JPH06145163A - Production of 6,6-dimethyl-3-oxa-2-oxobicyclo@(3754/24)3.1.0)hexane - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a synthetic intermediate for pyrethroid-based insecticide simply and industrially by treating a halomethylcyclopropanecarboxylic acid derivative with an alkali. CONSTITUTION:A halomethylcyclopropanecarboxylic acid derivative of formula I [X is halogen; R is H, lower alkyl, (substituted) aralkyl or (substituted aryl] is treated with an alkali to give the objective compound of formula II.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane which is useful as a synthetic intermediate for pyrethroid insecticides.

[0002]

2. Description of the Prior Art 6,6-Dimethyl-3-oxa-2-oxobicyclo represented by the formula (2) produced by the present invention
[3.1.0] Hexane is known to be an important intermediate in the synthesis of cis-chrysanthemic acid derivatives, which are known as highly active components of pyrethroid insecticides (AK Mandal,
DP Borude, R. Armugasamy, NR Soni, DG Jawal
kar, SW Mahajan, KR Ratman, and AD Goghare,
Tetrahedron, 42, 5715 (1986); Takano, Ogasawara, Hirama,
JP 61-183239 (1986); NF Janes, E
d., "Recent Advances in the Chemistry of Insect Con
trol "The Royal Society of Chemistry (1985)).

Conventionally, many methods for producing 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane represented by the formula (2) are known. For example, 1)
Method using cyclization reaction via addition elimination of isopropylideneiowilide to 2 (5H) -furanone (M. Sevrin, L.
Hevesi, A. Krief, Tetrahedron Lett. 3915 (1976));
2) Method of formation of pyrazolidine ring by addition of dimethyldiazomethane to 2 (5H) -furanone and formation of three-membered ring through denitrification by light irradiation (M. Franck-Neumann, Angew. Ch.
Em. Internat. Ed., 7, 65 (1968)); 3) Formation of hydroxymethylcyclopropane biscarboxylic acid ester by addition of diazomalonate ester to isoprenol, and method by lactonization and deesterification (W. Ando, I. . Ima
i, T. Migita, J. Org. Chem. 37, 3596 (1972)); 4)
Method by formation of three-membered ring by irradiation of diazoacetic acid isoprenyl ester (EA Shapiro, AB Diyatkin, O.
M. Nefedov, Izv. Akad. Nauk SSSR, Ser. Khim., 2189
(1990); Chem. Abstr. 114,121950s (1991)); 5) 3,
Method for obtaining γ-lactone form by carbonylation of 3-dihalo-1-hydroxycyclopropane with nickel carbonyl (Hirao, Hirano, Yamana, Okahiro, Agawa, JP-A-58-167581 (1983)); 6) Trichloro A method of cyclizing an acetic acid isoprenyl ester into a γ-lactone under the Kharasch reaction condition, and then reductively removing an excess chlorine atom to form a cyclopropane ring using a base (Takano, Ogasawara, Akiyama) , JP-A-60-2
52476 (1985)) and the like, but all of these methods have drawbacks as industrial production methods.

That is, in method 1), 2 (5H) -furanone is an expensive reagent and is difficult to obtain industrially, and isopropylidene diphenyl sulfide ylide is also industrially difficult to obtain. Method 2) is industrially difficult because of both the use of diazomethane and the photochemical reaction. The method 3) has drawbacks such as low selectivity of addition of diazomalonic acid to isoprenol, a large amount of by-products, and adoption of photoreaction. The method 4) has drawbacks such as the use of a diazo compound and a photoreaction. In method 5), the excessive use of the highly toxic nickel carbonyl is a factor that is difficult to be adopted industrially. Further, in the method 6), it is a troublesome method such that the chloro atom existing in excess as a substituent is purposely reductively removed.

[0005]

DISCLOSURE OF THE INVENTION In order to improve the above situation, the present inventors have decided to use 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane simply and industrially. As a result of diligent study on a production method that can be adopted, the inventors have found that the purpose can be easily achieved by treating the halomethylcyclopropanecarboxylic acid derivative represented by the general formula (1) with an alkali, and completed the invention.

[0006]

That is, the present invention provides a general formula

[0007]

[Chemical 3]

(Wherein, X represents a halogen atom, R represents a hydrogen atom, a linear or branched lower alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group. ) Represented by the following formula, which comprises the step of subjecting a halomethylcyclopropanecarboxylic acid derivative represented by

[0009]

[Chemical 4]

There is provided a method for producing 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane represented by:

The method of the present invention follows the route of the following (formula 1).

[0012]

[Chemical 5]

(In the formula, X represents a halogen atom, R represents a hydrogen atom, a linear or branched lower alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group. ).

The compound represented by the general formula (1) used as a starting material in the present invention can be easily produced, for example, according to the method represented by the following (formula 2). That is, by selectively dichlorinating the 3,3-dimethyl-4-pentenoic acid derivative represented by the general formula (3), the general formula (4)
The chloromethylcyclopropanecarboxylic acid derivative represented by the general formula (1 ′) is obtained by cyclization by a base treatment after leading to the 4,5-dichloro-3,3-dimethylpentanoic acid ester derivative represented by (Sakai, Sugimoto, Kondo,
See Japanese Patent Application No. 3-325021 and the following reference example).

[0015]

[Chemical 6]

Further, the chloromethylcyclopropanecarboxylic acid derivative represented by the general formula (1 ') can be easily converted into a bromomethyl form or an iodomethyl form by a halogen exchange reaction, so that the chloromethyl form can be easily contained in the general formula (1). ) A halomethylcyclopropanecarboxylic acid derivative represented by () is obtained (see the reference example below).

The substituent X in the halomethylcyclopropanecarboxylic acid derivative represented by the general formula (1) may be a chlorine atom, a bromine atom or an iodine atom, and R may be a hydrogen atom, a methyl group or an ethyl group. , N-propyl group,
i-propyl group, n-butyl group, i-butyl group, s-butyl group,
Lower alkyl group such as t-butyl group, amyl group, aralkyl group such as benzyl group, p-methylbenzyl group, p-chlorobenzyl group, phenyl group, aryl group such as p-methylphenyl group, p-chlorophenyl group, etc. Can be mentioned.

The alkali used in the method of the present invention includes alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium carbonate,
Examples thereof include alkali metal carbonates such as sodium bicarbonate, potassium carbonate and potassium bicarbonate. Alkali is used in 1.1-3.0 equivalents with respect to the halomethylcyclopropanecarboxylic acid derivative represented by the general formula (1).
-2.5 equivalents is sufficient.

This reaction is preferably carried out in the presence of a solvent, and examples of the solvent used include alcohols such as methanol, ethanol and propyl alcohol, water, dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and the like. The solvent may be used alone or in combination. Although the reaction proceeds at room temperature, it is desirable to heat to 50-100 ° C. in order to finish the reaction smoothly and promptly.

Immediately after completion of this reaction, the reaction of the formula (5)

[0021]

[Chemical 7]

It can be judged from NMR and infrared absorption spectrum that the hydroxymethylcyclopropanecarboxylic acid represented by the following formula is obtained. However, cyclization occurs while standing at room temperature, and it is represented by the formula (1). 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane is obtained in high yield.

[0023]

EXAMPLES The present invention will be described in more detail below with reference to examples and examples.

Reference Example 1

[0025]

[Chemical 8]

Ethyl 3,3-dimethyl-4-pentenoate 156 mg
(1.00 mmol), 355 mg of hexachloroethane (1.50 mmol),
And RuCl ₂ (PPh ₃ ) ₃ 5 mg (0.5 mol%) was dissolved in toluene 1.0 mL and heated to 120 ° C. under an argon atmosphere. The reaction is G
Followed by LC and was complete after 2 hours. Toluene was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane / ether = 20/1) 4,5-
195 mg of ethyl dichloro-3,3-dimethylpentanoate
Was obtained as a colorless oil (yield 86%).

¹ H-NMR (90 MHz) δ 1.15 (3 H, s), 1.20 (3
H, s), 1.27 (3H, t) 2.30 (1H, d, J = 15.0), 2.60 (1H,
d, J = 15.0), 3.58 (1H, dd, J = 12.3, 9.6), 4.01 (1H, d
d, J = 12.3, 2.7), 4.31 (1H, dd, J = 9.6, 2.7), 4.15 (2
H, q) .MS (low resolution) m / z: 231, 229, 227 (M ⁺ +1), 185, 183, 18
1 (M ⁺ -OC ₂ H ₅ ), 155 (M ⁺ -HCl ₂ ), 129, 119, 117, 105, 10
3, 87.

GLC conditions: column 2% EGA 1 m; N
₂ 40CC / min; temperature 100 ° C; holding time; 3,3-
Ethyl dimethyl-4-pentenoate 1.74 minutes, ethyl 4,5-dichloro-3,3-dimethylpentanoate 10.7
4 minutes.

Reference Example 2

[0030]

[Chemical 9]

Potassium t-butoxide 447 mg (3.98 m
mol, 2.00 eq) was dissolved in 16 mL of tetrahydrofuran under an argon atmosphere and cooled under dry ice-acetone. A solution of 452 mg (1.99 mmol) of ethyl 4,5-dichloro-3,3-dimethylpentanoate in tetrahydrofuran (4.0 mL) was added dropwise thereto over 30 minutes. After continuing stirring for 1 hour as it was, 5.0 mL of saturated ammonium chloride aqueous solution was added, and the temperature was gradually raised to room temperature. The reaction mixture was extracted with ether. The organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off to obtain 367 mg of ethyl 3-chloromethyl-2,2-dimethylcyclopropanecarboxylate as an almost colorless oily substance (yield 96.7%). This product is cis / by GLC analysis.
Trance was 85:15.

¹ H-NMR (90 MHz) δ 1.22 (3 H, s), 1.29 (3
H, s), 1.27 (3H, t), 1.5 (2H, m), 3.96 (2H, m), 4.12
(2H, q) .MS (low resolution) m / z: 155 (M ⁺ -Cl), 147, 145 (M ⁺ -OC ₂ H ₅ ), 1
41 (M ⁺ -CH ₂ Cl), 119, 117 (M ⁺ -COOC ₂ H ₅ ), 113 (M ⁺ -CH ₂ Cl-C
₂ H ₄ ), 95 (M ⁺ -CH ₂ Cl-CC ₂ H ₆ ).

GLC conditions: column 2% EGA 1m; N ₂
40 CC / min; temperature 100 ° C .; retention time ethyl cis-3-chloromethyl-2,2-dimethylcyclopropanecarboxylate 1.81 minutes, ethyl trans-3-chloromethyl-2,2-dimethylcyclopropanecarboxylate 2 .69 minutes, 4,5-dichloro-3,3-
Ethyl dimethylpentanoate 11.51 minutes.

Reference Example 3

[0035]

[Chemical 10]

Methyl 3-chloromethyl-2,2-dimethylcyclopropanecarboxylate (cis / trans = 82:
18) A mixture of 1.00 g (5.66 mmol) and NaI 2.54 g (17.0 mmol) was heated to reflux in 20 mL of acetone. After 24 hours, acetone was distilled off under reduced pressure, and the residue was extracted with ether. The ether layer was washed with saturated saline and dried over sodium sulfate. The crude product (1.37 g) obtained by distilling off the solvent ether under reduced pressure was separated and purified by column chromatography (silica gel, hexane / ether = 19: 1) to give cis-2,2-dimethyl-3- (3-2) as colorless oils. 710 mg of methyl iodomethylcyclopropanecarboxylate (47% yield) and 155 mg of methyl methyl trans-2,2-dimethyl-3-iodomethylcyclopropanecarboxylate (10% yield) were obtained.

¹ H-NMR (90 MHz, CDCl ₃ ) cis δ 1.18 (3
H, s), 1.25 (3H, s), 1.59 (1H, d, J = 8.4), 1.73 (1H,
m), 3.57 (2H, m), 3.66 (3H, s): Transformer body δ 1.36 (6
H, s), 1.36 (1H, d, J = 5.4), 1.96 (1H, ddd, J = 9.3, 7.
1, 5.4), 3.06 (1H, dd, J = 10.3, 9.3), 3.67 (3H, s), 3.
77 (1H, dd, J = 10.3, 7.2).

Example 1

[0039]

[Chemical 11]

In 2.0 mL of dimethylsulfoxide (DMSO),
0.62 g (11 mmol) of potassium hydroxide pellets was crushed into powder using a glass rod. In this, 2,2-dimethyl-
Ethyl 3-chloromethylcyclopropanecarboxylate (cis / trans = 86: 14) 0.955 g (5.01 mmol) DMSO
(3.0 mL) solution was added and heated to 95 ° C. under argon atmosphere. After 8 hours, the reaction solution was diluted with ether, and saturated brine was further added for washing. The ether layer was dried over sodium sulfate. The alkaline aqueous layer was acidified by adding 2M hydrochloric acid (about pH 2) and then extracted with ether. The ether layer was washed with saturated saline and dried over sodium sulfate.
The ether was distilled off under reduced pressure, and the neutral portion was 46 m.
g, 2,2-dimethyl-3 as a colorless oil from the acidic part
-544 mg of hydroxymethylcyclopropanecarboxylic acid was obtained (yield 76%). When this product was left as it was at room temperature for 2 days, all of it was 6,6-dimethyl-3-oxa-2-
It was confirmed that it was changed to oxobicyclo [3.1.0] hexane.

2,2-Dimethyl-3-hydroxymethylcyclopropanecarboxylic acid ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.22 (3H, s), 1.26 (3H,
s), 1.52 (1H, ddd, J = 8.4,8.3, 7.1), 1.60 (1H, d, J =
8.4), 3.96 (1H, dd, J = 11.9, 8.3), 4.00 (1H, dd, J = 11.
9, 7.1), 6.3 (2H, b): IR (liq. Film) 3350, 2950, 29
25, 1720, 1440, 1410, 1380, 1250, 1120cm ^-1 .

6,6-Dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.18 (3H, s), 1.19 (3H,
s), 1.96 (1H, dd, J = 6.3, 1.0), 2.05 (1H, ddd, J = 6.3,
5.5, 1.0), 4.16 (1H, ddd, J = 9.9, 1.0, 1.0), 4.37 (1
H, dd, J = 9.9, 5.5): MS m / z 126 (M ⁺ ), 111, 97, 90, 8
2, 81, 67: IR (liq. Film) 2950, 2925, 1760, 1740,
1450, 1380, 1360, 1280, 1215, 1175, 1110, 1090, 10
50, 970.

Example 2

[0044]

[Chemical 12]

78 mg (1.19 mmol) of powdered potassium hydroxide
And methyl 2,2-dimethyl-3-iodomethylcyclopropanecarboxylate (cis / trans = 75: 25) were heated to 90 ° C. for 14 hours under argon in 10. mL of dimethyl sulfoxide. The same post-treatment as in Example 1 was carried out to obtain 48 mg of 2,2-dimethyl-3-hydroxymethylcyclopropanecarboxylic acid as an acidic portion (yield 84
%). It was confirmed by NMR measurement that the product was all changed to 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane by leaving it to stand.

Example 3

[0047]

[Chemical 13]

Methyl 2,2-dimethyl-3-chloromethylcyclopropanecarboxylate (cis / trans = 82:
18) 89 mg (0.5 mmol) was dissolved in 1.5 mL of water-containing methanol (30%) containing 72 mg (1.3 mmol) of potassium hydroxide, and the mixture was stirred at room temperature for 14 hours. The solvent was distilled off from the reaction solution under vacuum. 2.0 mL of dimethylformamide was added to the mixture, and the mixture was heated at 95 ° C. for 14 hours in an argon atmosphere. The same post-treatment as in Example 1 was carried out to obtain 61 mg of 2,2-dimethyl-3-hydroxymethylcyclopropanecarboxylic acid as an acidic portion (yield 84
%). It was confirmed by NMR measurement that the product was all changed to 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane by standing.

Example 4

[00]

[Chemical 14]

In 1.5 mL of ethanol containing 85 mg (1.5 mmol) of potassium hydroxide, ethyl 2,2-dimethyl-3-chloromethylcyclopropanecarboxylate (cis / trans =
85:15) 195 mg (1.01 mmol) was added, and the mixture was heated to 90 ° C. under an argon atmosphere. After 24 hours, the heating was stopped and the same post-treatment as in Example 1 was carried out to prepare 2,2-dimethyl-
61 mg of 3-hydroxymethylcyclopropanecarboxylic acid was obtained (yield 42%). All the products were left to stand by leaving 6,6-dimethyl-3-oxa-2-oxobicyclo
The change to [3.1.0] hexane was confirmed by measuring NMR.

Example 5

[0052]

[Chemical 15]

Ethyl 2,2-dimethyl-3-chloromethylcyclopropanecarboxylate (cis / trans = 8) was added to 2.2 mL of ethanol containing 84 mg (2.0 mmol) of lithium hydroxide.
5:15) 165 mg (0.87 mmol) was added, and the mixture was heated to 90 ° C. under an argon atmosphere. After 24 hours, the heating was stopped and the same post-treatment as in Example 1 was carried out to obtain 2,2-dimethyl-3
-166 mg of hydroxymethylcyclopropanecarboxylic acid was obtained (yield 100%). All the products were left to stand by leaving 6,6-dimethyl-3-oxa-2-oxobicyclo
The change to [3.1.0] hexane was confirmed by measuring NMR.

Example 6

[0055]

[Chemical 16]

In 2.2 mL of ethanol containing 74 mg (1.8 mmol) of sodium hydroxide, ethyl 2,2-dimethyl-3-chloromethylcyclopropanecarboxylate (cis / trans =
85:15) 165 mg (0.87 mmol) was added, and the mixture was heated to 90 ° C under an argon atmosphere. After 24 hours, the heating was stopped and the same post-treatment as in Example 1 was carried out to prepare 2,2-dimethyl-
77 mg of 3-hydroxymethylcyclopropanecarboxylic acid was obtained (yield 53%). All the products were left to stand by leaving 6,6-dimethyl-3-oxa-2-oxobicyclo
The change to [3.1.0] hexane was confirmed by measuring NMR.

Claims (1)

[Claims] 1. A general formula: (Wherein, X represents a halogen atom, R represents a hydrogen atom, a linear or branched lower alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group) An alkali treatment of a halomethylcyclopropanecarboxylic acid derivative represented by the formula: A method for producing 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hexane represented by: