JPH0155255B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following formula (1) However, in the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R ² represents a lower alkyl group, a C ₃ to _{C 9} alkenyl group, or a phenyl group. However, in the above, R ¹ and R ² do not simultaneously represent a phenyl group, or R ¹ and R ² together represent (-CH ₂ )- ₃ ,
(−CH ₂ ) − ₄ or

[Formula], and R ³ represents a lower alkyl group, R ⁴ represents a lower alkyl group, a group OR ³ , a C ₃ -C ₉ alkenyl group,
or phenyl group optionally substituted with lower alkoxy, or

[Formula] represents a group, where R ³ and R ⁴ taken together, (-CH ₂
) ₋₄ ,

[Formula] or

[Formula] can be represented, and n represents 0 or 1, where R ³ and R ⁴ of the compound of formula (3) are combined to form a ring, R ⁴ represents a ring containing the ether bond and n=0, and the formula (3)
When the compound is another compound, R ⁴ has the same meaning as above and n=1. Regarding the method for producing the compound represented by the following, the compound of formula (1) above is prepared by an improved and easy operation, The present invention relates to a manufacturing method using a new synthetic route that can be produced industrially with good yield using inexpensive and easily available raw materials. β-Alkoxyketones and β-ketoacetals represented by the above formula (1) are known compounds that are useful and important as manufacturing intermediates in the fields of fragrances, agriculture, medicine, and the like. More specifically, the present invention is based on the following formula (2) However, in the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R ² represents a lower alkyl group, a C ₃ to _{C 9} alkenyl group, or a phenyl group. However, in the above, R ¹ and R ² does not simultaneously represent a phenyl group, or R ¹ and R ² together represent (-CH ₂ )- ₃ ,
(−CH ₂ ) − ₄ or

[Formula], and X and Y represent a lower alkyl group or a phenyl group, and X and Y together represent (-
CH ₂ ) − ₄ , (−CH ₂ ) − ₅ or (−CH ₂ ) − ₂ O(−CH ₂
)−
₂ , an enamine compound represented by and the following formula (3) However, in the formula, R ³ represents a lower alkyl group, and R ⁴ represents a lower alkyl group, a group OR ³ , a C ₃ -C ₉ alkenyl group, or a phenyl group optionally substituted with lower alkoxy, or

[Formula] represents a group, where R ³ and R ⁴ taken together represent (-CH ₂ )- ₄ ,

【formula】 or

The present invention relates to a method for producing the compound of formula (1), which comprises contacting a compound represented by the following formula in the presence of a Lewis acid. Conventionally, as a method for synthesizing β-alkoxyketones included in formula (1), a proposal has been known in which 1.4 times of alcohol is added to an α,β-unsaturated carbonyl compound. Furthermore, as a method for synthesizing β-ketoacetals included in formula (1), there is a known proposal to selectively acetalize only one carbonyl group of a 1,3-dicarbonyl compound. There is. However, in these conventional proposals, it is first necessary to synthesize the raw material α,β-unsaturated carbonyl compound or 1,3-dicarbonyl compound through complicated multiple steps, and furthermore, such complicated steps are necessary. After going through multiple steps, each process has the disadvantage of 1.4-addition reaction of alcohol or selective monoacetalization. Furthermore, the latter method has the disadvantage that it is difficult to avoid the formation of vinyl ether as a by-product. As another proposal, a method is known for synthesizing β-alkoxyketones and β-ketoacetals, for example, by a condensation reaction of silyl enol ether and acetal or trimethyl orthoformate in the presence of titanium tetrachloride. There is. This method has the disadvantage that the silyl enol ether used in the reaction is very expensive and its synthesis is complicated, making it unsuitable for industrial production. In addition, there is a drawback that the yield of β-alkoxyketones and β-ketoacetals is low. Until now, with regard to the production of β-alkoxyketones and β-ketoacetals, no manufacturing methods other than those previously proposed have been known at all, and no possibility of synthesis by such other manufacturing methods has been suggested at all. I have never been The present inventors have developed a new synthetic route that can industrially advantageously produce β-alkoxyketones and β-ketoacetals of formula (1) by overcoming the disadvantages and defects of the conventional proposals as described above. I've been doing a lot of research. As a result, by a new synthetic route in which the enamine compound of formula (2), which can be easily synthesized industrially and is inexpensive, and the acetal or orthoformate of formula (3) are brought into contact in the presence of a Lewis acid,
It has been discovered that the compound of formula (1) can be industrially advantageously produced with easy operation and good yield. Therefore, an object of the present invention is to obtain a compound of formula (1) that can be industrially advantageously produced by a new synthetic route.
To provide a method for producing a compound. The above objects and many other objects and advantages of the present invention will become more apparent from the following description. According to the method of the present invention, the target compound of formula (1) can be formed at once by bringing the enamine compound of formula (2) into contact with the acetal or trialkyl orthoformate of formula (3) in the presence of a Lewis acid. Can be done. The enamine compound of formula (2) can be easily synthesized by reacting a corresponding carbonyl compound and an amine in the presence of a catalyst according to a conventional method. The method of the present invention, including the step of forming the enamine compound of formula (2) above, can be schematically illustrated as follows. In the above, R ¹ , R ² , R ³ , R ⁴ , X, Y and n
has the same meaning as described above. In the above example, the reaction between the carbonyl compound of formula (4) and the amine of formula (5) was carried out in accordance with the enamine compound synthesis method known per se (enamine synthesis example literature: G. Stork
et al., J.Am.Chem.Soc., 85 , 207 (1963); S.
Hunig et al., OS, coll., 5 , 808 (1973). ],
For example, this can be easily carried out by bringing the compound of formula (4) and the compound of formula (5) into contact in the presence of a catalyst such as potassium carbonate or p-toluenesulfonic acid. For example, 1-(N
-morpholino)-1-cyclohexene can be obtained in a yield of about 80%. For example, equation (2), which can be obtained as described above,
In enamine compounds, examples of lower alkyl groups for R ¹ include C ₁ - such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.
Examples include C ₄ alkyl groups, particularly methyl groups. Examples of the lower alkyl group for ^R2 include the same alkyl groups as exemplified above for ^R1 , particularly _C3 to _C4 alkyl groups.
The lower alkyl groups of R ¹ and R ² may be either straight chain or branched alkyl groups. Also, R ²
Examples of _C3 - _C9 alkenyl groups include straight chain or branched alkenyl groups such as 1-propenyl, 2-methyl-1-propenyl, 6-methyl-5-hepten-2-yl-1-nonenyl. I can give an example. Further, regarding the phenyl groups of R ¹ and R ² , both R ¹ and R ² do not represent a phenyl group at the same time. Furthermore, R ¹ and R ² together form (−
_CH2 ) _-3 [cyclopentene], ( _-CH2 ) _-4 [cyclohexene],

[Formula] [3,4-dimethyl-1,3-cyclohexadiene] can be shown. Examples of such compounds of formula (2) include 1-(N-morpholino)-1-cyclohexene, 3,4-dimethyl-1-(N-morpholino)-
1,3-cyclohexadiene, 1-(N-piperidino)-1-hexene, 5-methyl-2-(N-morpholino)-2,4-hexadiene, 3-methyl-1-(N-morpholino)-1 -butene, β-(N
-piperidino)styrene, α-(N-morpholino)
Styrene, 3,7-dimethyl-1-(N-morpholino)-1,6-octadiene, N-methyl-N
-(1-cyclohexenyl)aniline, 1-(N-
Examples include morpholino)-1-cyclopentene and 1-(N-morpholino)-1-hexene. According to the method of the present invention, the target compound of formula (1) can be obtained by bringing the enamine compound of formula (2) as described above into contact with the compound of formula (3) in the presence of a Lewis acid. The above reaction can be carried out by bringing the compound of formula (2) and the compound of formula (3) into contact in the presence of a Lewis acid, preferably in a halogenated hydrocarbon solvent. Since the reaction proceeds at room temperature, there is no particular need for heating, but the reaction temperature can be, for example, about -60°C to about 40°C, more preferably about 0° to about 20°C. The reaction time can be selected as appropriate, for example about 0.5
hours to about 5 hours, more preferably about 1 hour to about 2 hours
An example of the reaction time is hours. In the reaction, the amount of the compound of formula (3) to be used relative to the compound of formula (2) can be appropriately selected. can. Further, the amount of Lewis acid to be used can be selected as appropriate, and for example, about 0.1 to about 2 mol, more preferably about 1 mol, per 1 mol of the compound of formula (2) can be exemplified. Further, examples of the halogenated hydrocarbon solvent include monochloromethane, dichloromethane, chloroform, carbon tetrachloride, monochloroethane, 1,2-dichloroethane, and mixtures thereof. The amount of these organic solvents used includes
Although there is no particular restriction, the amount may be, for example, about 2 to about 10 times the weight of the compound of formula (2). Further, examples of Lewis acids include titanium tetrachloride, tin tetrachloride, aluminum chloride, zinc chloride, boron trifluoride diethyl ether complex, boron trifluoride acetic acid complex, zinc bromide, and the like. After the solvent is distilled off, the reaction product can be purified by means such as vacuum distillation, if desired. In the compound of formula (3) used for the reaction with the enamine compound (2) above, examples of the lower alkyl group of R ³ are:
Examples include _C1 - _C5 alkyl groups, preferably _C1 - _C4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and the like. The same applies to R ³ in the group OR ³ of R ⁴ . Furthermore, examples of the lower alkyl group for R ⁴ include the same lower alkyl groups exemplified for R ³ above. Also, R ⁴
Examples of C ₃ -C ₉ alkenyl groups include R ² in formula (2)
The same alkenyl groups as already exemplified can be exemplified. Further, the phenyl group of R ⁴ may be substituted with a lower alkoxy group, such as a C ₁ -C ₄ alkoxy group, particularly a methoxy group. Furthermore, in the compound of formula (3), R ³ and R ⁴ are combined can be shown. Examples of such compounds of formula (3) include trimethyl orthoformate, triethyl orthoformate, acetaldehyde diethylacetal, acetaldehyde-di-n-butylacetal, butanal diethylacetal, 3-
Methylbutanal diisopropyl acetal, trans-2-butenal dimethyl acetal, trans-2-hexenal dimethyl acetal,
3,7-dimethyl-6-octenal diethylacetal, benzaldehyde diethylacetal, phenylacetaldehyde diethylacetal, p-anisaldehyde dimethyl acetal,
Examples include helional dimethyl acetal, 2-ethoxy-5-pentyltetrahydrofuran, 2-methoxytetrahydropyran, and 2-methoxy-4-methyltetrahydropyran. According to the present invention, the following formula (1) shown above However, in the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, and n represents 0 or 1, but here,
When R ³ and R ⁴ of the compound of formula (3) are combined to form a ring, R ⁴ represents the combined ring and n=0, and the compound of formula (3) In the case of other compounds, R ⁴ has the same meaning as above and n = 1. The compound represented by the following can be industrially produced with easy operation and in good yield using inexpensive and easily available raw materials. can be advantageously obtained. As is clear from the definition of n in the above formula (1),
When the compound of formula (3) has three groups OR ³ (that is, R ⁴ is also OR ³ ), the number of groups OR ³ in the compound of formula (1) formed is two, and the compound of formula (3) has 2 groups OR ³ (that is, R ⁴ is a group other than OR ³ ), the number of groups OR ³ in the compound of formula (1) formed is 1, and the compound of formula (3) has 1 When the compound of formula ( ¹ ) is formed ^{, the number of groups OR 3 is} It is zero. Examples of the compound of formula (1) obtained as described above include the following compounds. For example, 2-diethoxymethylcyclohexane, 2-dimethoxymethylcyclohexanone, 2
-β-ketoacetals such as methoxymethyl-3,4-dimethyl-3-cyclohexenone, 2-diethoxymethylhexanal, 3-dimethoxymethyl-5-methyl-4-hexen-3-one; 3-ethoxy -2-isopropylhexanal, 3-(4-methoxyphenyl)-2-isopropyl-3-methoxypropanol, 2-butyl-
3-ethoxybutanal 2-butyl-3-isopropoxy-5-methylhexanal, 2-butyl-3-ethoxy-3-phenylpropanol, 2
-(2-tetrahydropyranyl)hexanal,
2-(1-ethoxybutyl)-3,7-dimethyl-
6-octenal, 4-methoxy-3-(2-methyl-1-propenyl)-5-hepten-2-one, 4-ethoxy-3-(2-methyl-1-propenyl)-4-phenyl-2- Butanone, 2-(1
-ethoxyethyl)cyclohexanone, 2-(2
-butoxyethyl)cyclohexanone, 2-(1
-methoxy-2-butenyl)cyclohexanone,
2-(α-ethoxybenzyl)cyclohexanone,
2-(2-tetrahydropyranyl)cyclohexanone, 2-(1-methoxy-2-hexenyl)cyclohexanone, 2-(1-methoxy-2-methyl-3-(3,4-methylenedioxyphenyl)
propyl)cyclohexanone, 2-(5-pentyl-2-tetrahydrofuranyl)cyclohexanone, 2-(1-ethoxyethyl)cyclopentanone, 2-(4-methyl-2-tetrahydropyranyl)cyclopentanone, 2-( 1-ethoxy-3,
β-alkoxyketones such as 7-dimethyl-6-octenyl)cyclopentanone, 3-ethoxy-1-phenyl-1-butanone, 3-isopropoxy-5-methyl-2-phenylhexanal, and the like. Examples will now be given to illustrate some aspects of carrying out the method of the invention. Example 1 Synthesis of 2-diethoxymethylcyclohexanone: 0.05 mol (8.4
g) 1-(N-morpholino)-1-cyclohexene and 0.065 mol (9.6 g) of triethyl orthoformate, and 0.065 mol (16.9 g) of tin tetrachloride were stirred at about -40°C. , added under an argon atmosphere. After the addition, the mixture is further reacted at about 0° C. for about 1 hour under stirring conditions. water in the reaction mixture
Add 50 ml and stir for an additional hour at room temperature. The organic layer is separated, washed once with brine, and then neutralized and washed with saturated sodium hydrogen chloride solution. The organic layer is dried over anhydrous magnesium sulfate, and then dichloromethane is recovered. The obtained crude product was subjected to vacuum distillation to obtain 2 fractions with a boiling point of 83-84℃/2mmHg.
-Diethoxymethylcyclohexanone 9.0 g (yield 90%) was obtained. Example 2 Synthesis of 2-(α-ethoxybenzyl)cyclohexanone: 50 ml of dry dichloromethane and 0.065 mol (11.7 g)
of benzaldehyde diethyl acetal and stirred and cooled to -30°C. Then 0.065 mol (9.2
g) boron trifluoride diethyl ether complex,
It is added under an argon atmosphere and after about 5 minutes 0.05 mol (8.4 g) of 1-(N-morpholino)-1-cyclohexene is added as well. After the addition, the mixture is further reacted at room temperature for about 2 hours under stirring conditions. 50 ml of water is added to the reaction mixture, and the mixture is further stirred at room temperature for about 1 hour. The organic layer is separated, washed once with brine, and then neutralized and washed with saturated sodium bicarbonate solution. After drying the organic layer over anhydrous magnesium sulfate, dichloromethane is recovered. The obtained crude product was subjected to vacuum distillation to obtain 10.3 g (yield: 89%) of 2-(α-ethoxybenzyl)cyclohexanone as a fraction with a boiling point of 120-122°C/1.5 mmHg. Examples 3 to 28 In the same manner as in Examples 1 to 2, various β-ketoacetals and β -Alkoxyketones were synthesized. The results are shown in Table-1.

[Table] Hexene ethyl ^(C
) hexanal

【table】
hexanone

[Table] Pyracetal
Hexanal

Claims (1)

[Claims] 1. The following formula (2) However, in the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R ² represents a lower alkyl group, a C ₃ to _{C 9} alkenyl group, or a phenyl group. However, in the above, R ¹ and R ² do not simultaneously represent a phenyl group, or R ¹ and R ² together represent (-CH ₂ )- ₃ ,
(-CH ₂ ) _-4 or [Formula], and X and Y represent a lower alkyl or phenyl group, and X and Y together represent (-
CH ₂ ) − ₄ , (−CH ₂ ) − ₅ or (−CH ₂ ) − ₂ O(−CH ₂
)−
₂ , an enamine compound represented by and the following formula (3) However, in the formula, R ³ represents a lower alkyl group, R ⁴ represents a lower alkyl group, a group OR ³ , a C ₃ -C ₉ alkenyl group,
or a phenyl group optionally substituted with lower alkoxy, or a group of [Formula], where R ³ and R ⁴ are taken together to represent (-CH ₂
) _-4 , [Formula] or a compound represented by [Formula], which can be represented by the following formula (1), is brought into contact in the presence of a Lewis acid. However, in the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, and n represents 0 or 1, but here,
When R ³ and R ⁴ of the compound of formula (3) are combined to form a ring, R ⁴ represents a ring containing an ether bond and n=0, and the formula (3)
When the compound is another compound, R ⁴ has the same meaning as above and n=1.