Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B35/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving a change in the type of bonding between two carbon atoms already directly linked
  • C07B35/04—Dehydrogenation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B41/00—Formation or introduction of functional groups containing oxygen
  • C07B41/04—Formation or introduction of functional groups containing oxygen of ether, acetal or ketal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B41/00—Formation or introduction of functional groups containing oxygen
  • C07B41/06—Formation or introduction of functional groups containing oxygen of carbonyl groups

Definitions

• the present invention relates to a method of functionalising a chemical molecule having at least two conjugated or conjugatable double bonds or containing at least one double bond conjugated with an electron-rich structure.
• Said functionalisation is obtained by the addition of nucleophile compounds (Nu) comprising at least one atom chosen from among oxygen (O), nitrogen (N), sulphur (S), fluorine (F) or iodine (I).
• Nu nucleophile compounds
• Nu comprising at least one atom chosen from among oxygen (O), nitrogen (N), sulphur (S), fluorine (F) or iodine (I).
• the invention relates to a method of functionalising a chemical molecule having at least two double bonds or containing at least one double bond conjugated with an electron-rich structure, in the presence of an electrophorus mediator and a nucleophile compound.
• the functionalisation method can also include a system of electrochemical regeneration of the electrophorus mediator.
• Functionalisation is used in the context of the present invention to refer to the introduction of functional grouping in an unsaturated molecule, linear or cyclic, conjugated or conjugatable, having at least two double bonds or containing at least one double bond conjugated with an electron-rich structure.
• the functionalisation of a non-conjugated diolefin produces a functionalised conjugated diolefin (Formula I):
• Nucleophile compound is used in the context of the invention to refer to any chemical molecule with excess electrons and which is therefore capable of affecting species that are lacking electrons and which comprise at least one atom chosen from among oxygen (O), nitrogen (N), sulphur (S), fluorine (F) or iodine (I).
• the nucleophile compound preferably comprises an atom chosen from between oxygen (O) and sulphur (S).
• Electrophorus mediator is used in the context of the invention to refer to the so-called oxidised form (called oxoammonium or nitrosonium) of a molecule comprising at least one aminoxyl radical (Formula II): p in which R 1 and R 2 are groups, identical or different, cyclic or linear.
• the electrophorus mediator is preferably the oxoammonium form of a chemical molecule of the bi-permethylated aminoxyl radical family containing at least one aminoxyl radical.
• TEMPO 2,2,6,6-tetramethylpiperidinyl-1-oxy
• 4-acetamido-TEMPO Form III:
• the preparation of the mediator based on the aminoxyl radical can be carried out:
• the mediator can be used in stoichiometric quantity or in catalytic quantity, assisted by an electrochemical system.
• the functionalisation can be carried out at temperatures ranging from 0° C. to 80° C., preferably from 5° C. to 40° C., with a pH ranging from 0 to 13, preferably from 4 to 7, according to two methods:
• a first step the molecule to be functionalised, at least one equivalent of mediator and at least one equivalent of a nucleophile compound are successively added to a reaction chamber containing an organic or hydro-organic reaction medium.
• the mixture is subjected to mechanical or magnetic stirring for 1 to 10 hours, preferably for 2 to 5 hours.
• the reaction mixture is purified according to protocols known to those skilled in the trade.
• an aminoxyl radical is inserted in at least stoichiometric quantity in an electrolytic solution containing a support electrolyte.
• the aminoxyl is oxidised in oxoammonium (the mediator).
• the oxidation reaction takes place by subjecting the working electrode to a potential that can be comprised between 0 and 1.2 volts, preferably between 0 and 0.6 volts in relation to an Ag/AgNO 3 reference electrode.
• the potential is applied with the help of a generator and controlled by means of a potentiostat, until the aminoxyl radical is completely transformed into oxoammonium ions.
• the molecule to be functionalised and at least one equivalent of nucleophile are successively inserted.
• the amount of mediator can be 0.5 to 5 equivalents in relation to the molecule to be functionalised, preferably from 1 to 4 equivalents, according to the desired speed of reaction and the type of nucleophile.
• the solution can be stirred for a time comprised between 1 and 10 hours, preferably comprised between 2 and 5 hours.
• the obtained raw product is purified according to any protocol known to those skilled in the trade.
• An example of such a protocol is flash chromatography.
• the electrophorus mediator when used in catalytic quantity in the second step, it must be regenerated by an electrochemical system.
• a catalytic quantity of aminoxyl radical, the molecule to be functionalised and an at least equivalent quantity of nucleophile are successively added to the electrolytic solution.
• the reaction takes place with a basic pH.
• the working electrode can be subjected to a potential comprised between 0 and 1.2 volts, preferably between 0 and 0.6 volts in relation to a reference electrode.
• the electrophorus mediator is in a quantity ranging from 2% to 50% in relation to the molecule to be functionalised, preferably between 5% and 30%.
• the nucleophile can be a chemical molecule with excess electrons comprising at least one atom chosen from among oxygen (O), nitrogen (N), sulphur (S), fluorine (F) or iodine (I), preferably a chemical molecule chosen from among H 2 O, RCOO ⁇ , MeOH, N 3 ⁇ , SCN ⁇ , F ⁇ , I ⁇ or CH 3 S ⁇ .
• the nucleophile can be used according to the method of the invention in a quantity ranging from 1 to 10 equivalents and preferably from 1 to 5 equivalents.
• the nucleophile can be the solvent in which the reaction occurs.
• the reaction can take place in any electrochemical reaction chamber known to those skilled in the trade, closed or circulating, made up of at least one working electrode (anode) and one auxiliary electrode (cathode).
• the electrochemical reaction chamber can also preferably comprise a reference electrode that can be any reference electrode generally used for such reactions, for example, an Ag/AgNO 3 electrode, or a saturated calomel electrode (SCE).
• the reference electrode is preferably an Ag/AgNO 3 electrode. The presence of a reference electrode makes it possible to control the potential of the working electrode.
• the electrochemical reaction chamber comprises at least two or three electrodes.
• the electrochemical reaction chamber therefore comprises at least:
• auxiliary electrode separated from the working electrode by an ion-exchange membrane (for the system with two or three electrodes),
• the working electrode is separated from the auxiliary electrode by an ion-exchange membrane such as Nafion®, preferably a cation-exchange membrane such as Nafion® 423.
• an ion-exchange membrane such as Nafion®, preferably a cation-exchange membrane such as Nafion® 423.
• the potential applied to the work electron can be comprised between 0 and 1.2 volts, preferably between 0 and 0.6 volts in relation to the Ag/AgNO 3 reference electrode.
• the reaction medium which can be used according to the method of the invention, can be any reaction medium known to those skilled in the trade, allowing the oxidation of the aminoxyl radical to oxoammonium ions (the mediator) and the functionalisation reaction.
• Reaction medium is used in the context of the invention to refer to any medium that allows the solubilisation of the reactive species and of the support electrolyte if the reaction is carried out by the electrochemical method.
• An example of a reaction medium that can be used according to the invention is acetonitrile (ACN), tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO) and any other mixture of water/organic solvent.
• acetonitrile ACN
• dimethylformamide DMF
• these solvents can be used dry or in the presence of a quantity of water ranging from 1% to 80% and preferably 5% to 40% when the chosen nucleophile is water.
• the reaction medium also comprises a support salt that allows current to pass through the solution, at concentrations ranging from 0.02 M to 2 M, preferably from 0.05 M to 0.5 M.
• the salt can be chosen from among NaClO 4 , LiClO 4 , LiCl.
• the support salt used is NaClO 4 .
• the chemical molecule to be functionalised has at least two double bonds or contains at least one double bond conjugated with an electron-rich structure.
• the chemical molecule to be functionalised can be a linear or cyclic olefin.
• olefins can be mentioned as a functionalisable molecule, in particular an olefin chosen from among the polyunsaturated fatty olefins such as, for example, methyl-linoleate or methyl-linolenate.
• the functionalisation reaction and/or the oxidation reactions of the aminoxyl radical can be performed at a temperature ranging from 0° C. to 80° C., preferably from 2° C. to 40° C.
• the method can comprise an additional prior step of preparing the mediator.
• the aminoxyl radicals can be used in a quantity that can range from 1 to 4 equivalents in relation to the molecule to be functionalised, depending on the desired speed of reaction and the type of nucleophile.
• the aminoxyl radicals can be used in a quantity that can range from 5% to 100% and preferably from 5% to 30% in relation to the molecule to be functionalised, depending on the desired speed of reaction and the type of nucleophile.
• the use of a basic organic or hydro-organic reaction medium allows the regeneration of the reduced form of the mediator.
• Basic organic or hydro-organic medium refers to a medium with pH comprised between 7 and 12, preferably between 9 and 11.
• the base used in the reaction medium can be any organic or inorganic base, but it must be very capable of being oxidised by the mediator, for example, 2,6-lutidine or pyridine.
• the invention also comprises other arrangements that will emerge from the following description, which refers to examples of implementation of the invention.
• the cell of 50 cm 3 , in a medium of acetonitrile/water (12/1) contains:
• the electrochemical system consists of:
• the potential of the working electrodes is increased to 0.56 V/Ag/AgNO 3 (0.1 M).
• the electrical current drops from 50 mA at the start of the reaction to 1 mA after 6 hours of reaction and 580 coulombs consumed (6 F/mol).
• the treatment of the reaction medium consists of:
• the raw product (280 mg) is dissolved in 0.2 ml of acetone and eluted on a chromatographic column with 500 ml of ether/petroleum ether (1/3).
• the obtained product has a structure that conforms to the spectroscopic and spectrometric analyses:
• RMN 1 H TM H (300 MHz, CDCl 3 ): 7.22 (m, 2 H, J 15, H 12 , H 15 ); 6.68 (dd, 2 H, J 7, H 13 , H 14 ); 6.32 (dd, 2 H, J 15.1, H 11 , H 16 ); 3.66 (s, 3 H, H 1 ); 2.62 (q, 2 H, J 7.3, H 18 ); 2.57 (t, 2 H, J 6.5, H 9 ); 2.30 (t, 2 H, J 6.6, H 3 ); 1.61 (m, 2 H, H 6 ); 1.32 (m, 8 H, H 4 , H 5 , H 7 , H 8 ); 1.01 (t, 3 H, J 7.3, H 19 )
• RMN 13 C ⁇ C (300 MHz, CDCl 3 ): 200.9 (C 10 ), 200.6 (C 17 ); 174.4 (C 2 ); 140.4 (C 12 ); 140.3 (C 15 ); 138.3 (C 13 ); 138.2 (C 13 ); 132.2 (C 11 ); 132.0 (C 16 ); 51.5 (C 1 ); 41.1 (C 9 ); 34.3 (C 18 ); 34.0 (C 3 ); 29.0 (C 8 ); 29.0 (C 6 ); 28.9 (C 7 ); 24.4 (C 5 ); 14.1 (C 4 ); 8.1 (C 19 )
• reaction conditions and the quantities of reactive agents are strictly identical to those mentioned in example 1.
• the reaction is conducted on 1 millimole of methyl-linoleate at 45° C.
• the current drops from 55 mA to 0.5 mA in 4 hours after a consumption of 384 coulombs (4 F/mol).
• the treatment is identical to example 1.
• the ether/petroleum ether mixture (1/4) is used to perform the purification on chromatographic column.
• the obtained product with a yield of 94% is a mixture of 4 isomers multifunctionalised by a ketone with C 9 or C 13 .
• the double bonds of these isomers are conjugated.
• the electron displacement is therefore equal to 6 electrons.
• the following selectivities are observed: 46%: methyl 13-oxo-(9-cis, 11-trans)-octadecadienoate (Formula VI)
• RMN 1 H ⁇ H (300 MHz, CDCl 3 ): 7.44 (dd, 1 H, J 15.8, J 11.6, H 10 ); 6.12 (d, 1 H, J 15.30, H 13 ); 6.07 (dd, 1 H, J 10.67, H 12 ); 5.90 ⁇ 5.80 (m, 1 H, H 11 ); 3.63 (s, 3 H, H 1 ); 2.52 (t, 2 H, J 7.31, H 15 ); 2.29 (t, 2 H, J 6.43, H 3 ); 2.29 (q, 2 H, H 9 ); 1.59 (m, 4 H, H 4, H 16 ); 1.39 (m, 2 H, H 17 ); 1.29 (m, 10 H, H 18 , H 8 , H 7 , H 6 , H 5 ); 0.86 (t, 3 H, J 6, H 19 )
• RMN 13 C ⁇ C (300 MHz, CDCl 3 ): 201.0 (C 14 ), 174.3 (C 2 ); 142.7 (C 10 ); 137.0 (C 12 ); 129.3 (C 13 ); 126.9 (C 11 ); 51.4 (C 1 ); 41.1 (C 15 ); 34.0 (C 3 ); 31.5 (C 17 ); 29.4 (C 8 ); 29.2 (C 6 ); 29.1 (C 7 ); 29.0 (C 9 ); 28.2 (C 5 ); 24.8 (C 4 ); 24.0 (C 16 ); 22.5 (C 18 ); 13.9 (C 19 )
• RMN 1 H ⁇ H (300 MHz, CDCl 3 ): 7.44 (dd, 1 H, J 15.8, J 11.6, H 14 ); 6.12 (d, 1 H, J 15.30, H 11 ); 6.07 (dd, 1 H, J 10.67, H 12 ); 5.90 ⁇ 5.80 (m, 1 H, H 13 ); 3.63 (s, 3 H, H 1 ); 2.52 (t, 2 H, J 7.31, H 9 ); 2.29 (t, 2 H, J 6.43, H 3 ); 2.29 (q, 2 H, H 15 ); 1.59 (m, 4 H, H 4 , H 8 ); 1.39 (m, 2 H, H 7 ); 1.29 (m, 10 H, H 6 , H 16 , H 17 , H 18 , H 5 ); 0.86 (t, 3 H, J 6, H 19 )
• RMN 13 C ⁇ C (300 MHz, CDCl 3 ): 201.0 (C 10 ), 174.3 (C 2 ); 142.7 (C 12 ); 137.0 (C 14 ); 129.3 (C 11 ); 126.9 (C 13 ); 51.4 (C 1 ); 41.0 (C 9 ); 34.0 (C 17 ); 31.4 (C 3 ); 29.3 (C 16 ); 29.2 (C 7 ); 29.1 (C 5 ); 29.0 (C 15 ); 28.2 (C 6 ); 24.8 (C 4 ); 24.2 (C 8 ); 22.5 (C 18 ); 13.9 (C 19 )
• Reactions conducted using H 2 O as a nucleophile can be transposed to other nucleophiles such as methanol (MeOH).
• the reaction is then performed in the anhydrous acetonitrile.
• the methanol is added when the currents become residual.
• the cell of 50 cm 3 contains:
• the potential of the working electrodes is increased to 0.56 V/Ag/AgNO 3 (0.1 M)
• the electrical current drops from 40 mA at the start of the reaction to 1 mA after 3 hours of reaction and 230 coulombs consumed (2.4 F/mol).
• the treatment of the reaction medium is identical to that in example 1.
• the purification is carried out in on a silicon chromatographic column using a mix of ether/petroleum ether (1/4) as an eluent.
• the yield of purified product obtained is 16%.
• RMN 1 H ⁇ H (300 MHz, CDCl 3 ): 5.91 (dd, 1 H, J 15.5, J 11, H 12 ) 5.80 (dd, 1 H, J 11.10, H 11 ); 5.57 (dd, 1 H, J 15, H 13 ); 5.32 (m, 1 H, H 10 ); 3.56 (s, 3 H, H 1 ); 3.26 (m, 1 H, H 14 ); 3.19 (s, 3 H, H 15 ); 2.17 (t, 2 H, J 18, H 3 ); 2.00 (q, 2 H, J 12, H 9 ); 1.44 (m, 4 H, H 18 , H 19 ); 1.26 (m, 14 H, H 4 , H 5 , H 6 , H 7 , H 16 , H 17 ); 0.90 (t, 3 H, H 20 )
• RMN 13 C ⁇ C (300 MHz, CDCl 3 ): 174.2 (C 2 ), 134.1 (C 12 ); 131.8 (C 10 ); 131.5 (C 13 ); 129.1 (C 11 ); 78.8 (C 14 ); 55.6 (C 15 ); 51.3 (C 1 ); 34.1 (C 3 ); 33.2 (C 16 ); 29.3 (C 8 ); 29.0 (C 6 ); 28.6 (C 7 ); 28.1 (C 9 ); 27.7 (C 18 ); 26.9 (C 5 ); 25.2 (C 4 ); 25.1 (C 17 ); 22.5 (C 19 ); 13.9 (C 20 )
• the isomeric distribution is identical to that in example 2.
• reaction medium consists of:
• the stirring is performed continuously for 8 hours.
• the chromatographic yield is 24%.
• the mixture of isomers obtained has the following vinyl system (Formula XI): isomer 13-acetoxy-9, cis-11, trans-octadecadienoic acid, methyl-ester
• RMN 1 H ⁇ H (300 MHz, CDCl 3 ): 6.14 (dd, 1 H, J 15.1, J 11, H 12 ) 5.88 (dd, 1 H, J 11, H 11 ); 5.60 (dd, 1 H, J 15, H 13 ); 5.35 (m, 1 H, H 10 ); 5.18 (q, 1 H, J 6, H 14 ); 3.56 (s, 3 H, H 1 ); 2.17 (t, 2 H, J 6.5, H 3 ); 1.99 (m, 4 H, H 9 , H 16 ); 1.50 (q, 2 H, H 17 ); 1.40 (m, 8 H, H 4 , H 18 , H 19 , H 20 ); 1.26 (m, 8 H, H 5 , H 6 , H 7 , H 8 ); 0.90 (t, 3 H, H 21 )
• RMN 13 C ⁇ C (300 MHz, CDCl 3 ): 174.2 (C 2 ), 170.1 (C 15 ); 134.3 (C 13 ); 134.0 (C 12 ); 131.0 (C 10 ); 127.6 (C 11 ); 74.0 (C 14 ); 51.3 (C 1 ); 34.3 (C 17 ); 34.0 (C 3 ); 29.3 (C 8 ); 29.0 (C 6 ); 28.6 (C 7 ); 28.1 (C 9 ); 26.9 (C 5 ); 25.2 (C 4 ); 26.7 (C 19 ); 25.2 (C 4 ); 24.7 (C 18 ); 22.5 (C 20 ); 21.1 (C 16 ); 13.9 (C 21 )
• the isomeric distribution is identical to that in example 2.
• the cell of 50 cm 3 contains:
• Electrolysis is performed with a constant potential of 0.56 V/Ag/AgNO 3 (0.1 M) at 5° C.
• the electrical current drops from 75 mA to 1 mA after 6.5 hours of reaction and 1191 coulombs consumed (4 F/mol).
• the treatment of the reaction medium consists of:
• the raw product (320 mg) is dissolved in 0.5 ml of CH 2 Cl 2 , purified on a silicon column (ethyl acetate/petroleum ether: 1/1).
• the aromatic characteristic of the tropylium ion contributes greatly to the stability of the carbocation, which enables a long enough lifetime to withstand a nucleophile attack.
• the latter is immediately dehydrogenated by the oxoammonium and results in the carbonyl.
• the obtained product is an aromatic compound.
• the rate of unsaturation therefore increases by one unit according to the following steps:
• thermodynamic stability of the final aromatic structure allows the dehydration (step 4).
• the transformation is carried out in an electrochemical cell with three electrodes containing 40 cm 3 of ACN (0.1 M NaClO 4 ) and 2.5 cm 3 of H 2 O (5%).
• the electrolysis potential is set at 0.55 V/(Ag/AgNO 3 ).
• the mediator is obtained from acetamido-TEMPO (67 mg, 0.3 millimole). 400 ⁇ l of Lutidine and 258 ⁇ l of Bicyclo-(3,4,0)-nona-3,6-(1)-diolefin 2.10 ⁇ 3 mole are added.
• the electrochemical regeneration is optimal. A current drop from 150 mA to 0.5 mA can be seen in 110 minutes with an exchange of 402 coulombs corresponding to 2 F/mole.
• the initial amount of terpinene is 2 mmoles (273 mg). In both cases, 398 coulombs are consumed in 90 minutes.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Steroid Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)

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Cited By (5)

• 2004
  • 2004-03-12 FR FR0402619A patent/FR2867470B1/fr not_active Expired - Fee Related
• 2005
  • 2005-03-14 WO PCT/FR2005/000605 patent/WO2005097726A1/fr active Application Filing
  • 2005-03-14 AT AT05735540T patent/ATE411273T1/de not_active IP Right Cessation
  • 2005-03-14 EP EP05735540A patent/EP1723098B1/fr not_active Not-in-force
  • 2005-03-14 US US10/592,607 patent/US20070197790A1/en not_active Abandoned
  • 2005-03-14 DE DE602005010400T patent/DE602005010400D1/de active Active

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