EP1562888A1 - A process for the preparation of alkylidenecyclopentanone derivatives - Google Patents

A process for the preparation of alkylidenecyclopentanone derivatives

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Publication number
EP1562888A1
EP1562888A1 EP03758513A EP03758513A EP1562888A1 EP 1562888 A1 EP1562888 A1 EP 1562888A1 EP 03758513 A EP03758513 A EP 03758513A EP 03758513 A EP03758513 A EP 03758513A EP 1562888 A1 EP1562888 A1 EP 1562888A1
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Prior art keywords
group
formula
compound
representing
mixture
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German (de)
French (fr)
Inventor
Christian Chapuis
Hans Wüest
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Firmenich SA
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Firmenich SA
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11B—PRODUCING, e.g. BY PRESSING RAW MATERIALS OR BY EXTRACTION FROM WASTE MATERIALS, REFINING OR PRESERVING FATS, FATTY SUBSTANCES, e.g. LANOLIN, FATTY OILS OR WAXES; ESSENTIAL OILS; PERFUMES
    • C11B9/00—Essential oils; Perfumes
    • C11B9/0026—Essential oils; Perfumes compounds containing an alicyclic ring not condensed with another ring
    • C11B9/003—Essential oils; Perfumes compounds containing an alicyclic ring not condensed with another ring the ring containing less than six carbon atoms
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/27—Preparation of carboxylic acid esters from ortho-esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/34—Migration of groups in the molecule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • the present invention relates to the field of organic synthesis and more particularly to a new process for the preparation of a 2-al ylidene-3-oxo-cyclopentylacetate derivative, as defined further below.
  • Said process comprises the reaction of a 2-(l-hydroxyalkyl)- cyclopent-2-en-l-one derivative with a suitable orthoester or malonate to obtain an intermediate which undergoes a thermal rearrangement to give the desired final compound.
  • the 2-alkylidene-3-oxo-cyclopentylacetate derivative, as well as the 2-(l- hydroxyalkyl)-cyclopent-2-en-l-one derivative are also objects of the invention.
  • Cyclopentanone derivatives such as Hedione ® (methyl 3-oxo-2-pentyl-l- cyclopentaneacetate; origin Firmenich S.A.), methyl 3-oxo-2-(2-pentenyl)-l- cyclopentaneacetate (methyl jasmonate) or methyl 3-oxo-2-pentyl-l-cyclopentene-l- acetate, are very important ingredients of the perfumery industry. Consequently, there is a need for new intermediates, and processes for their preparation, which can be advantageously employed in the synthesis of the above-mentioned perfuming ingredients.
  • the present invention relates to a new process, aimed at the synthesis of a compound of formula (I), in the form of any one of its isomers or a mixture thereof,
  • R representing, taken separately, a Ci-Cs alkyl group or, taken together, forming, together with the carbon and oxygen atoms of said G, a C 3 -C 7 1,3-dioxacycloalkane ring
  • R 1 represents a n-butyl group or a CH 2 X, CHO or CH 3-n Z n group, X standing for a halogen atom or a (3c-ethyl-bicyclo[2.2.1]hept-5-ene-2r-yl)methyl group
  • n being 1 or 2 and Z standing for a C(OR) 2 , OR 3 or SR 3 group
  • R representing a group as defined previously for G
  • R 3 representing, taken separately, a C 1-7 benzyl, alkyl, cycloalkyl or oxacycloalkyl group or a C 1-7 acyl, sulfonyl or silyl
  • Preferred compounds of formula (I) or (H) are those wherein R 1 represents a n-butyl group or a CH 2 X, CHO or CH 3 - n Z ⁇ group, X standing for a halogen atom, n being 1 or 2 and Z standing for a OR 3 or SR 3 group, R and R 3 representing a group as defined above.
  • G represents a CO group or a C - 1,3- dioxacycloalkane group
  • R 1 represents a n-butyl group
  • a C(OR) 2 group R representing a group as defined above, a CH 2 C1 or a CH 2 Br group, or alternatively a CH 2 OR 3 group
  • R 3 representing a C 1 - 7 benzyl, alkyl, cycloalkyl or oxacycloalkyl group or a C 1-7 acyl, sulfonyl or silyl group
  • R represents a methyl group.
  • G represents a CO group
  • R 1 represents a n-butyl group
  • R 2 represents a methyl group.
  • the conversion of the compound of formula (II) into a compound of formula (I), may be carried out by reacting the former with an orthoester, or a malonate, derivative to obtain an intermediate of formula (IH) or (HI'), respectively
  • R 1 and R 2 are as defined in formula (I) or (II), and R 4 represents a R 2 group or a Si(R 5 ) 3 group wherein R 5 is a C C 4 alkyl group.
  • Said intermediate is subsequently thermally rearranged, e.g by a rearrangement of the Claisen type, and if necessary decarboxylated, to provide a compound of formula (I).
  • the isolation, or purification, of the intermediate (HI) or (HI'), prior to its conversion into (I), is not mandatory, so that the invention's process is carried out as a "one-pot" process.
  • Useful orthoesters or malonates are those of formula CH 3 C(OR 2 ) 3 or CH (COOR 4 ) 2 , respectively, R 2 and R 4 being defined above.
  • Preferred orthoesters or malonates are those wherein R 2 represents a methyl group. The orthoesters are preferred over-the-malonates.
  • the intermediate (in) or (HI') are advantageously obtained by reacting together the compound of formula (H) with an orthoester or a malonate derivative in the presence of an acid, such as a C O carboxylic acid, optionally halogenated, or a C O sulfonic acid.
  • an acid such as a C O carboxylic acid, optionally halogenated, or a C O sulfonic acid.
  • Non limiting examples of such an acid are acetic, propionic, pivalic, trifluoroacetic, camphor sulfonic acid and p-TsOH (para toluenesulfonic acid).
  • Said acid may be added in a catalytic amount, e.g. between 0.1 and 30 mol%, preferably between 5 and 20 mol%, with respect to the compound of formula (H).
  • the thermal rearrangement of the intermediate (HI) or (HI') is achieved by heating the reaction medium at a temperature comprised between 60° and 180°C, preferably between 90° and 120°C.
  • the intermediate (HI) will provide directly a compound of formula (I) after the thermal rearrangement.
  • the rearrangement of the intermediate (HI') will provide another malonate which will require a decarboxylation, more precisely a saponification followed by a decarboxylation and finally an esterification with an alcohol of formula R 2 OH, wherein R 2 has the meaning indicated in formula (I), to provide a compound of formula (I).
  • All the transformations carried out in the invention process may be performed in the presence or absence of a solvent.
  • a solvent such as the orthoester - and -malonate -derivatives -described- hereinabove, aromatics (e.g. toluene or xylene) or hydrocarbons (e.g. decane or decaline).
  • aromatics e.g. toluene or xylene
  • hydrocarbons e.g. decane or decaline
  • the thermal rearrangement is carried out under anhydrous conditions.
  • IR 3430, 2922, 2832, 1691, 1632, 1440, 1344, 1248, 1189, 1125, 1100, 972, 921, 789, 731.
  • IR 3429, 2972, 2865, 1739, 1690, 1632, 1439, 1347, 1248, 1111, 1063, 1030, 1000, 885, 789, 750.
  • IR 2949, 1720, 1649, 1454, 1435, 1362, 1158, 1079, 1000, 926, 736, 697.
  • IR 2955, 2930, 2870, 1736, 1702, 1629, 1608, 1458, 1435, 1407, 1377, 1260, 1230, 1192, 1150, 1093, 1051, 1002, 972, 892, 804, 791.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Wood Science & Technology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to the field of organic synthesis and more particularly to a new process for the preparation of a compound of formula (I), in the form of any one of its isomers or a mixture thereof, Formula (I) wherein, more preferably, G represents a C=O group, R1 represents a butyl group and R2 represents a methyl group. The process of the invention involves an 2-(1-hydroxyalkyl)-cyclopent-2-en-1-one derivative, as starting material, which can be then converted into a compound of formula (I) by a process comprising a thermal rearrangement. The 2-alkylidene-3-oxo-cyclopentylacetate derivative and the 2-(1-hydroxyalkyl)-cyclopent-2-en-1-one derivative are also an object of the invention.

Description

A PROCESS FOR THE PREPARATION OF A KYLIDENECYC OPENTANONE DERIVATIVES
Technical field
The present invention relates to the field of organic synthesis and more particularly to a new process for the preparation of a 2-al ylidene-3-oxo-cyclopentylacetate derivative, as defined further below. Said process comprises the reaction of a 2-(l-hydroxyalkyl)- cyclopent-2-en-l-one derivative with a suitable orthoester or malonate to obtain an intermediate which undergoes a thermal rearrangement to give the desired final compound.
The 2-alkylidene-3-oxo-cyclopentylacetate derivative, as well as the 2-(l- hydroxyalkyl)-cyclopent-2-en-l-one derivative are also objects of the invention.
Prior art
Cyclopentanone derivatives such as Hedione® (methyl 3-oxo-2-pentyl-l- cyclopentaneacetate; origin Firmenich S.A.), methyl 3-oxo-2-(2-pentenyl)-l- cyclopentaneacetate (methyl jasmonate) or methyl 3-oxo-2-pentyl-l-cyclopentene-l- acetate, are very important ingredients of the perfumery industry. Consequently, there is a need for new intermediates, and processes for their preparation, which can be advantageously employed in the synthesis of the above-mentioned perfuming ingredients.
In the literature there is no report, nor suggestion, of a process for the synthesis of a 2-alkylidene-3-oxo-cyclopentylacetate derivative, as defined below, involving the rearrangement of, a 2-(l-hydroxyalkyl)-cyclopent-2-en-l-one derivative as reported below.
Moreover, amongst the final compounds of the invention's process only methyl 3-oxo-2-pentylidene-cyclopentaneacetate is known in the prior art (S.Shicheng et al. in Youji Huaxue, 1986, 6, 453-6). However, said compound has been obtained by a process "totally'liifferent "from "the one of the present invention. Furthermore, the" 2-( - hydroxyalkyl)-cyclopent-2-en-l-one derivative, as defined further below, have not been reported or suggested in the literature. Description of the invention
The present invention relates to a new process, aimed at the synthesis of a compound of formula (I), in the form of any one of its isomers or a mixture thereof,
wherein G represents a C=O or C(OR)2 group, R representing, taken separately, a Ci-Cs alkyl group or, taken together, forming, together with the carbon and oxygen atoms of said G, a C3-C7 1,3-dioxacycloalkane ring; and a) R1 represents a n-butyl group or a CH2X, CHO or CH3-nZn group, X standing for a halogen atom or a (3c-ethyl-bicyclo[2.2.1]hept-5-ene-2r-yl)methyl group; n being 1 or 2 and Z standing for a C(OR)2, OR3 or SR3 group; R representing a group as defined previously for G; and R3 representing, taken separately, a C1-7 benzyl, alkyl, cycloalkyl or oxacycloalkyl group or a C1-7 acyl, sulfonyl or silyl group, or, taken together, forming, together with the carbon and oxygen or sulfur atom to which they are bonded, a C3-C7 1,3-dioxacycloalkane or 1,3-dithiacycloalkane ring; and b) R2 represents a linear or branched to C4 alkyl group. Said process comprises the conversion of a 2-(l-hydroxyalkyl)-cyclopent-2-en-l- one derivative of formula (IT), in the form of any one of its isomers or a mixture thereof,
wherein G and R1 have the meaning indicated in formula (I); into a compound of formula (I).
Preferred compounds of formula (I) or (H) are those wherein R1 represents a n-butyl group or a CH2X, CHO or CH3-nZπ group, X standing for a halogen atom, n being 1 or 2 and Z standing for a OR3 or SR3 group, R and R3 representing a group as defined above.
More preferably, in formula (I) or (H), G represents a CO group or a C - 1,3- dioxacycloalkane group, R1 represents a n-butyl group, a C(OR)2 group, R representing a group as defined above, a CH2C1 or a CH2Br group, or alternatively a CH2OR3 group, R3 representing a C1-7 benzyl, alkyl, cycloalkyl or oxacycloalkyl group or a C1-7 acyl, sulfonyl or silyl group, and R represents a methyl group. Even more preferably, G represents a CO group, R1 represents a n-butyl group and R2 represents a methyl group.
The conversion of the compound of formula (II) into a compound of formula (I), may be carried out by reacting the former with an orthoester, or a malonate, derivative to obtain an intermediate of formula (IH) or (HI'), respectively
m (nr)
wherein G, R1 and R2 are as defined in formula (I) or (II), and R4 represents a R2 group or a Si(R5)3 group wherein R5 is a C C4 alkyl group.
Said intermediate is subsequently thermally rearranged, e.g by a rearrangement of the Claisen type, and if necessary decarboxylated, to provide a compound of formula (I). The isolation, or purification, of the intermediate (HI) or (HI'), prior to its conversion into (I), is not mandatory, so that the invention's process is carried out as a "one-pot" process.
Useful orthoesters or malonates are those of formula CH3C(OR2)3 or CH (COOR4)2, respectively, R2 and R4 being defined above. Preferred orthoesters or malonates are those wherein R2 represents a methyl group. The orthoesters are preferred over-the-malonates.
A specific example of the overall invention's process is given in following scheme: Scheme (1)
(UJ)
1 9 wherein G, R and R are as defined in formula (I) or (H).
The intermediate (in) or (HI') are advantageously obtained by reacting together the compound of formula (H) with an orthoester or a malonate derivative in the presence of an acid, such as a C O carboxylic acid, optionally halogenated, or a C O sulfonic acid. Non limiting examples of such an acid are acetic, propionic, pivalic, trifluoroacetic, camphor sulfonic acid and p-TsOH (para toluenesulfonic acid). Said acid may be added in a catalytic amount, e.g. between 0.1 and 30 mol%, preferably between 5 and 20 mol%, with respect to the compound of formula (H).
The thermal rearrangement of the intermediate (HI) or (HI') is achieved by heating the reaction medium at a temperature comprised between 60° and 180°C, preferably between 90° and 120°C.
In the case where an orthoester derivative is used, it is understood that the intermediate (HI) will provide directly a compound of formula (I) after the thermal rearrangement. However, in the case where there is used a malonate derivative, the rearrangement of the intermediate (HI') will provide another malonate which will require a decarboxylation, more precisely a saponification followed by a decarboxylation and finally an esterification with an alcohol of formula R2OH, wherein R2 has the meaning indicated in formula (I), to provide a compound of formula (I).
All the transformations carried out in the invention process may be performed in the presence or absence of a solvent. Whenever a solvent is used, one can cite as non- -limiting examples -solvents -such as the orthoester - and -malonate -derivatives -described- hereinabove, aromatics (e.g. toluene or xylene) or hydrocarbons (e.g. decane or decaline). Preferably, and in particular for the invention processes involving a compound (IT) wherein R1 represents a substituted methyl or methylene group, the thermal rearrangement is carried out under anhydrous conditions.
The invention will now be described in further detail by way of the following examples, wherein the abbreviations have the usual meaning in the art, the temperatures are indicated in degrees centigrade (°C); the NMR spectral data were recorded with a 360MHz machine in CDC13, the chemical displacement δ are indicated in ppm with respect to the TMS as standard, the coupling constant J are expressed in Hz and all the abbreviations have the usual meaning in the art.
Example 1
Synthesis of 2-( 1 -hvdroxypentyl -2-cyclopenten- 1 -one
A solution of cyclopentenone (1.23 g, 15 mmol), pentanal (1.94 g, 22.5 mmol), rac-\,Y- bi-2-naphthol (429 mg, 1.5 mmol) and tributyl phosphine (606 mg, 3 mmol) in dry THF (12 ml) was stirred at 20°C under Argon for 3 hours. The solution was then passed through a short column of SiO2 (cyclohexane/Et2O 6:4) to obtain the pure title compound in 92% yield. IR: 3412, 2925. 2858, 1682, 1630, 1440
MS: 168 (M+, 0), 150(18), 135(10), 121(12), 111(100), 83(19), 55(16)
1H-NMR: 0.92 (t, J=7, 3H); 1.33 (m, 4H); 1.43 (s, 1OH); 1.68 (m, 2H); 2.45 ( , 2H);
2.60 (m, 2H); 4.46 (t, J=7, 1H); 7.49 (t, J=1.5, 1H) 13C-NMR: 14.0(q), 22.6(f), 26.6(f), 27.6(f), 35.3(f), 35.6(f), 67.7(d), 148.0(s), 158.1(d), 210.4(s)
Synthesis of methyl 3-oxo-2-pentylidene-l-cyclopentaneacetate
A mixture of 2-(l-hydroxypentyl)-2-cyclopenten-l-one (720 mg, 4.2 mmol) and pivalic acid (100 mg, 0.98 mmol) in trimethylorthoacetate (5 ml, 39.3 mmol) was heated at 1T5°C for 3 "hours with distillation of-MeOH. The concentrated reaction -mixture was bulb-to-bulb distilled to afford the title compound in 88% yield and in the form of a 66:34 (Z)I(E) mixture. Z isomer:
MS: 224(M+, 70), 167(18), 151(100), 133(23), 121(34), 109(54), 93(40), 79(46) 1H-NMR: 0.90 (t. J=7, 3H); 1.36 (m, 4H); 1.43 (m, IH); 2.19 (m, IH), 2.37 (m, 5H); 2.60 (dd, J=7,15, IH); 2.70 (m, IH); 3.70 (s, 3H); 5.90 (dt, J=2,7, IH) 13C-NMR: 14.0(q), 22.4(t), 25.3(f), 27.3(f), 31.5(f), 38.2(t), 38.7(d), 39.4(f), 51.7(q), 137.8(s), 141.6(d), 172.5(s), 207.6(s) E isomer:
MS: 224(M+, 70), 167(16), 151(100), 133(22), 121(29), 109(58), 93(36), 79(41), 67(22) 1H-NMR: 0.92 (t, J=7, 3H); 1.36 (m, 4H); 1.57 (m, IH); 2.19 (m, IH), 2.37 ( , 5H); 2.60 (dd, J=7, 15, IH); 2.71 (m, IH); 3.70 (s, 3H); 6.59 (dt, 1=2,1, IH)
13C-NMR: 13.9(q), 22.5(f), 25.3(f), 29.0(t), 30.8(f), 35.0(d), 35.8(f), 38.6(f), 51.8(q), 138.4(d), 139.8(s), 172.4(s), 206.4(s)
Example 2
Synthesis of other inventions compounds
a) General procedure for the preparation of the compounds of formula (II)
A solution of cyclopentenone (1.0 molar equivalents), the appropriate aldehyde (1.50 molar equivalents), l,F-bi-2-naρhthol (0.1 molar equivalents) and «Bu3P
(0.2 molar equivalents) in THF (800 ml/mol of cyclopentenone) is stirred at 20°C under Argon for 3-15 hrs. The crude reaction mixture is passed through a short column of SiO (chexane/Et2O 7:3) to separate the desired product from the starting aldehyde and nBu3P as well as form l,l'-bi-2-naphthol.
i) 2-( 1 -hyΦoxy-2,2-dimethoxyethyl -2-cyclopenten- 1 -one
Obtained in 96% yield according to the general procedure and using glyoxal-1,1- dimethyl acetal (in the form of a 45% solution, in tBuOMe) as starting aldehyde.
IR: 3430, 2922, 2832, 1691, 1632, 1440, 1344, 1248, 1189, 1125, 1100, 972, 921, 789, 731.
1H-NMR: 1.5 (brs, 1 H); 2.45 ( , 2H); 2.67 (m, 2H); 3.43 (s, 3H); 3.46 (s, 3H); 4.5 (s, 2H); 7.65 (t, J=3, IH). 13C-NMR: 27.0(f), 35.1(f), 55.3(q), 55.5(q), 67.6(d), 104.9(d), 147.7(s), 161.2(d),
209.2(s). MS: 186 (0, M+), 155 (4), 123 (15), 75 (100), 47 (12).
ii) 2-r2-( enzyloxyV 1 -hydroxyethyl] -2-cyclopenten- 1 -one
Obtained in 65% yield according to the general procedure and using (benzyloxy) acetaldehyde as starting aldehyde.
IR: 3420, 2930, 2855, 1695, 1632, 1495, 1452, 1327, 1249, 1193, 1098, 1028, 1000, 900. 1H-fNlMR: 2.42 (m, 2H); 2.61 (m, 2H); 3.20 (brs, 1 H); 3.47 (dd, J=4, 7, IH); 3.72 (dd,
J=4, 7, IH); 4.56, q, J=7, 2H); 4.67 (m, IH); 7.28, (m, 5H); 7.62 (t, J=3, IH). 13C-NMR: 26.8(f), 35.2(f), 66.9(d), 72.7(f), 73.3(f), 127.8(s), 127.8(2d), 128.5(2d),
137.8(s), 144.9(s), 160.0(d), 208.8(s). MS: 232 (0, M+), 111 (66), 91 (100), 65 (18).
iii) 2- 2-(Ethyloxy)- 1 -hydroxyethyl] -2-cyclopenten- 1 -one
Obtained in 27% yield according to the general procedure and using 2-ethyloxy- acetaldehyde as starting aldehyde.
IR: 3429, 2972, 2865, 1739, 1690, 1632, 1439, 1347, 1248, 1111, 1063, 1030, 1000, 885, 789, 750.
1H-NMR. 1.2 (t, 3H); 2.3 (m, IH); 2.45 (m, 2H); 2.62 (m, 2H); 3.4 (m, IH); 3.55 (m,
2H); 3.7 (m, IH); 4.65 (m, IH); 7.65 (dt, J=2, 3, IH). 13C- MR: 15.1(q), 26.8(f), 35.2(f), 61.8(f), 66.7(d), 72.9(f), 145.1(d), 159.9(s), 208.9(s). MS: 170 (1, M+.), 152 (23), 123 (15), 111 (100), 95 (20), 79 (18), 59 (19).
iv) 2-[(3-Ethylbicvclor2.2.1]hept-5-en-2-yl (hvdroxy)methyll-2-cvclopenten-l-one Obtained in 27 % yield according to the general procedure and using 1.1 molar equivalent of -a -6.5-. -1- -mixture of -cis-~endo/cis-exo eth lbicy-clo ^-^ Jb^pi-S-jene^.- carbaldehyde as starting aldehyde.
IR: 3500, 1703. 1H- MR (main isomer): 0.92 (t, J=7, 3H); 1.2-1.6 (m, 2H);1.86 (m, IH); 2.18 (m, IH); 2.31 (m, 2H); 2.4 (m, 2H); 2.6 (m, 2H); 2.95 (AB, 2H); 3.94 (d, J=7, IH); 5.97 (m, IH); 6.19 (m, IH); 7.36 (t, J = 3, IH). 13C- MR (main isomer): 13.3(q), 21.1(f), 33.3(d), 35.4(f), 38.1(f), 43.2(f), 44.1(d), 44.8(d), 45.9(d), 68.8(d), 134.5(d), 136.0(d), 147.5(s), 159.0(d), 210.1(s).
MS: cis-endo stereoisomer 1 232 (1, M1"), 167 (8), 165 (6), 149 (100), 137 (17), 111 (19), 66 (45); cis-endo stereoisomer 2 232 (3, M+), 167 (5), 165 (10), 149 (100), 137 (20), 111 (13), 66 (40); cis-exo stereoisomer 1 232 (2, M+), 167 (5), 165 (7), 149 (100), 137 (17), 107
(18), 66 (51); cis-exo stereoisomer 2 232 (3, M+), 167 (4), 165 (11), 149 (100), 137 (21), 111 (15), 66 (42).
b) General Procedure B for the Claisen rearrangement
A mixture of a compound (II) (1.0 molar equivalents), trimethyl-orthoacetate (1770 ml/mol of compound (H)) and pivalic acid (0.17 molar equivalents) was heated at 120°C for 3 hrs with distillation of MeOH. The reaction mixture was concentrated and bulb-to-bulb distilled to the corresponding compound (IH) as E:Z mixtures.
i) Methyl [2-f2,2-dimethoxyethylideney3-oxocyclopentyl]acetate Obtained in 96% yield according to the general procedure and using compound (H) described under a.i) as starting material. The reaction mixture was concentrated and bulb-to-bulb distilled (180°C/0.1 mbars) to afford title compound as a 3:2 E:Z mixture. TR (major isomer): 2950, 2831, 1726, 1701, 1656, 1438, 1366, 1244, 1167, 1124, 1080,
989, 967, 891. (minor isomer): 2949, 2831, 1725, 1701, 1653, 1436, 1363, 1261, 1168, 1124, 1080, 965, 892. -H- 4R-(major isomer): 1.-90 (m, IH); 2.10 (m, IH); 2.65 (m, lH);.2.45-(m, 3H); 3.31 (s, 3H); 3.35 (s, 3H); 3.71 (s, 3H); 5.12 (d, J= 7, IH); 6.48 (dd, J=7, 3, IH). (minor isomer): 1.90 (m, IH); 2.10 (m, IH); 2.65 (m, IH); 2.35 (m, 3H); 3.40 (s, 3H); 3.43 (s, 3H); 3.71 (s, 3H); 5.75 (dd, J=7, 3, IH); 5.90 (d, J-7, IH). 13C-NMR (major isomer): 26.5(f), 35.2(d), 35.3(f), 38.6(f), 51.7(q), 52.1(q), 52.7(q), 99.7(d), 143. l(s), 161.7(d), 172.2(s), 206.5(s). (minor isomer): 27.0(f), 34.7(f), 38.0(f), 38.5(d), 49.7(q), 49.8(q), 50.0(q), 97.2(d),
141.0(s), 161.1(d), 172.1(s), 206.7(s). MS(major isomer): 242 (20, M1"), 211 (80), 169 (100), 151 (96), 109 (59), 75 (73). (minor isomer): 242 (2, M+), 211 (30), 195 (22), 169 (100), 151 (40), 109 (30).
ii) Methyl {2-[2-(Benzyloxy)ethyridene~|-3-oxocvclopentyl| acetate
Obtained in 68% yield according to the general procedure and using compound (H) described under a.ii) as starting material.
IR: 2949, 1720, 1649, 1454, 1435, 1362, 1158, 1079, 1000, 926, 736, 697.
1H-NMR: 1.50 ( , 2H); 2.1-2.9 (m, 6H); 3.64 (s, 3H); 4.20 (d, J=7, 2H); 4.65 (AB, 2H); 6.68 (t, J=7, IH); 7.32 (m, 5H).
13C-NMR: 27.0(f), 35.2(d), 37.7(f), 38.8(f), 51.7(q), 67.1(f), 71.4(f), 126.9(2d), 127.4(d), 128.4(2d), 132.8(d), 136.6(s), 150.1(s), 172.6(s), 206.1(s)
MS: 288 (1, M+), 197 (27), 165 (9), 91 (100), 65 (9).
iii) Methyl {2-[2-(Ethyloxy)ethylidene]-3-oxocyclopentyl>acetate
Obtained in 53% yield according to the general procedure and using compound (H) described under aiii) as starting material. The product obtained is a mixture containing the E and Z isomer in a 1/1 ratio. TR: 2952, 1720, 1697, 1650, 1436, 1406, 1375, 1156, 1002, 929, 890, 790. 1H- MR: (E)-isomer: 1.2 (t, J=7, 3H); 1.5-2.7 (m, 7H); 3.5 (m, 2H); 3.7 (s, 3H); 3.75
(m, 2H); 6.62 (dt, J = 2, 5.5, IH); (Z)-isomer: 1.2 (t, J=7, 3H); 1.5-2.7 (m, 7H); 3.5 (m, 2H); 3.7 (s, 3H); 3.75 (m, 2H);
6.0 (dt, J=2, 5.5, IH). -MS: (E)-isomer: 226-(-78, -M÷,), 197 (20), 170 (40), -,53.(60), 125 (40), 111 (1QQ), 98 (43), 83 (65); (Z)-isomer: 226 (62, M\), 197 (40), 170 (40), 153 (100), 125 (97), 111(80), 98 (40), 83 (50).
iv) Methvir2-(3endo-ethylbicvclor2.2.11hept-5-en-2endo-vnmethylenel-3- oxocvclopentyl)acetate & methyl[2-(3exo-ethylbicvclo[2.2.1]hept-5-en-2exo- yl]methylene]-3-oxocvclopenfyl)acetate Obtained in 55% crude yield according to the general procedure and using compound (H) described under a.iv) as starting material.
IR: 2955, 2930, 2870, 1736, 1702, 1629, 1608, 1458, 1435, 1407, 1377, 1260, 1230, 1192, 1150, 1093, 1051, 1002, 972, 892, 804, 791.
1H-NMR: 0.92 (t, J=7, 3H); 1.42 (sext, J=7, 2H); 1.55 (m, 2H); 1.69 (m, 2H); 1.88 (m, IH); 2.05 (m, IH); 2.22 (m, 2H); 2.35 (m, 2H); 2.45 (m, IH); 2.50 (m, 2H); 2.62 (m, IH); 3.28 (s, 3H); 6.09 (m, 2H); 7.32 (m, IH). MS: 288 (A, M+), 207(7), 117(8), 44(14), 32(27), 28(100).
v) Ethyl["2-(3endo-ethylbicyclo 2.2.11hept-5-en-2endo-yl]methylene1-3- oxocvclopentyl acetate & Ethvir2-(3exo-ethylbicyclo["2.2.1 hept-5-en-2exo- yl]methylenel-3-oxocyclopenfyl acetate Using triethyl-orthoacetate instead of trimethyl-orthoacetate, and a bulb-to-bulb distilled (200°C/0.1 mbars) the title compound was obtained in 50% yield as a 1/2/3/4 mixture of 4 isomers ( cis-E/Z and endo/exo-isomers). IR: 2955, 2930, 2870, 1735, 1700, 1630, 1610, 1460, 1435, 1405, 1380, 1260, 1230,
1190, 1150, 1095, 1050, 1000. 1H-NMR (main isomer): 0.80 (t, 3H); 0.85-1.25 (m, 3H); 1.26 (t, 3H); 1.30-3.5 (m, 12H); 6.55, (d, J = 11, IH); 4.18 (q, J = 7, 2H); 6.05 ( , IH); 6.25 (m, IH).
13C-NMR (main isomer): 12.9(q), 14.3(q), 26.5(f), 34.6(d), 35.9(f), 38.4(f), 39.0(d),
42.9(d), 45.5(d), 46.7(f), 49.5(f), 49.9(d), 60.7(f), 134.9(d), 135.2(d), 136.8(s), 156.7(d), 172.1(s), 205(s). S: cis-endo diastereoisomer 1, 302 (4, -M1"), 237 (6), 236 (12), 20-7 -(100), 149 -(13), 117 (14), 91 (18); cis-endo diastereoisomer 2, 302 (20, M÷), 273 (17), 237 (11), 236 (14), 207 (100),
149 (19), 132 (36), 117 (56), 91 (42); cis-exo diastereoisomer 1, 302 (0, M+), 237 (22), 236 (7), 207 (100), 149 (16), 91
(15); cis-exo diastereoisomer 2, 302 (10, M+), 236 (10), 207 (100), 149 (19), 117 (22),
91 (28).

Claims

Claims
1. A process for the preparation of a compound of formula (I), in the form of any one of its isomers or a mixture thereof,
wherein G represents a C=O or C(OR) group, R representing, taken separately, a Ci-C5 alkyl group or, taken together, forming, together with the carbon and oxygen atoms of said G, a C3-C7 1,3-dioxacycloalkane ring; a) R1 represents a n-butyl group or a CH2X, CHO or CH3-nZn group, X standing for a halogen atom or a (3c-ethyl-bicyclo[2.2.1]hept-5-ene-2r-yl)methyl group; n being 1 or 2 and Z standing for a C(OR)2, OR3 or SR3 group; R representing a group as defined previously for G; and R3 representing, taken separately, a Cι,7 benzyl, alkyl, cycloalkyl or oxacycloalkyl group or a C1- acyl, sulfonyl or silyl group, or, taken together, forming, together with the carbon and oxygen or sulfur atom to which they are bonded, a C3-C 1,3-dioxacycloalkane or 1,3-dithiacycloalkane ring; and b) R2 represents a linear or branched Q to C4 alkyl group; said process comprising the conversion of a compound of formula (IT), in the form of any one of its isomers or a mixture thereof,
wherein G and R1 have the meaning indicated in formula (I); into a compound of formula (I).
2. A process according to claim 1, characterized in that the conversion is carried out by reacting a compound of formula (H), as defined in claim 1, with an orthoester, or a malonate, derivative of formula CH C(OR )3 or CH2(COOR )2, respectively, R bemg as defined in formula claim 1, to obtain an intermediate of formula (Til) or (HI'), respectively
wherein G, R1 and R2 are as defined in claim 1, and R4 represents a R2 group or a Si(R5)3 group wherein R5 is a Ci-C4 alkyl group, which, subsequently, is thermally rearranged and optionally decarboxylated.
3. A process according to claim 2, characterized in that the conversion is carried out by reacting a compound of formula (H) with an orthoester of formula CH3C(OR2) , wherein R2 is as defined in claim 1.
4. A process according to any one of claims 1 to 3, characterized in that R1 represents a n-butyl group or a CH2X, CHO or CH3-nZn group, X standing for a halogen atom, n being 1 or 2 and Z standing for a OR3 or SR3 group, R and R3 representing a group as defined in claim 1.
5. A process according to claim 4, characterized in that G represents a CO group or a C3-4 1,3-dioxacycloalkane group, R1 represents a n-butyl group, a C(OR)2 group, R representing a group as defined in claim 1, a CH2C1 or a CH2Br group, or alternatively a_ CElzOR group, R representing a Cι-7 benzyl, alkyl, cycloalkyl or oxacycloalkyl group or a C .η acyl, sulfonyl or silyl group, and R2 represents a methyl group.
6. A process according to claim 4, characterized in that G represents a CO group, R represents a n-butyl group and R represents a methyl group.
in the form of any one of its isomers or a mixture thereof, wherein G and R1 have the meaning indicated in any one of claims 1 or 4 to 6.
8. A compound according to claim 7, characterized in that G represents a CO group and R3 represents a butyl group.
9. A compound of formula
in the form of any one of its isomers or a mixture thereof, wherein G, R1 and R2 are as defined in any one of claims 1 or 4 to 6; provided that methyl 3-oxo-2-pentylidene- cyclopentaneacetate is excluded.
EP03758513A 2002-11-11 2003-10-30 A process for the preparation of alkylidenecyclopentanone derivatives Withdrawn EP1562888A1 (en)

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