JP2002212149A - METHOD FOR PRODUCING TETRAALKYLAMMONIUM FLUORIDE AND METHOD FOR PRODUCING beta-HYDROXYKETONE BY USING THE SAME - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for readily producing a tetraalkylammonium fluoride which is an excellent catalyst usable in an aldol reaction, and further to provide a method for producing a β-hydroxyketone by the aldol reaction using the catalyst. SOLUTION: A tetraalkylammonium salt represented by the formula: R1R2R3 R4N+X- [wherein, R1, R2, R3 and R4 are each a same or different alkyl group; and X- is an anion except a fluoride ion] is reacted with a fluoride salt of an alkali metal in an ether-based organic solvent to provide the tetraalkylammonium fluoride. The method for producing the β-hydroxyketone comprises reacting a silyl enol ether with a carbonyl compound in the presence of the tetraalkylammonium fluoride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing tetraalkylammonium fluoride and a novel method for producing β-hydroxyketone using tetraalkylammonium fluoride obtained by the method.

[0002]

2. Description of the Related Art To synthesize β-hydroxyketone by reacting a silyl enol ether with a carbonyl compound such as an aldehyde, a Lewis acid such as TiCl ₄ or SnCl ₄ is usually used in an equimolar amount. On the other hand, there is also known a method in which tetrabutylammonium fluoride (Bu ₄ N ⁺ F ⁻ ) is catalyzed by utilizing the strong affinity of a fluoride ion (F ⁻ ) for a silicon atom. In particular, when a silyl enol ether is reacted with a carbonyl compound such as an aldehyde in the presence of tetrabutylammonium fluoride, side reactions such as a dehydration reaction are suppressed as compared with an aldol reaction catalyzed by a Lewis acid, Target β-
Hydroxy ketone is obtained in good yield.

For example, using a catalytic amount of tetrabutylammonium fluoride, 1-trimethylsilyloxycyclohexene (silyl enol ether prepared from cyclohexanone) is reacted with an equimolar amount of benzaldehyde in tetrahydrofuran at a low temperature, and then acetate is added. It has been reported that treatment with an aqueous solution, an acid such as dilute hydrochloric acid, etc., gives the corresponding aldol product efficiently.

However, tetrabutylammonium fluoride used here is a viscous liquid and has a very high hygroscopicity. Moreover, its handling is not easy due to its unstable nature, which is easily decomposed at high temperatures. Moreover, the conventional methods for producing this compound are:
0% tetrabutylammonium hydroxide is neutralized with dilute hydrofluoric acid, and then reduced under reduced pressure of 0.5 mmHg for 30 to 40%.
A large amount of water must be removed at 15 ° C. for 15 hours and dried with phosphorus pentoxide, and this method is not an efficient method.

[0005]

SUMMARY OF THE INVENTION The present inventor thought that if the tetraalkylammonium fluoride can be easily produced, the industrial application value of the aldol reaction using the same as a catalyst would increase. That is, an object of the present invention is to provide a simple method for producing tetraalkylammonium fluoride, which is an excellent catalyst used in an aldol reaction, and a method for synthesizing β-hydroxyketone by an aldol reaction using the compound. It is. The present inventors have conducted various studies in order to solve the above problems, and as a result, have completed the present invention.

[0006]

The present invention provides the following formula:
(I):

Embedded image ^{R 1 R 2 R 3 R 4} N + X - (I) [ ^wherein, R ^1, R 2, ^{R 3} and ^{R 4} are the same or different alkyl group, X ^- is fluoride A tetraalkylammonium salt represented by the following formula (I) in an ether-based organic solvent:
I):

Embedded image embedded image R ¹ R ² R ³ R ⁴ N ⁺ F ⁻ (II) wherein R ¹ , R ² , R ³ and R ⁴ are as defined above. It is intended to provide a method for producing ammonium.

The present invention also relates to (A) the following formula (I):

Embedded image ^{R 1 R 2 R 3 R 4} N + X - (I) [ ^{wherein, R 1, R 2, R} 3 and ^{R 4} are the same or different alkyl group, X ^- is fluoride Which is an anion excluding a chloride ion] is reacted with an alkali metal fluoride salt in an ether-based organic solvent to obtain the following formula (II):

[Image Omitted] Tetraalkyl fluoride represented by R ¹ R ² R ³ R ⁴ N ⁺ F ⁻ (II) wherein R ¹ , R ² , R ³ and R ⁴ are as defined above. And (B) reacting a silyl enol ether with a carbonyl compound in the presence of the tetraalkylammonium fluoride.

In a preferred embodiment of the method, potassium fluoride is used as the alkali metal fluoride salt.

[0009] In another preferred embodiment of the method, X ^- is _{^{Cl -, Br -, IO 4}} -, BF 4 -, CF
_A tetraalkylammonium salt which is an anion selected from the group consisting of ₃ SO ₃ ⁻ and HSO ₄ ⁻ is used.

In another preferred embodiment of the present method, a tetraalkylammonium salt represented by the following formula (I)
II):

Embedded image R ¹ R ² R ³ R ⁴ N ⁺ HSO ₄ ⁻ (III) [wherein R ¹ , R ² , R ³ and R ⁴ are as defined above] Use bisulfate.

Further, in a preferred embodiment of the method for producing β-hydroxyketone of the present invention, the steps (A) and (B)
Is performed continuously in the same container.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the method for producing tetraalkylammonium fluoride of the present invention, a tetraalkylammonium salt (a salt other than a fluoride salt) is reacted with an alkali metal fluoride salt. As the alkyl group in the tetraalkyl ammonium salt used, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl,
Examples include alkyl groups such as t-butyl, n-pentyl, isopentyl, and n-hexyl.

Next, the tetraalkylammonium salt
As the nonions, Cl⁻, Br⁻, IO₄ ⁻, B
F₄ ⁻, CF₃SO₃ ⁻, HSO₄ ⁻And the like.
Especially HSO ₄ ⁻Reacts with alkali metal fluoride salts
It is a very suitable anion for.

As the alkali metal fluoride salt, potassium fluoride, sodium fluoride and lithium fluoride can be used. In particular, potassium fluoride dihydrate, which is industrially available at low cost, can be used for this reaction.

As the solvent used in this reaction, tetrahydrofuran, dioxane, isopropyl ether,
Examples include ether organic solvents such as ethyl ether and ethylene glycol dimethyl ether.

The molar ratio between the tetraalkylammonium salt and the alkali metal fluoride salt used in the reaction is usually 1: 1 to 1: 100, preferably 1:10 to 1:70.

The reaction temperature is preferably from 0 to 60 ° C., at which temperature the reaction is completed in about 30 minutes to about 2 hours.
The reaction is usually completed by mixing and stirring the tetraalkylammonium salt and the alkali metal fluoride salt at room temperature for about 1 hour. Of course, heating or cooling may be performed as appropriate depending on the reactivity of the chemical species that react with each other.

The tetraalkylammonium fluoride thus obtained can be separated and purified from the reaction solution. That is, after the reaction is completed, insoluble inorganic substances are filtered off,
By distilling off the solvent from the filtrate, a solid tetraalkylammonium fluoride can be obtained. Further, the solid can be purified by recrystallization according to a usual method.

The tetraalkylammonium fluoride obtained as described above can be stored as it is in a reaction solvent and used for the next reaction. In this case, a β-hydroxyketone is produced extremely easily and in a high yield by sequentially adding a silyl enol ether and a carbonyl compound (such as an aldehyde) to a reaction mixture containing a tetraalkylammonium fluoride, followed by mixing and stirring. can do.

A feature of the present invention is that tetraalkylammonium fluoride is efficiently produced in an ether solvent. This is because the aldol reaction between silyl enol ether and a carbonyl compound (such as an aldehyde) using this compound as a catalyst also proceeds in the same ether solvent. As a result, without taking out the tetraalkylammonium fluoride produced in the previous step,
It can be subjected to the next reaction (aldol reaction between silyl enol ether and carbonyl compound), thereby avoiding difficulties in handling tetraalkylammonium fluoride.

That is, in the process for producing β-hydroxyketone of the present invention, the reaction solution obtained by reacting the alkali metal fluoride salt with the tetraalkylammonium salt represented by the above formula (I) is successively added with silyl. It is preferred to add the enol ether and the carbonyl compound and react with each other.

The silyl enol ether used in this reaction is prepared in the presence of a base (typically a tertiary amine).
It can be obtained by reacting various carbonyl compounds with trialkylsilyl halide. Examples of the carbonyl compound used for this purpose include cyclohexanone, cyclopentanone, cycloheptanone, cyclooctanone, phenylpropanone, phenylbutanone, methyl ethyl ketone, diethyl ketone, cyclohexylpropanone, pyrrolidone, indolinone, indanone, and the like. .

On the other hand, as the carbonyl compound to be reacted with silyl enol ether, besides the above carbonyl compound, benzaldehyde, anisaldehyde, naphthyl aldehyde, naphthyl acetaldehyde, naphthyl propionaldehyde, cinnaaldehyde, nicotin aldehyde, furfural, piperonal, ethanal , Hexanal, propanal, butanal, pentanal and the like.

The molar ratio between the silyl enol ether and the carbonyl compound used in the reaction is usually from 1: 1 to 1:
3, preferably 1: 1 to 1: 1.5.

The molar ratio of the catalyst (tetraalkylammonium fluoride) to the reactive species (silyl enol ether) is usually from 1: 2 to 1: 200, preferably from 1: 5 to 1: 200.
1: 150.

The reaction temperature is preferably between -78 and 50 ° C., at which temperature the reaction is completed in about 15 minutes to about 5 hours. Of course, depending on the reactivity of the species reacting with each other,
Heating or cooling may be performed as appropriate.

The β-hydroxyketone thus obtained can be separated and purified from the reaction solution by a usual method. Separation of β-hydroxyketone from the reaction solution is performed as follows. That is, the reaction is stopped by adding water, and the mixture is extracted with an organic solvent. After washing the extract, it is concentrated under reduced pressure to obtain a silyl ether of β-hydroxyketone. The silyl ether moiety is then hydrolyzed under acidic conditions. The reaction mixture is diluted with water, extracted with an organic solvent, and the extract is washed, dried and concentrated under reduced pressure to obtain β-hydroxyketone. The purification of β-hydroxyketone can be performed by a usual method used for the purification of an organic compound, for example, distillation, recrystallization, sublimation, chromatography and the like.

Formula: R¹R²R³R⁴N⁺X⁻Indicated by
Tetraalkyl ammonium salt (X ⁻Is fluoride ion
Not)¹, R², R³, R⁴All
X is I, Br, Cl, IO₄, Cl
O₄, B (C₆H₅)₄, BF₄, CF₃SO₃, HSO
₄These tetraalkylammonium salts
Reacted with potassium metal fluoride salt. Gain in this way
Aldol reaction (see above silyleno
Β-hydroxyke
Catalytic activity for the reaction to produce tons).

As a result, when X is I, CIO ₄ , B (C ₆ H
₅ ) Tetrabutylammonium salt which is ₄ [Bu ₄ N ⁺ X
^- ], The desired β-hydroxyketone could not be obtained. Therefore, tetrabutylammonium salts having these as anions are not suitable as raw materials for producing tetrabutylammonium fluoride.

On the other hand, when X is Br or Cl,
Although the aldol reaction itself progressed, it was obtained separately.
Β-butylammonium fluoride
-The yield of hydroxyketone was low. From this,
Formula: R¹R²R³R⁴N⁺X ⁻Tetraalkyl represented by
Formula R¹R²R³R
⁴N⁺F⁻A tetraalkylammonium fluoride represented by
Catalytic activity in the aldol reaction of
It was suggested that it greatly depended on the structure of.

Furthermore, as a result of intensive studies based on such findings, tetrabutylammonium salt [Bu ₄ N ⁺ HSO ₄ ⁻ ] where X is HSO ₄ showed the most excellent catalytic activity. That is, the most preferred embodiment of the present invention for efficiently producing a β-hydroxyketone by catalyzing an aldol reaction between a silyl enol ether and a carbonyl compound (such as an aldehyde) is tetrabutylammonium bisulfate [B
U ₄ N ⁺ HSO ₄ ⁻ ] is reacted with potassium fluoride to produce tetrabutylammonium fluoride [Bu ₄ N ⁺ F ⁻ ], which is used as a catalyst for the aldol reaction without isolation. Become. In fact, tetrabutylammonium bisulfate is an important starting material in that it readily reacts with alkali metal fluoride salts such as potassium fluoride to give tetrabutylammonium fluoride.

[0032]

EXAMPLES Examples will be described below for specific explanations, but the present invention is not limited by these examples.

<Production Example> In a separatory funnel, tetrabutylammonium bromide
[Bu ₄ N ⁺ Br ⁻ ] (0.032 g, 0.10 mmol) is dissolved in dichloromethane (10 ml) and three times using a saturated aqueous solution of potassium thiocyanate containing excess SCN ⁻ ion over bromide ion present. Washed. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and then dried under reduced pressure to obtain tetrabutylammonium thiocyanate [Bu ₄
N ⁺ SCN ⁻ ] was obtained quantitatively.

B. The thus obtained tetrabutylammonium thiocyanate (0.03 g, 0.1 mmol) was suspended in water, excess concentrated sulfuric acid (1.5 ml) was added, and the mixture was stirred while appropriately cooling. The mixture was warmed to 75 ° C. The generated gas was led out of the system through a 33% aqueous NaOH solution. After 1 hour, the mixture was poured into water (30 ml). The resulting solution was saturated with KHSO ₄ and extracted with dichloromethane. The extracts were combined, washed with a saturated aqueous solution of sodium sulfate, and dried over sodium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was recrystallized from dichloromethane-hexane, and tetrabutylammonium bisulfate [Bu ₄ N ⁺ H
SO ₄ ⁻ ] was obtained. The yield was 0.036 g (yield 8
3%).

C. Amberlyst A-26 resin (CL type)
1N NaOH until no turbidity is observed in the silver nitrate test
The aqueous solution was passed through and changed to the OH form. The effluent was then washed with distilled water until neutral and subsequently flushed with methanol (200 l). Tetrabutylammonium bromide [Bu
_{^{4 N + Br -] (0.032g}} , 0.10m mol) was dissolved in methanol (3 ml), it was passed slowly treated resin as described above. Then eluted with methanol. The eluate was concentrated under reduced pressure to about 1 ml, and 0.5 MH ₂ SO ₄ was added until it became acidic. KHSO _{4 with} distilled water
A saturated aqueous solution (5 ml) was added and extracted with dichloromethane. The combined dichloromethane extract was washed with a saturated aqueous solution of KHSO _{4 and a} saturated aqueous solution of sodium sulfate, and dried over a molecular sieve. The solvent was distilled off under reduced pressure to obtain tetrabutylammonium bisulfate [Bu ₄ N ⁺ HSO ₄ ⁻ ] (quantitative yield).

Example 1 In a two-necked flask, tetrabutylammonium bisulfate [Bu ₄ N ⁺ HSO ₄ ⁻ ] (17 m
g, 0.05 mmol) and potassium fluoride dihydrate (240
mg, 2.5 mmol) and tetrahydrofuran (1 mmol)
l) was added. After stirring at room temperature for 1 hour, the mixture was cooled to -78 ° C. Benzaldehyde (61 μl, 0.60 mmol)
And 1-trimethylsilyloxycyclohexene (88 m
g, 0.5 mmol) was added dropwise. Mixture at -78 ° C for 30
Stirred for minutes. The reaction was quenched with water and extracted with ether. The ether layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, and concentrated under reduced pressure. A solution containing 1N hydrochloric acid (1 ml) in tetrahydrofuran (4 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hour. Water was added to the mixture and extracted with ether. The combined ether extracts were washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ether / hexane = 1: 4) to give 2- (1-hydroxy-1-phenylmethyl) cyclohexanone as a colorless oil. The yield was 93.0 mg (91% yield). Erythro: threo = 25: 75 (production ratio was determined by ¹ H-NMR).

<Examples 2 to 9> Following Example 1, but using benzaldehyde as one of the reaction substrates, the reaction was carried out under the conditions shown in Table 1, and the results shown in Table 2 were obtained. Incidentally, in either case, tetrabutylammonium salt _[Bu ^{4 N} + X ^-]
Was used in an amount of 10 mol%, and the erythro / threo ratio of the product β-hydroxyketone was determined by ¹ H-NMR analysis.

[0038]

[Table 1]

[0039]

[Table 2]

<Example 10> In Example 1, the amount of tetrabutylammonium bisulfate used was reduced to 1/10,
Example 1 was repeated except that the amount of potassium fluoride dihydrate used was also reduced to 0.5 equivalent and the reaction was extended to -40 ° C for 2 hours.
And 2- (1-hydroxy-1-phenylmethyl) cyclohexanone was obtained as a colorless oil. The yield is 86% and the erythro: threo ratio is 32:
68.

<Comparative Example 1> Tetrabutylammonium salt
X in [Bu ₄ N ⁺ X ⁻ ] represents I, ClO ₄ , BPh ₄
And the reaction of 1-trimethylsilyloxycyclohexene with benzaldehyde was attempted under the same conditions as in Example 1 except that the reaction temperature was room temperature (rt).
No reaction occurred at any X.

[0042]

According to the present invention, tetraalkylammonium fluoride can be produced more easily. Furthermore, if the tetraalkylammonium fluoride obtained by this method is used as a catalyst, β-hydroxyketone can be obtained in high yield. This increases the industrial value of the aldol reaction.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 211/63 C07C 211/63 // C07B 61/00 300 C07B 61/00 300

Claims (9)

[Claims] 1. A method for producing a tetraalkylammonium fluoride, comprising the following formula (I): R ¹ R ² R ³ R ⁴ N ⁺ X ⁻ (I) wherein R ¹ , R ² , R ³ and R ⁴ are the same or different alkyl groups, and X ⁻ is an anion other than a fluoride ion]. A method comprising the step of reacting with a fluoride salt. 2. The method according to claim 1, wherein the alkali metal fluoride salt is potassium fluoride. 3. X⁻Is Cl⁻, Br⁻, IO₄ ⁻, B
F₄ ⁻, CF₃SO ₃ ⁻And HSO₄ ⁻A group consisting of
Tetraalkylammonium, the selected anion
The method according to claim 1, wherein a salt is used. 4. The method according to claim 3, wherein a tetraalkylammonium bisulfate wherein X ⁻ is HSO ₄ ⁻ is used. 5. A process for producing β-hydroxyketone, comprising: (A) the following formula (I): R ¹ R ² R ³ R ⁴ N ⁺ X ⁻ (I) ¹ , R ² , R ³ and R ⁴ are the same or different alkyl groups, and X ⁻ is an anion other than a fluoride ion]. Reacting with a metal fluoride salt to obtain a tetraalkylammonium fluoride; and (B) reacting a silyl enol ether with a carbonyl compound in the presence of the tetraalkylammonium fluoride. 6. The method according to claim 5, wherein the alkali metal fluoride salt is potassium fluoride. 7. X⁻Is Cl⁻, Br⁻, IO₄ ⁻, B
F₄ ⁻, CF₃SO ₃ ⁻And HSO₄ ⁻A group consisting of
Tetraalkylammonium, the selected anion
The method according to claim 5 or 6, wherein a salt is used. 8. The method according to claim 7, wherein a tetraalkylammonium bisulfate wherein X ⁻ is HSO ₄ ⁻ is used. 9. The method according to claim 5, wherein the step (A) and the step (B) are continuously performed in the same vessel.