pressure to obtain 919 mg of a residue. Attempts were made to analyze this residue by the ¹ H-NMR-IS method, but there were many by-products, and the content of 2,2-isopropylidene bis [(4S) -4-t-butyl-2-oxazoline] was to be determined. I couldn't.

Claims (4)

[Claims] 1. The general formula (2) (In the formula, R ¹ and R ² each represent an alkyl group, * represents an asymmetric carbon atom.), And at least one selected from titanium alkoxides and lanthanoid metal trifluoromethanesulfonates. General formula (1) characterized by carrying out an intramolecular condensation reaction in the presence of (In the formula, R ¹ , R ² and * have the same meanings as described above.) A method for producing a bisoxazoline compound represented by the formula. 2. The production method according to claim 1, wherein the lanthanoid metal trifluoromethanesulfonate is ytterbium trifluoromethanesulfonate. 3. The production method according to claim 1, wherein the titanium alkoxide is titanium tetraisopropoxide. 4. The amount of at least one selected from titanium alkoxides and lanthanoid metal trifluoromethanesulfonates is 0.001 to 0.001 relative to bisamides.
The production method according to claim 1, wherein the production amount is 0.5 mol times.