CA1228869A - 2,2,5,5-tetra-alkyl-cyclohexane-1,4-dione and process for preparing the same - Google Patents

Abstract

The invention relates to novel tetra-alkyl-2,2,5,5-cyclohexanediones-1,4 of general formula (III): <IMG> in which R and R ', identical or different, represent an alkyl radical having 1 to 5 carbon atoms, and their process for the manufacture by alkylation of a 1,4-cyclohexadione. These compounds of formula (III) are useful as intermediates during the synthesis of cyclopropanic lactones of cis structure.

Description

1; 22 ~

This is a division of Canadian patent application No.
451455 filed April 6, 1984.

The subject of the present invention is new compounds of general formula (III):

10R, RR

IR '(III) in which R and R ', identical or different, represent an alkyl radical having from 1 to 5 atoms of carbon.
Advantageously, R and R ', identical or different fonts, represent a methyl, methyl or propyl radical.
Preferably R and R 'are identical and represent a methyl radical.
The present invention also relates to a process for the production of tetra-alkyl-2,2,5,5-cyclohexane-Diên as represented in formula (III):

R 'R (III) I R ' y ,;

hi in which R and Identical or different, represent an alkyl radical having from 1 to 5 carbon atoms, charac-theorize in that we carry out the alkylation of a cyclohexa-Dien of formula (II):

o (II) OJ n In preferential conditions of execution of the alkylation stage of the process of the invention:
- when the radicals R and R ', are identical, the tetraalkylation reaction can be carried out in one single step from cyclohexanedione-1,4 and a alkyl halide in hydrous medium, in tetrahydro-filled in the presence of an alkaline alcoholate;
- when the radicals R and R 'are identical or different, the alkylation reaction is carried out in two steps from a cyclohexanedione-1,4-dicarboxylate-2,5 ethyl under the same conditions as those described above above for tetraalkylation of 1,4-cyclohexanedione.
This alkylation stage can be illustrated by the following diagram:
/

. i than ~ 2; 2 ~ 3 ~ 69 o R there D

(II) R

R 'RÉ

(III) D can be R or R ', X = allogeneic (Cl, Bu or I) The starting cyclohexanedione-1,4 (II) is a compound easily accessible by reduction of hydro-quinine.
Tetraalkyl-2,2,5,5 cyclohexanediones-1,4 thus obtained are useful as intermediaries during the manufacture of tetra-alkyl-2,2,5,5 cyclohexanone-4 oïl and their sulfonylated derivatives, corresponding to the general formula (I):

R
4 (I) R ' GOLD' lie in which:
R and R ', identical or different, represent a radical alkyl having from 1 to 5 carbon atoms and R "represents a hydrogen atom or a radical -SOIR "', in which R"' represents an alkyl radical containing from 1 to 5 atoms of carbon or an aryl radical containing 6 to 14 atoms of carbon, which are useful for the synthesis of lactoses cyclopropanic structures gis as described in main application No. 451455 filed April 6, 1984.
These compounds of formula (If are obtained in particular by implementing a process characterized in that the 1,4-cyclohexanedione of formula (II) is alkylated:

(II) o to obtain, according to the present invention the tetra-alkyl-

2,2,5,5 cyclohexanediones-1,4 of formula (III):

R
RR (III) fi R ' in which R and R 'have the previous meanings, which we selectively reduce to obtain the tétera-2,2,5,5-alkyl cyclohexanone-4 oïl corresponding, of form-mule (I), in which R "represents a hydrogen atom, and that these products are transformed, if desired, into ~ 228869 corresponding sulfonylated derivatives of formula (I) in which R "represents an EVEN radical as defined previously.
In preferential conditions of execution of the selective reduction stage of the process of the invention of the main request, a monoenolate is formed beforehand the compound of formula (III), using an alcoholate alkaline. It is preferably carried out in a hydrous medium, in the tetrahydrofuran and at a temperature of around 0 C.
As the alkali alcoholate, a sodium alcoholate of a lower aliphatic alcohol having from 1 to 6 carbon atoms, preferably tert-butylate sodium or sodium tertioamylate.
The selective reduction proper is preferably carried out using a hydride such as di-isobutylaluminum hydride or a borohydride such than sodium borohydride.
Under very preferential conditions of the selective reduction stage of the process of the invention of the main request, said micro biological reduction, particularly using a feignis imperfecti, especially chosen in the group made up of Curvularia, Aspergillus, Moukère, Ceotrichum, Penicillium, Rhizopus, Click, Cunninghamella, Cylindrocarpon, Fusarium, Neurospora and Trichothecium.
The use of the above microorganisms feels the very important benefit of leading to a reduction selective and stereospecific of the diketonion compound in one cool configuration (S).
Among the microorganisms above, those chosen in the group consisting of Curvalaria lunata, Aspergillus Niger Aspergillus crush, Moukère racemosus and Penicilium chrysoqenum are especially preferred for the ~ 228869 level of selectivity and stereospecificity they allow to achieve.
The sulfonylation stage of the process the invention of the main application is carried out by prefect-darkens using a halide of an alkyl or arylsulfonic acid and, more particularly, using chloride mesyl or tolyl chloride, operating in medium hydra in the presence of a base and at a temperature about THAT.
there As previously mentioned, the compounds of formula (I) are themselves useful as intermediaries for the production of cyclopropanic lactoses corresponds gis structure dates corresponding to the general formula Vu R ' Jo (V) R

in which R and R ', identical or different, have the si-previously mentioned unifications.
These compounds of formula (V) are especially obtained by a process by which said compounds are transformed of formula (I) where R "represents a hydrogen atom, in corresponding sulfonylated derivatives which are oxidized using of a peracid, in lactoses of formula (IV):

R

D (IV) . R

OSo2Rl 'l : 122 ~ 3 ~ 69 where R, R 'and R "' have the meanings already indicated, then that we carry out in a basic medium a reaction of cyclopropanation of lactoses of formula (IV) to obtain the compounds sought.
These cyclopropanic lactoses of formula (V) cons-particularly valuable intermediaries in the synthesis of substituted cis-cyclopropane carboxylic acids, especially in the synthesis of cis-chrysanthemic acid or cis-dimethyl-2,2 (methyl-2 'propenyl-1') - 3 cycle-propane-l-carboxylic, which we know on the one hand, properties, in particular insecticides or olfactory of certain of its esters and secondly the interest as an mediates in the synthesis of other acid esters cycle-dihalogenovinyl propane carboxylates that have also remarkable insecticidal properties.
Cis-chrysanthemic acid (lR, 3S) constitutes so especially a particularly important intermediary in the synthesis of deltamethrin discovered by M.
ELLIOTT in 1974, this compound combining insect-exceptional aid for reduced toxicity towards higher organisms and low persistence in the natural environment.
Cyclopropanic lactoses of formula (V) constituting particularly valuable intermediaries in the synthesis of cyclopropane carboxylic acids undergone located in position 3 by a branched vinyl chain, the this application is particularly interesting from a industrial point of view insofar as it describes new compounds allowing the preparation of said lactoses in few steps, from products easily accessible and with operating conditions particularly simple and inexpensive in energy.
Furthermore, the intermediaries obtained pre-mostly feel as crystallized products es which greatly facilitates their purifications when these these are necessary.
The following examples illustrate the invention without however giving it any character limiting.

Example 1: Tetramethyl 2,2,5,5-cyclohexanedione-1,4.

4.48 g of 1,4-cyclohexanedione and 10.2 ml methyl iodide, dissolved in 100 ml of tetrahydro-filled with hydra at 0 C, 106 ml are added dropwise of a 1.5M solution of sodium tertio-amylate in the benzene, in one hour. When the addition is complete, the solution is stirred at 20 C for one hour.
After hydrolysis by addition of water and separation, the aqueous phase is extracted with ether. Organ phases-that are combined and then washed with water and dried. After evaporation, isolated by chromatography on a column of silica (eludant: ethyl acetate-hexane 20/80) and crystal-libation in hexane, 3.25 g of the expected compound.
Yield: 50%.
Melting point: QUE.
IF spectrum (Nujol *): 1700 cm 1 H NMR spectrum (60 MHz, QUE): 2.5 (s OH) 1.1 (s 12H).
Example 2: Tetramethyl-2,2,5,5-cyclohexanedione-1,4.

Step 1 :

a) 25.6 g of cyclohexanedione-1,4-dicarboxylate-2,5 ethyl and 10.4 g of sodium hydroxide in solution in a mixture of 200 ml of 95% ethyl alcohol and 50 ml of water, 13.7 ml of methyl iodide are added at 0 ° C. with stirring.
The solution obtained is then kept at QUE for 100 * (trademark) ~ 1; 228869 g hours. After evaporation of the solvent, the residue is taken up with water and then extract the ether. The ethereal solution is washed with salt water and dried. After evaporation we obtain 24 9 of crude oil.
b) The 24 g of the product obtained above are then stirred in 200 ml of 20% perchloric acid while QUE hangs tooth 2 hours 30 minutes. After extraction with chloride methylene and evaporation, the crude product is chromatographed prayed on silica column (eludant: ethyl acetate-hexane 40/60). 8.5 g of 2,5-dimethyl-cyclohexanedione are obtained.
1.4 (mixture of 2 diastereoisomers).
IF spectrum (film): 1700 cm 1 H NMR spectrum (60 MHz, Which):

3.0-2.2 (m OH) 1.1 (dJ-6Hz OH).
2nd step :

3 g of dimethyl-2,5-cyclohexanedione-1,4 and 2.6 ml of methyl iodide in solution in 30 ml of tetrahydro-filled with hydra, 28 ml of a 1.5 M solution are added at 0 ° C.
sodium tertio-amylate in benzene, in 15 minutes.
After hydrolysis with water and separation, the aqueous phase is extracted with ether. Organic phases are combined then washed with water and dried. After evaporation and puni-fixation by chromatography on a silica column (eludant:
ethyl acetate-hexane 20/80), 2.9 9 of tetera are obtained methyl-2,2,5,5-cyclohexanedione-1,4 (yield 82%) present both the same characteristics as the worthy obtained according to Example 1.
Example 3:

This example will illustrate the usefulness compounds according to the invention in the synthesis of lactoses cyclopropanic gis, without however conferring a character limiting to the present invention.

Acid lactis gis dimethyl-2,2- (methyl-2'-propenyl-1 '~ -3-cyclopropane 1-carboxylic.

From tetramethyl-2,2,5,5-cyclohexanedione-1.4 described in the examples above, the following steps:
i) 2,2,2-Tetramethyl 5-cyclohexanone-4-ol-1.

A 2 g of tetramethyl-2,2,5,5-cyclohexanedione-1,4 stirred in 12 ml of hydrous tetrahydrofuran, add drop by drop at -20 C, 8 ml of a 1.5M solution of tertio sodium amylate in benzene. The solution obtained is maintained for one hour at 0 C then the mixture is again brought to -QUE and 24 ml of a there solution of diisobutylaluminum hydride in hexane After 30 minutes at this temperature, add successively 1 ml of acetone, 1 ml of methanol and there ml ethyl acetate until precipitation of aluminum salts nium. After filtration and washing of the precipitate with ether, the organic phase is evaporated. The residue leads after croc-matography on silica column (eludant: ether-hexane 30/70) to 1.80 g of the expected compound (Yield: 88 ~). Point of fusion (after crystallization in ether) = THAT.
IF spectrum (film): 3420 - 1680 cm 1 H NMR spectrum (60 MHz, CDCl): 3.9 (m there) 2.6-1.7 (m OH) 1.2 (s OH) 1.1 (s OH) 1.05 (s OH) 0.9 (s OH).
ii) Tetramethyl-2,2,5,5-cyclohexanone-4 oïl mesylate 600 mg of the compound obtained in stage i) and 1 ml of triethylamine in 7 ml of hydrogen chloride of methylene an add 0.4 ml of mesyl chloride to QUE with stirring and 122886 ~

it is maintained for 30 minutes at this temperature. After hydrolysis with water and extraction with ether, the organ phase-that is washed with salt water and then dried and evaporated. We obtained after chromatography on a silica column (eludant: ethyl acetate-hexane 40/60) 850 mg of mesylate expected (Yield: 97%). Melting point (after crystal-libation in the ether-hexane mixture) = THAT.
IF spectrum (nujol): 1710 cm 1 H NMR spectrum (60 MHz, QUE): 4.8 (due J = 6 8Hz there) 3.0 (s OH) 2.6-1.9 (m OH) 1.2 (s OH) 1.15 (s OH) 1.10 (s OH) 0.95 (s OH) -iii) Lucid trimethyl-3,3,6-hydroxy-6-mesyloxy lactose ________________________________________________________

4-heptanoi ~ eu.
850 mg of mesylate obtained in ii) and 1 g of acid metachloroperbenzoic are stirred in 4 ml of chloride methylene an hydra. After 100 hours, the solution is filtered killed, the precipitate washed with methylene chloride and the organic phases are combined and then evaporated. We obtain after chromatography on a silica column (eludant: ax-ethyl hexane 60/40), 766 mg of the expected product (85% yield). Melting point (after crystallization in the ethyl acetate-ether mixture) = 128 C.

Specter there (nujol): 1700 cm 1 H NMR spectrum (60 MHz, CDC13): 4.8 (due J = 6 6 Hz there) 3.1 (s OH) 2.75 (m OH) 2.4 (m OH) 1.6 (s OH) 1.2 (s OH) 1.1 (s OH).
iv) Lactose of cis-dimethyl-2 ~ 2- (methyl-2 ~ -pro-___________ _ ________________________________________ pennies) -3-cyclopropane-l-carboxylic or lactose __ _________ ___ _________________________________________ thymic acid At 380 mg of mesy lactose obtained in iii) 1.15 ml are added to 4 ml of hydrous tetrahydrofuran of a 1.5M solution of sodium tertio-amylate in benzene to THAT. Let the temperature rise to QUE by 15 minutes. After hydrolysis with water, extraction with ether then wash the organic phase with salt water, dry and evaporate dried up. After chromatography on a silica column (eludant: ethyl acetate-hexane 40/60), 220 mg is obtained expected cyclopropanic lactose gis (Yield%).
Fusion = THAT.
Mass spectrum Mue = 168 (M) 153 124 109 95 81 67 55 43 IF spectrum (film): 1720 cm 1 H NMR spectrum (400MHz, CDC13): 1.92 (due J = 9.7 15.0 Hz there) 1.65 (due J = 5.1 15.0 there) 1.55 (d J = 7.7 Hey there) 1.44 (s OH) 1.41 (ddd J = 5.1 7.7 9.7 Hz there) 1.34 (s OH) 1.22 (s OH) 1.08 (s OH).
Liât. : H. Lehmkuhl, K. Meuler; Liebigs Ann. Chem, ll, 1841 (1978).
Preparation of cis-chrysanthemic acid or cis-dimethyl-2,2- ~ methyl-2'-propenyl-1 ') - 3-cyclopropane-1-carbooxylic .
racemic.
40 mg of lactose obtained above in iv) are heated in the presence of 146 mg of magnesium bromide vexa-hydrated in 0.25 ml of hydrous pyridine at 125 C for 14 hours. After acidification with 0.5 ml of hydrochloric acid that UN, the aqueous phase is extracted at Lyautey; the phases organics are combined, washed with hydrochloric acid then diluted with salt water, then dried and evaporated to dryness.
After chromatography on a silica column (eludant: axi-ethyl hexane 20/80), 35 mg of gis-pure chrysanthemum (Yield: 88%). Cis-chrysan- acid stick obtained is identical to an authentic sample described by J. Fini ni, J. d'Angelo, Tetrahedron Latvians (1976) 2441 and J. Ficini, S. Flou, J. d'Angelo, Tetrahedron Latvians (1983) 375.

Example 4: (+) - (S) -Tetramethyl-2,2,5,5-cyclohexanone-4-ol-1.
-Curvularia lunata NRRL 2380 preserved on solid medium (a) is seeded in liquid medium (b) and cultivated 48 hours at ~; 2288 ~ 9 24 C in a rotary incubator. The saying obtained according to Example 1 or 2 is added in 5% solution in ethanol at a final concentration of 500 mg per 1 liter of medium liquid. After 3 more days of stirring at 24 C, vapor phase chromatography of an extract obtained at ethyl acetate indicates 95 ~ conversion to cool which is isolated by colitis filtration, filter saturation with sodium chloride and repeated extraction with dichloro-methane. After drying and evaporation, 460 mg of Pale yellow crystallized product which is discolored with charcoal active and recrystallized from hexane to obtain the (S) (+) cool (252 mg). The mother liquor treatment allows to obtain another 100 mg of pure (S) cool.
Yield: 70 ~. Melting point (after crystallization in ether): THAT
IF spectrum (nujol): 3320 - 1680 cm 1 H NMR spectrum (60 MHz, CDC13): 3.9 (m there) 2.6-1.7 (m OH) 1.2 (s OH) 1.1 (s OH) 1.05 (s OH) 0.9 (s OH).
/ ~ / = +89.7 (c = 0.3 Meuh).
D
a) Solid medium: Glucose, 20 g; skate, 5 go Bacto-Yeast Extract, 5 g 'Bacto-Malt Extract, 5 g; Bacto-agar, 20 g, for 1 liter.
b) Liquid medium (Nakazaki et ci., J. Orge Chef., 44 (1979) 4588).
Vapor chromatography of a derivative cool isopropyl urethane on choral column (RCC-phenyl glycinamide) detects only one peak, which translates the presence of a single stereoisomer.
Example 5: (+) - (S) -tetramethyl-2,2,5,5-cyclohexanone-4 wing The following table shows the results leaves obtained by reducing the saying of example 1 or 2, ~; 22 ~ 18 ~

with different microorganisms, operating at a consensus 1 9/1 remote pull ~

/

at 9 Micro-organism OG product time% dol% saying expected reaction (S) formed residual area _ _ .. __ Curvularia lunata 75 H 98.2 _ 1.8 Aspergillus Niger 48 H 66.2 1 32.8 Aspergillus crush H 89.2 10.8 Moukère racemosus75 H 85.2 _ 14.8 Geotrichum candidum 119 H 31.7 _ 68.3 Penicilium hrysogenum 119 H 69.9 _ 30.1 the hizopus ¦ rrhizus119 H 30.5 _ 69.5 TOC 11145 _ Many strains of Aspergillus species Niger Moukère racemosus, Geotrichum candidum and Penicilium chrysogenum are readily available in various collections, notably in ATCC or NRRL.

2-tetramethyl-2 2 5 5-cyclohexanone-4-ol-1 mesylate 200 mg of the compound of Example 4 and 0.33 ml of triethylamine in 3 ml of hydrogen chloride of methylene an add 130 ml of mesyl chloride at 0 ° C. with stirring and it is maintained for 30 minutes at this temperature. After hydrolysis by addition of 2 ml of water and extraction at ether, the organic phase is washed with 1 ml of salt water then dried over MgSO4 and evaporated. We get after chromatography on a silica column (eludant: acetate ethyl-hexane 40/60) 283 mg of the expected mesylate.
(Yield: 97%).
Melting point (after crystallization in the mixture ether-hexane) = 56-57 C.
IF spectrum (Nujol): 1710 cm NMR spectrum H (60MHz, QUE): 4.8 (due J = 6.8 Hz there) 3.0 (s OH) 2.6-1.9 (m OH) 1.2 (s OH) 1.15 (s OH) 1.10 (s OH) 0.95 (s OH).
Que = +60.7 (c = 2.06 CHC13).
D

EXAMPLE 7:
Lactose (+) of cis-dimethyl-2,2- (methyl-2'-prop_ y y -1 ') - 3-cyclopropane-1-carboxylic.
Stage A:
:
Lactose y acid (S) trimethyl-3,3,6-hydroxy-6-mesyloxy-4-heptanoic.
283 mg of the mesylate obtained according to Example 6 and 0.33 g of metachloroperbenzoic acid are stirred in 2 ml of methylene chloride in hydra. After 100 hours, the solution is filtered, the precipitate washed with chloride methylene and the organic phases are combined and then evaporated. After column chromatography, silica (eludant: ethyl acetate-hexane 60/40) 255 mg of expected product. (Yield: 85%).
Melting point (after crystallization in the mixture ethyl acetate-ether): decomposition around 100 C.

IF spectrum (Nujol): 1700 cm 1 H NMR spectrum (60 MHz, CDC13): 4.8 (due J = 6 Hz there) 3.1 (s OH) 2.75 (m OH) 2.4 (m OH) 1.6 (s OH) 1.2 (s OH) 1.1 (s OH).
[a = +24 7 (1 9 CHCl) D

Stage B:
Lactose (+) (lR, 3S) of cis-dimethyl-2,2- (methyl-2'-) acid propenyl-1 ') - 3-cyelopropane-1-carboxylic or lactose (+) from cis-chrysanthememic (1R, 3S) acid.
At 126 mg of the lattate mesylate obtained according to the Stage A in 2 ml of hydrous tetrahydrofuran, the following is added 0.38 ml of a 1.5M solution of sodium tertio amylate in benzene at 0 C. The temperature is allowed to rise to 20 C in 15 minutes. After hydrolysis with water, it is extracted at ether then wash the organic phase with salt water. After ehromatography on a silica column (eludant: acetate ethyl-hexane 40/60), 73 mg of the batten are obtained eyelopropanic expected (Yield: 95%).
Melting point (after crystallization from hexane) 83-84 C.
Moult spectrum: 168 (M) 153, 124, 109, 95, 81, 67, 55, 43.
IF spectrum (film): 1720 eu 1 H NMR spectrum (400 MHz, CDCl3): 1.92 (due J = 9.7; 15.0 Hz there) 1.65 (due J = 5.1 15.0 Hz there) 1.55 (d J = 7.7 Hz there) 1.44 (s OH) 1.41 (ddd J = 5.1; 7.7; 9.7 Hz there) 1.34 (s OH) 1.22 (s OH) 1.08 (s OH).
[y = +78 (c = 1.2 in CHCl3).
(Literature: S. Terri, T. Inokuehi, R. Ci; J. Orge Chef.
Vol 48, p. 1944 (1983): [y 2 = 77.6 (c 1.8 in CHCl3), D

F = 83 C).

Claims (4)

The embodiments of the invention, concerning the-what an exclusive property right or lien is claimed, are defined as follows: 1. Tétra-alkyl-2,2,5,5 cyclohexanediones-1,4 de general formula (III):

(III) <IMGE>

characterized by the fact that:
R and R ', identical or different, represent a radical alkyl having 1 to 5 carbon atoms. 2. Compounds according to claim 1, characterized by the fact that R and R 'are identical and represent the methyl radical. 3. Process for the production of 2,2-tetraalkyl, 5.5 cyclohexanediones-1,4 of general formula (III):

(III) in which R and R ', identical or different, represent an alkyl radical having from 1 to 5 carbon atoms, characterized in that the alkylation of a 1,4-cyclohexadione is carried out formula (II):

(II) 4. Method according to claim 3, characterized in that:
- when the radicals R and R ', are identical, the tetraalkylation reaction can be carried out in one step starting from 1,4-cyclohexanedione and a halide of alkyl in an anhydrous medium, in tetrahydrofuran in pre-sence of an alkaline alcoholate;
- when the radicals R and R 'are identical or different, the alkylation reaction is carried out in two steps from a cyclohexanedione-1,4-dicarboxylate-2,5 ethyl under the same conditions as those described above above for tetraalkylation of 1,4-cyclohexanedione.