JPS581091B2 - Chikanketonno Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing substituted ketones by intermolecular dehydrohalogenation of organic halides and ketones in the presence of a caustic alkali and a catalyst. On the other hand, the present invention relates to a method for producing a substituted ketone, in which a ketone having at least one active hydrogen activated by one carbonyl group at the α-position carbon is reacted in the presence of a caustic alkali and a specific phosphonium salt.

It is known that a corresponding substituted ketone can be produced by reacting an organic halide with a ketone having an active hydrogen at the carbon α position relative to the carbonyl group in the presence of a caustic alkali and a catalyst. It can be expressed by the formula.

However, Hal represents a halogen atom and M represents an alkali metal.

For example, according to US Pat. No. 2,644,83, the reaction between allyl methyl ketone and alkyl halide is carried out in the presence of an alkali metal hydroxide.

Also, in British Patent No. 851,658, 1-chlor-
6-Methyl-5-hepten-2-one (hereinafter referred to as methylheptenone) is obtained from 3-methyl-2-butene (hereinafter referred to as P.C.) and acetone.

However, the yield of these methods is only 43% when caustic potash is used and 20% when caustic soda is used in the process described in the British patent specifications.

Furthermore, recently, according to Organic Synthetic Chemistry 2854 (1970), the follow-up results of the above-mentioned British patent were 35% for caustic potash;
In the case of caustic soda, it has been reported that it is only 5% or less, and it has been reported that the yield can be improved by adding dimethylformamide, dimethyl sulfoxide, etc.

Further, Japanese Patent Publication No. 40-22251 discloses that the yield can be improved by adding various amine compounds.

The present inventors have now discovered that the yield can be significantly improved by adding a specific phosphonium salt to this reaction.

It has also been found that when certain phosphonium salts are used as catalysts in accordance with the present invention, water can be present from the beginning of the reaction, resulting in great industrial benefits.

To explain in more detail, this reaction, as shown above,
Since it involves the production of water, it is virtually impossible to continue this process in a strictly anhydrous state; however, conventionally, the presence of water in this reaction system has a significant negative effect on the reaction yield, so it has been difficult to start the reaction. Since ancient times, it has been believed that the presence of large amounts of water should be strictly avoided, and it is common practice to limit the amount of water entrained in the reactants and to add a solid form of caustic alkali to the reaction system. Retekimaru Special Publication No. 40-22251 states that when amine catalysts are used, drying of the reactants is not critical, and in many cases even the presence of less than 2 moles of water per mole of organic halide is harmful. Although it is stated that this is not the case, all of the experimental series described in this publication started the reaction in a substantially anhydrous state.

In experiments conducted by the present inventors, for example, P. When C and acetone are reacted in the presence of a caustic alkali, a small amount of water in the acetone inhibits the progress of the reaction, and potassium iodide, sodium iodide, dimethylsulfone, sulfolane, tri- n-butylphosphine oxide,
Even when monomethylamine, dimethylamine, trimethylamine, monoethylamine; monohexylamine, ammonium chloride, etc. are added, the reaction yield clearly decreases due to the presence of water. Even considering the effect, only 2.0 moles of water relative to the organic halide was acceptable.

However, in the method of the present invention, not only water may be present in the reaction system, but also a water/organic halide molar ratio of 2.0.
If the reaction is preferably started at a temperature of 2.0 to 10.0, the substituted ketone can be produced with good reproducibility without substantially lowering the reaction yield compared to when the reaction is started in an anhydrous state. be able to.

In the method of the present invention, when the above amount of water is present, the caustic alkali can be present as an aqueous solution, and not only the reproducibility of the reaction results is good, but also the reproducibility of the reaction rate is good and uniform. The reaction proceeds at a fast rate, and it has many industrial advantages, such as ease of reaction temperature control, safety, simplification of equipment, and continuous operation.

In addition to the excellent reproducibility and advantages based thereon as described above, the method of the present invention also has the following advantages.

First of all, there is no need to use powdered or flaky caustic potash as the caustic alkali, and pelletized caustic alkali or caustic alkali aqueous solution, which can be obtained industrially at low cost, can be used.

In particular, the fact that caustic alkali can be used in the form of an aqueous solution facilitates the supply of caustic alkali to the reaction system and contributes to improving the working environment.

Second, when starting a reaction using a solid alkali in an anhydrous state or a state close to this, the solid caustic alkali may stick to the bottom of the reactor during the reaction, making it impossible to use the caustic alkali effectively. However, this problem can be solved by using a caustic alkali aqueous solution, although special consideration is required for reaction operations, especially stirring.

Third, the permissible amount of water contained in the reactants is greatly increased, making it possible to recover and reuse unreacted ketones extremely economically.

Fourth, in many cases, the amount of ketone used can be saved compared to conventional methods.

The phosphonium salt that can be used in the present invention has the general formula R3PR' or an unsubstituted cycloalkyl group having 6 or more carbon atoms or an aralkyl group having 7 or more carbon atoms, and X is an anion such as Cl, Br, I, OH, or NO3.

To explain these phosphonium salts more specifically,
R is a cyclohexyl group, an alkyl-substituted cyclohexyl group having an alkyl group having 1 to 18 carbon atoms as a substituent; R' is an alkyl group having 1 to 18 carbon atoms, an alkyl group having 1 to 18 carbon atoms; It is a phosphonium salt which is a cycloalkyl group having 6 to 7 carbon atoms or an aralkyl group having 7 to 30 carbon atoms, with or without as a substituent.

In the presence of water, the anion represented by X is (
Any anion may be used as long as it dissociates with R3PR')■, such as Cl■, Br■, I■, OH■ or NO3■ as mentioned above, but ClO■, CH3COO■,
SCN■, 03SOCH3■ As is clear from the reaction formula in the middle of the second page, this anion does not directly participate in the reaction of the present invention, so its type does not matter.

Examples of these phosphonium salts include tricyclohexylmethylphosphonium, tricyclohexylethylphosphonium, tricyclohexyl-n-butylphosphonium, tricyclohexylisobutylphosphonium,
tricyclohexyl n-propylphosphonium, tricyclohexylisopropylphosphonium, tricyclohexylamylphosphonium, tricyclohexylphosphonium, tricyclohexylheptylphosphonium,
Tricyclohexyldecylphosphonium, tricyclohexyllaurylphosphonium, tricyclohexyltetraterylphosphonium, tricyclohexylhexadecylphosphonium, tricyclohexylstearylphosphonium, tetracyclohexylphosphonium, tricyclohexylbenzylphosphonium, tri-4-methylcyclohexylethylphosphonium, Examples include salts of -4-methylcyclohexyl-n-butylphosphonium.

In the present invention, the above-mentioned phosphonium salts can not only be used alone, but also two or more kinds can be used in combination, if desired.

These phosphonium salts are usually about 0.001 to 20 mol %, preferably about 0.005 to 1 mol % based on the organic halide.
．． Used at a concentration of 0 mol%.

Furthermore, after the completion of the reaction, the above-mentioned phosphonium salt used in this reaction is either separated into an organic layer and an aqueous layer, and then concentrated from the organic layer, or an appropriate amount of ethers or nonpolar hydrocarbons is added as a precipitating agent. Alternatively, it can be easily recovered by using a cationic exchange resin.

The recovered catalyst retains its original catalytic activity.
This was experimentally confirmed by the present inventors.

This is surprising because other phosphonium salts that do not have a cyclohexyl group are often unstable under the reaction conditions of this reaction, especially in an alkaline aqueous atmosphere, and therefore their catalytic activity is often deactivated during the reaction. It was an experimental fact.

As described above, the phosphonium salt used as a catalyst in the present invention is economical because it can be recovered and used repeatedly.

Furthermore, these phosphonium salts exhibit extremely excellent catalytic ability, usually several tenths of that of other phosphonium salts.
can be used in a catalytic amount of

Although a wide range of organic halide and ketone ratios can be used, such as 2:1 to 1:20, generally ketones/
Organic halide molar ratios of about 3 to 10 are preferred.

In order to ensure a good yield of the substituted ketone, when the reaction is initiated with the caustic alkali in an anhydrous state or in the presence of a small amount of water, the amount of the caustic alkali is preferably 1.1 mol or more per mol of the organic halide.

In particular, when a large amount of water is present according to the above-mentioned preferred reaction conditions, it is used in an amount of 2 mol or more per 1 mol of organic halide and 0.3 mol or more per 1 mol of water.

The preferred amount of caustic alkali used is about 2.5 to 4 mol per mol of organic halide and about 0.35 to 0.0 mol per mol of water.
It is not necessary to use more than 85 moles of caustic alkali, generally more than 5 moles per mole of organic halide and more than 1 mole per mole of water.

Satisfactory results can be obtained by using inexpensive sodium hydroxide as the caustic alkali, but potassium hydroxide can also be used instead of or together with sodium hydroxide.

Caustic alkali can be added to the reaction system separately from water in the form of a solid having any physical form.45
It is particularly preferable to add it to the reaction system in the form of a caustic alkali aqueous solution with a concentration of ~75% by weight, which facilitates the supply of caustic alkali to the reaction system, provides a good working environment, and generally provides excellent reaction results. .

This reaction can be carried out at a reaction temperature of 0 to 150°C, but from the viewpoint of reaction rate and reaction yield, it is preferably carried out at a reaction temperature of 40 to 80°C.

If the reaction mixture does not boil at the reaction temperature, the reaction can generally be carried out under atmospheric pressure, but the reaction can also be carried out under increased pressure or slightly reduced pressure if desired.

Also, if one or more components in the reaction mixture boils at the reaction temperature, the reaction can generally be conveniently carried out under reflux at atmospheric pressure.

When using raw materials with a particularly low boiling point, the reaction may be carried out in close contact and under pressure.

The required reaction time varies depending on the reaction materials used, reaction temperature, etc., and the desired conversion rate, but generally speaking, it is desirable to carry out the reaction until almost the entire amount of organic halide is converted, and it is usually necessary to conduct the reaction until almost all of the organic halide is converted. Almost all of the organic halides are consumed.

In carrying out the method of the present invention, conventional liquid phase reaction operating methods and equipment can be used.

Usually, a mixture of an organic halide and a ketone is prepared, and the reaction is initiated by adding a caustic alkali, preferably an aqueous solution thereof, and a phosphonium salt to the mixture, which may contain water, in this order or in the reverse order.

As long as the preparation is completed within a few minutes to several tens of minutes, there is almost no difference in reaction results depending on the order of preparation.

As can be understood from this, "starting the reaction" as used in the present invention refers to organic halides, ketones, caustic alkalis, water (not added when starting the reaction in an anhydrous state),
It means charging a phosphonium salt and a phosphonium salt into a reaction system and bringing it to a predetermined reaction temperature, and has no stricter meaning.

The reaction is usually continued until almost all of the organic halide charged is consumed.

After the reaction, the hydrogen halide produced by the reaction between the organic halide and the ketone reacts with the caustic alkali, and the alkali halide or unreacted caustic alkali (if there is little water) precipitates. It exists as.

Usually, water is added to this reaction solution to dissolve the alkali halide or the caustic alkali that has not reacted with it and to separate the remaining organic halide, and then the organic layer is separated into an organic layer and an aqueous layer, and the organic layer is distilled. The product is separated by the following operations.

Unreacted ketones recovered at this time can be recycled and reused.

If the reaction solution contains raw materials with a relatively low boiling point such as acetone in an unreacted state, the unreacted raw materials are evaporated and separated at an appropriate point after the reaction and before separation into an organic layer and an aqueous layer. You can also.

Generally, the reaction solution containing precipitates of the alkali halide or unreacted caustic alkali is filtered to remove solids, and then the P solution is separated into an organic layer and an aqueous layer, and It is also possible to separate the produced ketones.

If unreacted caustic alkali exists as an aqueous solution in the above P solution, the separated aqueous layer may be recycled for the reaction as it is or after concentration and/or replenishment of caustic alkali as necessary. It is possible.

In the present invention, the raw material organic halide and ketone do not need to have a particularly highly reactive structure.

Examples of organic halides include alkyl halides such as methyl chloride, methyl bromide, 4-ethyl chloride, ethyl bromide, probyl chloride, probyl bromide, butyl chloride, butyl bromide, octyl chloride, and octyl bromide: 1-chloro-3- alkenyl halides such as butene, citronenyl chloride; allyl chloride, allyl bromide, methallyl chloride, crotyl chloride,
Allyl halides such as geranyl bromide, farnesyl chloride, and phthyl chloride; propargyl halides such as propargyl chloride; cyclohexyl halides, penzyl halides, and the like can be used.

It is also possible to use the corresponding iodides.

1 at the α-position carbon relative to the carbonyl group as a raw material ketone
Ketones having at least one active hydrogen activated by two carbonyl groups can be used.

Examples of such ketones include acetone, alkyl ketones such as methyl ethyl ketone, diethyl ketone, methyl probyl ketone, methyl isobutyl ketone, ethyl butyl ketone, methyl amyl ketone, methyl isoamyl ketone, methyl hexyl ketone; mesityl oxide, allyl acetone. unsaturated ketones such as , methylheptenone, and ionone; cycloaliphatic ketones such as cyclopentanone, cyclohexanone, and cycloheptanone; camphor, acetophenone,
Examples include phenylacetone.

Substituted ketones produced by the reaction of these organic halides with ketones include ketones useful in various organic synthesis reaction intermediates, fragrances, and the like.

For example, methylhebutenone, obtained by the reaction of prenyl chloride with acetone, is of particular importance as an intermediate in the synthesis of vitamin E and as an intermediate in perfumery.

Example 1 A 200 ml round bottom flask equipped with a thermometer, reflux condenser and stirrer was charged with P. C10.46g, acetone 51ml and P
．． Powdered NaOH or aqueous solution NaOH adjusted so that the molar ratio of H2O to C was 0 to 10 was added to P.O. Tricyclohexylethylphosphonium iodide 0. 4 3 8 g (
1 mole % based on P and C) was added and stirred vigorously for 5 hours under refluxing acetone.

After the reaction was completed, 40 ml of water was added to dissolve the precipitated sodium chloride, and methyl heptenone in the organic layer was dissolved in G.I. L. C
The yield was determined based on the theoretical amount.

Similarly, other reaction conditions were the same, tri-n-butylphosphine, ammonium chloride, and hydroxylethylamine were used as catalysts, and P. 1 for C
The reaction was carried out using a catalyst amount of mole%.

The results are shown in Figure 1. As is clear from this figure, when tricyclohexylethylphosphonium iodide is used as a catalyst, even if the water content of the reaction system changes, the effect on the yield of methylheptenone is small and a high yield can be obtained.

Example 2 Using the same reactor as in Example 1, P. C10.45g
, CH3COCH334.8ml, 65% NaOH aqueous solution 18.46g and (Cyclo-C6H11)3PC2H5IO
．． 0 2 1 8 g (0. 0 5 for P.C.
mole%) and n-decane (G, LC internal standard) were added, and the mixture was reacted with vigorous stirring for 4 hours under refluxing acetone.

Similarly, (n-C4H9)3PC2H5Br, (n-C4H9)4PBr, (Ph)3PCH2C6H5Br were treated with P.O.C. under the same reaction conditions. 1m for C
ole% was charged and reacted.

After the reaction was completed, the yield of methylheptenone and P. The conversion rate of C was determined.

The results are shown in Table 1.

The catalyst amount (mol% relative to p, c) in the table is (Cyclo
0.05 mol% for CaH11)3PC2H5I, 1 mol% for all other phosphonium salts.

Examples 3-9 Using the same reactor as in Example 1, P. C10.46g
, CH3COCH334.8ml, 65% NaOH aqueous solution 18.46g were prepared, and the following various phosphonium salts
．． 0.05 mole% of C was added, and the mixture was vigorously stirred for 5 hours under refluxing acetone.

After the reaction, G. L. MH was determined by C and the yield relative to the theoretical amount was determined.

Example 12 A 300 ml round bottom flask equipped with a thermometer, reflux condenser and stirrer was charged with P. C10.46g, acetone 34.8ml,
18.46 g of 65% NaOH and (Cyclo-C6H
11) 3PC2H, I0.439g (1 for P.C.
% by mole) and was vigorously stirred for 3 hours under reflux of acetone.

After completion of the reaction, the yield of methylheptenone and P. The conversion rate of C was found to be 61.2.
%, 99.8%.

Subsequently, P. CI0.45g, CH3COC
37 ml of H and 4 g of NaOH were added and reacted for 3 hours. After the reaction was completed, the yield of methylheptenone and P. The conversion rates of C were determined to be 51.6% and 94.3%, respectively.

In the same manner, 0.678 g (n-C4Ha)4PBr (2 mol % based on P and C) was charged and reacted for 3 hours under the same reaction conditions.

The yield of methylheptenone and the conversion rate of P and C are each 6
They were 1.2% and 99.0%.

Continuing with the above reaction, P. C10.45g, CH
Add 37 ml of 3COCH and 4 g of NaOH to 3
Time reacted.

Yield of methylheptenone and P. The conversion rate of C is 1
They were 3.6% and 34.0%.

Example 13 After completing the repeated reaction described in Example 11 using (Cyclo-C6H11)3PC2H5I as a catalyst, 30 ml of H2O was added to dissolve the precipitated sodium chloride, and the mixture was separated into an organic layer and an aqueous layer. .

After expelling acetone from the organic layer, ethyl ether 10
ml was added, a precipitate was formed.

The crystals obtained after filtering the precipitate were further washed with ethyl ether and dried under reduced pressure to obtain crystals 0.27P.

Using this product as a catalyst, the reaction was carried out for 2 hours under the same reaction conditions as in Example 11.

The yield of methylheptenone and P. The conversion rates of C were determined to be 64.5% and 98.5%, respectively.

Example 14 250 ml of concentrated hydrochloric acid was added to 154.3 g of linalool at 5°C, 100 ml of heptane was added, and the liquid was separated.
Washed 3 times with 1 ml of water.

Add 407 g of acetone to this solution and 1 65% NaOH aqueous solution 8. 6 4 g (Cyclo-C6H11)3
3.28 g of P-n-C4HgBr was added, and the mixture was reacted under heating under reflux for 3 hours.

7. Add 300 ml of water to the reaction mixture, separate the layers, and distill under reduced pressure to obtain geranyl acetone. 3P (yield 45%) was obtained.

Example 15 Methyl ethyl ketone 7 2 in a 500ml autoclave
．． 1g, allyl chloride 19.1g, 50% NaO
H aqueous solution 80g, (Cyclo-C6 H1,) 3P(CH2)
tt Add 1.07g of CH3Br and heat to 65% while stirring.
The reaction was carried out at ℃ for 4 hours.

G of the reaction mixture. L. As determined by C, 13.1 g of 1-methylallylacetone was produced.

The yield was 53%.

[Brief explanation of the drawing]

FIG. 1 shows the results of investigating the effect of the amount of water in the reaction system on the yield of methylheptenone when various catalysts were used in Example 1.

Claims (1)

[Scope of Claims] 1. At least one carbonyl group activated by one carbonyl group at the carbon α position relative to the organic halide and the carbonyl group.
When producing a substituted ketone by reacting a ketone having two active hydrogens in the presence of a caustic alkali and a catalyst,
As a catalyst, the general formula R, 3PR' A method for producing a substituted ketone, characterized in that the reaction is carried out using a phosphonium salt represented by a cycloalkyl group having 6 or more carbon atoms or an aralkyl group having 7 or more carbon atoms, and X is an anion.