GB2073754A - Preparation of 3,7,11- Trimethyl-2,4-dodecadienoates and Starting Materials Therefor - Google Patents

Preparation of 3,7,11- Trimethyl-2,4-dodecadienoates and Starting Materials Therefor Download PDF

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GB2073754A
GB2073754A GB8109962A GB8109962A GB2073754A GB 2073754 A GB2073754 A GB 2073754A GB 8109962 A GB8109962 A GB 8109962A GB 8109962 A GB8109962 A GB 8109962A GB 2073754 A GB2073754 A GB 2073754A
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
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    • C07F9/09—Esters of phosphoric acids

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Abstract

The invention relates to a process for the preparation of 3,7,11- trimethyl-2,4-dodecadienoates of the general formula /I/ <IMAGE> wherein R<1> represents hydrogen or a lower alkyl group, Z<1> stands for hydrogen, or R<1> and Z<1> together form a double bond, Z<2> and Z<3> each represent hydrogen or together form an ethylene group, R<2> and R<3> each denote a lower alkyl group, with the proviso that if Z<2> and Z<3> together form an ethylene group, R<1> may only stand for hydrogen, R<2> for methyl and R<3> for ethyl, characterized by reacting a compound of the general formula /II/ <IMAGE> wherein R<1>, Z<1>, Z<2>, Z<3> and R<3> have the above specified meanings, and Q represents a group of the general formula /IIIA/ or /IIIB/ <IMAGE> wherein R stands for a lower alkyl, phenyl or phenyl-/lower alkyl/group, and R<4> is a lower alkyl group, with a compound of the general formula /VI/ Li-Cu/R<2>/2 /Vi/ wherein R<2> has the above defined meaning. The compounds prepared according to the invention are insect growth regulators and can be used to advantage in plant protection. The starting materials of formula (II) are new.

Description

SPECIFICATION A Process for the Preparation of 3,7,11 -Trimethyl-2,4-Dodecadienoates and Intermediates Therefor The invention relates to a new proces for the preparation of 3,7,1 -trimethyl-2,4dodecadienoates of the general formula (I)
wherein R1 represents hydrogen or a lower alkoxy group, Z' stands for hydrogen, or R' and Zr together form a double bond, Z2 and Z3 each represent hydrogen or together form an ethylene group, R2 and R3 each denote a lower alkyl group, with the proviso that if Z2 and Z3 together form an ethylene group, R1 may only stand for hydrogen, R2 for methyl and R3 for ethyl.
Certain representatives of the compounds of the general formula (I) [e.g. isopropyl-[1 1-methoxy 3,7,11 -trimethyl-2(E),4(E)-dodecadienoate], hereinafter: methoprene, and ethyl-(3,7, 11 -trimethyl- 2(E),4(E)-dodecadienoate-, hereinafter: hydroprene] are commercial products and can be used in plantprotection and animal-breeding on a large scale as insect growth regulators.
Methoprene is highly effective in controling mosquito species [e.g. yellow fever mosquito (Aedes aegypti): W. L. Jakob, Mosq. Neus 32, 592 (1972), W. L. Jakob, J. Econ. Entomol. 66, 819 (1973); C.
A. Henrick et al., J. Agric. Food Chem. 24, 207 (1976)]; flies [e.g. house fly (Musca domestica): W. L.
Jacob, J. Econ. Entomol. 66, 819 (1973), W. F. Plapp and S. R. Vinson, Pestic. Bochem. Physiol. 3, 131 (1973); C. A. Henrick et al., J. Agric. Food Chem. 23, 396 (1975); P. B. Morgan et al., Can. Entomol 107, 413 (1975); C. A. Henrick et al., J. Agric. Food Chem. 24, 207 (1976)]; aphids [e.g. yellow mealworm (Tenebria molitor), C. A. Henrick et al., J. Agric. Food Chem.,-24, 207 (1976), pea louse (Acyrthosiphon pisum), C. A. Henrick et al., J. Agric. Food Chem., 24 207 (1976)], and cockroaches (e.g., Nauphoeta cinera; W. Radwan and F. Sehnal, Experienta 30, 615 (1974)).
Hydroprene is highly active on potato aphids [J. Benskin and Perron, Can Entomol. 105, 619 (1973)], mealybugs [R. A. Hamlen, J. Econ. Entomol. 68, 223 (1975); C. A. Henrick et al., Bioorganic Chemistry 7,235 (1978)] and other pests which attack stored grain (R. G. Strong and Diekman, J.
Econ. Entomol. 66,1167(1973)).
The 3,7,1 1-trimethyl-2,4-dodecadienoates containing a cyclopentane ring (I, R1=Z1=H, Z2+Z3=ethylene group, R2=CH3, R3=C2H5) exhibit a strong growth inhibiting activity on yellow fever mosquitos (Adese aegypti) and on budworms (Heliothis virescens) (C. A. Henrick et al., Bioorganic Chem. 7, 235 (1978)).
To prepare compounds of ethyl-(3,7,1 1-trimethyl-2(E),4(E)-dodecadienoate) type, C. A. Henrick et all have elaborated several methods [J. Org. Chem. 8 (1975)]. According to one of these syntheses 6,7-dihydro-citronellal is reacted with the anion of diethyl-2-oxopropylphosphate, the 2 oxo,6,10-dimethyl-3-undecene thus-obtained is treated with the lithium salt of acetic acid. The 3hydroxy-3,7,1 1 -trimethyl-4-undecenic acid thus-obtained is converted into the corresponding acid chloride with phosphoryl chloride and N-ethyl-diisopropyl amine. The reaction of the acid chloride thusobtained with ethanol gives the 2(Z) steroisomer of hydroprene and, due to the double bond migration, the corresponding 3,5-dodecadienoic acid derivative (10%).The main disadvantage of this method lies in the rather low yield of the esterification and in the considerable by-product formation.
According to an improved method of this process C. A. Henrick et al. started from 3,3-dimethylacrylic acid. When reacting this compound with the lithium compound of diisopropyl amine the corresonding dianion was obtained, which was reacted with 6,7-dihydro-citronellal. The 3-hydroxy-2isopropenyl-5,9-dimethyl-dodecanoic acid thus-obtained was thermally rearranged into 5-hdyroxy3,7,1 1 -trimethyl-2(Z)-dodecenoic acid, which was converted, in acidic medium, into a 6-membered lactone. This lactone was reacted with sodium methylate to obtain the 2(Z) stereoisomer of hydroprene which, by reacting with thiophenol, was converted into a 6.5:3.5 mixture of hydroprene and the 2(Z) stereoisomers thereof. The reaction is unfavourable because of the expensive starting material and the low yield of the reaction steps.
In a further method of C. A. Henrick et al. [J. Org. Chem. 40, 8 (1975); J. Agric. Food Chem. 23, 396 (1975)] 6,7-dihydrocitronellal was reacted with the lithium compound of 1-propylene. The 4 hydroxy-6,1 0-dimethyl-2-undecine thus-obtained was treated with orthoacetic ethylester, the ethyl (3,7,1 1-trimethyl-3,4-dodecadienoate) thus-obtained was converted with a base into a 6.5:3.5 mixture of hydroprene and the 2(Z) stereoisomer thereof. The method is less economic because of the rather low yield of certain reaction steps (e.g. the yield of the first step (addition) is 29%).
Recently G. Cardillo and al. have published a process for the preparation of the methyl ester analogue of hydroprene (I, R'=Z1=Z2=Z3=H, R2=R3=CH3) (J. C. S. Perkin 1. 1979, 1729). On starting from 3-methyl-3-buten-1 -ol a dianion was formed with 2 moles of butyl lithium, which was then reacted with 6,7-dihydro-citronellal to obtain 1 ,5-dihydroxy-3-methylene-7, 11 -dimethyl-dodecane.
This compound was acylated, the diacyl compound thus-obtained was partially hydrolyzed. The 5acetoxy-3-methylene-7, 11 -dimethyl-dodecan- 1 -ol thus-obtained was oxidized with Jones reagent to form the corresponding carboxylic acid, which was esterified with diazomethane, then the ester was converted into a mixture of 2(E),4(E), and 2(Z),4(E) stereoisomers with sodium hydride in the presence of crown ethers. The process is uneconomic because of the expensive starting material and reactants.
According to a method for the preparation of methoprene C. A. Henrick and al. [J. Org. Chem. 40, 1(1975)] started from 7-methoxy-6,7-dihydro-citronelall and acetoacetate.
The latter compound was dimerized in acidic medium, the dimer was treated with sodium alcoxide to obtain 3-methylglutaconate, which was condensed with 7-methoxy-6,7-dihydrocitronellal in the presence of alcoholic potassium hydroxide. The 1 1-methoxy-4-carboxy-3,7,1 1 -trimethyl- 2(Z),4(E)-dodecadienoic acid thus-obtained as decarboxylated by heating in the presence of 2,4dimethylpyridine. As main product, 1 1-methoxy-3,7,1 1-trimethyl-2(Z),4(E)-dodecadienoic acid was obtained from the reaction mixture, and also the unreacted starting material, a lactonization product and the 1 0-ethoxy-2,6,1 O-tdmethyl-1 3(Z)-undecadiene formed in consequence of the twofold decarboxylation could be isolated.The dodecadienoic acid was isomerized with thiophenol into a mixture of the 2(E), 4(E) and 2(Z),4(E) steroisomers, then the corresponding ammonium salt was formed, and the salt of the 2(E),4(E) stereoisomer was separated by crystallization. The acid recovered from the ammonium salt was treated with a mixture of thionyl chloride and dimethylformamide and the corresponding acid chloride thus-obtained was reacted with isopropanol to produce methoprene.
This method is less effective and economic because of the facts that even theoretically at least two moles of acetoacetate are necessary to produce one mole of methoprene; after the decarboxylation the separation of the side-products is rather complicated; a part of the methoxy group is eliminated when forming the acid chloride, and the end-product is contaminated with isopropyl-(3,7,1 1 -trimethyl- 2(E),4(E) 1 0-dodecatrienoate) and isopropyl-(3.7,11 -trimethyl-ll -chloro-2 (E),4(E)-dodecadienoate).
According to a further method of C. A. Henrick and al. (Bioorganic Chemistry 7,235 (1978)) ethyl[3-(3,7-dimethyl-1 -octylidene)-2-methyl-2-cyclopentene-carboxylate] is synethesized from 1 ethoxycarbonyl-cyclopropyl-triphenyl-phosphoniu m fluoroborate and diethyl-(2-oxopropylphosphonate). The reaction of these compounds gave ethyl-(3-diethyl-phosphoryl-2-methyl-1 - cyclopentene-carboxylate), which was reacted with 6,7-dihydro-cintronellal to obtain the cyclopentane analogue of hydroprene. The preparation of phosphonium fluoroborate used as starting material is very expensive and the yield of certain reaction steps is rather low (20% and 10%).
The aim of the present invention was to provide a more economic process for the preparation of the compounds of the general formula (I) possessing valuable biological effects, which comprises less reaction steps and which can be more readily carried out also in industrial scale.
According to the invention there is provided a process for the preparation of 3,7,11 -trimethyl 2,4-dodecadienoic acid derivatives of the general formula (I), wherein the substituents have the same meanings as above, which comprises reacting a compound of the general formula (li)
wherein R, Z1, Z2, Z3 and R3 have the above specified meanings, and 0 represents a group of the general formula (IIIA) or (IIIB),
-COR (IIIB) wherein R stands for a lower alkyl, phenyl or phenyl-(lower alkyl) group and R4 is a lower alkyl group, with a compound of the general formula (VI) Li-Cu (R2)2 (Vl) wherein R2 has the above defined meaning.
The term "lower alkyl" refers to straight or branched saturated aliphatic hydrocarbon groups containing 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl). The term "lower alkoxy" relates to straight or branched alkylether groups containing 1-4 carbon atoms, e.g.
methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. The "phenyl-(lower alkyl) group" may stand for benzyl or phenylethyl. The term "halogen atom" may be all the four halogen atoms, such as fluorine, chlorine, bromine or iodine, and represents perferably chlorine.
The reaction of the compounds of the general formula (II) and (VI) is preferably carried out in an organic solvent. As reaction medium preferably diethyl ether or tetrahydrofuran can be used. The reaction can be performed in a temperature interval ranging from --100C to --1000C, particularly between --500C and --800C. One proceeds preferably under an inert gas, as argon or nitrogen.
The starting materials of the general formula (II) are new and can be produced as follows: The starting materials of the general formula (II), wherein Q represents a group of the general formula (IIIA), can be prepared by reacting a compound of the general formula (IV)
wherein R1, Z1, Z2, Z3 and R3 have the above defined meanings, with a dialkyl-phosphoryl halide of the general formula (V)
wherein X stands for halogen and R4 has the above defined meaning.
The reaction is preferably carried out in an aprotic organic solvent (e.g. diethyl ether or tetrahydrofurane). One proceeds preferably in the presence of a strong base (e.g. alkali metal or alkali hydride, particularly sodium or sodium hydride, or organic bases as potassium tert. butoxide. The reaction is preferably performed under heating, particularly at the boiling point of the reaction mixture.
The starting materials of the general formula (II), wherein Q represents a group of the general formula (IIIB), can be prepared by reacting a compound of the general formula (IV) with a compound of the general formula (VII)
wherein R represents a lower alkyl, a phenyl or a phenyl-(lower alkyl group.
The reaction is preferably carried out in the presence of a catalytic amount of an acid (preferably an organic suifonic acid, particularly p-toluenesulfonic acid; or a mineral acid, preferably hydrochloric acid).
As reaction medium, preferably organic solvents (e.g. diethyl ether or tetrahydrofuran) are used.
The starting materials of the general formula (II) thus-obtained can be reacted with the compounds of the general formula (VI) after or without isolation.
The compounds of the general formula (IV) used for the preparation of the starting compounds of the general formula (II) are also new and can be prepared by reacting a citronellal derivative of the general formula (VIII)
wherein R' and Z' have the above defined meanings, with a dianion prepared from a 3-oxo-ester of the general formula (IX) Z-COOR5 (IX) wherein Z stands for an acetonyl or cyclopentanonyl group and R5 is a lower alkyl group, and by subjecting the product thus-obtained to an eliminated reaction.
The dialkyl-phosphoryl halides of the general formula (V) are commerical products. The dialkyl cuprous lithium compounds of the general formula (VI) can be prepared by reacting cuprous iodide with alkyl lithium.
In the reaction of the compounds of the general formula (IV), wherein Z2 and Z3 stand for hydrogen, with a dialkyl-phosphoryl halide of the general formula (V), a 7:3 mixture of the 2(Z),4(E) and 2(E),4(E) stereoisomars of the compounds of the general formula (II), wherein Q is a group of the general formula (IIIA), is obtained. The stereoisomers are not necessarily separated. The reaction of these products with a compound of the general formula (VI) is stereospecific and results in a 7:3 mixture of 2(E),4(E) and 2(Z),4(E) stereo-isomers. This mixture can be separated into the individual stereoisomers by column chromatography.
The 3,7,1 1-trimethyl-2,4-dodecadienoic acid can be isomerized into a 7:3 mixture of 2(E),4(E) and 2(Z),4(E) stereo isomers with thiophenol in a known way (C. A. Henrick et al.: J. Org. Chem. 40, 1 (1975)).
When reacting a compound of the general formula (IV), wherein Z2 and Z3 represent together an ethylene group, with a dialkyl-phosphoryl halide of the general formula (V), exclusively an enol phosphate of the general formula (II), wherein Q represents a group of the general formula (IIIA) of 2(Z),4(E) configuration is formed, which, by reacting with a dialkyl-cuprous lithium of the general formula (VI), can be converted into the corresponding compound of the general formula (I) of 2(E),4(Z) configuration.
A further advantage of the process according to the present invention is that exclusively the (E) isomer of the end product is formed, so the complicated procedures for the separation of the isomeric mixture, which result in a considerable loss of the yield, can be eliminated.
The process is illustrated by the following Examples of non-limiting character. Infrared spectra were measured on a Spectromom 200G spectrophotometer. 1H-NMR and '3C--NMR spectra were determined on a Jeol FX--100 spectrometer. Gas chromatograph was carried out with a Pye 105 instrument (10% SE-54 chromosorb. W 80-100, a gas column of 2 mmx2 m, carrier: He,190 2600, program 30(minute). Mass spectra were determined on JEOL JGC-20K and JMS-G1 SG-2 combined GC-Ms spectrometer (ionization potential 75 eV, 10 kV, 200A).
Example 1 Preparation of isopropyl-( 11 -methoxy-3,7,1 1 trimethyl-2(E),4(E)-dodecadienoate)) Methoprene; I: R1=CH3O, Z=Z2=Z3=H, R2=CH3, R3=iC3H) Method a.) 1.8 g of sodium hydride (0.16 moles), a 80% oily suspension are added to a solution of 13.2 g (0.042 moles) of isopropyl-(1 1-methoxy-3-oxo-7,1 1-dimethyl-4(E)-dodecenoate) in 250 ml of anhydrous ether under stirring, then the mixture is stirred for half an hour at room temperature.
Thereafter a solution of 12 g (0.0696 moles) of diethyl-chlorophosphate in 200 ml of anhydrous ether is dropwise added, and the reaction mixture is stirred for 8 hours. After cooling the solution is acidified to pH=4 with ethereous hydrochloric acid (under ice-cooling), then admixed with 100 ml of cold water.
The ethereous phase is separated, the aqueous phase is shaken with 100 ml of ether, the ether solutions are combined and washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off in vacuo. The residual crude product is purified by column chromatography (Kieselgel 60; a 7:3 mixture of hexane and acetone).
Yield: 17.6 g (96%) R0.4 According to 31P-NMR examination the product contains 70% of isopropyl-(11-methoxy-3- diethyl-phosphoryloxy-7,11-dimethyl-2(Z),4(E)-dodecadienoate) and 30% of isopropyl-( 11 -methoxy-3- diethyl-phosphoryloxy-7, 11 -dimethyl-2 (E),4(E)-dodecadienoate) .
lR(NaCI):1710,1640, 1615,1460,1380,1365,1270,1200,1140,1100,1010 cm~' 1H-NMR (CCl4): 0.9 (3H,d,J=6Hz, CH3), 1-1.8 (25H, m, CH, 3CH2, 6CH3), 2 (2H, m, CH3), 3 (3H, s, OCH3), 4 (%H, d, J=6Hz, CH2O).5 (1 H, h, J=5Hz, h, J=SHz, CHO), 5-68 (3H, m, CH=).
2.642 g (0.006 moles) of isopropyl-(1 1-methoxy-3-diethylphosphoryloxy-7,1 1-dimethyl-2,4- dodecadienoate) (a 7:3 mixture of 2(Z),4(E) and 2(E),4(E) stereoisomers) are dissolved in 50 ml of anhydrous ether, and the solution is cooled to -700C under argon. Then a solution of dimethyl-cuprous lithium (prepared from 3.82 g (0.02 moles) of cuprous iodide and 20 ml of a 5% ethereous methyl lithium solution containing 0.88 g (0.04 moles) of methyl lithium) in 100 ml of anhydrous ether cooled to -250C is added so that the temperature of the reaction mixture remains below -500C. after stirring at -700C for 4 hours the mixture is allowed to warm up to -1 00C, and 100 ml of a concentrated ammonium chloride solution are added.The ethereous solution is separated, the aqueous phase is extracted with 100 ml of ether, the ethereous extracts are combined, washed with a saturated sodium chloride solution and dried over magnesium sulfate. After filtering off the magnesium sulfate the solvent is distilled off in vacuo. The residual oily mass (1.9 g) analyzed by gas chromatography, shows a purity of 96% and contains 70% of isopropyl-(1 1-methoxy-3,7,1 1-trimethyl-2(E),4(E)- dodecadienoate) (Methoprene) and 30% of isopropyl-(1 1-methoxy-3,7,1 1-trimethyl-2(Z),4(E)- dodecadienoate), retention times are 26.5 and 22.7 minutes. The isomers are separated by column chromatography (Kieselgel 60, 10:0.2 mixture of benzene and isopropanol).
Yield (Methoprene): 0.86 g (51.6%) Rf=0.78 (hexane-acetone 7:3) IR(NaCI): 1710,1640,1610,1470, 1440,1380,1360,1230, 1160,1100,1080,1030,970 cm~' .
'H-NMR (CDCI3): 0.9 (3H, d, J=6Hz, CH3), 1.1-1.8 (19H, m, CH, 3CH2, 4CH3), 2.1 (2H, m, CH2), 2.3 (3H, d, J=1 .5 Hz, CH3), 3.2 (%H, s, OCH3),'5.1 (1 H, h, J=6Hz, CHO), 5.57 (1 H, m, CH=), 6.15 (2H, m, CH=) '3C-NMR: 13.8 (q), 19.6 (t), 21.3 (q), 22.0 (q), 25 (q), 33.2 (d), 37.2 (t), 40.1(t), 40.6 (t), 49.0 (q), 66.6 (d), 118.2 (d), 128.3 (d), 134.9 (d), 135.7 (d), 1 52.0 (d), 166.6 (s).
Ms: M* 310(8.9, mle 278(27), 236 (9),235 (10), 221(10), 193(13), 192(17), 153(32), 111 (33)73 (100),43 (26).
Yield (cis-Methoprene): 0.31 g (1 6.6%) Rf=0.86 (hexane-acetone 7:3) IR(NaCI): 1710,1610,1470,1455,1380,1360,1230,1155,1110,1030,980cm~' H-NMR(CDCl3): 0.9 3H,d,J=6Hz,CH3),1-1.8(19H,m,CH,3CH2,4CH3),1.97(3H,d,J=1.5 Hz, CH3), 2.1 (2H (2H, m, CH2), 3.2 (3H, s, OCH3), 5.1(1 H, h, J=6Hz, CHO), 5.60 (1 H, m, CH=) 6.15(2H, m, CH=).
Ms: M+310 (8), m/e 278 (6),235 (4),221 (5), 191(5), 153(18), 137(14), 111(34), (13), 73 (100), 69 (26), 43 (55).
Method b.) 0.28 g (0.04 moles) of lithium metal are dispersed in 6.0 ml of anhydrous ether, and a solution of 3.1 5 g (1.38 ml, 0.0222 moles) of sodium iodide in 6.0 ml of anhydrous ether is dropwise added under stirring at --100C under argon. The mixture is allowd to warm up to room temperature but stirring is continued until the reaction is completed.Then the mixture is boiled on water bath for 1 5-30 minutes, cooled to -200C and added to a suspension of 0.95 g (0.005 moles) of cuprous iodide in 30 ml of an hydros ether cooled to --200C. The ether solution of dimethyl-cuprous lithium thbs-obtained is added in portions to a solution of 0.65 g (0.00145 moles) of isopropyl-(1 1 -methoxy-3-diethylphosphoryloxy-7,1 1 -dimethyl-2,4-dodecadienoate) in 13 ml of anhydrous ether cooled to -700C so that the temperature of the mixture remains below -500C The reaction mixture is stirred at -600C for 5 hours then allowed to warm up to --10 OC and admixed with 25 ml of a concentrated aqueous solution of ammonium chloride.The ethereous phase is separated, the aqueous phase is shaken twice with a total amount of 20 ml of ether. The ethereous solutions are combinea, washed with 20 ml of saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated in vacuo. The residual pale yellow oil (0.45 g) is purified on a Keiselgel G F245 absorbent (a plate of 20x20 cm) with a 7:3 mixture of hexane and acetone. The separated product is washed off the plate with anhydrous acetone.
The acetone is distilled off in vacuo to yield 0.35 g (0.00112 moles, 78% of methoprnne Example 2 Preparation of ethyl-(3,7,11-trimethyl-2(E),4(E)-dodecadienoate) (Hydroprene; I: R'=Z'=Z2=Z3=H, R2=CH3, R3=C2H5) To a solution of 5.0 g (0.0185 moles) of ethyl-(3-oxo-7,1 1-dimethyl-4(E)-dodecaenoate) in 50 ml of anhydrous ether 1.15 g (0.0385 moles) of sodium hydride (20% oily suspensions are added under stirring, and the mixture is stirred for half an hour at room temperature. Then a solution of 4.5 g (0.026 moles) of diethyl-chlorophosphate in 50 ml of anhydrous ether is dropwise added, and the reaction mixture is boiled on water bath for 8 hours.Thereafter it is cooled, acidified to pH=4 with ethereous hydrochloric acid, admixed with 50 ml of cold water, the upper organic phase is separated, the aqueous phase is extracted with 50 ml of ether, the ethereous extracts are combined and washed with saturated sodium chloride, dried over mangesium sulfate, and the ether is distilled off in vacuo. The residual oily product is purified by column chromatography (Keiselgel 60, hexane, acetone 8:2).
Yield: 6.2 g (83%) Rf=0.50 According to 3'P-NMR examination the product contains 70% of ethyl-(3-diethyl-phosphoryloxy 7,11 -dimethyl-2(Z),4(E)-dodecadienoate) and 30% of ethyl-(3-diethyl-phosphoryloxy-7. 11 -dimethyl- 2(E),4(E)-dodecadienoate).
IR(NaCI): 1715,1640,1615,1460, 1380,1365,1270,1200, 1140,1100, 1O10cm1 rH-NMR (CC14): 0.9 (9H, d, J=6Hz, 3CH3), 1,1-1,8 (14H, m, 2CH, 3CH2, 2CH3), 2,2 (2H, m, CH2), 4,2 (4H, k, J=6Hz, OCH2), 5 (1 H, h, J=6Hz, OCH), 5,3-6,8 (3H, m, CH=).
1.4 g (0.0034 moles) of ethyl-(3-diethyl-phosphoryloxy-7,1 1 -dimethyl-2,4-dodecadienoate) (a 7:3 mixture of 2(Z),4(E) and 2(E),4(E) stereoisomers) are dissolved in 25 ml of anhydrous ether and the solution is cooled to -700C, under argon. Then a solution of dimethyl-cuprous lithium (prepared from 2.0 g (0.01 mole) of cuprous iodide and 12 ml of a 5% ethereous methyl lithium solution containing 0.88 g (0.04 moles) of methyl lithium) in 100 ml of anhydrous ether cooled to -250C is added under stirring so that the temperature of the reaction mixture remains below --500. The mixture is stirred for 4 hours at -700C, then allowed to warm up to -1 00C and admixed with 70 ml of a saturated aqueous ammonium chloride solution.The upper ethereous phase is separated, the aqueous solution is extracted with 50 ml of ether, the ethereous solutions are combined, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent is distilled off in vacuo. The residual oily mass (0.85 g), analyzed by gas chromatography, shows a purity of 95% and contains 70% of ethyl (3,7,11 -trimethyl-2(E),4(E)-dodecadienoate) and 30% of ethyl-(3,7, 11 -trimethyl-2 (Z),4(E)- dodecadienoate). The stereoisomers are separated by column chromatography (Keiselgel 60, benzeneethanol 10:0.2).
Yield (Hydroprene): 0.47 g (52.2%) Rf: 0.83 (hexane-acetone 7:3) IR (NaCI): 1710, 1640, 1600, 1460, 1380, 1360, 1220, 1140, 1030, 960 cm-l.
1H-NMR (CC14): 0.9 (9H, m, 3CH3), 1-1.8 (11 H, m, 2CH, 3CH2, CH3), 2 (2H, m, CH2), 2.15 (%H, d, J=1.5 Hz, CH3), 5.75 (1H, m, CH=), 6.15 (2H, m, CH=OH).
Ethyl-3,7-1 1 -trimethyl-2(Z),4(E)-dodecadienoate) Yield: 0.12 g (13.3%) Rf=0.86(hexane-acetone 7:3) 'H-NMR (CCl4): 0.9 (9H, m, 3CH3) 1-1.8 (11 H, m, 2CH, 3CH2, CH3), 1.95 (3H, d J=1 .5 Hz, CH3), 2.05 (2H, m, CH2), 5.60(1 H, m, CH=), 6.15 (2H, m, CH=CH).
Example 3 Preparation of isopropyl-(11-methoxy-7,11-dimethyl-3-butyl-2(E),4(E)-dodecadienoate) (butyl-Methoprene; I: R1=CH30, Z1=Z2=Z3=H, R2=C4Hg, R3=iC3H7) 2.11 g of isopropyl-(11-methoxy-3-diethyl-phosphoryloxy-7,11-dimethyl-2,4-dodecadienoate) prepared as described in Example 1 (containing a 7:3 mixture of 2(Z),4(E) and 2(B), 4(E) stereoisomers) are dissolved in 30 ml of anhydrous ether, and the solution is cooled to --700C, under argon.Then a solution of dibutyl-cuprous lithium (prepared from 3.06 g (0.012 moles) of cuprous iodide and 20 ml of a 1.63 M hexaneous butyl lithium solution containing 2.05 g (0.032 moles) of butyl lithium) in 25 ml of anhydrous ether cooled to -250C is added so that the temperature of the reaction mixture remains below -500C. After stirring for 3 hours at -600C the mixture is allowed to warm up to -1 00C and 70 ml of concentrated ammonium chloride solution are added. The upper ethereous phase is separated, the aqueous phase is extracted with 100 ml of ether, the organic phases are combined, washed with 25 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent is distilled off in vacuo.The residual oily product (1.56 g) analyzed by gas chromatography, shows a purity of 95% and contains 60% of isopropyl-1 1-methoxy-7,1 1-dimethyl-3-butyl-2(E),4(E)- dodecadienoate) and 40% of isopropyl(11-methoxy-7,11-dimethyl-3-butyl-2(Z),4(E)-dodecadienoate).
Retention times are 27.5 and 24.7 minutes. The stereoisomers are separated by column chromatography (Kieselgel 60, benzene-isopropanol 18:0.2).
Yield (butyl-Methoprene): 0.8 g (48.5%) R0.78 (hexane-acetone 7:3) IR(NaCI): 1710,1730,1605,1450, 1420,1380,1370,1250, 1150,1100,1070,1000,960 cm-.
rH-NMR (CCl4): 0.8-1.7 (29H, m, CH, 5CH2, 6CH3), 2 (4H, m, CH2), 3 (3H, s, OCH3), 4.8(1 H, h, J=6Hz, OCH), 5.45 (1 H, m, CH=, 5.99 (2H, m, CH=CH).
Ms: M+ 352 (2), m/e 320 (10), 278 (5.5), 235 (8.5), 233 (8.2), 211(3.5), 195 (25), 153 (56), 137(19), 109(16), 93(9), 73 (100),43 (68).
Example 4 Preparation of isopropyl-(3,7,11-trimethyl-2(E),4(E)-dodecadienoate) (I: R'=Z'=Z2=Z3=H, R2=CH3, R3=iC3H) 0.5 g (0.017 moles, 20% oily suspension) of sodium hydride are added to a solution of 2.2 g (0.078 moles) of isopropyl-(3-oxo-7,1 1-dimethyl-4(E)-dodecenoate) in 50 ml of anhydrous ether under stirring, and the mixture is stirred further for half an hour. Then a solution of 1.7 g (0.01 mole) of diethyl-chlorophosphate in 50 ml of anhydrous ether is dropwise added, and the mixture is boiled on water bath for 6 hours. After cooling the solution is acidified to pH=4 with ethereous hydrochloric acid and admixed with 25 ml of icy water.The upper organic phase is separated, the aqueous phase is extracted with ether, the organic phases are combined and washed with 25 ml of saturated sodium chloride, dried over magnesium sulfate, filtered, and the filtrate is distilled over magnesium sulfate, filtered, and the filtrate is distilled in vacuo. The residual oily product is purified by column chromatography (Kieselgel 60, hexane-acetone 7:3).
Yield: 2.67 g (82%) RO.55 According to 31P-NMR examination the product contains 70% of isopropyl-(3-diethyl phosphoryloxy-7,1 1 -dimethyl-2(Z),4(E)-dodecadienoate) and 30% of isopropyl-(3-diethyl phosphoryloxy-7, 11 -dimethyl-2(E),3(E)-dodecadienoate).
IR (NaCI): 1715,1640,1610,1460,1380,1360,1270,1200,1140,1100,1000cm~1 1H-NMR (CCl4): 0.9 (9H, m, 3CH3), 1-1.8 (20H, m, 2CH, 3CH2, 4CH2), 2 (2H, m, CH2), 4.2 (4H, k, J=6Hz, OCH2, 5 (1 H, h, J=6Hz, OCH), 5.3-6.5 (3H, m, CH=).
A solution of 1.1 g (0.0026 moles) of isopropyl-(3-diethyl-phosphoryloxy-7,1 1-dimethyl-2,4docecadienoate) (a 7:3 mixture of 2(Z), 4) and 2(E),4(E) stereoisomers) in 20 ml of anhydrous ether is cooled to -700C under argon. Then a solution of dimethyl-cuprous lithium (prepared from 1.53 g (0.008 moles) of cuprous iodide and 8 ml of a 5% ethereous methyl lithium solution containing 0.35 g (0.016 moles) of methyl lithium) in 50 ml of anhydrous ether cooled to -200C is added so that the temperature of the reaction mixture remains below -500C. Then the solution is stirred at -700C for 4 hours, allowed to warm up to -1 00C and admixed with 50 ml of concentrated ammonium chloride solution.The upper organic phase is separated, the aqueous phase is extracted with ether, the organic phases are combined, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and the solvent is distilled off in vacuo. The residual crude product shown, according to gas chromatography, a purity of 95% and contains 70% of isopropyl-3,7,1 1 -trimethyl-2(E),4(E)- dodecadienoate) and 10% of isopropyl-(3,7,1 1 -trimethyl-2(Z),4(E)-dodecadienoate). The stereoisomers are separated by column chromatography (Kieselgel 40, benzene-isoproparrol 10:0.2).
Yield: 0.4 g (55%) Ref=0.90 IR (NaCI): 1710,1640,1600,1460, 1380,1365,1220,1140, 1030,960cm1.
'H-NMR (CCl4): 0.9 (9H, m, 3CH3), 1-1.8 (14H, m, 2CH, 3CH2, 2CH3), 2 (2H, m CH2), 2.15 (3H, d, J=1 .5 Hz, CH3), 5.75 (1 H, m, CH=), 6.1 5 (2H, m, CH=CH).
Example 5 Preparation of isopropyl-( 11 -methoxy-3,7, 11 -trimethyl-2(E), 4(E)-dodecadienoate) (Methoprene, I: R1=CH3O, Z1=Z2=Z3-H R2=CH3, R3=iC3H7) 5 g (16 millimoles) or isopropyl-(1 1-methoxy-3-oxo-7,1 1-dimethyl-4(E)-dodecenoate) are dissolved in 20 g (200 millimoles) of isopropenyl acetate. Then 0.2 g (1.2 millimole) of anhydrous ptoluenesulfonic acid are added, and the reaction mixture is stirred for 6 hours, under stirring. The solution is cooled, 50 ml of ether are added, the ethereous solution is washed first with 50 ml of water then with 50 ml of saturated sodium chloride, dried over magnesium sulfate, filtered and the solvent is distilled off in vacuo.The residue (5.1 g of yellow oil) is filtered on a short column (50 g of Keiselgel 60, benzene-ethylacetate 3:2). After distilling off the eluent 3.5 g (62.5%) of isopropyl-(3-acetoxy-1 1 - methoxy-7, 11 -dimethyl-2(Z),4(E)-dodecadienoate) are obtained.
Ref=0.65 (hexane-acetone 5:1) According to a liquid chromatographic analysis the product may contain less than 2% of 2(Z),4(E) stereoisomer.
Retention time: 2(E),4(E) diasteromer: 5.3 minutes 2(Z),4(E) diasteromer: 6.6 minutes IR (NaCI): 1760,1710,1640,1610, 1450, 1380,1360,1245,1220,1 160,1130,1080,1060, 1000 cm~'.
1H-NMR (CCl4): 0.9 (3H, d, J=6Hz, CH3), 1-1.9 (19H, m, CH3, CH2, CH), 2.1 (2H, m, CH2), 2.22 (3E, s, OCCH3), 3.08 (3H, s, OCH3), 4.9 (1 H, h, J=5Hz, CHO), 5.2-6.3 (3H, m, CH=).
Ms: M+ 345 (2), mle 340 (4), 322 (6), 280 (15), 264 (7), 262 (5), 237 (8), 220 (10), 197 (15), 136(20), 124(12),95 (12),81 (16),73 (100), 69 (12),43 (85) A 5% ethereous solution of 0.83 g (38 millimoles) of methyl lithium is added to a suspension of 3.6 g (120 millimoles) of cuprous iodide in 100 ml of anhydrous ether under stirring and cooling (-300C), under argon. After stirring for further 5 minutes the reaction mixture is cooled to -700C and a solution of 1.7 g (5.6 millimoles) of isopropyl-(3-acetoxy-1 1-methoxy-7,1 1-dimethyl-2(Z),4(E)- dodecadienoate) in 25 ml of an hydros ether is dropwise added. The mixture is stirred at -2O0Cfor 3 hours, poured onto 100 mi of concentrated ammonium chloride, the ethereous phase is separated, and the aqueous phase is extracted twice with a total amount of 100 ml of ether. The ethereous extracts are combined washed with saturated sodium chloride, dried over magnesium sulfate, and the solvent is distilled off.
Yield: 1.2 g (82%) F+O.9 (hexane-acetone 7:3) B.p.: 140--142 C (6.66 Pa [According to scientific literature: 135--136 C (7.99 Pa, C.
A. Henrick et al.: J. Org. Chem.40, 1 (1975).] According to a liquid chromatographic analysis the product contains less than 2% of 2(Z),4(E) stereoisomer.
Retention time: 2(E),4(E) diastereomer: 2.33 minutes 2(Z),4(E) diastereomer: 2.83 minutes IR (NaCI): 1710, 1640,1610, 1470,1440,1380,1360, 1230,1160,1100,1080, 1030,970 cam-.
1H-NMR (CDCl3): 0.9 (3H, d, J=6Hz, CH3), 1.1-1.8 (19H, m, CH, CH2CH3), 2.1 (2H, m, CH2),2.3 (3H, d, J=1.5Hz, CH3), 3.2 (3H, s, OCH3), 5.1(1 H, h, J=6Hz, CHO), 5.75 (1 H, m, CH=), 6.15 (2H, m, CH=).
13C-NMR: 13.8 (q), 19.6 (t), 21.3 (q), 22.0 (q), 25 (q), 33.2 (d), 37.2 (t), 40.1(t), 40.6 (t), 49.0 (q), 66.6(d), 118.2(d), 128.3 (d), 134.9(d), 135.7(d), 152.0(d), 166.6(s).
Ms: M+ 310(9), m/e 278(27), 236(9), 235(10)221(10), 193(13), 192(17), 153 (32), 111 (33), 73 (100),43 (26).
Example 6 Preparation of ethyl-(3,7,1 1 -trimethyl-2(E),4(E)-dodecadienoate) (Hydroprene, I: R'=Z'=Z2=Z3=H, R2=CH3, R3=CzH5) To a mixture of 5 9 (18 millimoles) of ethyl-(3-oxo-7,1 1-dimethyl-4(E)-dodecenoate) and 20 9 (200 millimoles) of isopropenyl acetate 0.2 g (1.2 millimoles) of p-toluene-sulfonic acid are added, and the reaction mixture is stirred for 6 hours under stirring. Then it is cooled, diluted with 50 ml of ether, the ethereous solution is washed first with 25 ml of water then with 50 ml of saturated sodium chloride, dried over magnesium sulfate, and the solvent is distilled off. The residue (5.4 9 of a pale yellow oil) is filtered on a short column (50 9 of Kieselgel 60, benzene-ethylacetate 3:2).After distilling off the solvent 5 g (87%) of ethyl(3-acetoxy-7,1 1-dimethyl-2(Z),4(E)-dodecadienoate) are obtained.
Rf=0.72 (hexane-acetone 5:1) According to liquid chromatography the product contains less than 2% of 2(Z),4(E) stereoisomer.
Retention time: 2(E),4(E) diastereomer: 2.17 minutes 2(Z),4(E) diastereomer: 2.35 minutes IR (NaCI): 1760,1710,1610,1600, 1460,1380,1360,1420, 1220,1150,1120,1080, 1020 cm-1 rH-NMR (CCl4): 0.9 (9H, dm, CH3), 1-1.8 (11 H, m, CH, CH2, CH3), 2 (2H, m, CH2), 2.2 (3H, s, OCCH3), 4 (2H, q, J=6Hz, OCH2),5.1--6.3 (3H, m, CH=).
Ms: M+ 310(3), m/e 267(3), 183(10), 173(9), 155(16), 141 (10), 126(8), 95(7), 91(48), 83 (12), 81(11), 69 (27!,65 (20), 57 (32)56 (25), 55 (33), 43 (100), 41(55).
To a suspension of 5 9 (26 millimoles) of cuprous iodide in 100 ml of anhydrous ether cooled to -30 C an ethereous solution of methyl lithium (containing 1.1 9 (53 millimoles) of methyl lithium) is added under argon. After stirring for 5 minutes the reaction mixture is cooled to -700C and a solution of 3.5 9 (11 millimoles) of ethyl-(3-acetoxy-7,1 1 -dimethyl-2(Z),4(E)-dodecadienoate) in 20 ml of anhydrous ether is dropwise added. The reaction mixture is poured onto 100 ml of concentrated ammonium chloride solution, the organic phase is separated, and the aqueous phase is extracted twice with a total amount of 100 ml of ether. The ethereous solutions are combined, washed with an aqueous saturated sodium chloride solution dried over magnesium sulfate and the solvent is distilled off.
Yield: 2.2 g (73%) Rf = 0.92 (hexane-acetone 7:3) B.p.: 132-1350C (6.66 Pa (According to scientific literature: 137-1420C (39 Pa, C. A. Henrick et al.: J. Org. Chem.40., (1975)).
According to liquid chromatographic analysis the product may contain less than 2% of 2(Z),4(E) stereoisomer.
Retention time: 2(E),4(E) diastereomer: 2.05 minutes 2(Z),4(E) diasteromer: 2.35 minutes IR (NaCI): 1710,1640,1600,1460, 1380,1360,1220,1140, 1030,960cm-1 rH-NMR (CCl4): 0.9 (9H, m, CH3), 1-1.8 (11 H, m, CH, CH2, CH3), 2 (2H, m, CH2), 2.15 (3H, d, J=1 .5 Hz, CH3), 4 (2H, q, J=7Hz, OCH2), 5.75 (1 H, m, CH=), 6.15 (2H, m, CH=CH).

Claims (14)

Claims
1. A process for the preparation of 3,7,11 -trimethyl-2,4-dodecadienoates of the general formula (I)
wherein R1 represents hydrogen or a lower alkyl group, Z' stands for hydrogen, or R1 and Z1 together form a double bond, Z2 and Z3 each represent hydrogen or together form an ethylene group, R2 and R3 each denote a lower alkyl group, with the proviso that if Z2 and Z3 together form an ethylene group, R1 may only stand for hydrogen, R2 for methyl and R3 for ethyl, characterized by reacting a compound of the general formula (II)
wherein RX, Z1, Z2, Z3 and R3 have the above specified meanings, and 0 represents a group of the general formula (IIIA) or (IllS)
--COR (IllS) wherein R stands for a lower alkyl, phenyl or phenyl-(lower alkyl) group and R4 is a lower alkyl group, with a compound of the general formula (VI) LiQu(R2)2 (Vl) wherein R2 has the above defined meaning.
2. A process as claimed in claim 1, wherein the reaction is carried out under inert gas.
3. A process as claimed in claim 1, wherein the reaction is carried out under argon.
4. A process as claimed in any of claims 1 to 3 which comprises carrying out the reaction at a temperature between -1 000C to -1 00C.
5. A process as claimed in any of claims 1 to 4 which comprises carrying out the reaction at a temperature between -500C and -800C.
6. A process as claimed in any of claims 1-5, which comprises carrying out the reaction in an aprotic solvent.
7. A process as claimed in claim 6 wherein the aprotic solvent is diethyl ether or tetrahydrofuran.
8. A process as claimed in any of claims 1 to 7 wherein the compound of the general formula (II), wherein 0 represents a group of the general formula (IIIA) and R1, R3, Z1, Z2 and Z3 are as defined in claim 1, is obtained by the reaction of a compound of the general formula (IV)
wherein R1, Z1, Z2, z3 and R3 have the same meanings as above, and a compound of the general formula (V)
wherein R4 has the above-specified meaning and X represents halogen, and is used after or without isolation.
9. A process as claimed in any of claims 1 to 7 wherein the compound of the general formula (II), wherein Q represents a group of the general formula (IllS) and Ra, R3, Z1, Z2 and Z3 are as defined in claim 1 is obtained by the reaction of a compound of the general formula (IV) as defined in claim 8 and a compound of the general formula (VII)
wherein R is as defined in claim 1 and is used after or without isolation.
10. A process as claimed in claim 9 wherein the compound of the general formula (IV) is reacted with a compound of the general formula (VII) in the presence of a catalytic amount of an aromatic sulfonic acid.
11. A process as claimed in claim 10 wherein the aromatic sulphonic acid is p-toluenesulfonic acid.
1 2. A process as claimed in claim 1 substantially as hereinbefore described.
13. A process as claimed in claim 1 substantially as hereinbefore described with reference to the Examples.
14. Compounds of the general formula (II), as defined in claim 1.
GB8109962A 1980-04-01 1981-03-31 Preparation of 3,7,11-trimethyl-2,4-dodecadienoates and starting materials therefor Expired GB2073754B (en)

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HU76680A HU179373B (en) 1980-04-01 1980-04-01 Process for producing 3-alkyl-7,11-dimethyl-e-bracket-e-bracket closed,4-bracket-e-bracket closed-dodecadienic and 2-bracket-e-bracket closed,4-bracket-e-bracket closed,10-dodecatrienic acid inhibiting growth of insects
HU299780A HU181239B (en) 1980-12-16 1980-12-16 Process for the stereospecific preparation of 3,7,11-trimethyl-2,4-dodecadienic acid derivatives with inhibiting activity against growth of insects

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