This application claims the priority benefits of Provisional Patent Application Ser. No. US 61/088851 , filed on August 14, 2008 and of French Patent Application FR 0855591 filed on August 14, 2008, which are incorporated herein in their entirety.

The present invention relates to borated cyclopropyl or cyclobutyl derivatives and to a process for their preparation. Such derivatives can be used in particular for storing the corresponding boronic acid derivatives or as precursors of the boronic acid derivatives in Suzuki coupling reactions especially.

Suzuki-Miyaura coupling is an organometallic coupling between a boronic acid derivative and a halide or a triflate. This reaction has become a tool of choice for generating a carbon-carbon bond, in particular between two sp ² hybridised carbons, under a wide range of reaction conditions [1]. Although applications in the alkyl series appear much more limited, a very particular system has nevertheless been developed in this type of coupling, cyclopropane derivatives [2]. This keen interest in the cyclopropyl group is also associated with the analogy it has with the olefins. This parameter has resulted in its ever more frequent use in medicinal chemistry. Because this organometallic coupling is added to the available tools for the grafting of the cyclopropyl entity, various methods of obtaining borated derivatives of cyclopropane have thus been reported.

Numerous reports state that cyclopropyl boronates are accessible via cheleotropic addition reactions of carbenic species to a borated olefin.

OR Particular mention may be made of Simmons-Smith reactions carried out either on the free boronic acids [3] or on boronic esters [4-6]. Diazomethane decomposition reactions in the presence of palladium acetate have also been conducted on boronic esters, yielding, after hydrolysis of the esters, cyclopropylboronic acids (comprising a polysubstituted cyclopropane) [7, 8]. Similarly, such a cyclopropanation has been carried out on a methyliminodiacetic adduct [9]. These cycloaddition reactions can yield a wide range of polysubstituted cyclopropyl boronates.

Hydroborations of substituted cyclopropenes, catalysed by rhodium, have also been described and permit access to the polysubstituted cyclopropylboronic skeleton in an enantioselective manner [10].

A method of obtaining boronic derivatives of cyclopropane has recently been reported. It comprises treating trimethyl borate with cyclopropylmagnesium bromide, followed by hydrolysis. The process yields cyclopropylboronic acid with an isolated yield of 55%, contaminated by 5 to 10% boric acid [11].

It is to be noted, in fact, that, despite a relatively large group of tools permitting a ccess to po l yfu n ct i o nalised cyclopropyl boronates, unsubstituted cyclopropylboronic acid has for a long time remained supposedly inaccessible [12]. Like many boronic acids, it exhibits problems associated with its isolation; a first problem is associated with the presence of boric acid (hydrolysis of the C-B bond yielding boric acid, which itself results in the formation of salts which can change the appearance of the reaction media and even the effectiveness of the reactions).

In addition, the instability (dehydration to a boroxine form) of boronic acids can prove to be a problem in terms of the stoichiometry of the organic adduct to be employed.

The totality of these parameters means that boronic acids exhibit chronically a stability over time that is uncontrollable and therefore unreliable.

In addition, in the case of cyclopropylboronic acid, an apparent sublimation makes isolation even more tricky.

A first response to the problems of stability and isolation of boronic acids was provided by the works of Darses and Genet [13, 14], Batey [15] and Molander [16].

These teams demonstrated the value of potassium organotrifluoroborates. These derivatives are highly stable, the stabilisation being provided by the "complexing" of the electron vacancy by a lone pair of the third fluoride. Potassium organotrifluoroborates have thus been developed in the alkyl, vinyl and aryl series and are used in a large number of reactions [17, 18].

It is to be noted that potassium cyclopropyltrifluoroborate derivatives have been described and used in synthesis, and that potassium cyclopropyltrifluoroborate is now a commercial product.

However, potassi u m organotrifl uoroborates have at l east two major disadvantages. Their ionic nature renders them virtually insoluble in conventional organic solvents (even when the organic fragment is of small size). Furthermore, their preparation requires treatment of an intermediate of the boronic acid or ester type with a saturated solution of KHF ₂ (or HF), which has a marked corrosive nature. There has now been found a family of borated derivatives of cyclopropane or cyclobutane which are easy to isolate and handle on an industrial scale and which have increased stability compared with the corresponding boronic acids. In addition, these derivatives allow the corresponding boronic acids to be readily regenerated, especially by simple treatment in an acidic medium, while retaining good purity conditions. Accordingly, it has been shown, surprisingly, that, by regenerating the boronic acid in situ, in the reaction mixture, from the compounds of the invention, it was possible to carry out the Suzuki coupling reaction under conditions which are extremely simple to implement and to obtain high yields of greater than 80% and even greater than 90%.

Furthermore, a process has been developed which permits access to borated derivatives of cyclopropane or cyclobutane with high yields and high purity, especially yields of the order of from 50% to 80% and a purity of the order of from 95% to 100%. In addition, the process can readily be transposed to an industrial scale and can advantageously be carried out in a single batch (so-called "one-pot" process).

According to a first object, the invention therefore relates to compounds of formula (I):

in which:

Ri represents a cyclopropyl or cyclobutyl group; R2 represents a hydrogen atom, a Ci-Cβ-alkyl group, a Cβ-Cio-aryl group or an aralkyl group; the carbon atoms numbered 1 , 2, 3, 4 are each optionally substituted by one or two groups selected from d-Cβ-alkyl, Cβ-Cio-aryl and aralkyl; m is 1 or 2; n is 1 or 2.

In other words, the compounds according to the invention have the following formula:

in which:

Ri represents a cyclopropyl or cyclobutyl group;

R2 represents a hydrogen atom, a Ci-Cβ-alkyl group, a Cβ-Cio-aryl group or an aralkyl group; R'i, R' ₂ , R'3, R'4, R"i, R"2, R"3, R"4 independently represent a hydrogen atom, a Ci-C ₆ -alkyl, a C ₆ -Ci ₀ -aryl or an aralkyl, each R'i and each R"i being the same or different in each of the n units -[-CR'iR'V]- and each R' ₂ and each R" ₂ being the same or different in each of the m units -[-CR' ₂ R" ₂ -]-; m is 1 or 2; n is 1 or 2.

In the formula above,

-the carbon carrying R'i and R"i substituents corresponds to the carbon atom numbered 1 in formula (I),

-the carbon carrying R' ₂ and R" ₂ substituents corresponds to the carbon atom numbered 2 in formula (I),

-the carbon carrying R' ₃ and R"3 substituents corresponds to the carbon atom numbered 3 in formula (I), and

-the carbon carrying R ₄ and R" ₄ substituents corresponds to the carbon atom numbered 4 in formula (I).

The inventors have thus shown that by complexing the boron ic acids of cyclopropyl and cyclobutyl by a dialcohol amine, it was possible to obtain compounds having good stability. Without wishing to be limited to a particular theory, the coordination of the nitrogen lone pair appears to be an important factor for the stabilisation of the borated entity in so far as, by occupying the vacant orbital of the boron, it prevents any nucleophilic attack on that atom.

Preferably, m and/or n are 1.

Preferably, R2 represents a hydrogen atom.

Preferably, the carbon atoms numbered 1 , 2, 3, 4 are not substituted.

The cyclopropyl or cyclobutyl groups are not substituted.

According to a particularly preferred embodiment, the compounds of formula (I) are selected from cyclopropyldioxazaborocane and cyclobutyldioxazaborocane.

The compounds of the general formula (I) can be prepared by application or adaptation of any method that is known per se and/or is within the scope of the person skilled in the art, especially those described by Larock in Comprehensive Organic Transformations, VCH Pub., 1989, or by application or adaptation of the processes described in the examples which follow.

Step d) According to a second object, the invention therefore relates also to a process for the preparation of compounds of formula (I), which process comprises a step d) in which a boronic acid RiB(OH) ₂ is brought into contact with a dialcohol amine compound of formula (II) in a solvent:

(H) in which R ₂ , m, n, and the substituents optionally present on the carbon atoms 1 ,

2, 3, 4 are as defined hereinbefore.

There is no particular restriction regarding the nature of the solvent to be used, provided that it does not have an undesirable effect on the reaction or on the reagents involved. As examples of suitable solvents there may be mentioned polar aprotic solvents such as ethers, especially diethyl ether and tetrahydrofuran.

The reaction can take place in a wide range of temperatures. In general, it is carried out at room temperature.

Preferably, step d) is carried out under anhydrous conditions.

Steps b) and c) According to a preferred embodiment, the boronic acid RiB(OH) ₂ is prepared by a process which comprises: b) reacting, in a solvent, a compound RiLi or RiMgX with a compound B(OR ₃ ) ₃ , Ri being as defined hereinbefore, X being Cl or Br and R3 representing a CrCβ- alkyl or C ₆ -Ci ₀ -aryl group; and c) converting the resulting compound RiB(ORs) ₂ into RiB(OH) ₂ .

Preference is given to the use of RiLi, which is more reactive than RiMgX.

Preferably, the compound RiLi is added to B(OR ₃ ) ₃ . The inventors have in fact shown that this allows the yield and purity of the compound of formula (I) ultimately obtained to be improved.

As examples of borate compounds B(OR ₃ )3 which can be used in the process of the invention there may be mentioned especially B(OiPr ₃ ) ₃ or B(OMe) ₃ .

Preferably, step b) is carried out under an inert atmosphere. Preferably, step b) is carried out at a temperature of from -8O ⁰ C to O ⁰ C, especially at a temperature close to -4O ⁰ C.

The conversion of the boronate RiB(ORs)2 into the corresponding boronic acid is preferably carried out by acid hydrolysis, especially by adding an acidic or buffered solution having a pH of from 0 to 6, for example by adding a saturated ammonium chloride solution.

Step a) The compound RiLi can be prepared by any method known to the person skilled in the art. It can be prepared especially by a process which comprises a step a) in which a compound RrHaI, wherein Hal represents Cl or Br, is reacted with a lithiated derivative, for example an alkyllithium such as te/t-butyllithium, in an ether.

Preferably, the reaction is carried out under anhydrous conditions.

Preferably, the reaction is carried out at low temperature, especially at a temperature of from O ⁰ C to -8O ⁰ C, in particular at a temperature close to -4O ⁰ C.

According to a preferred embodiment, the compound RiLi is prepared by a process which comprises a step a) in which a compound RrHaI is reacted with a complex Li ⁺ Ar ^" , [Li. Ar] hereinbelow, in a solvent, wherein Hal is Cl or Br, and Ar represents an aromatic Cβ-Cio or heteroaromatic compound having from 5 to 7 ring members, said aromatic or heteroaromatic compounds optionally being substituted by a Ci-C ₆ -alkyl or C ₆ -Ci ₀ -aryl group.

This embodiment is particularly advantageous in that it is simple to carry out and is reliable, especially on an industrial scale.

As examples of complexes [Li.Ar] which can be used in the process of the invention there may be mentioned especially complexes in which the compound Ar represents a group naphthalene, di-te/t-butylbiphenyl (DBB), 2-phenylpyridine or quinoline.

Such complexes, which are obtained by electron transfer from the lithium to the aromatic or heteroaromatic compound Ar, can be prepared by any method known to the person skilled in the art. They can be prepared especially by bringing an aromatic compound into contact with metallic lithium in a polar aprotic solvent such as an ether. By way of example, the complex [Li. DBB] can be prepared according to the following reaction scheme:

The reaction between the lithium and the compound Ar can advantageously be carried out at room temperature (RT). However, because the reaction is slightly exothermic, it may be preferable to regulate the temperature on a large scale in order to avoid the formation of by-products.

The molar ratio of complex [Li. Ar] employed relative to the compound RiHaI can vary to a large degree. It can especially be stoichiometric and advantageously catalytic. Preferably, the molar ratio [Li. Ar] / RiHaI is from 0.1 to 2 molar equivalents and is preferably especially from 0.1 to 0.5 molar equivalent.

The complex [Li . Ar] is preferably a complex [Li. DBB] or [Li. naphthalene]. Advantageously, the complex [Li. DBB] allows the progress of the reaction to be monitored. At the start of the reaction, the complex gives a dark-blue colouration to the reaction mixture, which becomes red when all the complex has been consumed and turns dark-blue again when the lithiation reaction is finally complete.

According to a particularly preferred variant, the process is a "one-pot" process, that is to say steps a) to d), which permit the conversion of the compound RrHaI into a compound of formula (I), are carried out in succession in the same reactor without isolation of the species formed as intermediates.

The process is preferably carried out according to the following reaction scheme:

Li + arene

The process according to the invention can optionally also include a step e) in which the resulting product of formula (I) is isolated.

The compound of formula (I) so prepared can be recovered from the reaction mixture by conventional means. For example, the compounds can be recovered by removing the solvent from the reaction mixture by distillation or if necessary after removal of the solvent from the mixture of the solution by distillation, by pouring the residue into water followed by extraction with an organic solvent that is immiscible with water, and by removing the solvent from the extract by distillation. If desired, the product can also be purified further by various techniques, such as recrystallisation, reprecipitation or the various chromatography techniques, especially column chromatography or preparative thin-layer chromatography.

Definitions

As used hereinbefore and throughout the description of the invention, the following terms are to be understood as having the following meanings, unless indicated otherwise:

"Alkyl" denotes an aliphatic hydrocarbon-containing group which can be linear or branched and has from 1 to 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are linked to a linear alkyl chain. "Lower alkyl" means from 1 to 4 carbon atoms in the chain, which can be linear or branched.

"Aryl" or "aromatic group" denotes an aromatic monocyclic or polycyclic ring system having from 6 to 10 carbon atoms. The aryl groups are optionally substituted by one or more Ci-Cβ-alkyl or Cβ-Cio-aryl groups. As examples of aryl groups there may be mentioned especially phenyl, tolyl and naphthyl.

"Aralkyl" denotes an aryl-alkyl group, in which aryl and alkyl are as described in the present document. Preferred aralkyls contain a lower alkyl fragment. As examples of aralkyl groups there may be mentioned especially benzyl, 2-phenethyl and naphthalenemethyl.

"Heteroaryl" or "heteroaromatic group" denotes an aromatic monocyclic or polycyclic ring system having from 5 to 7 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. As examples of heteroaromatic groups there may be mentioned especially pyridine and quinoline.

According to another object, the invention relates also to the use of the compounds of formula (I) for storing boronic acid compounds RiB(OH) ₂ , Ri being as defined hereinbefore.

The invention relates also to the use of the compounds of formula (I) as precursors of boronic acid RiB(OH) ₂ , Ri being as defined hereinbefore.

The boronic acid RiB(OH) ₂ is preferably obtained by acid hydrolysis of the corresponding compound of formula (I).

The compounds of formula (I) can be used in particular as boronic acid precursors in Suzuki coupling reactions. The examples which follow illustrate the invention, but without limiting it. The starting materials used are products which are known or prepared by known procedures.

Example 1 : Cyclopropyldioxazaborocane

Powdered lithium in mineral oil (~ 30% by weight, 565 mg, 24.4 mmol, 2 eq.) is added under argon, at room temperature, to a solution of DBB (665 mg, 2.5 mmol, 0.2 eq.) in THF (7 ml distilled). The mixture is then stirred for 15 minutes at room temperature, before being cooled to -4O ⁰ C (internal temperature). A solution of cyclopropyl bromide (1 ml, 12.4 mmol, 1 eq.) in THF (4 ml) is then added dropwise at a speed such that the temperature is maintained at -4O ⁰ C. The solution is then stirred at -4O ⁰ C for about VA to 1 % hours. When the reaction is complete, the reaction mixture is added by means of a cannula, at -4O ⁰ C, within a period of 15 minutes, to a solution of B(OiPr) ₃ (2.8 ml, 12.4 mmol, 1 eq.) in THF (7 ml distilled). The mixture is then stirred for 30 minutes, the temperature of the bath being allowed to rise. After addition of Et ₂ O (10 ml) to the mixture, an NH ₄ CI solution (10 ml) is also added and stirring is continued for a further Vi hour. The aqueous and organic phases are separated, the aqueous phase is then extracted with Et ₂ O (2 x 10 ml), and the organic phases are combined and washed with a saturated NaCI solution (2 x 5 ml). The organic phase (yellow) is then dried over MgSO ₄ , and then diethanolamine in solution in iPrOH (4 ml, 3M, 12 mmol, 1 eq.) is added and the mixture is stirred for ^Λ A hour. After filtration of the MgSO ₄ and evaporation of the solvent, the resulting yellow-brown solid is washed with Et ₂ O until the filtrate is colourless and is then dried in vacuo. Cyclopropyl- dioxazaborocane is then obtained in pure form as a yellowish solid (1 .080 g, 7.3 mmol, 61 %). If diethanolamine is present in the product, washing with cold MeCN, or even recrystallisation (hot MeCN), may be required in order to purify the product.

¹ H NMR (DMSO-c/e, 300 MHz): δ = -0.70,-0.60 (tt, ³ J _cls(H i-H2) = 9.2 Hz, ³ J _tra ns ₍ HI-H2) = 6.3 Hz, 1 H, H ₁ ), -0.10,-0.05 (ddd, ³ J _tra ns ₍ HI-H2) = 6.3 Hz, ³ J _tr ans(H2-H2) = 4.7 Hz, ² J _gem

= 2.7 HZ, 2H, H ₂ trans), 0.06-0.1 1 (ddd, ³ J _{CIS (} H1-H2) = 9.2 HZ, ³ Jtrans(H2-H2) = 4.7 HZ,

² Jgem = 2.4 Hz, 2H, H _2C15 ), 2.65-2.72 (tdd, ³ J = 1 1 .7 Hz, ² J = 8.7 Hz, ³ J = 7.0 Hz, 2H, H ₄ ), 2.90-3.02 (tdd, ² J = 8.7 Hz, ³ J = 5.6Hz, ³ J = 3.1 Hz, 2H, H ₄ ), 3.50-3.56 (m,

2H, H ₃ ), 3.61-3.69 (td, ² J = 9.2 Hz, ³ J = 5.6Hz, 2H, H ₃ ), 6.67 (s br, 1 H, H ₅ ). ¹³ C NMR (DMSO-c/e, 75.5 MHz): δ = 1.76 (C ₂ ), 51.06 (C ₄ ), 62.73 (C ₃ ), Ci not detected. ¹¹ B NMR (DMSO-c/e, 96.8 MHz): δ = 12.0. MS (DCI-NH3, DCM) : m/z = 173.3 [M+NH4] ⁺ , 156.2 [M+H] ⁺ . Mp > 200 ⁰ C.

Example 2: Cyclobutyldioxazaborocane

Powdered lithium in mineral oil (~ 30% by weight, 565 mg, 24.4 mmol, 2 eq.) is added under argon, at room temperature, to a solution of DBB (665 mg, 2.5 mmol, 0.2 eq.) in THF (7 ml distilled). The mixture is then stirred for 15 minutes at room temperature, before being cooled to -8O ⁰ C (internal temperature). A solution of cyclobutyl bromide (1 .17 ml, 12.4 mmol, 1 eq.) in THF (4 ml) is then added dropwise at a speed such that the temperature is maintained at -8O ⁰ C. The solution is then stirred at -8O ⁰ C until the dark-blue colouration reappears (about 314 hours). When the reaction is complete, the reaction mixture is added by means of a cannula, at -8O ⁰ C, within a period of 15 minutes, to a solution of B(OiPr) ₃ (2.8 ml, 12.4 mmol, 1 eq.) in THF (7 ml distilled). The mixture is then stirred for 30 minutes, the temperature of the bath being allowed to rise. After addition of Et ₂ O (10 ml) to the mixture, an NH ₄ CI solution (10 ml) is also added and stirring is continued for a further Y ₂ hour. The aqueous and organic phases are separated, the aqueous phase is then extracted with Et ₂ O (2 x 10 ml), and the organic phases are combined and washed with a saturated NaCI solution (2 x 5 ml). The organic phase (yellow) is then dried over MgSO ₄ , and then diethanolamine in solution in iPrOH (4 ml, 3M, 12 mmol, 1 eq.) is added and the mixture is stirred for Vi hour. After filtration of the MgSO ₄ and evaporation of the solvent, the resulting yellow solid is washed with Et ₂ O until the filtrate is colourless and is then dried in vacuo. Cyclobutyldioxazaborocane is then obtained in pure form as a white solid (1.060 g, 6.3 mmol, 52%).

¹ H NMR (DMSO-c/e, 300 MHz), ppm: 6.54 (s, 1 H, H ₆ ), 3.73-3.65 (td, ² J = 9.1 Hz, ³ J = 5.4 Hz, 2H, H ₄ ), 3.59-3.53 (m, 2H, H ₄ ), 2.99-2.88 (tdd, ² J = 11.6 Hz, ³ J = 8.8 Hz, ³ J = 6.8 Hz, 2H, H ₅ ), 2.74-2.66 (m, 2H, H ₅ ), 1.90-1.64 (m, 6H, H ₂ +H ₃ ), 1.52-1.41 (m, 1 H, H ₁ ); ¹³ C NMR (DMSO-c/ ₆ , 75.5 MHz), ppm: 62.7 (C ₄ ), 51.5 (C ₅ ), 24.5 (C ₂ ), 22.1 (C ₃ ), Ci not detected; ¹¹ B NMR (DMSO-c/ ₆ , 96.8 MHz): δ = 11.8; MS

(DCI/NHs, MeOH) m/z: 187.3 [M-NH ₄ ] ⁺

Example 3: Use of cyclopropyldioxazaborocane in the Suzuki coupling reaction

The boronic acid coupling products were obtained under the conditions recorded in the table below, by applying procedures 3a) and 3b).

+ catalyst + ligand + K ₃ PO ₄ solvent

SIMes : 1 ,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene

The Suzuki coupling process has many advantages. The first is that the conditions are extremely simple to implement using catalysts which are readily available and usable (u n l i ke the rare model s issu ing from the l iteratu re relating to cyclopropylboronic acid) [19, 11]. The particularly short reaction times are also an element that simplifies the implementation of the process. Finally, it has been possible to carry out Suzuki couplings both with brominated derivatives and with chlorinated derivatives.

Example 3a): Coupling with brominated derivatives: Procedure:

Cyclopropyldioxazaborocane (1.5 eq.) is dissolved in a solution of 1 N HCI/NaCl _sa t (1 ml/mmol of dioxazaborocane); boronic acid is then extracted with MeTHF (1.5 ml/mmol of dioxazaborocane). It is added to a solution containing aryl bromide (1 eq .), PdCI ₂ dppf (0.5 eq.), PPh ₃ (0.1 eq.) and K ₃ PO ₄ (2 eq .) in toluene (1.5 ml/mmol), anhydrous. The mixture is then heated at 100 ⁰ C for 3 hours, under argon. After cooling, the organic phase is washed with water and then dried over MgSO ₄ and evaporated. The residue is then purified by flash chromatography (eluant: pure DCM). The fractions containing the product are then combined and evaporated.

4-cyclopropylacetophenone:

Yellowish liquid (41 1 mg, 2.57 mmol, 99%). ¹ H NMR (CDCI ₃ , 300 MHz), δ = 7.87 (d, ³ JHH = 8.5 Hz, 2H, H ₅ ), 7.14 (d, ³ J _HH = 8.5 Hz, 2H, H ₄ ), 2.58 (s, 3H, H ₈ ), 1 .96 (tt, ³ JHH = 8.4 Hz, ³ J _HH = 5.0 Hz, 1 H, H ₁ ), 1 .08 (ddd, ³ J _HH = 8.4 Hz, ³ J _HH = 5.0 Hz, ² J _gem = 6.6 Hz, 2H, H ₂ ), 0.80 (td, ³ J _HH = 4.8 Hz, ² J _gem = 6.7 Hz, 1 H, H ₂ ). ¹³ C NMR (CDCI ₃ , 75.5 MHz), δ = 197.7 (C ₇ ), 150.4 (C ₆ ), 134.6 (C ₃ ), 128.5 (C ₅ ), 125.5 (C ₄ ), 26.5 (Ce), 15.8 (CO, 10.4 (C ₂ ). Rf = 0.30 (DCM/EP 70 :30). Example 3b): Coupling with chlorinated derivatives:

Procedure:

Cyclopropyldioxazaborocane (1.5 eq.) is dissolved in a solution of 1 N HCI/NaCl _sa t

(1 ml/mmol of d ioxazaborocane), and the boron ic acid then formed is subsequently extracted with MeTHF (1.5 ml/mmol of dioxazaborocane). It is added to a solution of aryl chloride (1 eq.), Pd(OAc) ₂ (0.05 eq.), IMes (0.1 eq.) and K ₃ PO ₄ (2 eq.) in toluene (same volume as MeTHF) containing several drops of water. The mixture is then heated at 100 ⁰ C for 48 hours, under argon. After cooling, the organic phase is washed with water and then dried over MgSO ₄ and evaporated. The residue is then purified by flash chromatography (eluant: pure DCM). The fractions containing the product are then combined and evaporated.

4-cyclopropylacetophenone:

Yellowish liquid (72 mg, 0.45 mmol, 90%). ¹ H NMR (CDCI ₃ , 300 MHz), δ = 7.87 (d, ³ J _HH = 8.5 Hz, 2H, H ₅ ), 7.14 (d, ³ J _HH = 8.5 Hz, 2H, H ₄ ), 2.58 (s, 3H, H ₈ ), 1.96 (tt, ³ JHH = 8.4 Hz, ³ J _HH = 5.0 Hz, 1 H, H ₁ ), 1.08 (ddd, ³ J _HH = 8.4 Hz, ³ J _HH = 5.0 Hz, ² J _gem = 6.6 Hz, 2H, H ₂ ), 0.80 (td, ³ J _HH = 4.8 Hz, ² J _gem = 6.7 Hz, 1 H, H ₂ ). ¹³ C NMR (CDCI ₃ , 75.5 MHz), δ = 197.7 (C ₇ ), 150.4 (C ₆ ), 134.6 (C ₃ ), 128.5 (C ₅ ), 125.5 (C ₄ ), 26.5 (C ₈ ), 15.8 (C?), 10.4 (C ₂ ). Rf = 0.30 (DCM/EP 70 :30).

In this case, the coupling remains extremely effective in terms of isolated yield, but the reaction times are increased considerably. The cost of and ease of access to the chlorinated derivative nevertheless remain a major advantage and illustrate even more the flexibility of the method. REFERENCES

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