JPS5934708B2 - Method for producing 5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid ester - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula Tooru C2, (In the formula, R is an alkyl group.

) The present invention relates to a method for producing 5-cyanomethyl-2-oxocyclobentanecarboxylic acid ester represented by:

The compound of the present invention represented by the general formula (I) is useful as a precursor for producing diasmonoids.

In general, diasmonoids refer to fragrant components contained in diasmine flowers or their related compounds, such as diasmones, dihydrdiasmonates, methyl diasmonates, methyl dihydrodiasmonates, and diasmine lactones [E, H. Polak3Cosmetic
sand Perfumery, l, 46 (1973)]
. These compounds are famous for the so-called diasmine-like aroma that is essential to the characteristic aroma of diasmine, and are also sometimes considered important as base materials for reinforcing other aromas. There have been several reports on methods for producing diasmonoids [T, L, Ho, Sy
n.

Un for Co type, 1265 (1974)]. Among them, for example, for the synthesis of methyl diasmonate, there is a method using a cyclopentanone enamine derivative as a raw material [E,
Demole, etal, Helv, Chim. Ac
ta, 4, 692 (1962)], a method for causing a nucleophilic reagent to act on a cyclopentenone derivative [G. B゜dch
i,etal,,J,Org,Chem,,U,202
1 (1971), A.I. Meyers, etal.
J. Org, Chem, U, 175 (1973)],
A method using an intanone derivative as a starting material [Torii et al., J.
Org. Chem. , O, 462 (1975)], a method using an intermediate obtained by electrolysis of norbornane derivatives [Torii et al., J. Org. Chem. J'', 2
221 (1975)] and the like are publicly known. However, in all cases, there are several drawbacks such as difficulty in obtaining raw materials, low reaction selectivity, long reaction route, need for expensive reagents, difficulty in reaction operation, and low yield. ing. As a result of repeated studies on the industrial production of diasmonoids, the present inventors found that 5-cyanomethyl-2-oxocitalopentanecarboxylic acid ester represented by the general formula (1) is useful as a precursor for producing diasmonoids. This led to the discovery of a method for easily forming it.

Since the bicyclo compound used as a raw material in the present invention has an ester group at the 1st position and a carbonyl group at the 2nd position, the cleavage reaction of the cyclopropane ring by the cyanating agent proceeds very easily, and the direction of cleavage is also positionally selective. It is true.

Furthermore, since the cyclopentanone derivative obtained by the method of the present invention has an ester group at the 2-position and a cyanomethyl group at the 3-position, it can be easily converted into a diasmonoid.

Specifically, since the 2-position has an ester group as an activating group, it is possible to further introduce a substituent regioselectively at this position, and furthermore, after the reaction is completed, it is possible to introduce a substituent at the 2-position as an activating group. can be easily removed. Furthermore, the cyano group present in the substituent at the 3-position can be easily converted into other functional groups, such as ester groups. That is, the inventors have discovered that the compound represented by the general formula (1) is an important synthetic intermediate for the above-mentioned diasmonoids, and have completed the present invention. The bicyclo[3.1.0]hexane derivative represented by the general formula (wherein R is an alkyl group) used as a raw material in the method of the present invention can be obtained by allylating acetoacetate and then treating it with an azide. It is a compound that can be easily produced by adding the α-diazo-β-ketocarboxylic acid ester obtained under conditions for generating carbenes or carbenoids [Japanese Patent Application No. 50-23450 (Japanese Unexamined Patent Publication No. 51-128952)]
reference〕.

The method of the present invention requires that the bicyclo[3.1.0]hexane derivative represented by the general formula () and a cyanating agent be reacted under basic conditions. As the cyanating agent, hydrogen cyanide, acetone cyanohydrin, and metal cyanides such as potassium cyanide, sodium cyanide, copper cyanide, mercury cyanide, and aluminum cyanide can be used. In this method, it is essential to carry out the process under basic conditions.In particular, when using alkali metal cyanide, it establishes basic conditions by itself, so there is no need to coexist with other basic substances. When using hydrogen cyanide, examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Basic conditions can be established by using triethylamine, pyridine, etc. The reaction is preferably carried out in a solvent, and examples of the solvent include alcohols, ethers, and other media that do not directly participate in the reaction, such as dimethylformamide, N-methylpyrrolidone, acetonitrile, dimethylsulfoxide, hexamethylvosvoltriamide, etc. I can give an example. The reaction proceeds smoothly at room temperature without using any special heating or cooling means. When considering the reaction mechanism of the method of the present invention using metal cyanide as an example, it can be inferred that the reaction proceeds as shown in the following equation.

(In the formula, M is a metal ion and R is an alkyl group.

) As is clear from the above formula, the bicitalo ring of compound (1) is partially opened due to the attack by the CN anion of the cyanating agent, and the anionic species represented by the general formula (1), that is, the reaction formula shown above. A compound of (l[0) is formed, which is then converted to the final product (1) by acid treatment.The present invention will be further explained in detail with reference to Examples and Reference Examples below.

Reference example 1 L. The method of Weiler et al. [J. Amer. Chem.
SOc. , 96, lO82 (1974)], sodium hydride (480η, 20 m7
7! o1) in dry tetrahydrofuran (THF) (50
Suspend at m0.

Cool at 0°C and add methyl acetoacetate (2.32
9.20m71L01) was dissolved in THF (5ml) and added.

After 10 minutes, a solution of n-butyllithium (20n01) in n-hexane was gradually added dropwise.

After 15 minutes after the completion of the dropwise addition, allyl bromide (2.409,2
Dissolve 0m7fL01) in THF (5ml) and add.
Gradually raise the temperature to room temperature and continue stirring for 1 hour. The mixture was treated in a conventional manner, and the remaining oil was distilled under reduced pressure to obtain 1.959 methyl 3-oxo-16-heptenoate. Yield: 63
% Boiling point: 98-101 Reference example 2 Methyl 3-oxo-6-heptenoate (468Tf9,3
mTIL01), triethylamine (306η, 3 to 0
1) was dissolved in acetonitrile (5ml), and p-toluenesulfonyl azide (592η,
A solution of 3.01) in acetonitrile (1 mj) was added.

After stirring for about 2 hours, the solvent was distilled off under reduced pressure, and then diluted with ether (50 mO). This solution was washed with a 5% aqueous potassium hydroxide solution until the aqueous layer was no longer colored, and further washed with a saturated aqueous sodium chloride solution. The ether layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 2-diazo-3-oxo-6-heptenoate (530 w) as a yellow oil. It can be purified by vacuum distillation. Yield: 97
% Boiling point: 67-68℃/0.4mmHg Infrared absorption spectrum ((V7L: 2120, 1725
, 1655. Nuclear magnetic absorption spectrum (CCl4, δ):
2.10-2.57 (M, 2H), 2.70-3.08
(M, 2H), 3.77 (S, 3H), 4.65-5.
20 (M, 2H), 5.47-6.13 (M, 1H).
Reference Example 3 Under an argon atmosphere, methyl 2-diazo-3-oxo-16-heptenoate (4.559,2771Lm01) was dissolved in benzene (100ml), and anhydrous copper sulfate (2.59Lm01) was dissolved in benzene (100ml).
was added as a catalyst and heated to reflux while stirring for about 3 hours.

After confirming the disappearance of the raw materials using thin layer chromatography,
Filter using a layer of Celite. After removing the solvent from the filtrate under reduced pressure, the remaining oil is subjected to vacuum distillation. 2.589 2
Methyl -oxobicyclo[3.1.0]hexane-1-carboxylate was obtained as an oil.

Yield: 690t) Boiling point: 900C/0.777!77! Hg nuclear magnetic absorption spectrum (CCl4, δ): 1.33 (T, J2 5Hz
, 1H), 1.77-2.30 (M, 4H), 2030
~2.73 (M, 2H), 3.68 (S, 3H). Mass spectrum m/e (0t): 154 (55), 126 (
87), 123 (56), 113 (C?1), 67 (6
2), 66 (54), 59 (75). Infrared absorption spectrum (d1): 1755, 1725. Reference Example 4 Under an argon atmosphere, methyl 2-diazo-3-oxo-6-heptenoate (349,0.187 m01) was mixed with benzene (300 m01).
Acetylacetone copper complex (19) was added thereto, and the mixture was heated under reflux overnight while stirring.

After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by distillation. 1719 2-oxobicyclo [3.1.0]
Methyl hexane-1-carboxylate was obtained.

Yield: 60% Boiling point: 83-85℃/0.3m77! Hg Reference Example 5 Methyl 5-cyanomethyl-2-oxocyclopentanecarboxylate (362η, 2mm01) and lithium iodide (350w19, 2.6mm01) were dissolved in dimethylformamide (3ml), and while stirring at 120°C, Heat.

After 5 hours, the mixture is cooled and extracted with an aqueous ammonium chloride solution and ethyl acetate.

Wash with saturated aqueous sodium chloride solution and dry over anhydrous magnesium sulfate. After filtration, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=3:7). 3-Cyanomethyl-cyclopentanone of 148η was obtained as an oil. Yield: 60% Infrared absorption spectrum (Mll): 2240, 1740.
Mass spectrum m/e: 123, 83, 55, 41. Example 1 Under an argon atmosphere, dimethyl sulfoxide (1
5d), potassium cyanide (2.909,44110
1), 2-oxobicyclo[3.1.0]hexane-
Methyl 1-carboxylate (6.18f!, 40mm01)
Add.

After stirring at room temperature for about 3 days, the mixture is acidified with dilute hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After drying and concentration, the residue 7.249 was subjected to silica gel column chromatography (ethyl acetate; n-hexane 2:3) to obtain an oil. By recrystallizing this with ethyl acetate and n-hexane, white crystals of 5-
Methyl cyanomethyl-2-oxocyclopentanecarboxylate (4.79) was obtained. Yield: 65% Melting point: 49-50. C Infrared absorption spectrum (CffL-ri: 2250,175
5,1725. Nuclear magnetic absorption spectrum (CDCl3, δ
): 2.10-3.35 (M, 8H), 3.80 (S,
3H), mass spectrum Mv/e: 181, 141, 1
09. Example 2 Sodium cyanide (200η, 4m1) was added to dimethyl sulfoxide (2m1) under an argon atmosphere.
m01), methyl 2-oxobicyclo[3.1.0]hexane-1-carboxylate (462mg, 3m10I)
Add.

After stirring overnight at room temperature, the same post-treatment as in Example 1 was carried out to obtain methyl 5-cyanomethyl-2-oxocyclopentanecarboxylate having a mass of 328 η.

Yield 60%. Example 3 Under an argon atmosphere, hexamethylvosvortriamide (
3d) with potassium cyanide (260T!1f,47!L
lOl), methyl 2-oxobicyclo[3.1.0]hexane-1-carboxylate (462η, 31101) is added.

After stirring at room temperature for 24 hours, the same post-treatment as in Example 1 was performed to obtain methyl 5-cyanomethyl-2-oxocyclopentanecarboxylate having a concentration of 300 η.

Yield: 55% Example 4 Potassium cyanide (260η, 4m1) and methyl 2-oxobicyclo[3.1.0]hexane-1-carboxylate (462Tf9,3m7fL01) were added to dimethylformamide (3ml) under an argon atmosphere. ) is added.

After stirring at room temperature for 24 hours, the same post-treatment as in Example 1 was performed to obtain methyl 5-cyanomethyl-2-oxocyclopentanecarboxylate of 290~.

Yield: 53%

Claims (1)

[Claims] 1. A general formula characterized by reacting a bicyclo[3.1.0]hexane derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ with a cyanating agent under basic conditions. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Method for producing 5-cyanomethyl-2-oxo-cyclobentanecarboxylic acid ester represented by [wherein R is an alkyl group]. ]. 2. The method according to claim 1, wherein R is a lower alkyl group having 1 to 4 carbon atoms.