US3761495A - Epoxidized hydrocarbon acid esters having juvenile hormone activity - Google Patents

Epoxidized hydrocarbon acid esters having juvenile hormone activity Download PDF

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US3761495A
US3761495A US00169126A US3761495DA US3761495A US 3761495 A US3761495 A US 3761495A US 00169126 A US00169126 A US 00169126A US 3761495D A US3761495D A US 3761495DA US 3761495 A US3761495 A US 3761495A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
    • C07C403/16—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms not being part of —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
    • C07D303/42—Acyclic compounds having a chain of seven or more carbon atoms, e.g. epoxidised fats
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/16—Radicals substituted by halogen atoms or nitro radicals
    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S424/00—Drug, bio-affecting and body treating compositions
    • Y10S424/12—Fertilization attaching inhibition

Definitions

  • ABSTRACT A process is disclosed herein for the preparation of hydrocarbon acid esters of formula
  • R and R are alkyl groups containing two to four carbon atoms or R and R together are a poly methylene group containing four to five carbon atoms forming a cyclopentane or cyclohexane ring, R R and R are alkyl groups containing 1 2 carbon atoms and Z and Z together are a carbon-carbon double bond or an epoxide; whereby the appropriate ketone of formula RR C O is condensed with the ylid generated from either 4-oxopentyll -triphenylphosphonium iodide ethylene ketal or 4-oxohexyl-l-triphenylphosphonium iodide ethylene ketal, followed by acid treatment to remove the ketal, and yield the appropriate ketonic intermediate, which is treated successively with either of the preceding ylids and then acid treatment to yield a ketone of formula RR C CHCI-I CI-I CR CHCH CH COR"; the last
  • Juvenile hormone appears to control egg ripening and the normal development of the sexually mature insect from the larva. 1n the normal life cycle of the insect, the juvenile hormone must be present at the stage of the immature larva if it is to progress through the normal stages of larval development. However, the juvenile hormone must be absent if the mature larva is to metamorphose into the sexually mature insect. Presence of the juvenile hormone at this point in the development of the insect will prevent the emergence of the sexually mature form capable of reproduction, and contact of the eggs with the juvenile hormone will prevent normal embryonic development. These facts are of great importance in the control of insect populations.
  • hydrocarbon acid esters possess a very low order of toxicity to species other than insects.
  • this invention relates to a facile preparation of unsaturated hydrocarbon acid esters containing 18 to 25 carbon atoms which may be represented by formula I;
  • R and R represent alkyl groups containing from two to four carbon atoms or R and R together represent a polymethylene radical containing four to five carbon atoms which in conjunction with the carbon atom 11 to which they are bonded form a cyclopentane or cyclohexane ring, respectively;
  • R, R and R represent alkyl groups containing one to two carbon atoms and Z and Z together represent a carboncarbon double bond between carbon atoms and 11 or an epoxide.
  • the compounds of formula I of the process of this invention exhibit the biological activities of the juvenile hormone and are useful as means for controlling insect populations. More particularly, these compounds, when tested in standard pharmacological tests used in entomology, for example in the modified Tenebrio test described by Roller et al., in Life Sci., Vol. 4, p. 1617 (1965), exhibit the useful activity of the juvenile hormone.
  • the compounds of this invention of formula 1 When administered to the test insects in the manner described by Roller et al., cited above, the compounds of this invention of formula 1 cause the formation of typical pupal cuticle over the area of deposition.
  • the compounds of this invention of formula I may be formulated in the form of liquid sprays, in solution in suitable solvents such as lipophilic solvents, for example vegetable or mineral oils, or hydrocarbon solvents, or solvents which have both lipophilic or hydrophilic characteristics, for example, lower aliphatic ketones or polyhydric alcohols; or they may be dissolved in a lipophilic solvent such as exemplified above and may be formulated in the form of aqueous emulsions together with suitable surface'active agents such as emulsifiers and/or detergents, and other suitable excipients. They may also be formulated in the form of dusting powders together with suitable solid excipients.
  • suitable solvents such as lipophilic solvents, for example vegetable or mineral oils, or hydrocarbon solvents, or solvents which have both lipophilic or hydrophilic characteristics, for example, lower aliphatic ketones or polyhydric alcohols; or they may be dissolved in a lipophilic solvent such as exemplified above and may be formulated
  • hydrocarbon aced esters of formula l may be prepared in the following manner:
  • the starting materials for the process of the invention are the simple ketones of formula RRC 0 (II), in which R and R are as defined above. Most of these simple ketones are commercially available; the remaining starting materials are prepared by conventional methods. Such conventional methods for preparing ketones and aldehydes are described in textbooks on organic chemistry; for example, see P. Karrer, Organic Chemistry, 2nd ed., Elsevier Publishing Co., Inc., New York, 1946, pp. 149-169 and V. Migrdichian, Organic Synthesis," Vol. 1, Reinhold Publishing Corp., New York, 1957, pp. 100-129.
  • the latter dienones of formula IV are then treated with the anion prepared from a dialkylcarbomethoxymethyl or a dialkylcarbethoxymethyl phosphonate containing from 1 4 carbon atoms in the alkyl groups.
  • the latter compounds are conveniently prepared from methyl or ethyl chloroacetate and the appropriate tiralkyl phosphite in which the alkyl group contains from 1 4 carbon atoms each, and the anion is prepared therefrom by means of an alkali metal alkoxide containing from 1 4 carbon atoms or an alkali metal hydride.
  • hydrocarbon acid methyl, or ethyl, esters of formula I in which R, R R and R are as defined above, R is methyl or ethyl, respectively, and Z and Z together represent a carbon-carbon double bond between carbon atoms and 11.
  • the latter compounds are converted to the corresponding epoxides, the hydrocarbon acid esters of formula l in which R, R R, R and R are as defined in the first instance and Z and Z together represent an epoxide, by treatment with either a reagent selected from the group, N-bromoand N-chloro-succinimide and N-bromoand N-chloroacetamide, followed by treatment with an alkali metal alkoxide containing 1 4 carbon atoms, or by treatment with an organic peracid.
  • a reagent selected from the group, N-bromoand N-chloro-succinimide and N-bromoand N-chloroacetamide followed by treatment with an alkali metal alkoxide containing 1 4 carbon atoms, or by treatment with an organic peracid.
  • the principal advantage of the process of this invention is the fact that it proceeds from commercially available starting material to the desired final products in good yields and via a pathway involving relatively few steps.
  • a partically useful process of preparation of such compounds is especially advantageous.
  • 4-oxopentyl-l-triphenylphosphonium iodide ethylene ketal is prepared by treating commercially avaiable 5-chloro-2-pentanone in a solvent with a molar excess of sodium iodide, to obtain the corresponding 5-iodo-2-pentanone.
  • Preferred conditions for this reaction include the use of three equivalents of sodium iodide and of acetone as the solvent, and relfluxing for 0.5 to 2 hours.
  • 5-lodo-2-pentanone thus obtained is ketalized by treatment in a waterimmiscible solvent with a molar excess of ethylene glycol in the presence of small amounts of an acid catalyst, removing water from the reaction mixture as it is being formed.
  • Preferred reaction conditions include the use of three equivalents of ethylene glycol, 0.1 equivalent of p-toluenesulfonic acid, benzene as the solvent, and a water-separating device as part of the equipment. Refluxing the mixture for periods of time of from 8 to 24 hours yields 5-iodo-2- pentanone ethylene ketal.
  • Said last-named compound is treated with a molar excess of triphenylphosphine at a temperature within the range of from 50 to 150C in an inert solvent to yield 4-oxopentyl-l-triphenylphosphonium idoide ethylene ketal.
  • Preferred reaction conditions include the use of 1.1 equivalents of triphenylphosphine and of benzene as the solvent, and carrying out the reaction at the reflux temperature of the mixture, whereupon the desired compound crystallizes from the reaction mixture in a sufficiently pure state for immediate use.
  • 4-oxohexyl-l-triphenylphosphonium iodide ethylene ketal is prepared except that 6-chloro-3-hexanone is used instead of 5-chloro-2- pentanone.
  • the 4-oxopentyl-b l-triphenylphosphonium iodide ethylene ketal or 4-oxohexyl-l-triphenylphosphonium iodide ethylene ketal, thus prepared, may be converted to their corresponding ylids by treatment with a alkali metal alkoxide containing from one to five carbon atoms or an alkali metal hydride in a common solvent. Subsequent condensation of the appropriate ylid with a ketone of formula II described above, yields the ketone intermediates of formula III, described above, after acid treatment.
  • the next step of this process the conversion of the ketone intermediate of formula III to the dienone derivative of formula IV, may be accomplished in the same manner as above described conversion of the ketones of formula ll to the ketone intermediates of formula III except that an equivalent amount of the ketone intermediate of fomrula III is used instead of the ketone of formula II.
  • Ill the above preferred conditions relating to the previous step of the process I] Ill apply equally well to this present step, "I IV, including the conditions for the acid treatment to remove the ketal group from the resulting ethylene ketal derivative.
  • the dienone derivative of formula IV is treated with the anion prepared from a dialkylcarbomethoxymethyl or a dialkylcarbethoxymethyl phosphonate, preferably dimethylcarbomethoxymethyl phosphonate, obtained from methyl chloroacetate and trimethyl phosphite according to the method described by PC. Crofts in Quart. Rev. Chem. Soc., 12, 341 (1958) by the action of approximately an equivalent amount of an alkali metal hydride in an inert solvent or by the action of an approximately equivalent amount of an appropriate alkali metal alkoxide containing from one to four carbon atoms in an inert solvent.
  • This anion formation is performed preferably by mixing equivalent molar amounts of the appropriate dialkylcarbomethoxymethyl or dialkylcarbethoxymethyl phosphonate, preferably dimethylcarbomethoxymethyl phosphonate,
  • the alkyl groups in the above compounds contain from 1 4 carbon atoms.
  • Preferred conditions in the above reaction include agitating the reaction mixture at temperatures of from 10C to the boiling point of the mixture for periods of time of from 8 hours to 6 days, dilution with water, extraction with a water-immiscible solvent, and purification by chromatography, preferably on silica gel.
  • reaction conditions include the use of 1.1 equivalents of N-bromosuccinimide, of a 3:2 mixture of dimethoxyethane and water as solvent, of 1.1 equivalents of sodium methoxide, of reaction temperatures close to 0C, and of reaction times of 30 to 60 minutes.
  • the desired hydrocarbon acid esters of formula l thus obtained may be purified, preferably by chromatography on silica gel or on alumina.
  • the above compounds of formula 1 in which Z and Z are a carbon-carbon double bond may be treated with at least one molar equivalent of an organic peracid in an inert solvent at temperatures of from 20C to 20C., from 2 hours to 2 days in a manner similar to that described by K.l-l. Dahm, et al., J. I
  • hydrocarbon acid esters of formula 1, in which R, R R, R and R are as defined in the first instance and Z and Z together represent an epoxide are also obtained.
  • Preferred conditions include the use of 1.1 equivalents of perbenzoic or m-chloroperbenzoic acid, ether as solvent, a reaction temperature of 0C and a reaction time of 16 hours. Purification of the desired hydrocarbon acids esters may be effected as described above.
  • EXAMPLE 2 R and R ample I, is added followed by 15 ml of dimethylsulfoxide and the mixture stirred for minutes, forming the corresponding ylid of the phosphonium salt. Then, cyclohexanone (0.98 g., 10 meq.) in 9 ml. of dimethylsulfoxide is added over a period of 10 minutes and the mixture stirred for 1 hours at 6070C. After cooling to 220 C, the reaction mixuture is poured into 200 ml of water and extracted with pentane (100 50 50 50 ml.). The pentane extract is washed with water (3 X 50 ml.), dried over magnesium sulfate and evaporated at room temperature under vacuum, yielding an oil.
  • EXAMPLE 4 In the same manner as described for Example 2 but using an equivalent amount of cyclopentanone, 3- hexanone, 3-heptanone, 4-heptanone, 4-octanone or 5-nonanone, there may be obtained, 5-cyclopentylidenepentan-Z-one, 6ethyl-5-nonen-2-one, 6-ethyl-5- decen-2-one, 6-propyl-5-nonen-2-one, 6-propyl-5- decen-Z-one and 6-butyl-5-decen-2-one, respectively.
  • EXAMPLE 6 9-CYCLOHEXYLIDENE-6-METHYL-5-NONEN- 2-ONE (IV; R and R together (CH R and R each CH
  • the corresponding ylid of 4-oxopentyl-I-triphenylphosphonium iodide ethylene ketal is prepared in the same manner as described in Example 2, using 0.54 g of the 57 percent oil dispersion of sodium hydride and 5.85 g. of the phosphonium salt.
  • 5-cyclohexylidenepentan-Z-one (1.42 g, 8.6 meq.- prepared as described in Example 2, is added instead of cyclohexanone and the reaction is performed under the same conditions as described for Example 2.
  • EXAMPLE 8 In the same manner as described for Example 6, but using an equivalent amount of 5-cyclopentylidenepentan-2-one, 6-ethyl-5-nonen-2-one, 6-ethyl-5-decen- 2-one, 6-propyl-5-nonen-2-one, 6-propyl-5-decen- 2-one or 6-butyl-5-decen-2-one, prepared as described in Example 4, there may be obtained the dienone derivatives of formula IV, 9-cyclopentylidene-6-methyl-5- nonen-Z-one, l0-ethyl-6-methyltrideca-5,9-dien-2-one, l0-ethyl-6-methyltetradeca-5,9-dien-2-one, l0-propyl- 6-methyltrideca-5,9-dien-2-one, lO-propyl-6- methyltetradeca-S,9-dien-2-one and l0-butyl-6- methyltetradeca-S
  • dienone derivatives of formula IV 9-cyclohexylidene-6-ethyl-5-nonen-2-one, 9- cyclopentylidene-6-ethyl-5-nonen-2-one, 6,10-diethyldodeca-5,9-dien-2-one, 6,10-diethyltrideca-S,9-dien- 2-one, 6,10-diethyl-tetradeca-S,9-dien-2-one, 6-ethyllO-propyltrideca-S,9-dien-2-one, 6-ethyl-lO-propyltetradeca-5,9-dien-2-one and lO-butyl-6-ethyltetradeca- 5,9-dien-2-one, respectively.
  • EXAMPLE 10 methylpentadeca-6, l -dien-3-one, 1 1-propyl-7- methyltetradeca-6,l0-dien-3one, l l-propyl-7- methylpentadeca-6, l O-dien-3-one and 1 1-butyl-7- methylpentadeca-6,l0-dien-3-one; cyclohexylidene-7-ethyl-6-decen-3-one, 10-
  • cyclopentylidene-7-ethyl-6-decen-3-one 7,11-diethyltrideca-6,l0-dien-3-one, 7,1l-diethyltetradeca-6,10- dien-3-one, 7,1 1-diethylpentadeca-6,10-dien-3one, 7-ethyl-1 l-propyltetradeca-6,10-dien-3-one, 7-ethyl- 1l'propylpentadeca-,10-dien-3-one and l1-butyl-7- ethylpentadeca-6,10-dien-3-one, respectively.
  • PHOS- EXAMPLE 12 METHYL-10-CYCLOHEXYLIDENE-3,7- DIMETHYLDECA-2,6-DIENOATE (I, R and R together (CH,) R, R and R each CB and Z and Z together double bond)
  • Sodium hydrode (1.54 g of 57 percent mineral oil dispersion) is washed with pentane 20+10+10 ml) and benzene ml) added with stirring.
  • the resulting suspension is cooled to 15C and dimethylcarbomethoxymethyl phosphonate (6.21 g., 6 X 6.1 meq.), prepared as described in Example 1 l, in benzene (10 ml) is added dropwise with stirring.
  • the product may be purified by column chromatography on silica gel.
  • the title compound is characterized by its infrared and its nuclear magnetic resonance spectra and the molecular weight is confirmed by mass spectroscopy; y 2 1717 and 1647 cm, 1 3 4.31 (singlet, 1H), 4.90 (broad unresolved multiplet, 2H), 6.30 (singlet, 3H), 7.5 8.2 (complex absorption with a prominent double peak at 7.80, 15H), 8.2 8.8 (complex absorption, 91-1); M/e 290.
  • EXAMPLE 14 In the same manner as described for Example 12, but using an equivalent amount of 9-cyclopentylidene-6- methyl-S-nonen-Z-one, 10-ethyl-6-methyltrideca-5,9- dien-2-one, 10-ethyl-6-methyltetradeca-5,9-dien- 2-one, 10-propyl-6-methyltrideca-5,9-dien-2-one, 10- propyl-6-methyltetradeca-5,9-dien-2-one and l0-butyl- 6-methyltetradeca-5,9-dien-2-one, prepared as described in Example 8; 9-cyclohexylidene-6-ethyl-5- nonen-2-one, 9-cyclopentylidene-6-ethyl-5 -nonen- 2-one, 6,lO-diethyldodeca-S,9-dien-2-one, 6,10- diethyltrideca-S,9-dien-2-one, 6,10-
  • methyl 10-cyclohexylidene-3,7-dimethyldeca2,6-dienoate (252 mg., 0.87 meq.) is dissolved in 40 ml of ether and cooled to 0C.
  • m- Chloroperbenzoic acid (166 mg. 0.96 meq.) in 20 ml. of ether is added and the solution mixed and then allowed to stand at 0C for 16 hours.
  • the mixture is diluted with water and extracted with ether.
  • the ether extract is washed with 5 percent sodium bicarbonate, dried over magnesium sulfate and evaporated to yield the crude title compound as an oil. Purification is effected as described above.
  • ethyl 10,1l-epoxy-3,7-dimethyl1l-ethyltrideca-2,6-dienoate may be obtained.

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Abstract

A process is disclosed herein for the preparation of hydrocarbon acid esters of formula,

IN WHICH R1 and R2 are alkyl groups containing two to four carbon atoms or R1 and R2 together are a polymethylene group containing four to five carbon atoms forming a cyclopentane or cyclohexane ring, R3, R4 and R5 are alkyl groups containing 1 - 2 carbon atoms and Z1 and Z2 together are a carbon-carbon double bond or an epoxide; whereby the appropriate ketone of formula R1R2C O is condensed with the ylid generated from either 4oxopentyl-1-triphenylphosphonium iodide ethylene ketal or 4oxohexyl-1-triphenylphosphonium iodide ethylene ketal, followed by acid treatment to remove the ketal, and yield the appropriate ketonic intermediate, which is treated successively with either of the preceding ylids and then acid treatment to yield a ketone of formula R1R2C CHCH2CH2CR3 CHCH2CH2COR4; the last said compound is then treated with the anion prepared from a dialkylcarbomethoxymethyl or a dialkylcarboethoxymethyl phosphonate to yield the hydrocarbon acid esters of the above formula in which Z1 and Z2 together are a carbon-carbon double bond, said last compounds are oxidized to yield the hydrocarbon acid esters of the above formula in which Z1 and Z2 together are an epoxide. The hydrocarbon acid esters of this invention are useful for the control of insect populations and methods for their formulation and use for this purpose are given.

Description

United States Patent Findlay Sept. 25, 1973 EPOXIDIZED I-IYDROCARBON ACID ESTERS HAVING JUVENILE HORMONE ACTIVITY [76] Inventor: John A. Findlay, 682 George St.,
Fredericton, New Brunswick, Canada [22] Filedi Aug. 4, I971 [21] Appl. No.: 169,126
[30] Foreign Application Priority Data Oct. [3, 1970 Canada .r 095,437
[52] US. Cl. 260/348 A, 260/4109, 260/3485 L,
260/348.6, 424/278, 424/305, 424/DIG. l2 [Sl] Int. Cl C07d 1/22 [58] Field of Search 260/348 A Primary ExaminerNorma S. Milestone Attorney-Vito Victor Bellino et al.
[57] ABSTRACT A process is disclosed herein for the preparation of hydrocarbon acid esters of formula,
YW R! in which R and R are alkyl groups containing two to four carbon atoms or R and R together are a poly methylene group containing four to five carbon atoms forming a cyclopentane or cyclohexane ring, R R and R are alkyl groups containing 1 2 carbon atoms and Z and Z together are a carbon-carbon double bond or an epoxide; whereby the appropriate ketone of formula RR C O is condensed with the ylid generated from either 4-oxopentyll -triphenylphosphonium iodide ethylene ketal or 4-oxohexyl-l-triphenylphosphonium iodide ethylene ketal, followed by acid treatment to remove the ketal, and yield the appropriate ketonic intermediate, which is treated successively with either of the preceding ylids and then acid treatment to yield a ketone of formula RR C CHCI-I CI-I CR CHCH CH COR"; the last said compound is then treated with the anion prepared from a dialkylcarbomethoxymethyl or a dialkylcarboethoxymethyl phosphonate to yield the hydrocarbon acid esters of the above formula in which Z and Z together are a carbon-carbon double bond, said last compounds are oxidized to yield the hydrocarbon acid esters of the above formula in which Z and Z together are an epoxide. The hydrocarbon acid esters of this invention are useful for the control of insect populations and methods for their formulation and use for this purpose are given.
2 Claims, N0 Drawings EPOXIDIZED HYDROCARBON ACID ESTERS HAVING JUVENILE HORMONE ACTIVITY In 1967, Roller et al., Angew. Chem. lnternat. Edn., 6, 179 (1967), reported the elucidation of the major component of the extract ofjuvenile hormone from the giant silkworm moth. The structure of this component was established as methyl l-epoxy-7-ethyl-3,1ldimethyl-Z,6-tridecadienoate. This event has sparked an intensive investigation of the chemistry, biochemistry and biological properties ofjuvenile hormone in recent years.
Juvenile hormone appears to control egg ripening and the normal development of the sexually mature insect from the larva. 1n the normal life cycle of the insect, the juvenile hormone must be present at the stage of the immature larva if it is to progress through the normal stages of larval development. However, the juvenile hormone must be absent if the mature larva is to metamorphose into the sexually mature insect. Presence of the juvenile hormone at this point in the development of the insect will prevent the emergence of the sexually mature form capable of reproduction, and contact of the eggs with the juvenile hormone will prevent normal embryonic development. These facts are of great importance in the control of insect populations.
To date a variety of natureal and synthetic compounds have been shown to possess juvenile hormone activity, for example; farnesol, juvabione and methyl 7 ,12-dich1oro-3 ,7 ,12-trimethyldodec-Z-enoate, see C.E. Berkoff, The Chemistry and Biochemistry of Insect Hormones", Quarterly Reviews (The Chemical Society), 23, 372 (1969). However, many of these other compounds are not suitable for the practical control of insect population since they have, in addition, undesirable features such as low potency, complex methods of preparation, or toxic effects to other species.
It is the object of this invention to disclose a simple and efficient process for preparing hydrocarbon acid esters exhibiting potent juvenile hormone activity. These hydrocarbon acid esters possess a very low order of toxicity to species other than insects.
More specifically, this invention relates to a facile preparation of unsaturated hydrocarbon acid esters containing 18 to 25 carbon atoms which may be represented by formula I;
m poow m R l in which R and R represent alkyl groups containing from two to four carbon atoms or R and R together represent a polymethylene radical containing four to five carbon atoms which in conjunction with the carbon atom 11 to which they are bonded form a cyclopentane or cyclohexane ring, respectively; R, R and R represent alkyl groups containing one to two carbon atoms and Z and Z together represent a carboncarbon double bond between carbon atoms and 11 or an epoxide.
Certain intermediates and products of this invention are also included in this invention.
The compounds of formula I of the process of this invention exhibit the biological activities of the juvenile hormone and are useful as means for controlling insect populations. More particularly, these compounds, when tested in standard pharmacological tests used in entomology, for example in the modified Tenebrio test described by Roller et al., in Life Sci., Vol. 4, p. 1617 (1965), exhibit the useful activity of the juvenile hormone. When administered to the test insects in the manner described by Roller et al., cited above, the compounds of this invention of formula 1 cause the formation of typical pupal cuticle over the area of deposition.
For purposes of controlling insect populations, the compounds of this invention of formula I may be formulated in the form of liquid sprays, in solution in suitable solvents such as lipophilic solvents, for example vegetable or mineral oils, or hydrocarbon solvents, or solvents which have both lipophilic or hydrophilic characteristics, for example, lower aliphatic ketones or polyhydric alcohols; or they may be dissolved in a lipophilic solvent such as exemplified above and may be formulated in the form of aqueous emulsions together with suitable surface'active agents such as emulsifiers and/or detergents, and other suitable excipients. They may also be formulated in the form of dusting powders together with suitable solid excipients. Such preparations may contain from 0.1 to mg. of the active ingredient per liter of liquid or per kilogram of solid preparation, and may be applied to areas or to the plants infested by the insects which are to be controlled, by means of sprayingor dusting in the usual manner for controlling insect populations.
According to the process of this invention the hydrocarbon aced esters of formula l may be prepared in the following manner:
The starting materials for the process of the invention are the simple ketones of formula RRC 0 (II), in which R and R are as defined above. Most of these simple ketones are commercially available; the remaining starting materials are prepared by conventional methods. Such conventional methods for preparing ketones and aldehydes are described in textbooks on organic chemistry; for example, see P. Karrer, Organic Chemistry, 2nd ed., Elsevier Publishing Co., Inc., New York, 1946, pp. 149-169 and V. Migrdichian, Organic Synthesis," Vol. 1, Reinhold Publishing Corp., New York, 1957, pp. 100-129.
Condensation of the simple ketones of formula 11 with the ylid generated from either 4-oxopentyl-l-triphenylphosphonium iodide or 4-exehexyl-l-triphenylphosphonium iodide, see Example 1 for preparation, followed by acid treatment, yields the ketone intermediates of formula [II in which R and R are as defined above and R is methyl or ethyl, respectively. The latter compounds are in turn condensed again with either of the above ylids followed by acid treatment to yield the dienone derivative of formula IV in which R, R and R are as described above and R is either methyl or ethyl depending on whether the ylid from 4-oxopentyll-triphenylphosphonium iodide or 4-oxohexyl-1-triphenylphosphonium iodide is used, respectively.
The latter dienones of formula IV are then treated with the anion prepared from a dialkylcarbomethoxymethyl or a dialkylcarbethoxymethyl phosphonate containing from 1 4 carbon atoms in the alkyl groups. The latter compounds are conveniently prepared from methyl or ethyl chloroacetate and the appropriate tiralkyl phosphite in which the alkyl group contains from 1 4 carbon atoms each, and the anion is prepared therefrom by means of an alkali metal alkoxide containing from 1 4 carbon atoms or an alkali metal hydride. There are obtained the hydrocarbon acid methyl, or ethyl, esters of formula I in which R, R R and R are as defined above, R is methyl or ethyl, respectively, and Z and Z together represent a carbon-carbon double bond between carbon atoms and 11.
The latter compounds are converted to the corresponding epoxides, the hydrocarbon acid esters of formula l in which R, R R, R and R are as defined in the first instance and Z and Z together represent an epoxide, by treatment with either a reagent selected from the group, N-bromoand N-chloro-succinimide and N-bromoand N-chloroacetamide, followed by treatment with an alkali metal alkoxide containing 1 4 carbon atoms, or by treatment with an organic peracid.
It will be apparent to those skilled in the art that the compounds of this invention are capable of existing in many isomeric forms. This invention is not concerned with separating such isomers, although means for such separations are obvious to those skilled in the art.
The principal advantage of the process of this invention is the fact that it proceeds from commercially available starting material to the desired final products in good yields and via a pathway involving relatively few steps. In view of the great importance of compounds possessing juvenile hormone activity as means for controlling insect populations, a partically useful process of preparation of such compounds, as described more fully in the following sections, is especially advantageous.
First, 4-oxopentyl-l-triphenylphosphonium iodide ethylene ketal is prepared by treating commercially avaiable 5-chloro-2-pentanone in a solvent with a molar excess of sodium iodide, to obtain the corresponding 5-iodo-2-pentanone. Preferred conditions for this reaction include the use of three equivalents of sodium iodide and of acetone as the solvent, and relfluxing for 0.5 to 2 hours.
5-lodo-2-pentanone thus obtained is ketalized by treatment in a waterimmiscible solvent with a molar excess of ethylene glycol in the presence of small amounts of an acid catalyst, removing water from the reaction mixture as it is being formed. Preferred reaction conditions include the use of three equivalents of ethylene glycol, 0.1 equivalent of p-toluenesulfonic acid, benzene as the solvent, and a water-separating device as part of the equipment. Refluxing the mixture for periods of time of from 8 to 24 hours yields 5-iodo-2- pentanone ethylene ketal.
Said last-named compound is treated with a molar excess of triphenylphosphine at a temperature within the range of from 50 to 150C in an inert solvent to yield 4-oxopentyl-l-triphenylphosphonium idoide ethylene ketal. Preferred reaction conditions include the use of 1.1 equivalents of triphenylphosphine and of benzene as the solvent, and carrying out the reaction at the reflux temperature of the mixture, whereupon the desired compound crystallizes from the reaction mixture in a sufficiently pure state for immediate use.
In a similar manner, 4-oxohexyl-l-triphenylphosphonium iodide ethylene ketal is prepared except that 6-chloro-3-hexanone is used instead of 5-chloro-2- pentanone.
The 4-oxopentyl-b l-triphenylphosphonium iodide ethylene ketal or 4-oxohexyl-l-triphenylphosphonium iodide ethylene ketal, thus prepared, may be converted to their corresponding ylids by treatment with a alkali metal alkoxide containing from one to five carbon atoms or an alkali metal hydride in a common solvent. Subsequent condensation of the appropriate ylid with a ketone of formula II described above, yields the ketone intermediates of formula III, described above, after acid treatment. I have found it convenient to perform this condensation by preparing the ylid in situ in dimethylsufloxide solution by first adding approximately one molar equivalent of sodium hydride to an excess of the solvent, dimethylsulfoxide, to form the sodium methylsulfinyl carbanion. Subsequent addition of a solution of 4-oxopentyl-l-triphenylphosphonium iodide ethylene ketal or 4-oxohexyl-l-triphenylphosphonium iodide ethylene ketal in dimethylsulfoxide, under nitrogen at a temperature within the range of from 1535C, and stirring for a period of time of from 5-30 minutes yields the desired ylid. To this solution of the ylid thus obtained there are added 0.5 1.2 molar equivalents, preferably 0.1 molar equivalents, of the appropriate ketone of formula II, and the mixture is stirred at temperatures of from 20C to the boiling point of the mixture for periods of time of from 15 minutes to 24 hours. Dilution with water, extractions with a water-immiscible solvent, preferably n-pentane, and evaporation of the solvent yields a residue, the ethylene ketal of the ketone intermediate of formula III. The latter compound is preferably not isolated, but the residue obtained as described above is treated in an inert solvent, preferably tetrahydrofuran, with an acid, preferably dilute aqueous hydrochloric acid. In this manner the ketal group is removed and there is obtained the ketone intermediate of formula III.
The next step of this process, the conversion of the ketone intermediate of formula III to the dienone derivative of formula IV, may be accomplished in the same manner as above described conversion of the ketones of formula ll to the ketone intermediates of formula III except that an equivalent amount of the ketone intermediate of fomrula III is used instead of the ketone of formula II. Furthermore, I have found that the above preferred conditions relating to the previous step of the process I] Ill apply equally well to this present step, "I IV, including the conditions for the acid treatment to remove the ketal group from the resulting ethylene ketal derivative.
The dienone derivative of formula IV, thus obtained, is treated with the anion prepared from a dialkylcarbomethoxymethyl or a dialkylcarbethoxymethyl phosphonate, preferably dimethylcarbomethoxymethyl phosphonate, obtained from methyl chloroacetate and trimethyl phosphite according to the method described by PC. Crofts in Quart. Rev. Chem. Soc., 12, 341 (1958) by the action of approximately an equivalent amount of an alkali metal hydride in an inert solvent or by the action of an approximately equivalent amount of an appropriate alkali metal alkoxide containing from one to four carbon atoms in an inert solvent. This anion formation is performed preferably by mixing equivalent molar amounts of the appropriate dialkylcarbomethoxymethyl or dialkylcarbethoxymethyl phosphonate, preferably dimethylcarbomethoxymethyl phosphonate,
with sodium hydride in benzene, stirring the reaction mixture at a temperature of from C to the boiling point of the mixture until the sodium hydride dissolves in the reaction mixture. The alkyl groups in the above compounds contain from 1 4 carbon atoms.
Addition of the appropriate dienone derivative of formula IV, described above, to the prepared solution of one of the above anions yields the corresponding methyl or ethyl ester of formula l in which R, R R, R are as defined in the first instance, R is methyl or ethyl respectively and Z and Z together represent a carbon-carbon double bond between carbon atoms 10 and 11.
Preferred conditions in the above reaction include agitating the reaction mixture at temperatures of from 10C to the boiling point of the mixture for periods of time of from 8 hours to 6 days, dilution with water, extraction with a water-immiscible solvent, and purification by chromatography, preferably on silica gel.
Treatment of the latter compounds of formula I with 0.7 to 1.3 molar equivalents of N-bromoor N- chlorosuccinimide or N-bromoor N-chrloacetamide in solution in a mixture of 1.5 to 4 parts of dimethoxyethane and 1 part of water, followed by treatment of the reaction product with a molar excess of an alkali metal alkoxide containing 1 4 carbon atoms, all reactions being carried out at temperatures of from 10C to 10C, for to 120 minutes in a manner similar to that described by Corey et al., J. Am. Chem. Soc., 90, 5618 (1968), afford the hydrocarbon acid esters of formula l in which RR, R R? and R are as defined in the first instance Z and Z together represent an epoxide. Preferred reaction conditions include the use of 1.1 equivalents of N-bromosuccinimide, of a 3:2 mixture of dimethoxyethane and water as solvent, of 1.1 equivalents of sodium methoxide, of reaction temperatures close to 0C, and of reaction times of 30 to 60 minutes. The desired hydrocarbon acid esters of formula l thus obtained may be purified, preferably by chromatography on silica gel or on alumina.
Alternatively, the above compounds of formula 1 in which Z and Z are a carbon-carbon double bond may be treated with at least one molar equivalent of an organic peracid in an inert solvent at temperatures of from 20C to 20C., from 2 hours to 2 days in a manner similar to that described by K.l-l. Dahm, et al., J. I
Am. Chem. Soc., 89, 5292 (1967). In this manner the hydrocarbon acid esters of formula 1, in which R, R R, R and R are as defined in the first instance and Z and Z together represent an epoxide, are also obtained. Preferred conditions include the use of 1.1 equivalents of perbenzoic or m-chloroperbenzoic acid, ether as solvent, a reaction temperature of 0C and a reaction time of 16 hours. Purification of the desired hydrocarbon acids esters may be effected as described above.
The following formulae, in which R, R R, R, R Z and Z are as defined in the first instance, and Examples are illustrative of this invention.
EXAMPLE 1 l. 4OXOPENTYL-l-TRIPHENYLPHOSPHONlUM IODIDE ETHYLENE KETAL A. 5-Iodo-2-pentanone Commerical 5-chloro-2-pentanone (4.82 g, 0.04 mole) and sodium iodide (180.0 g, 0.12 mole) are dissolved in ml acetone and refluxed for 1 hour. The acetone is evaporated, the residue dissolved in water and extracted twice with ether. The combined ether phases are washed with 0.1 N sodium thiosulfate to remove free iodine, dried over anhydrous magnesium sulfate, filtered, and evaporated, to yield the title compound as a light yellow liquid, y S 2955, 1710 cm 1 3 6.81, 7.44,7.87, 8.00. A sample is purified by distillation to b.p. 94C/14 mm Hg, but partial decomposition occurs during distillation and the bulk of the material is used without purification in the subsequent step.
In one such experiment the yield obtained was 58 per cent of theory. B. 5-lodo-2-pentanone Ethylene Ketal 5-lodo-2-pentanone (68 g, 0.32 mole), obtained as described above, p-toluenesulfonic acid (6.1 g, 0.032 mole), and ethylene glycol (51.8 g, 0.96 mole) are refluxed together with 800 ml benzene in an apparatus equipped with a water separator for 24 hours. The reaction mixture is cooled, diluted with 1,250 ml 5 percent sodium bicarbonate solution, and extracted twice with 625 ml portions of ether. The combined ether extracts are washed with 400 ml. 0.1N sodium thiosulfate to remove excess iodine, dried over soidum sulfate, filtered, evaporated, and the residue is distilled under reduced pressure, to yield the title compound with b.p. 76C/0.05 mm Hg, y ii 2955, 1375, 1115 cm", 'r '3 6.06, 6.75, 8.21, 8.69. C. 4-Oxopentyl-1-tripheny1phosph0nium lodide Ethylene Ketal Triphenylphosphine (11.2 g, 0.0429 mole) is dissolved in 35 ml benzene and 10 ml benzene are distilled off to remove traces of water. 5-lodo-2-pentanone ethylene ketal 10.0 g, 0.039 mole), obtained as described above, is added and the mixture is refluxed for 1 hour. The title compound crystallizes from the reaction mixture, is filtered off and washed with dry ether, m.p. 210215C, y B 1435, 1110 cm. 2. 4-OXOl-1EXYL-l-TRlPl-lENYLPl-IOSPHONIUM lODlDE ETHYLENE KETAL Following the procedures A, B and C of Example 1, part 1, but using an equivalent amount of 6-chloro-3- hexanone, described by B. Helferich and V. Bollert, Chem. Ber., 94, 505 (1961), instead of 5-chloro-2- pentanone, 4-oxohexyl-1-triphenylphosphonium iodide ethylene ketal may be obtained.
EXAMPLE 2 R and R ample I, is added followed by 15 ml of dimethylsulfoxide and the mixture stirred for minutes, forming the corresponding ylid of the phosphonium salt. Then, cyclohexanone (0.98 g., 10 meq.) in 9 ml. of dimethylsulfoxide is added over a period of 10 minutes and the mixture stirred for 1 hours at 6070C. After cooling to 220 C, the reaction mixuture is poured into 200 ml of water and extracted with pentane (100 50 50 50 ml.). The pentane extract is washed with water (3 X 50 ml.), dried over magnesium sulfate and evaporated at room temperature under vacuum, yielding an oil. The oil is dissolved in tetrahydrofuran (TI-IF) (20 ml) and treated with aqueous hydrochloric acid (20 ml. of IN soln.) overnight (14 hr.) at room temperature with stirring. After evaporation of the TI-IF under reduced pressure at room temperature, the aqueous mixture is extracted with ether (20 I5 ml.), and the ether extract washed with water to neutrality, dried over magnesium sulfate and evaporated at room temperature under reduced pressure to yield the title compound, y f 2 l7l9 cm, 73 4.97 (broad unresolved triplet, IH), 7.3 8.2 (complex absorption, 8H 7.87 (singlet, 3H), 8.3 8.7 (broad band, 6H), and the mass spectrum displayed a molecular ion at M/e 166. This product is suitable for the next step, see Example 6. In one experiment performed according to this procedure the yield was 80 percent based on cyclohexanone.
EXAMPLE 3 6-ETI-IYL-5 -OCTEN-2ONE (III; R and R C I-I, and R CH By following the procedure of Example 2 but using an equivalent amount of 3-pentanone instead of cyclohexanone, there is obtained the title compound; 1' 4.97 (broad unresolved triplet, 1H), 7.2 8.3 (complex absorption, 8H), 7.85 (singlet, 3H), 9.03 (triplet, 6H, J II cps); mass spectrum displayed a molecular ion at M/e I54.
EXAMPLE 4 In the same manner as described for Example 2 but using an equivalent amount of cyclopentanone, 3- hexanone, 3-heptanone, 4-heptanone, 4-octanone or 5-nonanone, there may be obtained, 5-cyclopentylidenepentan-Z-one, 6ethyl-5-nonen-2-one, 6-ethyl-5- decen-2-one, 6-propyl-5-nonen-2-one, 6-propyl-5- decen-Z-one and 6-butyl-5-decen-2-one, respectively.
EXAMPLE 5 In the same manner as described for Example 2, but using an equivalent amount of 4-oxohexyl-I-triphenylphosphonium iodide ethylene ketal instead of 4- oxopentyl-l-triphenylphosphonium iodide and one of the appropriate ketones of formula II, cyclohexanone, cyclopentanone, 3-pentanone, 3-hexanone, 3- heptanone, 4-heptanone, 4-octanone or S-nonanone, there may be obtained the ketone intermediates of formula III, 6-cyclohexylidenehexan-3-one, 6- cyclopentylidenehexan-3-one, 7 -ethyl-6-nonen-3-one, 7-ethyl-6-decen-3-one, 7-ethyI-6-undecen-3-one, 7-propyl-6-decen-3-one, 7-propyl-6-undecen-3-one and 7-butyl-6-undecen-3-one, respectively.
EXAMPLE 6 9-CYCLOHEXYLIDENE-6-METHYL-5-NONEN- 2-ONE (IV; R and R together (CH R and R each CH The corresponding ylid of 4-oxopentyl-I-triphenylphosphonium iodide ethylene ketal is prepared in the same manner as described in Example 2, using 0.54 g of the 57 percent oil dispersion of sodium hydride and 5.85 g. of the phosphonium salt. To the thus prepared ylid, 5-cyclohexylidenepentan-Z-one (1.42 g, 8.6 meq.- prepared as described in Example 2, is added instead of cyclohexanone and the reaction is performed under the same conditions as described for Example 2. Following the deketalization step with hydrochloric acid in THF and subsequent working-up according to the description in Example 2, there is obtained the title product as an oil; 'y Z l7l9 cm, T 'S 4.93 (broad unresolved multiplet, 2H), 7.4 8.1 (complex absorption, 12H), 7.87 (singlet, 3H), 8.2 8.7 (complex absorption, 9H). The mass spectrum displayed a molecular ion at M/e 234. This product is suitable for the next step, see Example 12.
In one experiment performed according to this procedure the yield was 76 percent of theory based on 5- cyclohexylidenepentan-Z-one.
EXAMPLE 7 l0-ETHYL-6-METHYLDODECA-5,9-DIEN-2-ONE (IV; R and R C H and R and R CH;,)
By following the procedure of Example 6 but using an equivalent amount of 6-ethyl-5-octen-2-one, prepared as described in Example 3, instead of 5- cyclohexylidenepentan-2-one, there is obtained the title compound; y Z 1719 cm, 13 4.93 (broad unresolved multiplet, 2H), 7.4 8.2 (complex absorption, 12H, 7.87 (singlet, 3H), 8.3 and 8.4 (two broad singlets, partially superimposed, 3H), 9.03 (triplet, 6H, J= l2 c.p.s.). The mass spectrum displayed a molecularion at M/e 222.
EXAMPLE 8 In the same manner as described for Example 6, but using an equivalent amount of 5-cyclopentylidenepentan-2-one, 6-ethyl-5-nonen-2-one, 6-ethyl-5-decen- 2-one, 6-propyl-5-nonen-2-one, 6-propyl-5-decen- 2-one or 6-butyl-5-decen-2-one, prepared as described in Example 4, there may be obtained the dienone derivatives of formula IV, 9-cyclopentylidene-6-methyl-5- nonen-Z-one, l0-ethyl-6-methyltrideca-5,9-dien-2-one, l0-ethyl-6-methyltetradeca-5,9-dien-2-one, l0-propyl- 6-methyltrideca-5,9-dien-2-one, lO-propyl-6- methyltetradeca-S,9-dien-2-one and l0-butyl-6- methyltetradeca-S,9-dien-2-one, respectively.
EXAMPLE 9 In the same manner as described for Example 6, but using an equivalent amount of 6- cyclohexylidenehexan-3-one, 6-
cyclopentylidenehexan-3-one, 7-ethyl-6-nonen-3-one, 7-ethyI-6-decen-3-one, 7-ethyl-6-undecen-3-one, 7-propyl-6-decen-3-one, 7-propyl-6-undecen-3-one or 7-butyl-6-undecen-3-one, prepared as described in Example 5, instead of 5-cyclohexylidenepentan-Z-one,
there may be obtained the dienone derivatives of formula IV, 9-cyclohexylidene-6-ethyl-5-nonen-2-one, 9- cyclopentylidene-6-ethyl-5-nonen-2-one, 6,10-diethyldodeca-5,9-dien-2-one, 6,10-diethyltrideca-S,9-dien- 2-one, 6,10-diethyl-tetradeca-S,9-dien-2-one, 6-ethyllO-propyltrideca-S,9-dien-2-one, 6-ethyl-lO-propyltetradeca-5,9-dien-2-one and lO-butyl-6-ethyltetradeca- 5,9-dien-2-one, respectively.
EXAMPLE 10 methylpentadeca-6, l -dien-3-one, 1 1-propyl-7- methyltetradeca-6,l0-dien-3one, l l-propyl-7- methylpentadeca-6, l O-dien-3-one and 1 1-butyl-7- methylpentadeca-6,l0-dien-3-one; cyclohexylidene-7-ethyl-6-decen-3-one, 10-
cyclopentylidene-7-ethyl-6-decen-3-one, 7,11-diethyltrideca-6,l0-dien-3-one, 7,1l-diethyltetradeca-6,10- dien-3-one, 7,1 1-diethylpentadeca-6,10-dien-3one, 7-ethyl-1 l-propyltetradeca-6,10-dien-3-one, 7-ethyl- 1l'propylpentadeca-,10-dien-3-one and l1-butyl-7- ethylpentadeca-6,10-dien-3-one, respectively.
EXAMPLE ll DIMETHYLCARBOMETl-IOXYMETHYL PHONATE Following the general procedure described by PC. Crofts in Quart. Rev. Chem. Soc., Vol. 12, p. 341 (1958), methyl chloroacetate (1.9 g.) and trimethyl phosphite (16.6 g) are heated together at 160C bath temperature overnight, and the reaction mixture is distilled under reduced pressure to yield the title compound with with hp. 110-135C/35 mm, y f 3 3000, 2900, 1755 cm", T S 6.1, 6.3, 6.8, 7.2. In one experiment carried out according to the above procedure the yield was 42.5 percent of theory.
In the same manner, but using ethyl chloroacetate as starting material, dimethylcarbethoxymethyl phosphonate is obtained.
PHOS- EXAMPLE 12 METHYL-10-CYCLOHEXYLIDENE-3,7- DIMETHYLDECA-2,6-DIENOATE (I, R and R together (CH,) R, R and R each CB and Z and Z together double bond) Sodium hydrode (1.54 g of 57 percent mineral oil dispersion) is washed with pentane 20+10+10 ml) and benzene ml) added with stirring. The resulting suspension is cooled to 15C and dimethylcarbomethoxymethyl phosphonate (6.21 g., 6 X 6.1 meq.), prepared as described in Example 1 l, in benzene (10 ml) is added dropwise with stirring. When the evolution of hydrogen ceases, 9-cyclohexylidene-6-methyl-5- nonen-2-one (1.43 g., 6.1 meq.), prepared as described in Example 6, is added and the mixture refluxed overnight. After cooling the solution is washed with dilute hydrochloric acid (1N), aqueous sodium bicarbonate (0.05 M), water and then dried over magnesium sulphate and evaporated yielding the title compound as a light yellow oil, which on thin layer chromatography (TLC) showed no appreciable amount of starting ketone of formula IV (R and R =--(CH R and R CH This oily product was suitable for the next step, see Example 15.
The product may be purified by column chromatography on silica gel. The title compound is characterized by its infrared and its nuclear magnetic resonance spectra and the molecular weight is confirmed by mass spectroscopy; y 2 1717 and 1647 cm, 1 3 4.31 (singlet, 1H), 4.90 (broad unresolved multiplet, 2H), 6.30 (singlet, 3H), 7.5 8.2 (complex absorption with a prominent double peak at 7.80, 15H), 8.2 8.8 (complex absorption, 91-1); M/e 290.
In one experiment performed according to the above procedure the yield was 94 percent of theory based on 9-cyclohexylidene-6-methyl-5-nonen-2-one.
In the same manner, but using dimethylcarboethoxymethyl phosphonate instead of dimethylcarbomethoxymethyl phosphonate, ethyl l0-cyclohexylidene-3,7- dimethyldeca-2,6-dienoate is obtained.
EXAMPLE 13 METHYL 3,7-DIMETHYL-l l-ETHYLTRIDECA- 2,6,10-TRIENOATE (I; R and R C 11 R R and R CH and Z and Z together double bond) By following the procedure of Example 13 but using an equivalent amount of 10-ethyl-6-methyldodeca-5,9- dien-2-one, prepared as described in Example 7, instead of 9-cyclohexylidene-6-methyl-5-nonen-2-one, there is obtained the title compound; y 2 1717 and 1647 cm, 1 3 4.33 (singlet, 1H), 4.91 (broad unresolved multiplet, 2H), 6.33 (singlet, 31-1), 7.5 8.2 (complex absorption with a prominent double peak at 7.83 and 7.86, 1511), 8.30 and 8.38 (two broad singlets, 3H), 9.03 (triplet, 6H, J= ll cps); M/e 278.
In the same manner, but using dimethylcarboethoxymethyl phosphonate instead of dimethylcarbomethoxymethyl phosphonate, ethyl 3,7-dimethyl-l l-ethyltrideca-2,6,l0-trienoate is obtained.
EXAMPLE 14 In the same manner as described for Example 12, but using an equivalent amount of 9-cyclopentylidene-6- methyl-S-nonen-Z-one, 10-ethyl-6-methyltrideca-5,9- dien-2-one, 10-ethyl-6-methyltetradeca-5,9-dien- 2-one, 10-propyl-6-methyltrideca-5,9-dien-2-one, 10- propyl-6-methyltetradeca-5,9-dien-2-one and l0-butyl- 6-methyltetradeca-5,9-dien-2-one, prepared as described in Example 8; 9-cyclohexylidene-6-ethyl-5- nonen-2-one, 9-cyclopentylidene-6-ethyl-5 -nonen- 2-one, 6,lO-diethyldodeca-S,9-dien-2-one, 6,10- diethyltrideca-S,9-dien-2-one, 6,10-diethyltetradeca- 5,9-dien-2-one, 6-ethyl-lO-propyltrideca-S,9-dien- 2-one, 6-ethyl-lO-propyltetradeca-S,9-dien-2-one, lbutyl-6-ethyltetradeca-5,9-dien-2-one, prepared as described in Example 9 or lO-cyclohexylidene-7-methyl- 6-decen-3-one; l l-ethyl-7-methyltrideca-6,10-dien- 3-one; l0-cyclopentylidene-7-methyl-6-decen-3-one, l l-ethyl-7-methyltetradeca-6,l0-dien-3-one, ll-ethyl- 7-methylpentadeca-6,l0-dien-3-one,
ll-propyl-7-methyltetradeca-6,l0-dien-3-one,l lpropyl-7-methylpentadeca-6,l0-dien-3-one and butyl-7-methylpentadeca-6,10-dien-3-one; 10- cyclohexylidene-7-ethyl-6-decen-3-one, l0- cyclopentylidene-7-ethyl-6-decen-3-one, 7,1l-diethyltrideca-6,l0-dien-3-one, 7,1l-diethyltetradeca-6,l0- dien-3-one, 7,1l-diethylpentadeca-6,10-dien-3-one,7- ethyl-l 1-propyltetradeca-6,10-dien-3-one, 7-ethyl-1 lpropylpentadeca-6,10-dien-3-one and 11-butyl-7- ethylpentadeca-6,10-dien-3-one, prepared as described in Example 10, instead of 9-cyclohexylidene-6-methyl -nonen-2-one and using either dimethylcarbomethoxymethyl phosphonate or dimethylcarboethoxymethyl phosphonate depending on whether the methyl or ethyl ester is desired, there may be obtained the hydrocarbon acid methyl and ethyl esters of formula 1, methyl and ethyl l0-cyclopentylidene-3,7-dimethyldeca-2,6- dienoate, 3,7-dimethyl l l-ethyltetradeca-2,6,10- trienoate 3,7-dimethyl-l l-ethylpentadeca-2,6,l0- trienoate, 3,7-dimethyl-1 l-propyltetradeca-2,6,10- trienoate, 3,7-dimethyl-l l-propylpentadeca-2,6,l0- trienoate, l l-butyl-3,7-dimethyIpentadeca-2,6,l0- trienoate, l0-cyclohexylidene-7-ethyl-3-methyldeca- 2,6-dienoate, deca-2,6-dienoate,
EXAMPLE l5 METHYL 3,7-DlMETHYL-9-( l-OXASPIRO[2.5 OCT-2YL)-2,6-NONADIENOATE l; R and R together -(CH,),-, R, R and R CH and Z and 2 together are an epoxide) Methyl l0-cyclohexylidene-3,7-dimethyldeca-2,6- dienoate (252 mg, 0.87 meq.), prepared as described in Example 12, is dissolved in 15 ml of dimethoxyethane and ml of water. N-Bromosuccinimide (170 mg., 0.96 meq.) is added and the mixture stirred for 1 hour. Extraction with ether (3 X 10 ml), followed by washing with dilute hydrochloric acid (5 ml of l percent), water (2 X 5 ml.), drying over magnesium sulfate and evaporation affords a clear yellow oil.
This crude product is dissolved in absolute methanol (15 ml), cooled to 0C and treated with sodium methoxide (72 mg). After stirring at 0C for one-half hour the solvent is evaporated under reduced pressure, water (10 ml) and ether (10 ml) added, the ethereal layer decanted and the aqueous layer extracted with ether 10 ml.). The joined ethereal extracts are washed with water, dried over magnesium sulfate, and the solvent evaporated to yield an oil which was subjected to preparative TCL on silica gel developing with chloroform. Elution of zones gives the title compound and starting triene ester, methyl l0-cyclohexylidene-3,7- dimethyldeca-2,6-dienoate. The title compound is characterized by its infrared and nuclear magnetic resonance spectra, and the molecular weight of the product is confirmed by mass spectroscopy: 'y Z 1717 and 1647 cm, T '3 4.30 (singlet, 1H), 4.83 (unresolved multiplet, 1H), 6.30 (singlet, 3H), 7.31 (triplet, J= c.p.s.), 7.6-8.1 (complex absorption with two very close singlets at 7.83 and 7.86 (9H), 8.2 8.8 (complex absorption, 15H); M/e 306.
In one experiment performed according to this procedure the yield was 43 percent of theory based on the starting triene ester and 20 percent of the starting triene ester was recovered.
Alternatively, methyl 10-cyclohexylidene-3,7-dimethyldeca2,6-dienoate (252 mg., 0.87 meq.) is dissolved in 40 ml of ether and cooled to 0C. m- Chloroperbenzoic acid (166 mg. 0.96 meq.) in 20 ml. of ether is added and the solution mixed and then allowed to stand at 0C for 16 hours. The mixture is diluted with water and extracted with ether. The ether extract is washed with 5 percent sodium bicarbonate, dried over magnesium sulfate and evaporated to yield the crude title compound as an oil. Purification is effected as described above.
In the same manner, but using an equivalent amount of ethyl 10cyclohexylidene-3,7-dimethyldeca-2,6- dienoate instead of methyl l0-cyclohexylidene-3,7- dimethyldeca-2,6-dienoate, ethyl 3,7-dimethyl-9-(1- oxaspiro[2.5]-oct-2yl)-2,6-nonadienoate may be obtained.
EXAMPLE l6 METHYL 10,11-EPOXY-3,7-DlMETHYL-l l- ETHYLTRlDECA-2,6-D1ENOATE (l, R and B C,H R, R and R CH and Z and Z together.
are an epoxide) By following the procedure of Example 15 but using an equivalent amount of methyl 3,7-dimethyl-1 l-ethyltrideca-2,6,10-trienoate, prepared as described in Example 13, instead of methyl 10-cyclohexylidene-3,7- dimethyldeca-2,6-dienoate, there is obtained the title compound, 'y Z 1717 and 1647 cm; 73 4.33 (singlet, l H), 4.86 (unresolved multiplet, 1H),6.30(singlet, 3H), 7.30 (triplet, J= 9 c.p.s., 1H), 7.81 and 7.84 (two singlets superimposed to a broad band, 9H), 8.30/8.37 (central peaks of a broad unresolved multiplet, 6H), 8.48/8.60 (broad singlets, 3H), 8.87-9.30 (complex absorption, 6H); M/e 294.
In the same manner but using an equivalent amount of ethyl 3,7-dimethyl 11-ethyltrideca-2,6,lO-trienoate instead of the corresponding methyl ester described above, ethyl 10,1l-epoxy-3,7-dimethyl1l-ethyltrideca-2,6-dienoate may be obtained.
EXAMPLE 17' In the same manner as described for Example 15, but using an equivalent amount of the products, the hydrocarbon acid esters of formula I, listed respectively in Example 14, instead of methyl -cyclohexylidene-3,7- dimethyldeca-2,6-dienoate, there may be obtained the corresponding hydrocarbon acid methyl and ethyl esters of formula I, listed respectively below, in which Z and Z together represent a 10,11-epoxide:
Methyl and ethyl 3,7-dimethyl-9-(1-oxaspiro[2l4]- hept-2y1)-2,6-nonadienoate,
10,1 1-Epoxy-3,7-dimethy1-l l-ethyltetradeca-2,6-
10,1 1-Epoxy-7-ethy1-3-methyl-1 1 -propy1tetradeca- 2,6-dienoate,
10,1 1-Epoxy-7-ethyl-3-methyl-1 l-propylpentadeca- 2,6-dienoate,
10,1 l-Epoxy-l 1-buty1-7-ethy1-3-methylpentadeca- 2,6-dienoate,
3-Ethyl-7-methyl-9-( 1 -oxaspiro[2.5 ]-oct-2yl)-2,6-
- nonadienate,
3-Etl1yl-7-methyl-9-(1-oxaspiro[2.4]-hept-2yl)-2,6-
nonadienoate,
10,1 l-Epoxy-3,1 l-diethyl-7-methyltrideca-2,6-
dienoate,
l0,11-Epoxy-3,l1-diethyl-7'methyltetradeca-Z 6- dienoate,
10,11-Epoxy-3,11-diethy1-7-methylpentadeca-2.6-
dienoate,
10,1 l-Epoxy-3-ethyl-7-methyl-l l-propyltetradeca- 2,6-dienoate,
10,1l-Epoxy-3-ethyl-7-methyl-l1-propylpentadeca- 2,6-dienoate,
10,11-Epoxy-ll-butyl-3-ethyl-7-methylpentadeca- 2,6-dienoate,
3,7-diethyl-9-( l-oxaspiro[2.5 ]-oct-2yl)-2,6-
nonadienoate,
3,7-diethyl-9-(1-oxaspiro[2.4]-hept-2yl)-2,6-
nonadienoate,
10,1 l-Epoxy-3,7,l l-triethyltrideca-2,6-dienoate,
10,1 1-Epoxy-3,7,11-triethyltetradeca-2,6-dienoate,
10,1 l-Epoxy-3,7,l 1-triethylpentadeca-2,-dienoate,
10,1l-Epoxy-3,7-diethyl-1 1-propyltetradeca-2,6-
dienoate,
10,1 l-Epoxy-3,7-diethyl-l l-propylpentadeca-2,6-
dienoate and,
10,1l-Epoxy-l1-butyl-3,7-diethylpentadeca-2,6-
dienoate.
The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. Compounds of the formula COOR

Claims (1)

  1. 2. A compound as claimed in claim 1 wherein R1 and R2 together are a polymethylene radical containing five carbon atoms and wherein each of R3, R4 and R5 is methyl.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931257A (en) * 1973-08-24 1976-01-06 Hoffmann-La Roche Inc. Polyene compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931257A (en) * 1973-08-24 1976-01-06 Hoffmann-La Roche Inc. Polyene compounds

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