NO744186L - - Google Patents

Description

PROCEDURE FOR THE PRODUCTION OF CYCLOHEXANONE OR CYCLOPENTANONE DERIVATIVES.

The present invention relates to a method for the production of cyclohexanone derivatives or cyclopentanone derivatives. More particularly, the invention relates to a method for the production of 2,3-disubstituted cyclohexanone derivatives or 2,3-disubstituted cyclopentanone derivatives from unsubstituted or substituted cyclohex-2-en-1-one or unsubstituted or substituted cyclopent-2-en-1 -on.

!2,3-disubstituted cyclohexanone derivatives or cyclopentanone-r

derivatives produced by the method according to the invention are usable as medicines, agricultural chemicals, perfumes or intermediates thereof, i.e. steroids, terpenoids, prostaglandins, jasomones or pyrethroids. According to the invention, the usable compounds can be prepared easily and in relatively high yields. "C^V\

2,3-disubstituted cyclohexanone derivatives and 2,3-disubstituted . cyclopentanone derivatives produced according to the present invention are expressed by the following formulas (4-A) and (4-B).

2,3-disubstituted cyclohexanone derivatives:

In 2,3 di substituted cyclopentanone derivatives:<:>

■

In formulas (4-A) and (4-B) R1?R2, R3, R4, R5, R&, R7 and

Rg the same or different, and each represents a hydrogen atom or a monovalent organic group; two of them may be bound together to form a ring; and R₂ and R₂ are the same or different and each represent a monovalent organic group.

according to the method according to the present invention, the cyclohexanone derivatives with formula (4-A) or the cyclopentanone derivatives with formula (4-B) can be prepared by a method which includes:

(a) a first step wherein a cyclohexenone derivative of formula (1-A) or a cyclopentenone derivative of formula (1-B)

in which R1? R 2 , R 3 , R 4 , R 5 , R g , R 7 and R g may be the same or different and each represents a hydrocarbon atom or a monovalent organic group, and two of these groups may be bonded to each other to form a ring, reacting with a organic copper-lithium compound of formula (2)

wherein RB is a monovalent organic group and the two RB groups may be the same or different,

Y means a monovalent anion and

n is 1 or 2,

or a complex of the organic copper-lithium compound with an organic phosphorus compound in the presence of an aprotic inert organic medium, and

(b) a second step where the product obtained in the first step reacts with an organic halogen compound of formula

(3)

where RA means a monovalent organic group and X means a halogen atom,

in the presence of a nitrogenous or sulfurous polar organic solvent.

.According to the above process, the reaction of cyclo-

IN

The hexenone derivative of formula (1-A) or the cyclopentenone derivative of formula (1-B) with the organic copper-lithium compound of formula (2) in the introduction of an organic group (Rg) in (3-stil- lation of the cyclohexenenone derivative of formula (1-A) or the cyclopentenone derivative of formula (1-B), and then, by

let the resulting reaction product react with the organic halogen compound (3) in nitrogen-containing or sulfur-containing aprotic, polar, organic solvent, the organic group (RA) can be introduced in the oc position of the carbonyl group of the starting materials. Accordingly, the present invention provides a method for the production of 2,3-disubstituted cyclohexanone derivatives (4-A) or 2,3-disubstituted cyclopentanone derivatives (4-B) by successive introduction of organic groups (R„ and R.) in 6-position and a-position of the cyclohexenone derivatives (1-A) and the cyclopentenone derivatives (1-B).

The method according to the invention will be described in more detail in the following.

[i] First step

1-1. Cy^l^sksenonderi vater__(l-A)_:

The cyclohexenone derivatives used as starting material

in the first step of the process according to the invention is a compound expressed by the above-mentioned general formula (1-A).

In formula (1-A), R^-Rg means a hydrogen atom or a monovalent organic group, such as an alkyl, cycloalkyl, alkenyl, alkynyl or aryl group. These groups can be bonded to each other to form a ring. It will be readily understood that these organic groups are non-reactive with the organic copper-lithium compounds. Preferred monovalent hydrocarbon groups are those containing 1-20 carbon atoms, and the ring formed by these groups is preferably 3-7 membered.

Typical examples of these compounds are:

(A-I) cyclohex-2-en-l-one

(A-2) 2-Methylcyclohex-2-en-1-one

(A-3) 3-Methylcyclohex-2-en-1-one

in

I(A-4) isophorone (A-5) carbon

(A-6) 2,3-Dimethylcyclohex-2-en-1-one

(A-7) 2-keto-1-methyl-A<3->octalin

(A-8) l-keto-A<2->octalin t (A-9) 4-ester -3,17-dione

(A-10) 1(5a)-androstene -3,17-dione

(A-ll) 5-pregnene-3|3-ol-7,20-dione-acetate

1-2^ 2yM?P®D£?n22iÉ?£iYate£_iiz§l:

The cyclopentenone derivative of the general formula (1-B) can

is also used as a starting material in the present invention.

In formula (1-B), R 1 - R 1 represents a hydrogen atom or a monovalent organic group, such as an alkyl, cycloalkyl, alkenyl, alkynyl or aryl group. These groups can be linked together to form a ring. It will be easily understood that these groups are non-reactive with the organic copper-lithium compounds

to be described. Preferred monovalent organic groups are those containing 1-20 carbon atoms, and the ring formed by these groups is preferably 3-7 membered.

Typical examples of these compounds are:

(B-l)• cyclopent-2-en-l-one

(B-2) 3,4-Dimethylcyclopent-2-en-1-one

(B-3) 3,4,4-trimethylcyclopent-2-en-1-one

(B-4) 2-Methylcyclopent-2-en-1-one

(B-5) 3-Methylcyclopent-2-en-1-one

(B-6) 4-Methylcyclopent-2-en-1-one

(B-7) 3-isopropylcyclopent-2-en-1-one

(B-8) 2,3,4-trimethylcyclopent-2-en-l-one (B-9) 4-isopropyl-2,3-dimethylcyclopent-2-en-l-one (B-10) 3-ethyl -2-methylcyclopent-2-en-1-one

(B-ll) 2,3-Dimethylcyclopent-2-en-1-one

(B-12) 3-methyl-2-amylcyclopent-2-en-1-one

(B-13) 1(8)-hydroinden-2-one

(B-14) 8(9)-Hydroinden-1-one

(B-15) 2-Hydroinden-1-one

;l-3_. Organic copper r-lithium compound Ice (2)_:

According to the method according to the invention, the above-mentioned cyclohexenone derivative (1-A) or the above-mentioned cyclopentenone derivative (1-B) reacts with the organic copper-lithium compound of formula Cu(R_) LiY„ , in which the symbols have the front

B nz—n'

stated meaning and when n is 2 the above formula will be Cu(R_ a ,) z -Li (2'),i;in the presence of an aprotic inert organic

medium. It is believed that as a result of this the following reactions with the formulas (L) .cells (M) take place

Examples of R_, in the general formula (2) representing the organic copper-lithium compound are alkyl-, alkenyl-, alkynyl-, aralkyl-, aralkenyl-, aralkynyl-, alkoxyalkyl-,

alkoxy-alkenyl and alkoxyalkynyl groups. Preferred Rg groups are those containing 1-20 carbon atoms. Examples of Y are chlorine, bromine, iodine and cyano groups.

The organic copper-lithium compound can be easily prepared by allowing a corresponding organic lithium compound to react with a cuprosalt in an inert medium in an atmosphere of nitrogen.

Examples of suitable organic lithium compounds are shown in the following: | Alkyl lithiums

(2-1) methyl-lithium

(2-2) ethyl lithium

(2-3) n-propyl lithium

(2-4) i—propyl lithium

(2-5) n-butyl lithium

(2-6) t-butyl lithium

(2-7) n-pentyl-lithium

(2-8) n-hexyl-lithium (2-9) cyclohexyl-lithium

(2-10) n-heptyl-lithium

(2-11) n-octyl-lithium

(2-12) n-nonyl-lithium

Alkenyl lithiums

(2-13) vinyl-lithium

rv

(2-14) 1-prop.-cis-1-enyl-lithium

(2-15) 1-prop.-trans-1-enyl-lithium

(2-16) 1-oct.-cis-5-enyl-lithium (2-17) 1-oct.-trans-1-enyl-lithium

(2-18) 1-Oct.-cis-1-enyl-lithium

(2-19) 1-Oct.-trans-1-cis-5-dienyl-lithium

Alkynyl lithiums

(2-20) 1-oct.-1-ynyl-lithium

(2-21) 1-but.-1-ynyl-lithium

(2-22) 1-pent.-1-ynyl-lithium

(2-23) 1-hex-1-ynyl-lithium

(2-24) 1-hep.-1-ynyl-lithium (2-25) 1-oct.-1-ynyl-lithium

Aralkyl lithiums, ■ '

(2-26) 1-(8-phenyl)-octyl-lithium

Aralkenyl lithiums

(2-27)' 1-(2-phenyl)-vinyl-lithium

(2-28) 1-(8-phenyl)-oct.-trans-l-enyl-lithium (2-29) 1-(8-phenyl)-oct.-cis-l-enyl-lithium

in

j Aralkynyl lithium urns

(2-30) 1-(8-phenyl)-oct-5-ynyl-lithium

Alkoxyaralkyl lithiums

(2-31) 1-(3-tetrahydropyranyloxy)-octyl-lithium

(2-32) 1-bis(3,7-tetrahydropyranyloxy)-octyl-lithium

Alkoxyalkenyl lithiums

(2-33) 1-(3-tetrahydropyranyloxy)-oct.-trans-l-enyl-lithium (2-34) 1-bis(3,7-tetrahydropyranyloxy)-oct.-trans-l-enyl-lithium ( 2-35) 1-(3-Tetra-hydropyranyloxy)-oct-trans-1-cis-5-dienyl-lithium

. Alkoxyalkynyl lithiums

(2-36) 1-(3-α-ethoxy)-ethoxy)-oct-5-ynyl-lithium

Siloxyalkenyl lithiums

(2-37) 1-(3-t-butyldimethylsiloxy)-oct.-trans-1-enyl-lithium.

The cuprous salts which can react with the organic lithium compounds to form the organic copper-lithium compounds (2) can e.g. be cuprous chloride, cuprous bromide, cuprous iodide and cuprous cyanide.

A particular example of preparing the organic copper-lithium compound from the organic lithium compound and the cuprous salt consists of allowing the lithium compound to react with the cuprous salt at room temperature to -78°C for several hours, e.g. at -78°C for 0.5 hours, using an inert medium such as a hydrocarbon (e.g. pentane, hexane or heptane)

or an ether (e.g. diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane) .......

The compound of formula (II) can be used as a complex with

a trivalent phosphorus compound., such as trialkylphosphines

(e.g. triethyl phosphite or tri-n-butyl phosphite), trialkyl phosphites (e.g. trimethyl phosphite, triisopropyl phosphite or tri-n-butyl phosphite) triphenylphosphine or hexamethylphosphorus triamide. ,Ofte.the application of the complex tends to give an oct

replacement of the final product.

According to the method according to the invention, the cyclohexenone derivative of formula (1-A) or the cyclopentenone derivative of formula (1-B) first reacts with the above-mentioned organic copper-lithium compound in the presence of an aprotic organic medium.

The cyclohexenone derivative or cyclopentenone derivative and the organic copper-lithium compound react stoichiometrically in equimolar amounts. Usually the cyclohexenone derivative or the cyclopentenone derivative is used in an amount of 0.5 to 2 mol, preferably 0.8 to 1.2 mol per moles of the organic copper-lithium compound.

o ^ o

The reaction temperature is -78 C to^approx. 50 C. However, it is sufficient that the reaction is carried out at room temperature for 10 minutes to 2 hours. The reaction takes place sufficiently even when the temperature is lower than the above specified range, e.g. when it is -100°C.

The reaction is carried out in the presence of an organic medium, which

is an aprotic, organic medium that is liquid at the reaction temperature and not reactive with the reaction reagent. Such aprotic, inert, organic media include various aprotic inert, liquid media also nitrogen-containing or sulfur-containing aprotic polar organic solvents. Examples of these organic media are saturated hydrocarbons, such as pentane, hexane, heptane or cyclohexane, aromatic hydrocarbons, such as benzene, toluene or xylene, ethers, such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether, hexamethyl-phosphorus triamide, N,N -dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane and N-methylpyrrolidone. Inert solvents, such as pentane, which have been used to prepare the organic copper-lithium compounds can be used directly as such aprotic organic solvents. In this case, the starting cyclohexenone derivative (1-A) or cyclopentenone derivative (1-B) is added to the reaction system in which the organic copper-lithium compound has been prepared to carry out the reaction.

![ll] Second step

II-l^ Reactant in second_stage:

According to the method according to this invention, the reaction product obtained by the reaction in the first step reacts with the organic halogen compound of formula

where RA is a monovalent organic group and

X means a halogen atom,

in the presence of the nitrogen-containing or sulfur-containing aprotic organic solvent to form the desired 2,3-disubstituted cyclohexanone derivative of formula (4-A) or 2,3-disubstituted cyclopentanone derivative of formula (4-B) .

Suitable RA groups: are those containing 1 - 20 carbon atoms, and chlorine, bromine and iodine are suitable as group X.

Examples of suitable organic halogen compounds are shown below.

3-1. Alkyl halides:

Methyl iodide, ethyl iodide, n-propyl iodide, n-butyl iodide, n-amyl iodide, n-hexyl iodide, n-heptyl iodide, n-octyl iodide, n-nonyl iodide, n-decyl iodide, isopopyl iodide, isobutyl iodide, methyl bromide, ethyl bromide, n- propyl bromide, n-butyl bromide, n-amyl bromide, n-hexyl bromide, n-heptyl bromide, n-octyl bromide, n-nonyl bromide, n-decyl bromide, isopropyl bromide, isobutyl bromide, methyl chloride, ethyl chloride, n-propyl chloride, n-butyl chloride, n-amyl chloride, n-hexyl chloride, n-heptyl chloride, n-octyl chloride, n-nonyl chloride, n-decyl chloride, isopropyl chloride, and isobutyl chloride.

3-2^ cy^l2al]5ylz^l02 carvers:

Cyclopentyl iodide, cyclohexyl iodide, cyclopentyl bromide, cyclohexyl bromide, cyclopentyl chloride and cyclohexyl chloride.

3-3^ AilS?5y5:ll}5i29carvers:

Allyl iodide, 2-butenyl iodide, 3-butenyl iodide, cis-2-pentenyl-

Iodide, trans-2-pentenyl iodide, 4-pentenyl iodide, cis-2-hexenyl iodide, trans-2-hexenyl iodide, cis-2-heptenyl iodide, trans-2-heptenyl iodide and bromides or chlorides corresponding to these iodides.

3-4^ _Alkynyl halides:

Propargyl iodide, 2-butynyl iodide, 2-pentynyl iodide, 3-pentynyl iodide, 2-hexynyl iodide, 2-heptynyl iodide, and bromides or chlorides corresponding to these iodides.

3-5. Halogenalkenyl halides:

1,3-dichloropropene, 1,3-dichloro-2-butene, 1,3-dichloro-2-pentene and iodides or bromides corresponding to these chlorides. 3-6. Alkoxyalkyl halides: Chloromethyl methyl ether, chloromethyl ethyl ether, chloromethyl benzyl ether, chloroethyl phenyl ether and iodides or bromides corresponding to these chlorides.

3-7^ AE5lkyl-ha^o^enides:

Benzyl chloride, (3-phenethyl chloride, 3-phenylpropyl chloride and iodides or bromides corresponding to these chlorides.

3-8^ _^E3l^enyl halides:

3-bromo-l-phenyl-l-propene.

3-9^ Aralkynyl halides:

3-bromo-l-phenyl-l-propyne.

3-10._Halogen esters:

Methyl bromoacetate, ethyl bromoacetate, methyl 3-bromopropionate, ethyl 2-bromopropionate, methyl 7-bromoheptanate, methyl 7-bromo-2-heptenate and chlorides and iodides corresponding to these bromides.

3-ll_. _Halogen ketones:

Bromoacetone, a-bromoacetophenone, and bromides or chlorides to-

In corresponding to these bromides. in

3-12. Halogen-nitriles:

Chloroacetonitrile, 3-chloropropionitrile, 6-chlorohexanonitrile, 6-chloro-4-hexenonitrile and iodides or bromides corresponding to these chlorides. 3-13._Halogenamides: Chloroacetyl-N,N-diethylamine. 3-14._Halogen acetals: Chloroacetaldehyde-dimethylaceta], chloroacetaldehyde-diethylacetal, chloroacetaldehyde-ethylene acetal, and iodides or bromides corresponding to these chlorides.

II-2_ Other_stage:

It is important that the second-stage reaction according to the present invention is carried out in the presence of the nitrogen-containing or sulfur-containing aprotic, polar, organic solvent. This can lead to a marked increase in the reaction yield in the second step.

These nitrogen-containing or sulfur-containing aprotic polar organic solvents can be any inert polar organic solvents capable of dissolving the reaction product resulting from the first step and the organic halogen compound of formula (3). The reactivity of the anion can be increased by carrying out the reaction of the second step in the presence of such a solvent and as a result the yield of the reaction in the second step increases.

Suitable nitrogen-containing or sulfur-containing polar organic solvents are those which contain 1 - 3 nitrogen or sulfur atoms in the molecule and which are inert in the reaction system in the second step.

Examples of preferred nitrogen-containing or sulfur-containing polar organic solvents are hexamethylphosphorus triamide,

In N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, formaldehyde-dimethylmarcaptal-S-oxide, sulfolane, N-methylpyrrolidone, tetramethylurea, acetonitrile, nitrobenzene and dimethylcyanamide. Furthermore, several aprotic, polar, organic solvents can also be used with advantage, such as e.g. tetra-methylethylene-diamine, tetraethylethylenediamine, triethylenediamine, triethylamine, pyridine, a,cc'-dipyridyl, 1,5-diazabicyclo[4 ,3,0]-5-nonene and 1,5-diazabicyclo[5,4,0j- The 5th decade.

The second-step reaction according to the invention can be carried out by

bringing the reaction product obtained in the first step into intimate contact with the organic halogen compound of formula (3) in the presence of the nitrogen-containing or sulfur-containing,

the polar organic solvent at the same temperature as in the first step, e.g. at a temperature in the range between -100 - 50°C.

To carry out the second-step reaction in a nitrogen-containing or sulfur-containing organic solvent, it is common practice to e.g. carrying out the first-step reaction in such a nitrogen-containing or sulfur-containing organic solvent and mixing the resulting reaction mixture with the organic halogen compound (3) or its solution in an aprotic, inert, organic solvent. An alternative method is to carry out the first-step reaction in an aprotic, inert, organic solvent, other than a nitrogen-containing or sulfur-containing organic solvent, adding the nitrogen-containing or sulfur-containing polar organic solvent to the resulting reaction mixture and then mixing the mixture with the organic halogen compound (3) or its solution in an aprotic, inert, organic solvent. In short, the requirement here is that the second-stage reaction is carried out in the presence of the nitrogen-containing or sulphur-containing, polar, organic solvent, and by doing this the yield of end product in the second stage can be further increased.

According to the present invention, the desired cyclopentanone-

in the derivative (4-B) is produced in a higher yield by adding

[the reaction product, obtained from the cyclopentenone derivative (1-B)

in the first step, to the organic halogen compound of formula (3) or its dissolution in an aprotic inert organic medium in a non-oxidizing atmosphere in the presence of the nitrogen-containing or sulfur-containing aprotic organic solvent to allow the reaction product reacts with the organic halogen compound. At this point, it is desirable to add the reaction product from the first step as gradually as possible to the organic halogen compound

(3) or its dissolution.

A preferred embodiment of the second-stage reaction according to the present invention consists in mixing the reaction product from the first stage with approx. 0.8 to approx. 5 mol, based on the starting cyclohexenone derivative or cyclopentenone derivative used, of the organic halogen compound (3) or its solution in the presence of approx. 0.8 to approx. 10 moles, based on the starting cyclohexenone or cyclopentenone derivative, of the nitrogen-containing or sulfur-containing, aprotic, polar, organic compound, and allow the mixture to react, usually at a temperature of not more than 50°C, preferably 10 to 30°C,

for a period of approx. 30 minutes to approx. 20 hours. After the reaction, the cyclohexanone derivative water (4-A) or the cyclopentanone derivative water (4-B) is separated and purified by e.g. the aforementioned methods

The reaction product is treated e.g. with a basic, strongly electrolytic, aqueous solution, e.g. an ammoniacal, aqueous, saturated solution of ammonium chloride, in approx. 0.1 to 1 hour to hydrolyze the product, and then extracted by treatment with an ether such as diethyl ether, a saturated hydrocarbon such as pentane or hexane. an aromatic hydrocarbon, such as benzene or toluene, or a halogenated hydrocarbon, such as methylene chloride or chloroform. Where the nitrogen-containing or sulfur-containing, aprotic, polar, organic solvent used in the second-stage reaction is a strongly basic compound, such as tetramethylethylenediamine, it is preferred to use an acidic, aqueous solution, such as a dilute, aqueous solution of hydrochloric acid, instead of the above-mentioned basic - highly electrolytic, aqueous solution.

The organic phase thus extracted is then thoroughly washed

with water or a strongly electrolytic, aqueous solution, is sufficiently dried with anhydrous sodium sulfate and concentrated to obtain a crude product. The cyclohexanone derivative or the cyclopentanone derivative of formula (4-A) or (4-B)

with high purity can be obtained by purifying the crude product by distillation or column chromatography.

As described above in detail, the method according to this invention makes it possible to produce cyclohexanone derivatives (4-A) and cyclopentanone derivatives (4-B), which are useful compounds as medicines, agricultural chemicals, perfumes and their intermediates, in high dividends and with commercial advantage. The first-stage and second-stage reactions can in particular be carried out in the same solvent and the commercial importance of the present method is great.

The following examples illustrate the method according to the invention in more detail.

[ Part A - SYNTHESIS OF CYCLOHEXANONE DERIVATIVES in EXAMPLES A-I

350 mg (50 mmol) of metallic lithium was added to 50 ml of anhydrous diethyl ether and 3.6 g (25 mmol) of methyl iodide was added dropwise at 0°C in an atmosphere of nitrogen. Subsequent stirring of the mixture for 1-2 hours gave an ether solution of methyllithium.

The solution was cooled to -78°C, and a solution of 3.9 g (10 mmol) of a tri-n-butylphosphine complex, with cuprous iodide in 20 ml of ether was added dropwise to the solution. The mixture was stirred for 10 minutes to give a complex of tri-n-butylphosphine with dimethyl copper-lithium.

960 mg (10 millimoles) of cyclohex-2-en-1-one was allowed to react with the complex at room temperature for 1 hour and 5 ml of hexamethyl-phosphorus triamide (HMPA for short) was added to the reaction mixture and the mixture was stirred for 10 minutes. The reaction mixture turned from yellow-green to black. When 3.4 g (20 mmol) of allyl iodide was added to the reaction mixture, the reaction mixture immediately turned gray.

The stirring was continued overnight (approx. 15 hours) in this condition and after reaction, approx. 50 ml of an ammoniacal saturated aqueous solution of ammonium chloride was added to the reaction mixture to work it up, and then it was extracted with ether. The resulting ether phase was washed with water and dried with anhydrous sodium sulfate to give 3.690

g of a concentrated raw product. The product was distilled under reduced pressure and separated.

165 mg (1.5 mmol) of 3-methylcyclohexanone (boiling point 102 - 104°C/104 mmHg) were obtained. The yield was 15%, based on starting cyclohex-2-en-l-one (the yield was calculated on the same basis hereafter). Gas chromatograph (SE30, 10%) of this product corresponds the same to an authentic sample of 3-methylcyclohexanone.

Furthermore, 918 mg (6.0 millimoles) of 2-allyl-3-methyl-

in cyclohexanone, (boiling point 111°C./122 mmHg) in a yield of 60%.

Infrared absorption (liquid-film)

characteristic absorption

3080, 1710, 1645, 910 cm

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6( ppm)

in

Mass spectrum (m/e)

;<;>152 (M<+>)

EXAMPLE A- 2

A solution of 3.9 g (10 millimoles) of a tri-n-butyl-phosphine complex of cuprous iodide was added, at -78°C, to an ether solution of methyl lithium, prepared in the same manner as in Example A-I, and the mixture was allowed to stand for 15 minutes. Then a solution of 960 mg (10 millimoles) of cyclohex-2-en-1-one in 50 ml of ether was further added dropwise. The color of the reaction mixture changed from white to yellow. The mixture was stirred overnight at room temperature and then 3.4 g (20 mmol) of allyl iodide was added, whereupon the reaction immediately turned gray. Stirring of the mixture was continued for one day and the treatment was the same as in Example A-I to separate and purify the product. 93 mg were obtained

(0.8 millimol) 3-methylcyclohexanone in a yield of 8%. 640 mg (4.2 millimoles) of 2-allyl-3-methylcyclohexanone were also extracted in a yield of 42%.

EXAMPLE A- 3

A solution of 1.9 g (10 mmol) of cuprous iodide in 5 ml of HMPA was added at -78°C to an ether solution of methyllithium, prepared in the same manner as in Example A-I, and the mixture was stirred for 10 minutes. Then 960 mg (10 millimoles) of cyclo-hex-2-en-1-one was added, and the mixture was stirred for one hour at room temperature. The reaction product was worked up, separated and<!>purified by ordinary methods.

1.520 g of the crude product was obtained. Analyzes of the product showed that 207 mg (1.8 millimoles) of 3-methylcyclohexanone were obtained in a yield of 18% and 739 mg (4.9 millimoles) of 2-allyl-3-methylcyclohexanone in a yield of 49% .

EXAMPLE A- 4'

To 10 millimoles of tri-n-butylphosphine complex of dimethyl copper-lithium, prepared in the same manner as in Example A-I, 960 mg (10 millimoles) of cyclohex-2-en-1-one were added, and they reacted for 1 hour at room temperature. Then 5 ml of tetramethylethylenediamine was added and the mixture was stirred for 10 minutes. The reaction mixture turned from yellow-green to white-green. When 3.4 g (20 mmol) of allyl iodide was added, the reaction mixture turned gray. Stirring of the mixture was continued overnight. The product was treated in the same manner as in Example A-I, and the ether extract obtained was sufficiently washed with dilute hydrochloric acid, dried and concentrated. 3.016 g of the crude product was obtained. The crude product was purified to give 194 mg (1.7 mmol) of 3-methylcyclohexanone in a 17% yield and 579 mg (3.8 mmol) of 2-allyl-3-methylcyclohexanone in a 38% yield.

EXAMPLE A-5

To 10 millimoles of tri-n-butylphosphine complex of dimethyl copper-lithium, prepared in the same manner as in Example A-I, was added 10 millimoles (960 mg) of cyclohex-2-en-l-one, and they were reacted for 1 hour at room temperature . Then 5 ml of dimethylformamide was added and a precipitate immediately formed. After stirring the priming mixture, 3.4 g (20 millimoles) of allyl iodide was added and allowed to stand overnight. The product obtained was worked up and purified by usual methods. 3.659 g of a crude product was obtained. Analyzes of the product showed that 106 mg (1.0 millimol) of 3-methylcyclohexanone was obtained in a yield of 10% and 448 mg (3.0 millimol) of 2-allyl-3-methylcyclohexanone in a yield of 30%.

in

[ EXAMPLE A- 6

A triethyl phosphite complex of cuprous iodide, prepared by stirring 1.9 g (10 mmol) of cuprous iodide and 1.82 g (10 mmol) of triethyl phosphite at room temperature for 30 minutes was added at -78°C to an ether solution of methyllithium, prepared in the same manner as in Example A-I. The mixture was stirred for 30 minutes to form a tan triethyl phosphite-

in complex of dimethyl copper-lithium. To the mixture was added 960 mg (10 millimoles) of cyclohex-2-en-1-one, and the mixture was stirred for a further 1 hour at room temperature. The reaction mixture turned yellow-grey. Then became 5

ml of HMPA added, and the mixture was further stirred for 10 minutes, followed by the addition of 3.4 g (20 millimoles) of allyl iodide, whereby the reaction mixture became cream colored. Stirring of the reaction mixture was continued overnight. The reaction mixture was treated in the same way as in Example 1

to separate and purify the product. 3.210 g of the crude product was obtained and analysis of it showed that 52 mg (0.5 millimoles)

of 3-methylcyclohexanone was obtained in a yield of 5% and 843 mg (5.5 millimoles) of 2-allyl-3-methylcyclohexanone in a yield of 55%.

COMPARISON EXAMPLE

To 10 millimoles of tri-n-butylphosphine complex of dimethyl copper-lithium, prepared in the same manner as in Example A-I, was added 10 millimoles (960 mg) of cyclohex-2-en-1-one. They were allowed to react for one hour at room temperature. The ether was then evaporated under reduced pressure. An additional 50 mL of dimethoxyethane and 3.4 g (20 mmol) of allyl iodide were added and stirring of the mixture was continued overnight at room temperature. The mixture was then worked up to separate and purify the product. 1.347 g of crude product was obtained. Analyzes thereof showed that 260 mg (2.3 millimoles) of 3-methylcyclohexanone in a yield of 23% and 244 mg-(1.6 millimoles) of 2-allyl-3-methylcyclohexanone in a yield of 16% were obtained.

EXAMPLE A-7

In the same way as in Example A-I, 20 millimoles of tri-n-butylphosphine complex of dimethyl copper-lithium were allowed to react with 20 millimoles of (1.92 µg) cyclohex-2-en-1-one at room temperature for one hour. Then 5 ml of HMPA was added and the mixture was further stirred

in

stirred for 10 minutes. To the reaction mixture was added 5.0 g (40 mmol) of 1,3-dichloro-2-butene, and the mixture was stirred overnight at room temperature, followed by the same treatment as in Example A-7 to separate and purify the product, 11.70 g of the crude product were obtained. Analyzes of it showed that 321 mg (2.9 millimoles) of 3-methylcyclohexanone were obtained in a yield of 14%, and 1.35 g (6.7 millimoles) of 2-(3'-chloro-2<1-> butenyl)-3-methylcyclohexanone in a yield of 33%. The analysis values of this product were as follows:

Boiling point

150°C/120 mmHg

Infrared absorption (liquid-film)

characteristic absorption

1710, 1660 cm"<1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6( ppm)

Mass spectrum (m/e)

202 (M<+>)

EXAMPLE A-8

3.9 g (10 millimoles) tri-n-butylphosphine complex of cuprous iodide was dissolved in 50 ml anhydrous diethyl ether and 12.8 ml (20 millimoles) of a 15% by weight hexane solution of n-butyllithium was added to the reading at - 78°C. The mixture was stirred for 30 minutes; and the mixture turned reddish brown.

When 960 mg (10 mmol) of cyclohex-2-en-1-one was added to the reaction mixture, it turned black-brown. The reaction mixture

I was stirred for an additional 1 hour at room temperature and then in i

5 HMPA was added and a black precipitate formed. After stirring the mixture for an additional 10 minutes, 2.8 g (20 mmol) of methyl iodide was added. Stirring of the mixture was then continued for 3 hours at room temperature. The reaction mixture was treated in the same manner as in Example A-I to give 3.656 g of the crude product.

The crude product was distilled to remove the phosphine compound, and then the product was separated by column chromatography. 59 mg (0.4 millimoles) of 3-n-butylcyclohexanone were obtained which corresponded to a separately prepared, authentic sample of 3-n-butylcyclohexanone. 951 mg (5.7 millimoles) of 2-methyl-3-n-butylcyclohexanone (108-109°C/25 mmHg) were also obtained in a yield of 57%.

c The analytical values for this product were as follows:

Infrared absorption (liquid film)

1710 cm"<1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride 5, ( ppm) )

Mass spectrum (m/e)

168 (M<+>)

EXAMPLE A-9

In the same manner as in Example A-8, 10 millimoles of a tri-n-butylphosphine complex of di-n-butylcopper-lithium were reacted with 10 millimoles (960 mg) of cyclohex-2-en-l-one at room temperature for 1 hour. Then 5 ml of HMPA was added and the mixture was stirred for 10 minutes. Then 1.8 g (12 millimoles) of methyl bromoacetate was further added and the reaction was carried out at room temperature for 4 hours. The reaction mixture was worked up in the usual way and the crude product was separated and purified by column chromatography.

IN

!556 mg (3.6 millimoles) of 3-n-butylcyclohexanone were obtained in a yield of 36%. 633 mg (2.8 millimoles) of 2-carbomethoxymethyl-3-n-butylcyclohexanone was also obtained in a yield of 28%.

This product's analytical values were as follows:

Infrared absorption (liquid film)

characteristic absorption

1735, 1710, 1170 cm"<1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride„ 6 ( ppm)

Mass spectrum (m/e)

226 (M<+>)

EXAMPLE A- 10 r?

1.9 g (10 mmol) of cuprous iodide and 1.82 g (10 mmol) of triethyl phosphite were dissolved in 50 ml of anhydrous diethyl ether, and the solution was stirred at room temperature for 130 minutes in an atmosphere of nitrogen to form a triethyl phosphite complex of cuprous iodide. This solution was cooled to -78°C, and then 12.8 ml (20 mmol) of a 15% by weight hexane solution of n-butyllithium was added. After stirring for 30 minutes, 960 mg (10 millimoles) of cyclohex-2-en-1-one was added and the mixture was further stirred for one hour at room temperature. Then 5 ml of HMPA was added and after stirring for 10 minutes, 3.6 g (20 mmol) of ethyl-(3-bromopropionate) was added. The mixture was further stirred at room temperature for 4 hours. The reaction mixture was treated in the same manner as in Example A-I for to give 4.20 g of the crude product The crude product was separated and purified by column chromatography.

288 mg (1.9 millimoles) of 3-n-butylcyclohexanone were obtained in a yield of 19%. 1.045 g (4.1 mmol) 2-(2-carboethoxy-i).

I ethyl)-3-n-butylcyclohexanone was also obtained in a yield of 41%. The analytical values of this product are as follows:

Infrared absorption (liquid film)

1735, 1710, 1160-1170 cm<-1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 5 ( ppm)

Mass spectrum (m/e)

254 (M<+>)

EXAMPLE A- 11

1.9 g (10 mmol) of cuprous iodide and 1.24 g (10 mmol) of trimethyl phosphite were dissolved in 20 ml of anhydrous diethyl ether and the solution was stirred for one hour at room temperature in an atmosphere of nitrogen to prepare a trimethyl phosphite complex of cuprous iodide. This solution was cooled to -78°C, and then

12.8 ml (20 millimoles) of a 15% by weight hexane solution of n-butyllithium added. After stirring the mixture for 30 minutes, 960 mg (10 millimoles) of cyclohex-2-en-1-one was added, and the mixture was further stirred for one hour at room temperature. Then 5 ml of HMPA was added and the mixture was stirred for 10 minutes. Then 2.3 g (10 millimoles) of methyl 7-bromoheptanoate was added and the mixture was further stirred overnight at room temperature. The reaction mixture was worked up in the same manner as in Example A-I to give 4.79 g of the crude product. The crude product was separated and purified by column chromatography to give 613 mg (4.0 mmol) of 3-n-butylcyclohexanone in a 40% yield. 244 mg (0.8 mmol) of 2-(6-carbomethoxyhexyl)-3-n-butylcyclohexanone was obtained in a yield of 8%.

The analytical values for this product are as follows: [infrared absorption (liquid film) at 1735, 1730, 1170 cm"<1>

Nuclear magnetism resonance spectrum

( carbon tetrachloride, 6 ( ppm))

Mass spectrum (m/e)

296 (M<+>)

EXAMPLE A- 12

20 millimoles of a tri-n-butylphosphine complex of di-n-butylcopper-lithium, prepared in the same manner as in Example A-8

was allowed to react with 2.76 g (20 mmol) of isophorone (3,5,5-tri-methyl-2-cyclohexenone) at room temperature for 2 hours. Then 5 ml of HMPA was added and the mixture was further stirred for 10 minutes. Then 4.5 g (50 mmol) of methallyl chloride was further added and the mixture was stirred overnight at room temperature. The reaction mixture was treated in the same manner as in Example A-I to give 11.27 g of the crude product. The crude product was distilled and separated and purified by column chromatography to give 345 mg (1.76 mmol) of 3,5,5-trimethyl-3-n-butylcyclohexanone in a 9% yield. In gas chromatographic analyzes (SE 30 10%), this product corresponds to an authentic sample of 3,5,5-trimethyl-3-n-butylcyclohexanone. 990 mg (3.96 millimoles) of 2-methallyl-3,5,5-trimethyl-3-n-butylcyclohexanone were also obtained in a yield of 20%. The analytical values of this product are as follows:

Infrared absorption (liquid film)

1715, 1665, 895 cm<-1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6 ( ppm))

Mass spectrum (m/e)

250 (M<+>)

EXAMPLE A- 13

20 millimoles of tri-n-butylphosphine complex of di-n-butyl-copper-lithium, prepared in the same manner as in Example A-8, was allowed to react with 3.0 g (20 millimoles of L-(-)-carbon(2 -methyl-5-isopropenyl-2-cyclo<p>hexenone) at room temperature for 1 hour in an atmosphere of nitrogen. Then 5 ml of HMPA was added and the mixture was stirred for 10 minutes. Then 4.8 g (40 mmol) propargyl bromide was added, and the mixture was stirred overnight at room temperature. The reaction mixture was worked up in the same manner as in Example A-I to give 7.55 g of the crude product. The crude product was separated and purified by column chromatography to give 2, 78 g (13.4 millimoles) of 2-methyl-3-n-butyl-5-isopropenylcyclohexanone in a yield of 67%, which corresponded to a separately prepared authentic sample of 2-methyl-3-n-butyl-isopropenyl- cyclohexanone by gas chromatography. 1.08 g (4.4 mmol) of 2-methyl-2-propargyl-3-n-butyl-5-isopropenyl cyclohexanone was also obtained. The analytical values of this product are as follows:

Infrared absorption (liquid film)

3300, .2100, 1710, 1645, 895 cm"<1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6 ( ppm))

Mass spectrum (m/e)

246 (M<+>)

EXAMPLE A- 14

10 millimoles of a di-n-butyl-copper-lithium tri-n-butylphosphine complex, prepared in the same manner as in Example A-8, reacted with 1.50 g (10 millimoles) of D-(+)-carbon (2-methyl-5-isopropenyl-2-cyclohexenone) at room temperature for 1.5 hours in an atmosphere of nitrogen. Then 5 ml of HMPA was added,

and the mixture was stirred for 10 minutes. An additional 7.1 g (50 mmol) of methyl iodide was added and the mixture was stirred at room temperature for 4 hours. The mixture was treated in the same manner as in Example A-I to give 4.21 g of the crude product. The crude product was distilled to separate and purify it. 126 mg (0.6 millimoles) of 2-methyl-3-n-butyl-5-isopropenyl-cyclohexanone were obtained in a yield of 6%. 1.72 g (7.7 mmol) of 2,2-dimethyl-3-n-butyl-5-isopropenylcyclohexanone was also obtained in a yield of 77%. The analytical values of the product are as follows:

Boiling point

90 to 91°C/0.1 mmHg

Infrared absorption (liquid film)

1710, 1645, 890 cm<-1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6 ( ppm))

Mass spectrum (m/e)

222 (M<+>)

EXAMPLE A- 15

A mixture of 950 mg (5 mmol) of copper iodide and 820 mg (5 mmol) of hexamethylphosphorus triamide was dissolved in 10 ml of anhydrous diethyl ether, and the solution was stirred for 30 minutes at room temperature in an atmosphere of nitrogen to prepare a hexamethylphosphorustriamide complex of cupro-iodide.

in

To the same solution was added at -78°C an ether solution of methyllithium, prepared from 1.8 g (12.5 millimoles) of methyl iodide, 175 mg (25 millimoles) of metallithium and 20 ml of anhydrous diethyl ether in the same manner as in Example A-I , and the mixture was stirred for 30 minutes.

480 mg (5 mmol) cyclohex-2-en-1-one was then added, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture turned from yellow-green to black. Then 2.5 ml of HMPA was added and the mixture was stirred for 10 minutes. 1.7 g of allyl iodide was further added and stirring of the mixture was continued overnight. The reaction mixture was worked up in the same manner as in Example A-I, and extracted with ether, followed by thorough washing with water, drying and concentration to give 1.317 g of crude product.

37 mg (0.3 millimoles) of 3-methylcyclohexanone were obtained in a yield of 6%. 486 mg (3.2 millimoles) of 2-allyl-3-methylcyclohexanone were thus obtained in a yield of 64%.

EXAMPLE A- 16

A solution of 76 ml (24 mmol) of 0.32M n-octyl lithium was added at -78°C to a solution of a complex of 2.29 g (12 mmol) of cuprous iodide with 2.42 g (12 mmol) of tri -n-butylphosphine in 20 ml of anhydrous diethyl ether, and the mixture was stirred for 30 minutes. Then, 1.26 g (13.2 mmol) of cyclohex-2-en-1-one was added to the reaction mixture, and the mixture was stirred for 1 hour. Then 6 mL of HMPA and 4.09 g (239 mmol) of benzyl bromide were added and the mixture was stirred for an additional 15 hours at room temperature. After the reaction, the reaction mixture was worked up in the same way as in Example A-I to give 11.6 g of the crude product. This crude product was separated and purified by column chromatography (support, silica gel; elution solvent, benzene-ethyl acetate).

250 mg (1.2 millimoles) of 3-n-octylcyclohexanone were obtained

in a dividend of 10%.

;There was also obtained 2.71 g (9.0 millimoles) of 3-n-octyl-2-benzyl-

Icyclohexanone in a yield of 76%. The analytical values of this product are as follows:

infrared absorption (liquid film)

characteristic absorption

3000, 1940-1800, 1710, 1600, 730, 700 cm"<1>

Nuclear magnetic resonance spectrum

(carbon tetrachloride, 6 (ppm))

Mass spectrum (m/e)

300 (M<+>)

Part B - SYNTHESIS OF CYCLOPENTENONE DERIVATIVES

EXAMPLE B-l

2.3 g (12 mmol) of cuprous iodide and 2.4 g (12 mmol) of tri-n-butylphosphine were added to 30 ml of anhydrous diethyl ether, and the solution was stirred for approx. 1 hour at room temperature in an atmosphere of...nitrogen. Then the solution was cooled to -78°C, and 12.8 mL (20 mmol) of a 15% by weight hexane solution of n-butyllithium was added, followed by stirring the mixture for an additional 30 minutes. Then became 820 mg

(10 mmol) of cyclopent-2-en-1-one was added and the mixture was further stirred at -78°C for one hour. 3.6 g (20 millimoles) of hexamethylphosphoric triamide (KMPA, abbreviated) was added and the mixture was stirred for approx. 10 minutes' at -78°C. Furthermore, 1.4 g (10 mmol) of methyl iodide was added, and the mixture was stirred for a further 30 minutes at 0°C. After the reaction, the reaction mixture was treated with approx. 50 ml of an ammoniacal saturated aqueous solution of ammonium chloride and extracted with ether. The resulting ether phase was washed with water,

and dried with anhydrous sodium sulfate to give 4.959 g of a concentrated crude product. This crude product was subjected to column chromatography (silica gel) to separate and purify it. 252 mg (1.8 millimoles) of 3-n-butylcyclopentanone were obtained

in a yield of 18%, which corresponded in gas chromatogram (SE30,

110%)', infrared absorption spectrum and mass spectrum with

• a separately prepared authentic sample of 3-n-butylcyclopentanone.

459 mg (3.0 millimoles) of 2-methyl-3-n-butyl-cyclopentanone were also obtained in a yield of 30%. The analytical values of this product are as follows:

Infrared absorption (liquid film)

_1

1740 cm

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6( ppm))

Mass spectrum (m/e)

154 (M<;l>")

EXAMPLE B- 2

1.9 g (10 mmol) of cuprous iodide and 2.0 g (10 mmol) of tri-n-butylphosphine were added to 20 ml of anhydrous diethyl ether, and the solution was stirred for about 1 hour at room temperature in an atmosphere of nitrogen and then cooled to -78° C. Then 12.8 mL (20 mmol) of a 15% by weight hexane solution of n-butyllithium was added and the mixture was stirred for an additional

30 minutes. Then 820 mg (10 millimoles) of cyclopent-2-en-l-

on was added and the mixture was further stirred for one hour at -78°C. Then 5 ml of MHPA was added and the mixture was stirred for approx. 10 minutes at -78°C. The reaction mixture was warmed to room temperature and gradually added to a solution of 7.1 g (50 millimoles) of methyl iodide in 10 ml of ether at room temperature in an atmosphere of nitrogen. The mixture was further stirred for 30 minutes and then worked up, extracted,

washed and dried in the same manner as in Example B-1 to give 3.076 g of a concentrated crude product. The product was separated and purified by column chromatography (silica gel). 190 mg were obtained

(1.4 millimoles) of 3-n-butylcyclopentanone in a yield of 14%.

812 mg (5.2 millimoles) of 2-methyl-3-n-butyl-cyclopentanone were in

!

|also obtained in a yield of 52%.

EXAMPLE B- 3

In the same manner as in Example B-1, 20 millimoles of n-butyl lithium were allowed to react with 820 mg (10 millimoles) of cyclopent-2-en-1-one in the presence of 12 millimoles of cuprous iodide. Then 5 ml of HMPA was added and the mixture was stirred for 10 minutes at room temperature. Then 1.7 g (12 mmol) of methyl iodide was added and the mixture was

area for a further approx. 15 hours at room temperature. The reaction mixture was worked up, extracted, washed and dried

the same way as in Example B-1 to give 1,451 g of concentrated crude product, which was then separated and purified by column chromatography (silica gel). 12 mg (0 .1 millimol) 3-n-butylcyclopentanone in a yield of 12 mg (0.1 millimol) 3-n-butylcyclopentanone in a yield of 1%. 376 mg (2.4 millimoles) of 2-methyl-3-butylcyclopentanone was also obtained in a yield of 24%. '

EXAMPLE B- 4

In the same manner as in Example B-1, 20 millimoles of n-butyl lithium were reacted with 820 mg (10 millimoles) of cyclopent-2-en-1-one in the presence of 12 millimoles of tri-n-butyl-phosphine complex of cupro -iodide. Then 5 ml of tetramethylethylenediamine was added and the mixture was stirred at room temperature for approx. 10 minutes. The reaction mixture was added to a solution of 7.1 g

(50 millimoles) of methyl iodide in 10 ml of ether at room temperature under a nitrogen atmosphere. Then the mixture was further stirred for 30 minutes and then worked up, extracted, washed and dried in the same manner as in Example B-1 to give 3.898 g of a concentrated crude product which was subjected to column chromatography (silica gel) to separate and purify it. It was obtained 3 20

mg (2.3 millimoles) of 3-n-butylcyclopentanone in a yield of 23%. 320 mg (2.1 millimoles) of 2-methyl-3-n-butylcyclopentanone was also obtained in a yield of 21%.

EXAMPLE B- 5

In the same manner as in Example B-2, 20 millimoles of n-butyllithium was reacted with 820 mg (10 millimoles) of cyclopent-2-en-l-one in the presence of 2.62 mg (10 millimoles) of triphenylphosphine and 10 millimoles cuprous iodide.

(Then 5 ml of dimethyl sulfoxide was added and the mixture was stirred for about 10 minutes at room temperature. The reaction mixture was added to a solution of 7.1 g (50 mmol) of methyl iodide in 10 ml of ether at room temperature under a nitrogen atmosphere.

The mixture was then stirred for an additional 30 minutes and worked up, extracted, washed, dried and concentrated. The product was subjected to column chromatography (silica gel) to

purify and separate it, 360 mg (2.6 mmol) of 3-n-butylcyclopentanone was obtained in a yield of 26%. 250 mg (1.6 mmol) of 2-methyl-3-n-butylcyclopentanone was also obtained in a yield

of 16%.

EXAMPLE B- 6

In the same manner as in Example B-2, 20 millimoles of n-butyl lithium were reacted with 820 mg (10 millimoles) of cyclopent-2-en-l-one in the presence of 1.43 g (10 millimoles) of cuprobromide and 6.2 g ( 20 millimol) triphenyl phosphite. Then 5 ml of dimethylformamide was added and the mixture was stirred for approx. 10 minutes at room temperature. The resulting reaction mixture was added to a solution of 7.1 g (50 mmol) of methyl iodide in 10 ml of ether at room temperature in an atmosphere of nitrogen. The mixture was then stirred for a further 30 minutes and worked up, extracted, washed, dried, concentrated and subjected to column chromatography in the same manner as in Example B-1. 290 mg were obtained

(2.1 millimoles) of 3-n-butylcyclopentanone in a yield of 21%.

220 mg (1.4 millimoles) of 2-methyl-3-n-butylcyclopentanone were further obtained in a yield of 14%.

EXAMPLE B- 7

To 10 ml of anhydrous diethyl ether, 0.45 g (5 millimoles) of cuprocyanide and 10 ml of pyridine were added and the mixture was stirred for approx. one hour at room temperature in an atmosphere of nitrogen. Then 6.4 ml (10 millimoles) of a 15% by weight hexane solution of n-butyllithium was added and the mixture was stirred for 30 minutes. Then 410 mg (5 millimoles) of cyclopent-2-en-1-one was added, and the mixture was further stirred at -78°C for 1 hour. The reaction mixture was warmed to room temperature and gradually added to a solution of 7.1

g (50 millimoles) of methyl iodide in 10 ml of ether at room temperature in a

Jnitro!genatmosphere. The mixture was stirred for an additional 30 minutes and then worked up, extracted, washed, dried, concentrated and separated in the same manner as in Example B-1 to give 130 mg (0.9 mmol) of 3-n-butylcyclopentanone in an 18% yield . 80 mg (0.5 mmol) of 2-methyl-3-n-butylcyclopentanone was also obtained in a yield of 10%.

EXAMPLE B-8

To 20 ml of anhydrous diethyl ether, 2.0 g (10 millimoles) of tri-n-butylphosphine and 1.9 g (10 millimoles) of cuprous iodide were added, and the mixture was stirred for approx. 1 hour and then cooled to -78 oC. Then 12.8 ml (20 millimoles) of a 15% by weight hexane

in

solution of n-butyllithium added and the mixture was stirred for 30 minutes. 820 mg (10 mmol) of cyclopent-2-en-1-one was added and the mixture was stirred for 1 hour at -78°C. Then 5 ml of HMPA was added, and the mixture was stirred for approx. 10 minutes at -78°C, followed by warming the reaction mixture to room temperature. The solution was gradually added dropwise to a solution of 3.06 g (20 mmol) of methyl bromoacetate in 10 ml of ether at room temperature in an atmosphere of nitrogen. Stirring of the mixture was continued for a further 2 hours and then the reaction mixture was worked up, extracted, washed and dried in the same manner as in Example B-1 to give 4.781 g

of a concentrated crude product, which was separated and purified

by column chromatography' (silica gel) 600 mg (4.3 millimoles) of 3-n-butylcyclopentanone were obtained in a yield of 43%.

300 mg (1.4 millimoles) of 2-carbomethoxymethyl-3-n-butylcyclopentanone were also obtained in a yield of 14%. The analysis values of this product are as follows:

Infrared absorption (liquid film)

1730 - 1740, 1160-1120 cm<-1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6 ( ppm)

• Mass spectrum (m/e)

212 (M<+>)

EXAMPLE B-9

To 20 ml of anhydrous diethyl ether, 1.24 g (10 millimoles) of trimethylphosphite and 1.9 g (10 millimoles) of cuprous iodide were added, and the mixture was stirred at room temperature for approx. 1 hour in an atmosphere of nitrogen. The reaction mixture was then cooled to -78°C and 12.8 ml (20 millimoles) of a 15% by weight hexane solution of n-butyl lithium was added. The mixture was stirred for 30 minutes. Then 820 mg (10 millimoles) of cyclopent-2-en-1-one was added and the mixture was stirred for one hour at -78°C. Then 5 ml of HMPA was added and the mixture was stirred for 10 minutes at -78°C. An additional 1.53 g (10 mmol) of methyl bromoacetate was added and the mixture was stirred for 2 hours at 0°C. The reaction mixture was worked up, extracted, washed, dried and concentrated to give 3.128 g of a crude product which was separated and purified by column chromatography (silica gel). 303 mg (2.2 millimoles) of 3-n-butylcyclopentanone were obtained in a yield of 22%. 256 mg (1.2'millimol) of 2-carbomethoxymethyl-3-n-butylcyclopentanone i was also obtained in a yield of 12%.

EXAMPLE B- 10

To 30 ml of anhydrous diethyl ether was added 4.7 g (12 millimoles) tri-n-butylphosphine complex of cupro iodide and then 12.8

ml (20 millimoles) of a 15% by weight hexane solution of n-butyllithium added at -78°C in a nitrogen atmosphere. The mixture was stirred for 30 minutes at -78°C and then 820 mg (10 millimoles) of cyclopent-2-en-l-one was added. The mixture was stirred at room temperature for another 2 hours. Then 5 ml of HMPA was added and the mixture was stirred for 10 minutes.An additional 1.84 g (12 mmol) of methyl bromoacetate was added

and the mixture was stirred further for approx. 15 hours at room temperature. The reaction mixture was worked up, extracted, washed, dried and concentrated to give 3.868 g of a crude product which was separated and purified by column chromatography (silica gel). 282 mg (2.0 millimoles) of 3-n-butylcyclopentanone were obtained in a yield of 20%. 97 mg (0.5 mmol) of 2-carbomethoxymethyl-3-n-butylcyclopentanone was also obtained in a yield of 5%.

! EXAMPLE B-II To 30 ml of anhydrous diethyl ether was added 350 mg (50 millimoles) of metallic lithium and 3.6 g (25 millimoles) of methyl iodide was added dropwise at 0°C in an atmosphere of nitrogen. The mixture was then stirred for approx. 2 hours to make

an ether solution of methyllithium. The solution was added dropwise to a solution of 1.9 g (10 mmol) of cuprous iodide in 20 ml of anhydrous diethyl ether at -78°C in a nitrogen atmosphere. The mixture was stirred for an additional 30 minutes and 820 mg

(10 millimoles) of cyclopent-2-en-l-one was added to it. The reaction temperature was raised to room temperature and the mixture was further stirred for approx. 1 hour. The reaction mixture turned from light yellow to yellow. 5 ml of HMPA was added to the reaction mixture, and the mixture was stirred for approx. 10 minutes. The reaction mixture turned from yellow to brown. Additional,

3.4 g (20 millimoles) of allyl iodide was added, and the mixture was stirred for approx. 15 hours at room temperature. The mixture worked

over to blackish brown. The reaction mixture was then worked up, extracted, washed, dried and concentrated in the same manner as in Example B-1 to give 990 mg of a crude product which was subjected to column chromatography (silica gel) to separate and purify

the. 30 gmg (0.3 millimoles) of 3-methylcyclopentanone were obtained in a yield of 3%. This product corresponded in gas chromatogram (SE 30), infrared absorption spectrum and mass spectrum to a separately prepared, authentic sample of 3-methylcyclopentanone. 100 mg (0.7 millimoles) of 2-allyl-3-methylcyclopentanone were also obtained in a yield of 7%. The analytical values of this product were as follows:

Infrared absorption (liquid film)

3100, 1740, 1640 cm"<1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride id, 6 ( ppm)

Mass spectrum (m/e)

138 (M<+>)

EXAMPLE B-12

To 30 ml of anhydrous diethyl ether was added 280 mg (40 millimoles) of metallic lithium and 2.84 g (20 millimoles) of methyl iodide was added dropwise at 0°C in an atmosphere of nitrogen. The mixture was stirred for approx. 3 hours to form methyllithium. This solution was added dropwise at -78°C in a nitrogen atmosphere to 20 ml of an ether solution of a cuprous iodide/tri-n-butylphosphine complex, prepared from 2.09 g (Ui.millimol) of cuprous iodide and 2.22

g (11 mmol) of tri-n-butylphosphine, and the mixture was stirred for 30 minutes. To the mixture was added 820 mg (10 mmol) of cyclopent-2-en-l-one, and the mixture was stirred at -78°C for 1

hour. A further 5 ml of HMPA was added and the mixture was stirred for approx. 10 minutes. The resulting solution was warmed to room temperature and gradually added dropwise to a solution of 8.40 g (50 mmol) of allyl iodide in 10 mL of ether. The mixture was then stirred for 1 hour at room temperature and then worked up, extracted, washed, dried and concentrated

triturated in the same manner as in Example B-1 to give 5.138 g of a crude product, which was separated and purified by column chromatography (silica gel). 150 mg (1.5 millimoles) of 3-methylcyclopentanone were obtained in a yield of 15%. 350 mg (2.5 millimoles) of 2-allyl-3-methylcyclopentanone was also obtained in a yield of 25%.

EXAMPLE B- 13

Metallic lithium (140 mg, 20 mmol) was added to 10 mL of anhydrous diethyl ether and 1.42 g (10 mmol) of methyl iodide was added dropwise at 0°C in an atmosphere of nitrogen. The mixture was stirred for approx. 2 hours to produce methyllithium.

This solution was added dropwise at -78°C in a nitrogen atmosphere to 10 ml of an ether solution of a trimethyl phosphite complex of cuprous iodide, prepared from 2.09 g (11 mmol) of cuprous iodide and 1.36 g (11 mmol) of trimethyl phosphite. was stirred for 30 minutes. Then 820 mg (10 millimoles) of cyclopent-2-en-1-one was added, and the mixture was stirred further for 1 hour at -78°C. Then 5 ml of HMPA was added to the mixture and the mixture was stirred for approx. 5 minutes. This

IN

The solution was gradually added dropwise to a solution of 1.53 g (20 mmol) of allyl chloride in 20 ml of ether, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was worked up, extracted, washed, dried and concentrated in the same manner as in Example B-1 to give 1.099 g of a crude product, which was subjected to column chromatography (silica gel) to separate and purify it. 150 mg (1.5 millimoles) of 3-methylcyclopentanone were obtained in a yield of 15%. 125 mg

(0.9 mmol) 2-allyl-3-methylcyclopentanone was also obtained in a yield of 9%.

EXAMPLE B- 14

In the same manner as in Example B-13, 10 millimoles of methyllithium solution was prepared, and this solution was added dropwise at -78°C in a nitrogen atmosphere to a solution of HMPA-. complex of cuprous iodide, prepared from 2.09 g (11 mmol) of cuprous iodide and 1.80 g (11 mmol) of HMPA in 10 ml of ether. The mixture was stirred for 30 minutes. Then 820 mg (10 millimoles) of cyclopent-2-en-1-one was added and the mixture was further stirred for 1 hour at -78°C. Then 5 ml of HMPA was added, and the mixture was stirred for approx. 5 minutes. The mixture was gradually added to a solution of 8.40 g (50 mmol) of allyl iodide in 10 ml of ether, and the mixture was further stirred for 1 hour at room temperature. The reaction mixture was worked up, extracted, washed, dried and concentrated in the same manner as in Example B-1 to give 2.574 g of a crude product which was subjected to column chromatography (silica gel) to separate and purify it. 210 mg (2.2 millimoles) of 3-methylcyclopentanone were obtained in a yield of 22%. 70 mg

(0.5 mmol) 2-allyl-3-methylcyclopentanone was also obtained in a 5% yield.

EXAMPLE B-15

1.66 g (10 millimoles) of triphosphite and 1.9 g (10 millimoles) of cuprous iodide were added to 20 ml of anhydrous diethyl ether and the solution was stirred for approx. one hour at room temperature in a nitrogen atmosphere. The solution was then cooled to -78°C, and 12.8 mL (20 mmol) of a 15% by weight hexane solution of n-butyl lithium was added. The mixture was stirred for 30 minutes and

1820 mg (10 millimoles) of cyclopent-2-en-1-one were added. The mixture was further stirred for 1 hour at -78°C. The reaction mixture was warmed to room temperature. The mixture was gradually added dropwise at room temperature to a solution

of 4'72 g (50 millimoles) of chloromethylethyl ether in 20 ml of ether. The mixture was further stirred for 1 hour and then worked up,

extracted, washed, dried, concentrated and subjected to column chromatography in the same manner as in Example B-1 to give 2.936 g

of a raw product. Analysis of the product showed that 267 mg (1.9 millimoles) of 3-n-butylcyclopentanone was obtained in a yield of 19%. 308 mg (1.6 mmol) of 2-ethoxymethyl-3-n-butylcyclopentanone was also obtained in a yield of 16%. The analytical ones

in

the values of this product are as follows:

Infrared absorption (liquid film)

1740, 1110 cm"<1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6 ( ppm)

Mass spectrum (m/e)

198 (M<+>)

EXAMPLE B-16

In the same manner as in Example B-2, 20 millimoles of n-butyllithium were reacted with 820 mg (10 millimoles) of cyclopent-2-en-l-one in the presence of 1.9 g (10 millimoles) of cuprous iodide and 2.0 g ( 10 millimoles) tri-n-butyl phosphate in. Then 5 ml of HMPA was added and it reacted with the reaction product for approx. 10 minutes at -78°C. The reaction mixture was gradually added to a solution of 1.51 g (20 mmol) of chloroacetonitrile in 10 ml of ether and then the mixture was further stirred for 2 hours. The reaction mixture was worked up, extracted, washed and dried in the same manner as in Example B-1 to give 4.307 g of a concentrated crude product which was then subjected to column chromatography (silica gel) to separate and purify it. 461 mg (3.3 millimoles) of 3-n-butylcyclopentanone were obtained in a yield of 33%. 208 mg (1.2 mmol) of 2-cyanomethyl-3-n-butylcyclopentanone was also obtained in a yield of 12%. The analytical values of this product were as follows:

Infrared absorption (liquid film)

2210, 1740 cm"<1>

Nuclear magnetic resonance spectrum

( deuterochloroform, 6 ( ppm))

EXAMPLE B-17

In the same manner as in Example B-2, 20 millimoles of n-butyllithium were reacted with 820 mg (10 millimoles) of cyclopent-2-en-l-one in the presence of 1.9 g (10 millimoles) of cuprous iodide and 2.0 g ( 10 millimol) tri-n-butyl-phosphine. Then 5 ml of HMPA was added and it reacted with the reaction product at -78°C for 10 minutes. The resulting mixture was added dropwise at room temperature to a solution of 2.1 g (20 millimoles) of α-phenacyl chloride in 20 ml of ether, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was worked up, extracted, washed and dried in the same way as in example B-1. to give 6.934 g of a concentrated crude product which was subjected to column chromatography (silica gel)

to separate and purify it. 351 mg (2.5 millimoles) of 3-n-butylcyclopentanone were obtained in a yield of 25%. 200 mg (0.8 mmol) of 2-phenacyl-3-n-butylcyclopentanone was also obtained in a yield of 8%. The analytical values of this product were as follows:

Infrared absorption (liquid film)

3080, 1740, 1690, 1600, 760, 690 cm"<1>

in

I Nuclear magnetic resonance spectrum ; ' ( deuterochloroform, 6 ( ppm))

Mass spectrum (m/e)

258 (M<+>)

EXAMPLE B-18

In the same manner as in Example B-2, 20 millimoles of n-butyllithium were reacted with 820 mg (10 millimoles) of cyclopent-2-en-l-one in the presence of 1.9 g (10 millimoles) of cuprous iodide and 2.0 g ( 10 millimoles) tri-n-butylphosphine. Then 5 ml of HMPA was added and reacted with the reaction product at -78°C for 10 minutes. An additional 3.4 g (20 mmol) of benzyl bromide was added to this solution and the mixture was stirred for 1 hour at room temperature. The reaction mixture was worked up, extracted, washed and dried in the same manner as in Example B-1 to give 6.559 g of a concentrated crude product which was subjected to column chromatography

(silica gel) to separate and purify it. 208 mg (1.5 millimoles) of 3-n-butylcyclopentanone were obtained in a yield of 15%. 1.37 g (6.0 mmol) of 2-benzyl-3-n-butylcyclopentanone was also obtained in a yield of 60%. The analytical values of this product are as follows:

Infrared absorption (liquid film)

3040, 1740, 1605, 750, 700 cm<-1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride.. 6 ( ppm))

' Mass spectrum ( m/ e)

230 (M<+>)

EXAMPLE B-19

In the same manner as in Example B-2, 20 millimoles of n-butyllithium were reacted with 820 mg (10 millimoles) of cyclopent-2-en-l-one in the presence of 1.9 g (10 millimoles) of cuprous iodide and 2.0 g ( 10 millimol) tri-n-butyl-phosphines. Then 5 ml of HMPA was added and reacted with the reaction product at -78°C for approx. 10 minutes. To it

to the resulting solution, 3.0 g (20 mmol) of N,N-diethylchloroacetamide was further added and the mixture was stirred for a further 30 minutes at room temperature. The reaction mixture was worked up, extracted, washed and dried in the same manner as in Example B-1 to give 6.254 g of a concentrated crude product, which was subjected to column chromatography (silica gel) to

separate and clean it. 422 mg (3.0 millimoles) of 3-n-butylcyclopentanone were obtained in a yield of 30%. 550 mg (2.2 millimoles) of α-(2-oxo-5-n-butylcyclopentyl)-N,N-diethylacetamide was also obtained in a yield of 22%. The analytical values of this product were as follows:

Infrared absorption (liquid film)

1740, 1640 cm"<1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6 ( ppm))

Mass spectrum (m/e)

253 (M<+>)

EXAMPLE B- 20

76 mL (23.6 mmol) of 0.31 M n-octyllithium was added to a (solution of a complex of 2.25 g (11.8 mmol) of cuprous iodide and 2.38 g (11.8 mmol) of tri-n- butylphosphine in 20 mL of anhydrous diethyl ether, and the mixture was stirred for 30 minutes, then 1.06 g (13.0 mmol) of cyclopent-2-en-1-one was added, and the mixture was stirred at -78°C for 1 hour An additional 6 mL of HMPA and 4.03 g (23.6 mmol) of benzyl bromide were added, and the mixture was stirred for an additional 15 hours at room temperature. After the reaction, the mixture was worked up in the same manner as

in Example B-1 to give 11.4 g of a crude product which was subjected to column chromatography (support, silica gel; elution solvent, benzene-ethyl acetate) to separate and purify it. 90 mg (0.46 millimoles) of 3-n-octylcyclopentanone were obtained in a yield of 4%. 1.03 g (3.6 millimoles) of 2-benzyl-3-n-octylcyclopentanone was also obtained in a yield of 31%. The analytical values of this product are as follows:

Infrared absorption (liquid film)

characteristic absorption

3000, 1940-1800, 1735, 1600, 700 cm"<1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6 ( ppm))

Mass-^ spectrum ( m/ e)

286 (M<+>)

EXAMPLE B- 21

A mixture of 1.6 g (6.7 millimoles) of trans-l-iodo-l-octene and

5.1 mL (6.7 mmol) of 1.31 M n-butyllithium was stirred at -78°C for 30 minutes in 6 mL of hexane. The resulting solution was allowed to react with 1.3 g (3.3 mmol) of tri-n-butyl-phosphine-copper-(I)-iodo complex in 20 mL of ether at -15 to -20°C for 20 minutes. A solution of 270 mg (3.3 mmol) of cyclopent-2-en-l-one in

5 mL of ether was added to the resulting solution, and the mixture was stirred at -78°C for 15 minutes. The resulting

•the mixture was added to a solution of 1.8 g (6.8 millimoles)

imethyl-7-iodo-5-heptynate in 5 ml of ether and then 5 ml of HMPA and 5 ml of ether. The mixture was stirred for 1 hour and worked up in the same way as in Example B-1 to give 3.15 g of a crude product. It was found by thin-layer chromatography and gas chromatography that this crude product is a complex mixture. As a result of analyzes by "mass fragmentography" and gas chromatography and mass spectrum and separation by preparative thin layer chromatography, 15 mg (0.05 millimoles, 2% yield) of 5,6-dehydro-11,15-deoxy-prostaglandin were obtained E2 methyl ester.

The analytical values of this product are as follows:

Infrared absorption (liquid-film)

characteristic absorption

3000, 2200, 1735, 1590, 1160, 970 cm<-1>

Nuclear magnetic resonance spectrum

( carbon tetrachloride, 6 ( ppm)

Mass spectrum (m/e)

332 (M<+>), 317, 314, 301, 275, 273, 261, 259

247, 245, 231, 193, 163, 140, 121, 109, 91,

79, 67, 55, 41

Claims (6)

1. Process for the production of cyclohexanone derivatives or cyclopentanone derivatives with the following formula (4-A) or (4-B) in which R1? R2, R1, R4, R5, Rg, R7 and Rg are the same or different and mean a hydrogen atom or a monovalent organic group, two of these groups possibly forming a ring; R, is a monovalent organic group; and Rp is a monovalent organic group, characterized by the fact that one (a) reacts a cyclohexenone derivative of formula (1-A) or a cyclopentenone derivative of formula (1-B) in which notwithstanding Rg has the above meaning, with an organic copper-lithium compound of formula (2) wherein RB has the above meaning, Y means a monovalent anion and n is 1 or 2 and when - n is 2, two R^ groups are the same or different, or with a complex thereof with a trivalent, organophosphorus compound in the presence of an aprotic, inert, organic medium, and in. -in (b) reacting the resulting reaction product with an organic halogen compound of formula (3) in which RA has the above meaning and X means a halogen atom, in the presence of a nitrogenous or sulphurous, aprotic t in polar organic solvent. 2. Method according to claim 1, characterized in that each of the substituents R^ - Rg in the above formulas (1-A), (1-B), (4-A) and (4-B) is a term selected from the group consisting of a hydrogen atom and alkyl, cycloalkyl, alkenyl, alkynyl and aryl groups, containing 1-20 carbon atoms. b 3. Process according to claim 1 or 2, characterized in that RA and Rg in the formulas (2), (3), (4-A) and (4-B) are each organic groups, containing 1-20 carbon atoms. 4. Method according to claims 1-3, characterized in that said reactions (a) and (b) are carried out at a temperature of from -78°C to 50°C. 5. Method according to claims 1-4, characterized in that said reactions (a) and (b) are carried out in the presence of a nitrogenous or sulphurous, aprotic polar organic solvent. 6. Process for the production of cyclopentanone derivatives with formula (4-B) according to one of claims 1-5, characterized in that the reaction product, which is obtained by reacting the cyclopentenone derivative of formula (1-B) with the organic copper-lithium compound of formula (2) or a complex thereof with a trivalent organic phosphorus compound in the presence of an aprotic inert organic liquid , is added in a non-oxidizing atmosphere to the organic halogen compound of formula (3) or its solution in an aprotic inert organic medium to react said reaction product with said organic halogen compound.