US3835192A - Precursor of sesquiterpine derivatives of the eremophilane group - Google Patents

Precursor of sesquiterpine derivatives of the eremophilane group Download PDF

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US3835192A
US3835192A US00154960A US15496071A US3835192A US 3835192 A US3835192 A US 3835192A US 00154960 A US00154960 A US 00154960A US 15496071 A US15496071 A US 15496071A US 3835192 A US3835192 A US 3835192A
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Der Linde L Van
J Witteveen
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/613Unsaturated compounds containing a keto groups being part of a ring polycyclic
    • C07C49/617Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system
    • C07C49/643Unsaturated compounds containing a keto groups being part of a ring polycyclic a keto group being part of a condensed ring system having three rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/40Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with ozone; by ozonolysis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation 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
    • C07C45/63Preparation 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation 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
    • C07C45/64Preparation 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 functional groups containing oxygen only in singly bound form
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation 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
    • C07C45/65Preparation 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 splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation 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
    • C07C45/65Preparation 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 splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C07C45/66Preparation 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 splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation 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
    • C07C45/67Preparation 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation 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
    • C07C45/67Preparation 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
    • C07C45/68Preparation 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
    • C07C45/70Preparation 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 with functional groups containing oxygen only in singly bound form
    • C07C45/71Preparation 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 with functional groups containing oxygen only in singly bound form being hydroxy groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation 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
    • C07C45/67Preparation 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
    • C07C45/68Preparation 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
    • C07C45/72Preparation 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
    • YGENERAL 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
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S585/00Chemistry of hydrocarbon compounds
    • Y10S585/929Special chemical considerations
    • Y10S585/947Terpene manufacture or recovery

Definitions

  • the invention relates to product and process for the preparation of sesquiterpene derivatives of the eremophilane group.
  • sesquiterpenes having an eremophilane skeleton are characterized by a bicyclo [4-4-0] decane structure, as shown in the formula of FIG. 1, with methyl substituents at the positions and 6, and a branched chain C substituent at the position 8.
  • the invention relates more particularly to those structures in which both methyl groups are disposed on the same side of the molecule (i.e., on the same side of a plane drawn through the carbons of the sixmembered rings), while the substituent at C is either disposed at the opposite side or connected with the C by means of a double bond.
  • Said group of compounds will be referred to hereinafter by the name of nootkatane group.
  • Valerianol occurs in the oil of Valeriana officinalis
  • a-Vetivone (formula of FIG. 3) is found in vetiver oil (from Vetiveria zizanoides)
  • nootkatone (formula of FIG. 4) is found in the oil of the Alaska yellow cedar (Chamaecyparis nootkatensis) and in a great number of citrus oils, specifically grapefruit oil (from Citrus paradisi).
  • Nardostachone (formula of FIG. 5) is a constituent of spikenard oil (from Nardostachis jatamansi).
  • Nootkatone (fonnula of FIG. 4) may be prepared by oxidation of valencene (formula of FIG. 6) with tertiary butyl chromate [cf. J. Food Sci., 30, 876 (1965)]. If (+)valencene is used as the starting material, it will yield optically active nootkatone which is dextrorotatory, as is the natural isomer, and has the absolute configuration which is shown in the formula of FIG. 4.
  • a disadvantage of the aforementioned method for the preparation of nootkatone is that valencene is not sufficiently commercially available in an economical way to warrant its use.
  • Nootkatone may also be prepared from nootkatene by a process consisting of various steps (see the Dutch Pat. Application No. 69,14545, laid open for public inspection), a substance which, in accordance with Acta Chim. Scand., 11, 1157 (1957), may be isolated from the wood of Chamaecyparis nootkatensis, giving a yield of about 0.25 percent.
  • the sesquiterpenes thus obtained are not optically active, but are mixtures of equal amounts of optical antipodes; for example, of (+)nootkatone (FIG. 4) and ()nootkatone (FIG. 7).
  • the compound having the formula of FIG. 8 is new. According to the invention it can be produced easily on a technical scale if methylpropenyl ketone (formula of FIG. 9), in accordance withthe reaction 1, is condensed with 2-methylsabina-ketone (formula of FIG. 10) under the influence of a strong base, such as sodium hydride or sodium amide.
  • a strong base such as sodium hydride or sodium amide.
  • sabinene is oxidized with a strong oxidizing agent, such as ozone, into sabina ketone having the formula of FIG. 12, and into this sabina ketone a methyl group is introduced in the activated a-position, for instance, by direct methylation with methyl iodide or dimethylsulphate, or by the introduction of a group which by means of reduction can be converted into a methyl group, such as a methylene group or a hydroxymethylene group (see reaction 2).
  • Sabina ketone may be prepared by means of a synthetic process as well [see J. Org. Chem, 33, 1656 (1968)].
  • optically active sesquiterpenes of the nootkatane series If the reaction 1 is carried out with optically active and dextrorotatory 2methyl-sabina ketone (which is derived from laevorotatory l-sabinene), there is obtained optically active and laevorotatory 5,6-dimethyl-8-isopropyltricyclo [4.4.0.0 l-decene-3-one having the absolute configuration, as shown in the formula of FIG. 13.
  • the compound having the formula of FIG. 8 is treated with acid, as described in the examples.
  • Compounds having a carbon skeleton, as in the formula of FIG. 1, representing the desired configuration are formed upon opening of the cyclopropane ring. This process is shown in the reaction scheme 3, if dextrorotatory 5,6-dimethyl-8-isopropyl-tricyclo [4.4.0.0' 1-decene-3- one (FIG. 8) is used as the starting material. If the laevorotatory isomer is used as the starting material, it is understood that in this instance the optical antipodes will be formed. Reaction of the compound having the formula of FIG.
  • FIG. 17 yields l1-halodihydro-nootkatone, having the formula of FIG. 18, identical with the product which can be obtained from nootkatone (having the formula of FIG. 7) by the addition of hydrohalic acid.
  • This product may also be formed directly from 7-halodihydro-nootkatone (having the formula of FIG. 16), e.g., by treatment with a moderately concentrated sulphuric acid in the presence of hydrohalic acid or a halide.
  • a conversion of the compound of FIG. 8 into the compound of FIG. 18 in high yield and directly may be effected by adding hydrohalic acid in ethanol, followed by addition of sulphuric acid and water.
  • ll-l-Iydroxydihydronootkatone (FIG. 19) is also formed upon treatment of the compound of FIG. 17 with water in acid medium.
  • Dehydrohalogenation of ll-halodihydronootkatone or dehydration of 11-hydroxydihydronootkatone yields mixtures of a-vetivone (FIG. 20) and nootkatone (FIG. 7) which can be separated from one another.
  • the relative quantities of the compounds of FIGS. 20 and 7 will vary depending on the method of dehydrohalogenation or dehydration employed in the process. Dehydrohalogenation with sodium acetate in glacial acetic acid will afford a nearly complete conversion into nootkatone. This is also true if the acetate of 11-hydroxydihydronootkatone is subjected to pyrolysis. On being treated with a catalytic amount of a strong acid, such as p-toluene-sulphonic acid, at an elevated temperature, ll-hydroxydihydronootkatone will mainly yield the a-vetivone.
  • a strong acid such as p-toluen
  • Suitable methods are, for example, dehydrohalogenation by heating with a base, such as potassium hydroxide or potassium methoxide in methanol or with an organic nitrogen base, such as dimethylaniline or picoline and dehydration by treating with phosphorus oxychloride or thonyl-chloride in pyridine.
  • a base such as potassium hydroxide or potassium methoxide in methanol
  • an organic nitrogen base such as dimethylaniline or picoline
  • reaction temperature C. A solution of 128 g of sabina ketone in 160 ml of glacial acetic acid and 200 g of N-piperidinemethanol was refluxed for 15 hours (reaction temperature C.). After cooling the reaction mixture was poured out onto a mixture of water, ice and hydrochloric acid. The oil layer was separated and the aqueous layer was extracted three times with 200 ml of pentane each time. Oil layer and extracts were combined, washed until neutral, dried and filtered off. After removal of the solvent and distillation, there was thus obtained 30 g of 2- methylene-sabina ketone. B.p. 67C. at 2 mm.
  • reaction product was present in the aqueous layer in the form of a salt of the Mannich base.
  • the acid aqueous layer was rendered alkaline with sodium carbonate and was extracted three times with 100 ml of carbon tetrachloride each time. After drying and evaporation of the solvent there was thus obtained 142 g of Mannich base.
  • the Mannich base was quatemized by boiling with 100 g of methyl iodide. The solid was sucked off and washed with toluene. There was thus obtained 150 g of quaternary ammonium salt.
  • This salt was boiled with 60 g of sodium carbonate in a mixture of 500 ml of methanol and 60 ml of water for 2.5 hours. The reaction mixture was poured out into water and extracted four times with 200 ml of pentane.
  • EXAMPLE VIII The aqueous mixture was extracted three times with 50 ml of chloroform each time. The combined extracts were washed with 50 ml of a 5 percent solution of sodium bicarbonate, 50 ml of water and 50 ml of a saturated solution of sodium chloride successively. After drying and filtering, the solvent was removed under reduced pressure. The residue (5.6 g) solidified on standing. Crystallization from hexane with 10 percent of benzene yielded 4.1 g of ll-chlorohydronootkatone (formula of FIG. 18), mp. 84.5-85.5C.
  • the main fraction (2.35 g) had a b.p. of 161163C. at 2 mm and consisted of 1 1-hydroxydihydronootkatone (formula of FIG. 19) with a content of more than 95 percent (gas chromatographic analysis). [a 155 (C H Ol-l).
  • the residue (4.3 g) consisted, as shown by analysis by means of nuclear magnetic resonance spectometry, of a mixture of about percent nootkatone, 10 percent a-vetivone and 5 percent of the acetate of ll-hydroxydihydronootkatone. This mixture was fractionated. There was thus obtained 3.4 g of nootkatone (formula of FIG. 7), b.p. 122l23C. at 1 mm. Content, shown by gas chromatographic analysis, 92 percent. 237 m (C H OH)-E,,,,, 16,400. M.p. 3335C.

Abstract

Sesquiterpene derivatives of the eremophilane group e.g., avetivone and nootkatone which are useful aroma chemicals are prepared from 5,6-dimethyl-8-isopropyl-tricyclo (4.4.0.08.10) 1decene-3-one.

Description

United States Patent 1191 Van Der Linde et al.
11] 3,835,192 1451 Sept. 10,1974
PRECURSOR 0F SESQUITERPINE DERIVATIVES OF THE EREMOPHILANE GROUP Inventors: Leendert Maarten Van Der Linde,
Huizen; Jan Gerardus Witteveen,
Naarden; Harmannus Boelens, Huizen, all of Netherlands Assignee: N. V. Chemische Fabriek Naarden Filed: June 21, 1971 Appl. No.: 154,960
Foreign Application Priority Data June 19, 1970 Netherlands 7009040 US. Cl. 260/586 R, 252/522, 260/586 C, 260/63l.5, 260/675.5 Int. Cl. C07c 49/44 Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwartz Attorney, Agent, or Firm-Stevens, Davis, Miller & Mosher ABSTRACT Sesquiterpene derivatives of the eremophilane group e.g., a-vetivone and nootkatone which are useful aroma chemicals are prepared from 5,6-dimethyl-8- isopropyl-tricyclo [4.4.0.0 l-decene-3-one.
1 Claim, 23 Drawing Figures PATENTEflSEPIOIQM Y 3.835.192.
REACTION 2.
' FIG 5,
5541* 'FIG.12 Fl 10 a G. RG1 V FIG.14
. INVENTORS LEENDERT MAARTEN VAN DER LINDE U JAN GERARDUS WITTEVEEN HARMANNUS BOELENS W flw M WTTORNEYS PRECURSOR OF SESQUITERPINE DERIVATIVES OF THE EREMOPI-IILANE GROUP The invention relates to product and process for the preparation of sesquiterpene derivatives of the eremophilane group.
sesquiterpenes having an eremophilane skeleton are characterized by a bicyclo [4-4-0] decane structure, as shown in the formula of FIG. 1, with methyl substituents at the positions and 6, and a branched chain C substituent at the position 8.
The invention relates more particularly to those structures in which both methyl groups are disposed on the same side of the molecule (i.e., on the same side of a plane drawn through the carbons of the sixmembered rings), while the substituent at C is either disposed at the opposite side or connected with the C by means of a double bond. Said group of compounds will be referred to hereinafter by the name of nootkatane group.
Several members of said group are important components of essential oils [cf., for example, Perf. & Ess. Oil Rec., 59, 280 (1968)].
Valerianol (formula of FIG. 2) occurs in the oil of Valeriana officinalis, a-Vetivone (formula of FIG. 3) is found in vetiver oil (from Vetiveria zizanoides), nootkatone (formula of FIG. 4) is found in the oil of the Alaska yellow cedar (Chamaecyparis nootkatensis) and in a great number of citrus oils, specifically grapefruit oil (from Citrus paradisi).
Nardostachone (formula of FIG. 5) is a constituent of spikenard oil (from Nardostachis jatamansi).
Nootkatone (fonnula of FIG. 4) may be prepared by oxidation of valencene (formula of FIG. 6) with tertiary butyl chromate [cf. J. Food Sci., 30, 876 (1965)]. If (+)valencene is used as the starting material, it will yield optically active nootkatone which is dextrorotatory, as is the natural isomer, and has the absolute configuration which is shown in the formula of FIG. 4.
A disadvantage of the aforementioned method for the preparation of nootkatone is that valencene is not sufficiently commercially available in an economical way to warrant its use.
Nootkatone may also be prepared from nootkatene by a process consisting of various steps (see the Dutch Pat. Application No. 69,14545, laid open for public inspection), a substance which, in accordance with Acta Chim. Scand., 11, 1157 (1957), may be isolated from the wood of Chamaecyparis nootkatensis, giving a yield of about 0.25 percent.
For the synthesis of nootkatone (FIG. 4) and a-vetivone (FIG. 3), respectively, there have been described a series of chemical processes on a laboratory scale which, it is true, are of scientific interest, but are not suitable for a technical preparation. As starting materials there were used: 4,4-dicarboethoxypimelic'aciddinitrile [see Chem. Comm., 26 (1969)], 4-ethoxy A tetra-hydroacetophenone [see Chem. Comm., 1,152 (1968)], and dimethyl y ketopimelate [see Tetrahedron Letters, 1,239 (1970)] and 2-carbomethoxy-4-isopropylidenecyclohexanone [see Chem. Comm, 753 (1967)], respectively.
The sesquiterpenes thus obtained are not optically active, but are mixtures of equal amounts of optical antipodes; for example, of (+)nootkatone (FIG. 4) and ()nootkatone (FIG. 7).
. desired.
The compound having the formula of FIG. 8 is new. According to the invention it can be produced easily on a technical scale if methylpropenyl ketone (formula of FIG. 9), in accordance withthe reaction 1, is condensed with 2-methylsabina-ketone (formula of FIG. 10) under the influence of a strong base, such as sodium hydride or sodium amide.
2-Methyl-sabina ketone (formula of FIG. 10) has been described [see J. Prakt. Chem, 90, 314 (1915)] and can easily be prepared from the monoterpene sabinene having the formula of FIG. 11, a natural and common product (see, for example, Gildemeister and Fr. I-Ioffmann Die 'atherischen Ole, Band Illa, page 114 and following).
For this purpose, sabinene is oxidized with a strong oxidizing agent, such as ozone, into sabina ketone having the formula of FIG. 12, and into this sabina ketone a methyl group is introduced in the activated a-position, for instance, by direct methylation with methyl iodide or dimethylsulphate, or by the introduction of a group which by means of reduction can be converted into a methyl group, such as a methylene group or a hydroxymethylene group (see reaction 2). Sabina ketone may be prepared by means of a synthetic process as well [see J. Org. Chem, 33, 1656 (1968)].
The process makes it possible to prepare optically active sesquiterpenes of the nootkatane series. If the reaction 1 is carried out with optically active and dextrorotatory 2methyl-sabina ketone (which is derived from laevorotatory l-sabinene), there is obtained optically active and laevorotatory 5,6-dimethyl-8-isopropyltricyclo [4.4.0.0 l-decene-3-one having the absolute configuration, as shown in the formula of FIG. 13. However, if the reaction is carried out with laevorotatory Z-methyl-sabina ketone (from dextrorotatory dsabinene), the dextrorotatory optical antipode having the absolute configuration, shown in the formula of FIG. 14, is obtained. If optically inactive Z-methylsabina ketone (from natural or synthetic d.1-sabinene) is used as starting material, there is also obtained optically inactive 5,6-dimethyl-8-isopropyl-tricyclo [4'4'0'0 l-decene-3-one which is a mixture of equal parts of the optical antipodes having the formulae of FIGS. 13 and 14.
In order to obtain sesquiterpenes of the nootkatane group, the compound having the formula of FIG. 8 is treated with acid, as described in the examples. Compounds having a carbon skeleton, as in the formula of FIG. 1, representing the desired configuration are formed upon opening of the cyclopropane ring. This process is shown in the reaction scheme 3, if dextrorotatory 5,6-dimethyl-8-isopropyl-tricyclo [4.4.0.0' 1-decene-3- one (FIG. 8) is used as the starting material. If the laevorotatory isomer is used as the starting material, it is understood that in this instance the optical antipodes will be formed. Reaction of the compound having the formula of FIG. 8 with sulphuric acid in an aqueous medium leads to ring opening and yields 5 ,6-dimethyl-8-isopropylbicyclo [4.4.0] 1,9- decadiene-3-one, having the formula of FIG. 15. Reaction with a hydrohalogenic acid, e.g., hydrogen chloride in the presence or the absence of a polar solvent, such as ethanol or ether, on the other hand, leads to ring opening with substitution at C there is thus formed 7-halodihydronootkatone, e.g., 7-chloro-dihydro-nootkatone having the formula of FIG. 16. From this product other sesquiterpenes of the nootkatone group may be prepared in a simple manner. This will be illustrated by means of a number of examples which follow.
By splitting off hydrohalic acid from 7-halogen-dihydro-nootkatone by treatment with a base, e.g., an organic base, such as dimethylaniline, there is formed as the major product 5,6-dimethyl-8-isopropyl-bicyclo [4.4.0] 1,7-decadiene-3-one, having the formula of FIG. 17, while in addition thereto there is formed a-vetivone having the formula of FIG. 20 and a small quantity of 5,6-dimethyl-8-isopropyl-bicyclo [4.4.0] 1,9-decadiene-3-one, having the formula of FIG. 15. Upon treatment with hydrohalic acid, the compound of FIG. 17 yields l1-halodihydro-nootkatone, having the formula of FIG. 18, identical with the product which can be obtained from nootkatone (having the formula of FIG. 7) by the addition of hydrohalic acid. This product may also be formed directly from 7-halodihydro-nootkatone (having the formula of FIG. 16), e.g., by treatment with a moderately concentrated sulphuric acid in the presence of hydrohalic acid or a halide. A conversion of the compound of FIG. 8 into the compound of FIG. 18 in high yield and directly may be effected by adding hydrohalic acid in ethanol, followed by addition of sulphuric acid and water. ll-l-Iydroxydihydronootkatone (FIG. 19) is also formed upon treatment of the compound of FIG. 17 with water in acid medium.
Dehydrohalogenation of ll-halodihydronootkatone or dehydration of 11-hydroxydihydronootkatone (FIG. 19) yields mixtures of a-vetivone (FIG. 20) and nootkatone (FIG. 7) which can be separated from one another. The relative quantities of the compounds of FIGS. 20 and 7 will vary depending on the method of dehydrohalogenation or dehydration employed in the process. Dehydrohalogenation with sodium acetate in glacial acetic acid will afford a nearly complete conversion into nootkatone. This is also true if the acetate of 11-hydroxydihydronootkatone is subjected to pyrolysis. On being treated with a catalytic amount of a strong acid, such as p-toluene-sulphonic acid, at an elevated temperature, ll-hydroxydihydronootkatone will mainly yield the a-vetivone.
Other suitable methods are, for example, dehydrohalogenation by heating with a base, such as potassium hydroxide or potassium methoxide in methanol or with an organic nitrogen base, such as dimethylaniline or picoline and dehydration by treating with phosphorus oxychloride or thonyl-chloride in pyridine.
On using dextrorotatory 5,6 dimethyl-8- isopropyltricyclo [4.4.0.0 l-decene-3one (FIG. 14) there is obtained optically active andlaevorotatory a-vetivone, as well as laevorotatory nootkatone. 1f laevorotatory compound of FIG. 14 is used as the starting material, there is obtained dextrorotatory a-vetivone and dextrorotatory nootkatone.
The process and compounds according to the invention open up new pathways for the technically and economically feasible synthesis of nootkatane type sesquiterpenes and derivatives, which are useful aroma chemicals in the compounding of perfume and flavour concentrates, for use in the industry of foods, drinks and perfumed articles.
EXAMPLE I 2-methyl-sabina ketone (formula of FIG. 10)
172 g of Sabinene, [a] D 93.1 percent, content 83 percent, shown by gas chromatographic analysis, was dissolved in 100 ml of ethyl acetate. The ozone was introduced into the mixture at C. until saturation. The solvent was eliminated under reduced pressure and the ozonide thus obtained was decomposed by the addition of a 20 percent solution of sodium sulphite. The oil layer was separated off and the aqueous layer was extracted with 200 ml of ether. Oil layer and ethereal extracts were combined, washed with 50 ml of water, dried over calcium chloride and filtered. After removal of the solvent, the crude sabina ketone was fractionated. There was thus obtained 128 g of sabina ketone (formula of FIG. 12), boiling point 7980C. at 8 mm,
[a] D 37.8 (C H OH), n 1.4705. Gas chromatographic analysis showed a content of 98 percent.
A solution of 128 g of sabina ketone in 160 ml of glacial acetic acid and 200 g of N-piperidinemethanol was refluxed for 15 hours (reaction temperature C.). After cooling the reaction mixture was poured out onto a mixture of water, ice and hydrochloric acid. The oil layer was separated and the aqueous layer was extracted three times with 200 ml of pentane each time. Oil layer and extracts were combined, washed until neutral, dried and filtered off. After removal of the solvent and distillation, there was thus obtained 30 g of 2- methylene-sabina ketone. B.p. 67C. at 2 mm. A considerable quantity of the reaction product was present in the aqueous layer in the form of a salt of the Mannich base. The acid aqueous layer was rendered alkaline with sodium carbonate and was extracted three times with 100 ml of carbon tetrachloride each time. After drying and evaporation of the solvent there was thus obtained 142 g of Mannich base. The Mannich base was quatemized by boiling with 100 g of methyl iodide. The solid was sucked off and washed with toluene. There was thus obtained 150 g of quaternary ammonium salt. This salt was boiled with 60 g of sodium carbonate in a mixture of 500 ml of methanol and 60 ml of water for 2.5 hours. The reaction mixture was poured out into water and extracted four times with 200 ml of pentane.
The combined extracts were washed with water, dried and filtered. After the removal of the solvent and distillation there was obtained an additional 60 g of 2- methylenesabina ketone. B.p. 6667C. at 2 mm, n 1.4881 [a] 64.6 (C I-I OI-I) l ,,,,,,,226 mm (C H OHk 9.400.
The l.R. spectrum showed bands at: 3.25 5.82 6.08 7.00 7.16 7.34 7.52 7.88 10.80 11.08 11.59 11.83 and 12.52 micron.
g of 2- methylene-sabina ketone were dissolved in ml of hexane and, after the addition of 1 g of a 5 percent platina on carbon catalyst, hydrogenated at 45C. and a hydrogen pressure of 0.35 at. The catalyst was filtered off and the filtrate was evaporated and distilled. There was thus obtained 72 g of 2-methyl-sabina ketone (formula of FIG. 10). B.p. 6062C. at 1 mm, n 1.4666, [01],, 30.8 (C l-1 01i).
The 1.R. spectrum showed bands at: 3.25 5.80 7.23 7.31 7.34 7.51 8.47 10.65
- 11.27 11.62 11.89 micron.
EXAMPLE 11 5,6-dimethyl-8-isopropyl-tricyclo decene-3-one (formula of FIG. 8)
In a S-litre-three-necked reaction flask, equipped with stirrer, dropping funnel and cooler (cooling agent ethanol at 60C.) there was prepared a solution of sodium amide in liquid ammonia from 3.9 g (0.17 gr. atom) of sodium and 750 ml of liquid solid ammonia in the presence of a catalytic amount of ferric nitrate.
To this mixture there was added, with stirring, in 45 minutes a solution of 26 g (0.17 mol) of 2-methylsabina ketone (formula of FIG. 10) prepared by the same method as described in Example I, [a] 2030.8 (C H OH), in 75 ml of dry dimethoxyethane.
Upon simultaneous substitution with 300 ml of dry dimethoxyethane, the ammonia was for the greater part removed from the reaction mixture by evaporation. To the dark-coloured solution thus obtained there was added dropwise, with passing of dry nitrogen, 16 g (0.19 mol) of trans 3-pentene-2-one dissolved in 75 ml of dry dimethoxyethane at a temperature of -20 to 25 in 2.5 hours. After a further 30 minutes stirring, at 20C., the reaction mixture was poured out into a mixture of 100 ml of saturated ammonium chloride and 900 ml of water. The aqueous mixture thus obtained was extracted three times with 150 ml of ether. The
ethereal extract was washed three times with 100 ml of a 10 percent solution of sodium chloride, dried over magnesium sulphate and filtered. After separation of the solvent, the residue was distilled under reduced pressure. There was thus obtained 25 g of 5,6-dimethyl- 8-isopropyl-tricyclo [4.4.0.0 1-decene-3-one (formula of FIG. 8). Yield 67.5 percent (theory) with a content of about 98 percent, (shown by gas chromatographic analysis). B.p. 131-132C. at 1 mm. A sample for analysis was crystallized from hexane. M.P. 70.7 71.6
l,,,,,,265 mm (C H OI-Ik 19.500.
[a] 216 (C H OH). The mass spectrum showed important peaks at m/e 218 (55 percent) M", 176 (69 percent), 175 (57 percent), 161 (49 percent), 147 (62 percent), 133 (100 percent), 105 (96 percent), 91 (58 percent), 43 (58 percent) and 41 (89 percent).
The I. R. spectrum showed important absorptions at: 3.23 5.99 6.12 6.97 7.08 7.25 7.30 7.35
7.46 7.85 8.00 9.48 9.68 11.45 11.85 12.10 and 12.31 11.. The N.M.R. spectrum (60 Me, percent solution in C D gave signals at:
8=0.60 (3H, doublet, J 6 centipoises); 0.67 (3H, singlet);
0.73 (3H, doublet, J 5.5 centipoises); 0.78 (3H, doublet,
J 5.5 centipoises); 5.98 (1H, singlet).
EXAMPLE III After 10 minutes stirring at room temperature, the reaction mixture was poured out into water. The aqueous mixture was extracted with carbon tetrachloride (two times 25 ml). The combined extracts were washed two times with a 5 percent solution of sodium bicarbonate and two times with water.
After drying over magnesium sulphate and filtering, the solvent was removed under reduced pressure and the residue was distilled in a ball tube furnace. There was thus obtained 0.6 g of 5,6-dimethyl-8-isopropylbicyclo- [4.4.0] 1,9-decadiene-3-one (formula of FIG. 15).
The N.M.R. spectrum (60 Mo, 10 percent solution in carbon tetrachloride) gave the following signals: 80.80 i 1.10 (12H); 5.60 (1H, broadened singlet); 86.10 (2H), broadened singlet).
From a 10 percent solution in C D the following data could be obtained:
80.60 (3H, doublet), J 6 centipoises); 0.70 (31-1, sin- 80.75 (6H, doublet), J 6 centipoises); 5.75 5.9(31-1, multiplet).
The LR. spectrum showed bands at: 3.30 6.01 6.15 6.29 7.08 7.23 7.32 7.37 7.75 7.80
- 8.33 11.06 11.42 11.73 and 12.22 micron.
EXAMPLE 1V 7-chloro-dihydronootkatone (formula of FIG. 16)
To 55 ml of a saturated solution of dry hydrochloric acid gas in absolute ethanol there was added with sitrring at 20C. 7.0 g of (0.032 mol) 5,6-dimethyl-8-isopropyl-tricyclo [4.4.0.0 1-decene-3-one (formula of FIG. 8) (obtained by the method described in Example 11). After all solids had idssolved, the mixture was stirred for another 5 minutes at 20C. and then poured out into water. The aqueous mixture was extracted four times with 50 ml of chloroform each time.
The combined extracts were washed with 50 ml of a 5 percent solution of sodium carbonate and two times with 50 ml of water. After drying over magnesium sulphate and filtering, the solvent was removed under reduced pressure. There was thus obtained 8.5 g of viscous oil which crystallized slowly. After recrystallization from hexane there was obtained 7.2 g of 7-chloro-dihydronootkatone (formula of FIG. 16), mp. 67-69C. A sample for analysis was once again crystallized from hexane, m.p. 68. 2 694C. The N.M.R. spectrum (60 Me, 10 percent solution in tetra) showed signals at:
60.97 (3H, doublet, J about 6 centipoises);
81.07 (6H, doublet, J 5.5 centipoises);
81.35 (3H, singlet) and 85.65 (1H, doublet, J 1.7 centipoises).
The IR. spectrum showed absorptions at:
- 7.78 8.32-8.44-11.07-11.29-11.43-11.85-12.26and 12.64 micron.
EXAMPLE V 1l-chlorodihydronootkatone (formula of FIG. 18) from the compound of FIG. 8
To 8 ml of a saturated solution of dry hydrochloric acid gas in absolute ethanol there was added with stirring at room temperature: 4 g (0.018 mol) of 5,6- dimethyl-8-isopropyltricyclo [4.4.0.0 1-decene- 3-one (formula of FIG. 8) (obtained by the process described in Example 11, contents showed by gas chromatographic analysis, about 98 percent). Stirring was continued for another minutes at 20C. after all the crystals had dissolved. The solution was subsequently cooled to C. and to this solution there was added dropwise 32 ml of a mixture of concentrated sulphuric acid and water (2:1, V/V), while the temperature was held between 5 and 10C. The mixture thus obtained was stirred for 3 hours at room temperature and was subsequently poured out into water. The aqueous solution was extracted four times with 50 ml of carbon tetrachloride each time. The combined extracts were washed with a 5 percent solution of sodium bicarbonate and with water, and dried over magnesium sulphate. After separation of the solvent, the residue solidified. Crystallization of the residue from hexane/benzene yielded 4.1 g of 1 1-chloro-dihydronootkatone (formula of FIG. 18). mp. 8485C. A sample for analysis was once again crystallized from hexane/benzene. M.p. 84.5 862C. The N.M.R. spectrum (60 Mc, 10 percent solution in carbon tetrachloride) gave signals at: 80.99 (3H, doublet, J 6 centipoises);
81.10 (3H, singlet);
81.57 (6H, singlet);
85.61 (1H, broadened singlet).
The IR. spectrum showed absorptions at:
8.33 9.02 11.07 11.47 11.82 and 12.23 micron.
EXAMPLE VI 11-chlorodihydronootkatone (formula of FIG. 18) from the compound of FIG. 16
1.0 g of 7-chlorodihydronootkatone (formula of FIG. 16), obtained by the process described in Example IV, was mixed at room temperature with 10 ml of concentrated hydrochloric acid (38 percent). Subsequently, such an amount of glacial acetic acid was added that the mixture became clear (about 1.5 ml). After 2.5 hours stirring at room temperature (20C.) the mixture was poured out into water. The aqueous mixture was extracted twice with 25 mlof carbon tetrachloride. The combined extracts were washed until neutral and dried over magnesium sulphate. After removal of the solvent, the residue was crystallized from hexane. There was thus obtained 0.6 g of 11- chlorodihydronootkatone (formula of FIG. 18), mp. 8084C.
The N.M.R. spectrum showed that the sample contained some 5,6-dimethyl-8-isopropyl-bicyclo [4.4.0] 1,9-decadiene-3-one (formula of FIG. 15).
EXAMPLE VII 5 ,6-dimethyl-8-isopropyl-bicyclo [4.4.0] 1 ,7- decadiene-3-one (formula of FIG. 17) from compound of FIG. 16
9.0 g of 7-chlorodihydronootkatone (formula of FIG. 16), obtained by the process described in Example IV, was dissolved in 80 g of freshly distilled dimethylaniline. The solution was heated, with stirring, in 1.5 hour at l40-l50C. After cooling, the mixture was poured out into 300 ml of water and acidified with 2N hydrochloric acid to pH 3. The aqueous mixture was extracted three times with 100 m1 of carbon tetrachloride each time. The combined extracts were washed twice with 50 ml of 2N hydrochloric acid, 50 ml of a 5 percent solution of sodium bicarbonate and twice with 50 ml of water successively. After drying over magnesium sulphate and filtering, the solvent was removed and the residue was distilled. (Boiling point l20-125C. at 2 mm). There was thus obtained 7 g of chlorine-free product, percent of which, as shown by gas chromatographic and nuclear magnetic resonance analysis, consisted of 5 ,6-dimethyl-8-isopropyl-bicyclo [4.4.0] 1,7-decadiene-3-one (formula of FIG. 17), while in the remaining 30 percent about 20 percent a-vetivone (formula of FIG. 20) and some percentages of 5,6- dimethyl-S-isopropyl-bicyclo [4.4.0] 1,9-decadiene- 3-one (formula of FIG. 15) was discovered.
The pure 1,7-dienone (formula of FIG. 17) was isolated by means of preparative gas chromatography (2 m, A inch column with 10 percent DEGS at 200C). The N.M.R. spectrum (60 Mo, 10 percent solution in carbon tetrachloride) gave signals at:
81.02 (6H, doublet, J 7 centipoises);
81.10 (3H, singlet);
85.40 (1H, singlet, w h/2 4 centipoises);
85.67 (1H, broadened singlet);
A 10 percent solution in C D gives the following data:
80.70 (31-1, doublet, J 6 centipoises);
80.82 (3H, singlet);
80.90 (6H, doublet, J 7 centipoises);
85.28 (1H, broadened singlet);
85.88 (1H, broadened singlet);
8The IR. spectrum showed absorptions at: 5.98 6.14 7.01 7.08 7.26 7.31 7.39 7.81- 8.23 10.01 10.49 11.03 11.64 and 12.15 micron.
EXAMPLE VIII The aqueous mixture was extracted three times with 50 ml of chloroform each time. The combined extracts were washed with 50 ml of a 5 percent solution of sodium bicarbonate, 50 ml of water and 50 ml of a saturated solution of sodium chloride successively. After drying and filtering, the solvent was removed under reduced pressure. The residue (5.6 g) solidified on standing. Crystallization from hexane with 10 percent of benzene yielded 4.1 g of ll-chlorohydronootkatone (formula of FIG. 18), mp. 84.5-85.5C.
EXAMPLE IX l1-hydroxydihydronootkatone (formula of FIG. 19) from the compound of FIG. 17
4g of the mixture of dienone obtained by the process described in Example VII was dissolved in 40 ml of a mixture of concentrated sulphuric acid and water (v/v, 1:1), cooled to 0C. The solution was stirred for 15 minutes at 20C. and poured out onto 200 ml of icewater. The acid aqueous mixture was washed once with 20 ml of hexane and was subsequently extracted three times with 60 ml of chloroform each time. The combined extracts were washed with 100 ml of a percent solution of bicarbonate and two times with 50 ml of a saturated sodium chloride solution. After drying over magnesium sulphate and filtering, the solvent was removed and the residue was distilled. The main fraction (2.35 g) had a b.p. of 161163C. at 2 mm and consisted of 1 1-hydroxydihydronootkatone (formula of FIG. 19) with a content of more than 95 percent (gas chromatographic analysis). [a 155 (C H Ol-l).
l,,, ,,238 mm, e 14,700 (C H OH). The IR. spectrum showed absorptions at: 2.77 2.91 5.98 6.17 7.00 7.09 7.26 7.32
7.41 7.75 7.80 11.08 11.48 11.83 and 12.14 g. The N.M.R. spectrum (60 Mc, percent solution in tetra) showed signals at:
80.98 (3H, doublet, J 6 centipoises);
81.07 (3H, singlet);
81.10 (3H, singlet);
81.13 (3H, singlet) and 85.65 (1H, broadened singlet).
The mass spectrum showed peaks at:
m/e 59 (100 percent), 121 (36 percent), 178 (29 percent), 118 (27 percent), 41 (21 percent), 43 (21 percent), 136 (19 percent), 123 (13 percent), 91 (12 percent), and 163 (12 percent).
EXAMPLE X a-vetivone (formula of FIG. 20) and nootkatone (formula of FIG. 7) from the compound of FIG. 18
2.0 g of 11-chlorodihydronootkatone (formula of FIG. 18), obtained by the process described in Example V, was dissolved in 20 ml of dimethylaniline and was heated with stirring at 145C. for 2 hours. The reaction mixture was poured out into 100 ml of water and acidified with 2N hydrochloric acid to pH 5. The aqueous mixture was extracted with 30 mlof carbon tetrachloride four times. The combined extracts were washed five times with 20 ml of 2N hydrochloric acid, once with 20 ml of a 5 percent solution of sodium bicarbonate and once with water. After drying over magnesium sulphate and filtering, the solvent was removed and the residue distilled. There was thus obtained 1.2 g of viscous oil, b.p. 180-112C. at 1 mm, which consisted of a-vetivone (formula of FIG. 20) and nootkatone (formula of FIG. 7) in a ratio of about 3:5, as was shown by gas chromatographic analysis.
The pure isomers were obtained by means of preparative gas chromatography. (Filling of column 20 percent OV 17, 3m ,4; inch, isotherm at 200). There was thus obtained: nootkatone, m.p. 3536C., l 237 mm'e 16,200. IR. spectrum: 3.25 5.99- 6.16 7.08 7.25 7.30 7.41 11.82 and 12.22 1.. N.M.R. spectrum:
80.96 (3H, doublet, J 6 centipoises);
81.10 (3H, singlet);
81.70 (3H, broadened singlet);
84.68 (2H, broadened singlet) and 85.62 (1H, broadened singlet). Mass spectrum m/e: 218 (M+) (18 percent); 41 (100 percent); 79 (66 percent); 91 (64 percent); 147 (57 percent); 121 (55 percent); 93 (50 percent); 39 (50 percent); 55 (46 percent); 77 (46 percent); and 133 (35 percent); a-Vetivone.
l,,,,,,233 nme 12,800 (C I-I OH) I.R. spectrum: 5.98 6.16 7.00 7.08 7.25 7.30 7.41-11.08 -and 11.48 ,u. N.M.R. spectrum: 80.96 (31-I, singlet);
81.00 (3I-I, doublet, J about 6 centipoises); 81.72 (6H, broadened singlet) and 85.62 (1H, broadened singlet). Mass spectrum:
(26 percent); 203 (26 percent); 105 (25 percent); 121
(24 percent); and 55 24 percent).
EXAMPLE XI Nootkatone (formula of FIG. 7 from compound of FIG. 18
5 g (0.02 mol) of ll-chloronootkatone (formula of FIG. 18), obtained by the process described in Example V, was dissolved in 30 ml of glacial acetic acid, 2.1 g (0.025 mol) of dry powdered sodium acetate was added thereto and the resultant mixture was boiled for 20 minutes. After being poured out into water, the mixture was extracted three times with 50 ml of carbon tetrachloride each time. The combined extracts were washed two times with 30 ml of water, once with 30 ml of a 5 percent solution of sodium bicarbonate and flnally two times with 20 ml of a saturated sodium chloride solution. After drying and filtering, the solvent was removed under reduced pressure. The residue (4.3 g) consisted, as shown by analysis by means of nuclear magnetic resonance spectometry, of a mixture of about percent nootkatone, 10 percent a-vetivone and 5 percent of the acetate of ll-hydroxydihydronootkatone. This mixture was fractionated. There was thus obtained 3.4 g of nootkatone (formula of FIG. 7), b.p. 122l23C. at 1 mm. Content, shown by gas chromatographic analysis, 92 percent. 237 m (C H OH)-E,,,,, 16,400. M.p. 3335C.
EXAMPLE XII Nootkatone (formula of FIG. 7) and a-vetivone (formula of FIG. 20) from the compound of FIG. 19
To a solution of 15 g (0.064 mol) of l l-hydroxydihydronootkatone (formula of FIG. 19) in ml of solid pyridine there was added dropwise with stirring and external cooling with ice-water 28 g of phosphorus oxychloride in 15 minutes. The stirring was continued for another three hours at 0C., whereupon the mixture was poured out onto ice. After acidification with 4N sulphuric acid to pH 3, the mixture was extracted four times with 50 ml of carbon tetrachloride each time. The combined extracts were washed two times with 50 ml of 2N sulphuric acid, once with water, and once with a 5 percent solution of sodium bicarbonate, and once with a saturated solution of sodium chloride. After drying over magnesium sulphate and filtration, the solvent was removed under reduced pressure. The residue yielded on distillation 10.3 g of a colourless viscous oil, b.p. -120C/l mm, which, as shown by gas chromatographic and nuclear magnetic resonance analysis appeared to consist of nootkatone (formula of FIG. 7) and a-vetivone (formula of FIG. 20) in a ratio of about 6:4. The pure isomers could be isolated therefrom by preparative gas chromatography.
What is claimed is:
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3[835,192 v DATED September 10, 1974 INVENTOMS) Leendert Maarten Van Der Linde, et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown beiow:
[73] Change "N.V. Chemische Fabriek Naarden" to Naarden International N.V.
[54] correct spelling of SESQUITERPENE Signed and Sealed this Twenty-first D f September 1976 [SEAL] A ttest:
RUTH C. MASON (nmmisxioncr of Parents and Trademarks
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US3925477A (en) * 1971-11-12 1975-12-09 Hoffmann La Roche Tricyclo{8 5,3,1,0{hu 3,8{b {9 undecan-2-ones and the corresponding mono- and di-unsaturated derivatives
US3962340A (en) * 1974-01-11 1976-06-08 Takasago Perfumery Co., Ltd. 1,2,6-Trimethyltricyclo[5,3,2,02,7 ]dodeca-5-one
US3963782A (en) * 1974-04-01 1976-06-15 Takasago Perfumery Co., Ltd. 5-Acetyl-1,2,6-trimethyltricyclo[5,3,2,02,7 ]dodeca-5-ene
US4322559A (en) * 1979-09-03 1982-03-30 Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) 4(5)-Acetyl-9,9-dimethyltricyclo-[4,4,0,18,10 ]-undec-1-ene, its preparation and use in perfumery compositions and as an odorant
US20040005343A1 (en) * 2002-07-03 2004-01-08 Zhu Betty C. R. Dihydronootkatone and tetrahydronootkatone as repellents to arthropods
US20040157935A1 (en) * 2001-08-17 2004-08-12 Gregg Henderson Extracts of vetiver oil as a repellent and toxicant to ticks and cockroaches
US6890960B1 (en) 1999-10-19 2005-05-10 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Vetiver oil extracts as termite repellent and toxicant
WO2010019489A2 (en) * 2008-08-13 2010-02-18 Salk Institute For Biological Studies Method for making terpene derivatives
CN102070482A (en) * 2010-12-31 2011-05-25 中山大学 Derivatives of natural product S6-2, and preparation method and use thereof as anti-tumor medicines

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US3510510A (en) * 1966-06-30 1970-05-05 Procter & Gamble Novel reactions of 4-acyloxy-3-caranols and novel bicyclic compounds resulting from said reactions

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3925477A (en) * 1971-11-12 1975-12-09 Hoffmann La Roche Tricyclo{8 5,3,1,0{hu 3,8{b {9 undecan-2-ones and the corresponding mono- and di-unsaturated derivatives
US3962340A (en) * 1974-01-11 1976-06-08 Takasago Perfumery Co., Ltd. 1,2,6-Trimethyltricyclo[5,3,2,02,7 ]dodeca-5-one
US3963782A (en) * 1974-04-01 1976-06-15 Takasago Perfumery Co., Ltd. 5-Acetyl-1,2,6-trimethyltricyclo[5,3,2,02,7 ]dodeca-5-ene
US4322559A (en) * 1979-09-03 1982-03-30 Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) 4(5)-Acetyl-9,9-dimethyltricyclo-[4,4,0,18,10 ]-undec-1-ene, its preparation and use in perfumery compositions and as an odorant
US4363754A (en) * 1979-09-03 1982-12-14 Henkel Kommanditgesellschaft Auf Aktien 4(5)-Acetyl-9,9-dimethyltricyclo-[4,4,0,18,10 ]-undec-1-ene, its preparation and use in perfumery compositions and as an odorant
US6890960B1 (en) 1999-10-19 2005-05-10 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Vetiver oil extracts as termite repellent and toxicant
US6906108B2 (en) 2001-08-17 2005-06-14 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Extracts of vetiver oil as repellent and toxicant to ants, ticks, and cockroaches
US20040157935A1 (en) * 2001-08-17 2004-08-12 Gregg Henderson Extracts of vetiver oil as a repellent and toxicant to ticks and cockroaches
US6897244B2 (en) 2002-07-03 2005-05-24 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Dihydronootkatone and tetrahydronootkatone as repellents to arthropods
US20040005343A1 (en) * 2002-07-03 2004-01-08 Zhu Betty C. R. Dihydronootkatone and tetrahydronootkatone as repellents to arthropods
US20050171213A1 (en) * 2002-07-03 2005-08-04 Zhu Betty C.R. Dihydronootkatone and tetrahydronootkatone as repellents to arthropods
WO2010019489A2 (en) * 2008-08-13 2010-02-18 Salk Institute For Biological Studies Method for making terpene derivatives
WO2010019489A3 (en) * 2008-08-13 2010-05-20 Salk Institute For Biological Studies Method for making terpene derivatives
US20110152563A1 (en) * 2008-08-13 2011-06-23 Noel Joseph P Method for making terpene derivatives
US8865930B2 (en) 2008-08-13 2014-10-21 Salk Institute For Biological Studies Method for making terpene derivatives
CN102070482A (en) * 2010-12-31 2011-05-25 中山大学 Derivatives of natural product S6-2, and preparation method and use thereof as anti-tumor medicines

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