US20070197790A1

US20070197790A1 - Method for the functionalization of conjugated or conjugatable derivatives assisted by a tempo-type electrophoric mediator

Info

Publication number: US20070197790A1
Application number: US10/592,607
Authority: US
Inventors: El Mustapha Belgsir; Tony Breton; Denis Liaigre
Original assignee: Centre National de la Recherche Scientifique CNRS
Current assignee: Centre National de la Recherche Scientifique CNRS
Priority date: 2004-03-12
Filing date: 2005-03-14
Publication date: 2007-08-23
Also published as: ATE411273T1; WO2005097726A1; FR2867470A1; FR2867470B1; DE602005010400D1; EP1723098A1; EP1723098B1

Abstract

The invention relates to a method for the functionalization of a chemical molecule having at least two double bonds or containing a double bond which is conjugated with a structure that is rich in electrons in the presence of a TEMPO-type electrophoric mediator and a nucleophilic agent. The functionalization method can also include a system for electrochemical regeneration of the electrophoric mediator.

Description

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).
Among the advantages of the method according to the invention, the following are notable:
the rate of unsaturation of the functionalised molecule is not reduced after functionalisation;
the functionalisation is assisted by an oxidation mediator,
the transformations are carried out under normal conditions of temperature and pressure.
In very general terms, 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.
According to a specific embodiment of the invention, 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. By way of example, 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 mediatoris 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 R₁and R₂are groups, identical or different, cyclic or linear.
According to the invention, 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.
An example of the above is 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) or 4-acetamido-TEMPO (Formula III):
The preparation of the mediator based on the aminoxyl radical can be carried out:
either by electrochemical oxidation of said aminoxyl radical with the anode of an electrochemical system according to, for example, Semmelhack et al. (J. Am. Chem. Soc., 1983, 105, 4492-4494);
or by the action of a strong acid on said aminoxyl radical. The oxoammonium form is then obtained in the form of salts according to Golubev et al. (Ser. Khim. 1965, 1927).
According to the invention, the mediator can be used in stoichiometric quantity or in catalytic quantity, assisted by an electrochemical system.
When the mediator is used in stoichiometric quantity, 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:
The Chemical Method:
In 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. In a second step, the mixture is subjected to mechanical or magnetic stirring for 1 to 10 hours, preferably for 2 to 5 hours. In a third step, the reaction mixture is purified according to protocols known to those skilled in the trade.
The Electrochemical Method:
In a first step, 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/AgNO₃reference 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.
In a second step, with zero potential, the molecule to be functionalised and at least one equivalent of nucleophile are successively inserted.
In this case, 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.
In a third step, 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.
According to another specific embodiment of the invention, when the electrophorus mediator is 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.
In this case, 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%.
According to the invention, regardless of whether it is in stoichiometric mode or catalytic mode, 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 H₂O, RCOO⁻, MeOH, N₃ ⁻, SCN⁻, F⁻, I⁻ or CH₃S⁻.
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/AgNO₃electrode, or a saturated calomel electrode (SCE). The reference electrode is preferably an Ag/AgNO₃electrode. The presence of a reference electrode makes it possible to control the potential of the working electrode.
In particular, the electrochemical reaction chamber comprises at least two or three electrodes. The electrochemical reaction chamber therefore comprises at least:
one working electrode,
one auxiliary electrode separated from the working electrode by an ion-exchange membrane (for the system with two or three electrodes),
a reference electrode (for the system with three electrodes),
a generator,
a potentiostat (for the system with 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.
According to the invention, 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/AgNO₃reference 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.
Preferably, when the molecule to be functionalised is not water soluble, acetonitrile (ACN) or dimethylformamide (DMF) are used according to the invention. 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.
In the case of the electrochemical method, 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. By way of example, the salt can be chosen from among NaClO₄, LiClO₄, LiCl. Preferably, in an organic or hydro-organic medium, the support salt used is NaClO₄.
According to the invention, 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. In this way, the chemical molecule to be functionalised can be a linear or cyclic olefin.
In the specific case of polyunsaturated fatty olefins, the application of the method according to the invention produces new molecules in which the initial double bonds are conjugated again.
By way of example, 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.
According to the method of the invention, 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.
According to yet another specific embodiment of the invention, the method can comprise an additional prior step of preparing the mediator.
Therefore, according to the method of the invention, in the case of the chemical method, 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.
Therefore, according to the method of the invention, in the case of the electrochemical method, 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.
In the event of using the mediator in catalytic quantity, 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 according to the invention refers to a medium with pH comprised between 7 and 12, preferably between 9 and 11.
Indeed, the presence of a base B⁻ allows mediamutation between the reduced form (hydroxylamine) and the oxidised form (oxoammonium or mediator) of the aminoxyl radical (Formula IV):
In this way, the aminoxyl radicals formed are oxidised once again at the anode.
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.
In addition to the preceding arrangements, the invention also comprises other arrangements that will emerge from the following description, which refers to examples of implementation of the invention.
The following examples illustrate the invention but do not limit it in any way.

EXAMPLE 1

Functionalisation of Methyl-Linolenate by a Catalytic Quantity of Acetamido-Tempo Assisted by Electrochemistry in the Presence of Water.
The cell of 50 cm³, in a medium of acetonitrile/water (12/1) contains:
NaClO₄at 0.2 mol.l⁻¹
300.10⁻³ml of 2,6-lutidine
64 mg of acetamido-TEMPO (0.3 mmol)
330.10⁻³ml (1 mmol) of methyl-linolenate 99.5%.
The electrochemical system consists of:
2 vitreous carbon working electrodes (50×20×2 mm)
1 platinum auxiliary electrode (20×20 mm) isolated from the working electrode by a cation-exchange membrane. This system makes it possible to prevent a reduction of the aminoxyl radicals at the auxiliary electrode.
1 Ag/AgNO₃(0.1 M) reference electrode; E=0.54 V/ESH
1 generator-potentiostat.
During electrolysis, the potential of the working electrodes is increased to 0.56 V/Ag/AgNO³(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:
evaporating the acetonitrile;
resuming in 20 ml of diethyl ether and extracting the support salt and the oxoammonium ions with 2 times 20 ml of water;
decanting and drying the organic phase on MgSO₄;
evaporating the solvent.
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 recovered fraction (87 mg, Rf=0.5) is a mixture of fatty esters with a mass of 306 g.mol⁻¹, monofunctionalised by a carbonyl and having 3 double bonds, two of which are conjugated.
After elution by 300 ml of ethyl acetate, 120 mg (35%) of doubly functionalised methyl 9,16-dioxo-10,12,14-octadecatrienoate with triple conjugation of double bonds is recovered (formula V):
The obtained product has a structure that conforms to the spectroscopic and spectrometric analyses:
(methyl 9,16-dioxo-10,12,14-octadecatrienoate)
RMN ¹H: ^TM _H(300 MHz, CDCl₃): 7.22 (m, 2 H, J 15, H₁₂, H₁₅); 6.68 (dd, 2 H, J 7, H₁₃, H₁₄); 6.32 (dd, 2 H, J 15.1, H₁₁, H₁₆); 3.66 (s, 3 H, H₁); 2.62 (q, 2 H, J 7.3, H₁₈); 2.57 (t, 2 H, J 6.5, H₉); 2.30 (t, 2 H, J 6.6, H₃); 1.61 (m, 2 H, H₆); 1.32 (m, 8 H, H₄, H₅, H₇, H₈); 1.01 (t, 3 H, J 7.3, H₁₉)
RMN ¹³C: δ_C(300 MHz, CDCl₃): 200.9 (C₁₀), 200.6 (C₁₇); 174.4 (C₂); 140.4 (C₁₂); 140.3 (C₁₅); 138.3 (C₁₃); 138.2 (C₁₃); 132.2 (C₁₁); 132.0 (C₁₆); 51.5 (C₁); 41.1 (C₉); 34.3 (C₁₈); 34.0 (C₃); 29.0 (C₈); 29.0 (C₆); 28.9 (C₇); 24.4 (C₅); 14.1 (C₄); 8.1 (C₁₉)
MS: m/z=320(6%), 289(2%), 263(5%), 163(15%), 57(100%), 55(59%).

EXAMPLE 2

Functionalisation of methyl-linoleate by a Catalytic Quantity of TEMPO Regenerated by Electrochemistry in the Presence of Water:
The 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 C₉or C₁₃. 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 ¹H: δδ_H(300 MHz, CDCl₃): 7.44 (dd, 1 H, J 15.8, J 11.6, H₁₀); 6.12 (d, 1 H, J 15.30, H₁₃); 6.07 (dd, 1 H, J 10.67, H₁₂); 5.90−5.80 (m, 1 H, H₁₁); 3.63 (s, 3 H, H₁); 2.52 (t, 2 H, J 7.31, H₁₅); 2.29 (t, 2 H, J 6.43, H₃); 2.29 (q, 2 H, H₉); 1.59 (m, 4 H, H_4,H₁₆); 1.39 (m, 2 H, H₁₇); 1.29 (m, 10 H, H₁₈, H₈, H₇, H₆, H₅); 0.86 (t, 3 H, J 6, H₁₉)
RMN ¹³C: δδ_C(300 MHz, CDCl₃): 201.0 (C₁₄), 174.3 (C₂); 142.7 (C₁₀); 137.0 (C₁₂); 129.3 (C₁₃); 126.9 (C₁₁); 51.4 (C₁); 41.1 (C₁₅); 34.0 (C₃); 31.5 (C₁₇); 29.4 (C₈); 29.2 (C₆); 29.1 (C₇); 29.0 (C₉); 28.2 (C₅); 24.8 (C₄); 24.0 (C₁₆); 22.5 (C₁₈); 13.9 (C₁₉)
MS: m/z=308(22%), 277(6.2%), 177(27%), 151(70%), 107(38%), 99(86%), 95(81%), 81(100%).
43%: methyl 9-oxo-(10-trans, 12-cis)-octadecadienoate (Formula VII)
RMN ¹H: δ_H(300 MHz, CDCl₃): 7.44 (dd, 1 H, J 15.8, J 11.6, H₁₄); 6.12 (d, 1 H, J 15.30, H₁₁); 6.07 (dd, 1 H, J 10.67, H₁₂); 5.90−5.80 (m, 1 H, H₁₃); 3.63 (s, 3 H, H₁); 2.52 (t, 2 H, J 7.31, H₉); 2.29 (t, 2 H, J 6.43, H₃); 2.29 (q, 2 H, H₁₅); 1.59 (m, 4 H, H₄, H₈); 1.39 (m, 2 H, H₇); 1.29 (m, 10 H, H₆, H₁₆, H₁₇, H₁₈, H₅); 0.86 (t, 3 H, J 6, H₁₉)
RMN ¹³C: δ_C(300 MHz, CDCl₃): 201.0 (C₁₀), 174.3 (C₂); 142.7 (C₁₂); 137.0 (C₁₄); 129.3 (C₁₁); 126.9 (C₁₃); 51.4 (C₁); 41.0 (C₉); 34.0 (C₁₇); 31.4 (C₃); 29.3 (C₁₆); 29.2 (C₇); 29.1 (C₅); 29.0 (C₁₅); 28.2 (C₆); 24.8 (C₄); 24.2 (C₈); 22.5 (C₁₈); 13.9 (C₁₉)
MS: m/z=308(12%), 277(6.1%), 237(34%), 166(21%), 151(29%), 95(100%), 81(46%).
6%: methyl 13-oxo-(9-cis, 11-cis)-octadecadienoate (Formula VIII)

5%: methyl 9-oxo-(10-cis, 12-cis)-octadecadienoate (Formula IX)

EXAMPLE 3

Functionalisation of Methyl-Linoleate by a Catalytic Quantity of TEMPO Regenerated by Electrochemistry in the Presence of Methanol.
Reactions conducted using H₂O 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 cm³contains:
NaClO₄at 0.5 mol.l⁻¹
300.10⁻³ml of 2,6-lutidine
64 mg of acetamido-TEMPO (0.3 mmol)
330.10⁻³ml (1 mmol) of methyl-linolenate 99.5%
all in anhydrous acetonitrile.
During electrolysis, the potential of the working electrodes is increased to 0.56 V/Ag/AgNO³(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%.
The obtained molecules have the conjugated system shown below, the rest of the molecule remaining unchanged (Formula X):

isomer 13-metoxy-9, cis-11, trans-octadecadienoic acid, methyl-ester
RMN ¹H: δ_H(300 MHz, CDCl₃): 5.91 (dd, 1 H, J 15.5, J 11, H₁₂) 5.80 (dd, 1 H, J 11.10, H₁₁); 5.57 (dd, 1 H, J 15, H₁₃); 5.32 (m, 1 H, H₁₀); 3.56 (s, 3 H, H₁); 3.26 (m, 1 H, H₁₄); 3.19 (s, 3 H, H₁₅); 2.17 (t, 2 H, J 18, H₃); 2.00 (q, 2 H, J 12, H₉); 1.44 (m, 4 H, H₁₈, H₁₉); 1.26 (m, 14 H, H₄, H₅, H₆, H₇, H₁₆, H₁₇); 0.90 (t, 3 H, H₂₀)
RMN ¹³C: δ_C(300 MHz, CDCl₃): 174.2 (C₂), 134.1 (C₁₂); 131.8 (C₁₀); 131.5 (C₁₃); 129.1 (C₁₁); 78.8 (C₁₄); 55.6 (C₁₅); 51.3 (C₁); 34.1 (C₃); 33.2 (C₁₆); 29.3 (C₈); 29.0 (C₆); 28.6 (C₇); 28.1 (C₉); 27.7 (C₁₈); 26.9 (C₅); 25.2 (C₄); 25.1 (C₁₇); 22.5 (C₁₉); 13.9 (C₂₀)
MS: m/z=324(18%), 293(4%), 254(15%), 253(80%), 221(12%), 167(63%), 97(100%).
The isomeric distribution is identical to that in example 2.

EXAMPLE 4

Functionalisation of Methyl-Linoleate by a Twice Stoichiometric Quantity of Oxoammonium Salts in an Anhydrous Acetic Acid Medium:
In the case of functionalisation by CH₃CO₂, the reaction is performed in an anhydrous acetic acid medium in order to obtain immediate functionalisation by the acetate ions after the formation of the carbocation. The quantity of mediator used is 2 equivalents. The reaction medium consists of:
40 cm³of glacial acetic acid
312 mg of TEMPO (2 mmol)
330.10⁻³ml (1 mmol) of methyl-linolenate 99.5%.
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 ¹H: δ_H(300 MHz, CDCl₃): 6.14 (dd, 1 H, J 15.1, J 11, H₁₂) 5.88 (dd, 1 H, J 11, H₁₁); 5.60 (dd, 1 H, J 15, H₁₃); 5.35 (m, 1 H, H₁₀); 5.18 (q, 1 H, J 6, H₁₄); 3.56 (s, 3 H, H₁); 2.17 (t, 2 H, J 6.5, H₃); 1.99 (m, 4 H, H₉, H₁₆); 1.50 (q, 2 H, H₁₇); 1.40 (m, 8 H, H₄, H₁₈, H₁₉, H₂₀); 1.26 (m, 8 H, H₅, H₆, H₇, H₈); 0.90 (t, 3 H, H₂₁)
RMN ¹³C: δ_C(300 MHz, CDCl₃): 174.2 (C₂), 170.1 (C₁₅); 134.3 (C₁₃); 134.0 (C₁₂); 131.0 (C₁₀); 127.6 (C₁₁); 74.0 (C₁₄); 51.3 (C₁); 34.3 (C₁₇); 34.0 (C₃); 29.3 (C₈); 29.0 (C₆); 28.6 (C₇); 28.1 (C₉); 26.9 (C₅); 25.2 (C₄); 26.7 (C₁₉); 25.2 (C₄); 24.7 (C₁₈); 22.5 (C₂₀); 21.1 (C₁₆); 13.9 (C₂₁)
MS: m/z=352(6%), 351(15%), 309(15%), 308(54%), 240(42%), 207(30%), 152(100%), 135(52%).
The isomeric distribution is identical to that in example 2.

EXAMPLE 5

Functionalisation of 1-Phenyl-Cyclohexene by a Stoichiometric Quantity of Oxoammonium Ions in the Presence of Water.
It is known that 2 equivalents of oxoammonium ions are required for monofunctionalisation by OH⁻ and oxidation of the formed enol. Since this method no longer requires mediamutation of the oxidised and reduced species for regeneration, no base is used and the reaction medium is therefore neutral.
After complete electrochemical oxidation of 4 millimoles of acetamido-TEMPO by the electrochemical system, 2 millimoles of 1 phenylcyclohexene are added. The stirring is performed continuously for 8 hours. The treatment of the reaction medium is identical to that used in example 1. The eluent is a mix of ether/petroleum ether (3/1). A yield of 92% of purified product is obtained with a selectivity of 100%. The functionalisation of the double bond produces 1-phenylcyclohexene-3-one (Formula XII):
It should be noted that when the reactions are conducted with a single equivalent of acetamido-TEMPO, the conversion only reaches 50%, which is in line with the proposed reaction mechanism.

EXAMPLE 6

Synthesis of Tropone from Cycloheptatriene in the Presence of Water and a Catalytic Quantity of TEMPO Regenerated by Electrochemistry (Formula XIII).
The cell of 50 cm³contains:
40 ml of acetonitrile/water (12/1)
NaClO₄at 0.3 mol.l⁻¹
600.10⁻³ml of 2,6-lutidine
64 mg of acetamido-TEMPO (0.3 mmol)
316.10⁻³ml (3 mmol) of cycloheptatriene 97%.
Electrolysis is performed with a constant potential of 0.56 V/Ag/AgNO³(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:
evaporating the acetonitrile;
resuming in 40 ml of water and extracting by 3 times 20 ml of CH₂Cl₂;
decanting and drying the organic phase on MgSO₄;
evaporating the solvent.
The raw product (320 mg) is dissolved in 0.5 ml of CH₂Cl₂, purified on a silicon column (ethyl acetate/petroleum ether: 1/1). The recovered tropone (305 mg; 96%, Rf=0.6) has a purity of 99% GC.
The aromatic characteristic of the tropylium ion, a reaction intermediary, contributes greatly to the stability of the carbocation, which enables a long enough lifetime to withstand a nucleophile attack. In the case of functionalisation by a hydroxyl, the latter is immediately dehydrogenated by the oxoammonium and results in the carbonyl.
Functionalisations by S⁻ and N⁻ nucleophiles are obtained by replacing water with the suitable salts, e.g.: KSCN, NaN₃, etc.
The following examples describe the application of the invention to cyclic diolefins in C₆in the presence of 1 to 10% of water in the reaction medium. This reaction is applicable regardless of the substituents of the cycle in C₆.
In the case of cyclic diolefins in C₆, regardless of whether or not the alkene functions are conjugated, the obtained product is an aromatic compound. The rate of unsaturation therefore increases by one unit according to the following steps:
1. formation of a delocalised cyclic carbocation by reaction of an oxoammonium;
2. conjugation of the double links in the case, of a reactive comprising 2 non-conjugated double links;
3. nucleophile attack of OH⁻ and formation of the enol;
4. dehydration of the enol to lead to an aromatic cycle.
The mechanism is identical to that described in the case of the polyunsaturated fatty olefins, but the thermodynamic stability of the final aromatic structure allows the dehydration (step 4).

EXAMPLE 7

Aromatisation of Bicyclo-(3,4,0)-Nona-3,6-(1)-Diolefin (Formula XIV)
The transformation is carried out in an electrochemical cell with three electrodes containing 40 cm³of ACN (0.1 M NaClO₄) and 2.5 cm³of H₂O (5%). The electrolysis potential is set at 0.55 V/(Ag/AgNO₃). The mediator is obtained from acetamido-TEMPO (67 mg, 0.3 millimole). 400 μl of Lutidine and 258 μl of Bicyclo-(3,4,0)-nona-3,6-(1)-diolefin 2.10⁻³mole 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 reaction medium is evaporated. 20 ml of ether diethyl and 40 ml of a solution of HCL at 5% are added. The stirring is performed continuously for 15 minutes. After decanting, the aqueous solution is extracted with two times 20 ml of ether diethyl. The organic phases are grouped together and washed with 20 ml of H₂O. The organic phase is then dried on MgSO₄. The ether diethyl is evaporated and the raw product is separated on a column of silicon. The elution is performed with a mixture of petroleum ether: diethyl ether (2.5:1; RF=0.5). The yield of the synthesis is 96% of indane (Formula XV):

EXAMPLE 8

Aromatisation of α- and γ-Terpinenes (Formulae XVI): Synthesis of P-Cymene (Formula XVII)
The general conditions for electrolysis are identical to those implemented for the aromatisation of the Bicyclo-(3,4,0)-nona-3,6-(1)-diolefin.
The initial amount of terpinene is 2 mmoles (273 mg). In both cases, 398 coulombs are consumed in 90 minutes.
The treatment of the solutions is identical to that described in the case of the Bicyclo-(3,4,0)-nona-3,6-(1)-diolefin.
The transformation is quantitative and 96% of p-cymene (258 mg) is obtained.

Claims

1. Method of functionalising a chemical molecule having at least two double bonds or containing one double bond conjugated with an electron-rich structure, in the presence of an electrophorus mediator and a nucleophile agent.

2. Method according to claim 1, characterised in that it also includes a system of electrochemical regeneration of the electrophorus mediator.

3. Method according to claim 1, characterised in that the electrophorus mediator is the oxidised form (oxoammonium or nitrosonium) of a molecule comprising at least one aminoxyl radical of Formula II:

in which R₁and R₂are groups, identical or different, cyclic or linear.

4. Method according to claim 1, characterised in that the electrophorus mediator is the oxoammonium form of a chemical molecule from the bi-permethylated aminoxyl radical family, very preferably bi-permethylated aminoxyl radical containing at least one aminoxyl radical.

5. Method according to claim 1, characterised in that this electrophorus mediator is 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) or 4-acetamido-TEMPO of Formulae III:

6. Method according to claim 1, characterised in that the electrophorus mediator is used in stoichiometric quantity, according to a chemical method or an electrochemical method.

7. Method according to claim 6, characterised in that the functionalisation is carried out at temperatures ranging from 0° C. to 80° C., preferably from 5° C. to 40° C.

8. Method according to claim 6, characterised in that the functionalisation is carried out with a pH ranging from 0 to 13, preferably from 4 to 7.

9. Method according to claim 6, characterised in that the functionalisation carried out using the chemical method comprises:

a first step, in which the molecule to be functionalised, at least one equivalent of mediator and at least one equivalent of the nucleophile compound are successively added to a reaction chamber containing an organic or hydro-organic reaction medium;

a second step in which the mixture is subjected to mechanical or magnetic stirring for 1 to 10 hours, preferably for 2 to 5 hours;

a third step in which the reaction mixture is purified.

10. Method according to claim 6, characterised in that characterised in that the functionalisation carried out according to the electrochemical method comprises:

a first step in which an aminoxyl radical is inserted in at least stoichiometric quantity in an electrolytic solution containing a support electrolyte;

a second step in which, with zero potential, the molecule to be functionalised and at least one equivalent of nucleophile are successively inserted;

a third step in which the obtained raw product is purified.

11. Method according to claim 10, characterised in that 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/AgNO₃reference electrode.

12. Method according to claim 10, characterised in that 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.

13. Method according to claim 10, characterised in that the solution can be stirred for a time comprised between 1 and 10 hours, preferably comprised between 2 and 5 hours.

14. Method according to claim 10, characterised in that the electrophorus mediator is used in catalytic quantity and the electrophorus mediator is regenerated by an electrochemical system.

15. Method according to claim 14, characterised in that the reaction takes place in an electrochemical reaction chamber, closed or circulating, made up of at least one working electrode (anode) and one auxiliary electrode (cathode), also comprising a reference electrode.

16. Method according to claim 15, characterised in that the reference electrode is an Ag/AgNO₃electrode, or a saturated calomel electrode (SCE), preferably an Ag/AgNO₃electrode

17. Method according to claim 14, characterised in that 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.

18. Method according to claim 14, characterised in that 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.

19. Method according to claim 14, characterised in that the reaction takes place with a basic pH, comprised between 7 and 12, preferably between 9 and 11.

20. Method according to claim 14, characterised in that 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%.

21. Method according to claim 1, characterised in that the reaction takes place in a reaction medium allowing the oxidation of the aminoxyl radical to oxoammonium ions (the mediator) and the functionalisation reaction and the solubilisation of the reactive species and of the support electrolyte if the reaction is carried out by the electrochemical method, chosen from among acetonitrile (ACN), tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO) and any other mixture of water/organic solvent.

22. Method according to claim 21, characterised in that when the molecule to be functionalised is not water soluble, acetonitrile (ACN) or dimethylformamide (DMF) are 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.

23. Method according to claim 10, characterised in that the reaction medium 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.

24. Method according to claim 23, characterised in that the salt is chosen from among NaClO₄, LiClO₄, LiCl.

25. Method according to claim 14, characterised in that the reaction medium is a basic organic or hydro-organic medium with pH comprised between 7 and 12, preferably between 9 and 11

26. Method according to claim 25, characterised in that the reaction medium comprises an organic or inorganic base that cannot be oxidised by the mediator, for example 2,6-lutidine or pyridine.

27. Method according to claim 25, characterised in that the organic or hydro-organic medium contains NaClO₄as the support salt.

28. Method according to claim 1, characterised in that the nucleophile is 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 comprising an atom chosen from among H₂O, RCOO⁻, MeOH, N₃ ⁻, SCN⁻, F⁻, I⁻ or CH₃S⁻.

29. Method according to claim 1, characterised in that the nucleophile is used in a quantity ranging from 1 to 10 equivalents and preferably from 1 to 5 equivalents.

30. Method according to claim 1, characterised in that the chemical molecule to be functionalised is a linear or cyclic olefin

31. Method according to claim 30, characterised in that the chemical molecule to be functionalised is a polyunsaturated fatty olefin.

32. Method according to claim 1, characterised in that 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.

33. Method according to claim 1, characterised in that it comprises an additional prior step of preparing the mediator.

34. Method according to claim 33, characterised in that in the chemical method, the aminoxyl radicals are used in a quantity ranging from 1 to 4 equivalents in relation to the molecule to be functionalised

35. Method according to claim 33, characterised in that in the electrochemical method, the aminoxyl radicals are 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.