Process for preparing alkyl substituted beta-methylene compounds

Abstract

The disclosure relates to a process for alkylating an active beta-methylene substrate (I) with a secondary alkyl or cycloalkyl group comprising reacting at a temperature of at least 100°C, said substrate (I) with a compound of formula AX where A is a secondary alkyl C3-C15 alkyl or a C3- C10 cycloalkyl and X is Cl or F, in the presence of (i) a reaction media having a dielectric constant lower than 30 and (ii) a base.

Description

PROCESS FOR PREPARING ALKYL SUBSTITUTED BETA-METHYLENE COMPOUNDSFIELD OF THE DISCLOSURE

[0001] The present disclosure relates to a process for alkylating an active beta-methylene substrate with a secondary alkyl or cycloalkyl group.BACKGROUND OF THE DISCLOSURE

[0002] Alkylation of substrates containing active beta-methylenes is a chemical reaction typically involving the presence of a base and an alkylating group.

[0003] The beta-methylenes are generally those placed between two functional groups able to receive and delocalize the negative charge of the carbo-anion generated from the base reacting with a hydrogen linked to the methylene.

[0004] This reaction becomes less efficient when one of the hydrogen atoms of the methylene has been already replaced by an alkyl group. In this situation in fact, the entry of the second alkyl group, especially if sterically hindered, becomes competitive with other reactions, such as elimination, and the overall yield is reduced.

[0005] Among various substrates, a-malonic esters derivatives are particularly interesting. Those compounds can be used as electron donor compounds in the preparation of Ziegler-Natta heterogeneous catalysts for the polymerization of olefins. Moreover, their reduction to diols followed by a further methylation step, allows the production of 1,3 -diether derivatives which are also used in the preparation of Ziegler-Natta catalysts.

[0006] Accordingly, it would be particularly interesting to develop an efficient synthetic approach for the preparation of mono and di-alkyl substituted beta-methylene substrates and in particular of certain di-alkyl substituted malonic esters.

[0007] Cabrera-Rivera et al ((2017) Solvent and Catalyst-Free Microwave- Assisted Decarboxylation of Malonic Acid Derivatives; Green and Sustainable Chemistry, 7, 270-280) describes the alkylation of diethyl 2-propylmalonate with various alkylating agents (RI or RBr) in the presence of a base and solvent and mild conditions (tBuOK / THF at room temperature or NaHMDS / THF from -15°C to room temperature). The alkylation with 2-halopropane (halogen being I or Br) took place with a yield of 74%.1FE7699-WO-01

[0008] In WO2014 / 130582 diethyl 2-methylmalonate is alkylated with bromocyclopentane at 100°C using sodium ethoxide as base. The yield was 77%wt.

[0009] In view of the above, it would be important to have available a more efficient process for the alkylation of substrates containing active beta-methylenes involving use of hindered alkylating agents such as cycloalkyl groups.SUMMARY OF THE DISCLOSURE

[0010] The applicant has now discovered that such a desired process is feasible when certain starting products are used and reaction conditions are observed.

[0011] It is therefore an object of the present disclosure a process for the alkylation of a substrate of formula (I)where:R1group is hydrogen or a C1-C15 hydrocarbon group;R2groups, equal or different to each other, are selected from the groups of formula (II) to (VIII) below(II) (III) (IV) (V) (VI) (VII) (VIII) in which Ar is a Ce-Cis aryl group, R3groups, equal or different to each other, are selected from C1-C10 hydrocarbon groups and R4are, same or different, H or R3; said process comprising reacting at a temperature of at least 100°C, said substrate (I) with a compound of formula AX where A is a secondary C3-C15 alkyl or a C3-C10 cycloalkyl and X is Cl or F, in the presence of (i) a reaction media having a dielectric constant, measured at 25°C, lower than 30 and (ii) a base with the proviso that when both R2groups have formula (III), R1group is not hydrogen.2FE7699-WO-01DETAILED DESCRIPTION OF THE DISCLOSURE

[0012] Preferably, R1group is a primary C1-C10 alkyl group, more preferably Ci-Cs, especially Ci-Ce linear or branched alkyl or cycloalkyl group.

[0013] R2groups are preferably selected from groups of formula (II) or (III), more preferably from groups of formula (III).

[0014] Preferably, R3is selected from Ci-Cs, preferably Ci-Ce linear or branched alkyl groups.

[0015] The reaction temperature is preferably above 110°C, more preferably above 120°C and in particular above 130°C, the range 120-160°C being particularly preferred.

[0016] In the compound of formula AX, A is preferably a secondary C3-C10 alkyl or a C3-C10 cycloalkyl, preferably a Cs-Ce cycloalkyl, and X is Cl or F. Preferably, A is chosen among isopropyl, sec-butyl, 2-pentyl, cyclopentyl and cyclohexyl group, with cyclohexyl being the most preferred. In combination with the most preferred A groups, X is preferably chlorine.

[0017] As mentioned, the dielectric constant (at 25°C) of the reaction media must be lower than 30, preferably lower than 25 and more preferably lower than 20 and especially lower than 10. In a particularly preferred embodiment, it may range from 3 to 10.

[0018] It is well known to the skilled in the art that dielectric constant value of chemicals is typically found in chemistry manuals and also freely available in internet sites of chemical manufacturers, providers of apparatus / software for electromagnetic measurements and chemical inventories (for example Chemical Book internet site). If desired, direct measurement of dielectric constant is possible by using apparatuses commercially available from several companies such as Rohde& Schwarz, Brookhaven Instruments, Agilent Technologies, which also make available further information on measuring methods and procedures.

[0019] Although not mandatory, the preferred reaction media or diluents also have a boiling point higher than 100°C preferably above 110°C, more preferably above 120°C, in particular in the range 130-150°C and in any case higher than the reaction temperature.

[0020] In a particularly preferred embodiment, the reaction media or diluent also acts as alkylating agents AX.

[0021] Preferred reaction media or diluents are anisole, chlorobenzene, dibutyl ether, xylenes. Among them, particularly preferred are cyclohexyl chloride and cyclopentyl chloride with cyclohexyl chloride being the most preferred.3FE7699-WO-01

[0022] The base can be selected from those typically used by the skilled in the art in this type of reactions. For example, it can be chosen among metal alkoxides, metal hydrides and metal amides. According to one preferred embodiment, it is preferably selected among alkoxides of formula R50M where R5is a C1-C10 hydrocarbon group, preferably alkyl, and M is Na or K. Particularly preferred, among them, are the alkoxides in which R5is a C1-C5 alkyl group and M is Na or K. Especially preferred compounds are potassium tert-butoxide, sodium tert-butoxide, potassium ethoxide, sodium ethoxide. As a preferred aspect, whenever possible, such preferred alkoxides are used in combination with the reaction media or diluents being also alkylating agent.

[0023] According to another preferred embodiment, the base is selected from metal hydrides MHZwhere M is a metal belonging to group I-II of the periodic table of elements and z is the valence of the metal. Among them, NaH, LiH and KH are the most preferred.

[0024] Preferred metal amides are those of formula MNR2 where M is Na, Li or K and R is H or Ci-Cs alkyl group. Specific examples are NaNH2, KNH2 and lithium diisopropylamide (LDA).

[0025] In carrying out the above-specified process, the reactants can be brought into contact with each other according to any order whatsoever. It constitutes a preferred embodiment, however, adding the substrate, optionally dispersed in an aliquot of the reaction medium, to a solution of the base dispersed in the reaction medium.

[0026] The amount of reaction medium / diluent is generally not critical. It is in the ordinary skills of the artisan to select the proper amount balancing the need of increasing the reactant concentration with the need of having a sufficient volume to allow an efficient stirring.

[0027] Throughout the present disclosure and claims, the term “equivalent(s)” refers to molar equivalent s) of the relevant compound.

[0028] When the diluent is also alkylating agent, the minimum amount used should be also necessary to perform the alkylation efficiently. In this case, the total amount expressed in equivalents per equivalent of substrate is at least 3, preferably at least 4 and especially in the range 5-8. In a preferred aspect of this embodiment, the excess of diluent / alkylating agent is recovered at the end of the reaction step, for example by distillation, and used in a further alkylation reaction.4FE7699-WO-01

[0029] The amount of alkylating agent AX, is usually in excess with respect to the substrate. Preferably, at least 1.2, more preferably at least 1.4 and especially from 1.5 to 3 equivalents of AX with respect to substrate (I) are used.

[0030] Also the base is preferably used in small excess with respect to substrate (I). Preferably, at least 1.05 more preferably from 1.1 to 1.5 equivalents per equivalent of substrate are used.

[0031] Reaction time may range from 1 to 50 hours, more preferably from 3 to 30 hours and especially from 5 to 25 hours.

[0032] At the end of the reaction, customary aqueous work-up is carried out to remove acid and / or base reaction residues.

[0033] The reaction product is preferably extracted with an apolar hydrocarbon solvent, such as iso-hexanes and then dried.

[0034] The process of the present disclosure provides alkylated beta-methylene compounds in very high yield, generally higher than 75%, preferably higher than 80% and in some cases even higher than 85% with respect to the starting substrate (I).

[0035] As mentioned above, when both R2groups of substrate (I) are selected from formula (III), the deriving products alkylated beta-methylene compounds are malonates derivatives of formula (IX)

[0036] where A, R1and R3have the same meanings previously specified.

[0037] In a preferred embodiment, A is a C3-C10 cycloalkyl , R1is a primary C1-C10 alkyl group and R3is a Ci-Ce linear or branched alkyl group.

[0038] Such compounds can be used as such as internal donors in the preparation of Ziegler-Natta solid catalyst components or can be subject to further reactions, such as reduction and methylation, generating 1,3 -di ethers that are also used as internal donors. Examples of such further reactions are disclosed in W02024 / 008862 Al the relevant part of which is herein enclosed by reference.5FE7699-WO-01

[0039] The following examples are given in order to further illustrate and not limit the present disclosure.EXAMPLES

[0040] Example 1: Synthesis of diethyl 2-cyclohexyl-2-isopentylmalonate

[0041] To a 3 L round bottom flask equipped with mechanical stirrer, thermometer and Dean-Stark apparatus, under nitrogen atmosphere, cyclohexyl chloride (1.7 kg, 14.0 mol, 7.3 eq) is added, followed by potassium ethoxide 98% (163 g, 1.9 mol, 1.0 eq). The mixture is heated at 70°C with an oil bath and diethyl 2-isopentylmalonate 98% (450 g, 1.9 mol, 1.0 eq) is added dropwise and heated at the same temperature for 1.5 hours. Then oil temperature is raised to 145°C to achieve an internal temperature of 135°C, removing approximatively 150 mL of condensate at T= 110-120°C. The mixture is allowed to react at 135°C for 5.5 hours. Successively, the mixture is cooled to 70 °C and potassium ethoxide 98% (25 g, 0.29 mol, 0.15 eq). Again, the slurry is heated at 70 °C for 1.5 hours and then at 135°C for 4 hours, removing additional condensate at T= 110-120°C. At the end, the mixture is siphoned in a 6 L flask containing 1 L of hydrochloric acid 0.8 M and 0.5 L of iso-hexanes. The aqueous phase is discharged and the organic one washed twice with 300 mL of water. The organic phase is evaporated at 140°C / 20 mbar for 2 hours, to obtain as a residue in the boiler diethyl 2-cyclohexyl-2-isopentylmalonate as an orange oil, 586 g, purity 86.4% (based on GC area).

[0042] The distilled fraction from the organic phase is subjected to azeotropic removal of residual water (T= 60-70°C p=760 mbar), then distilled obtaining the following fractions:

[0043] 1. 190 g of colorless liquid, T= 60-88°C p= 440-340 mbar, containing cyclohexyl chloride 30% wt;

[0044] 2. 1281 g of colorless liquid, T= 80-88°C p= 340-130 mbar, containing cyclohexyl chloride 98.1 % wt. This fraction has been used to perform the experiment reported in Example 2.

[0045] 3. 84 g of colorless liquid, T= 70-42°C p= 130-20 mbar, containing 95.6% wt cyclohexyl chloride.

[0046] Example 2: Synthesis of diethyl 2-cyclohexyl-2-isopentylmalonate

[0047] Same procedure of Example 1, 1.17 kg (98.1%, 10 mol, 5.1 eq) of cyclohexyl chloride recovered from Example 1. Diethyl 2-cyclohexyl-2-isopentylmalonate is obtained as an orange oil, 583 g, purity 88.0% (based on GC area).6FE7699-WO-01

[0048] Example 3: Synthesis of diethyl 2-cyclohexyl-2-isopentylmalonate

[0049] To a 250 mL round bottom flask equipped with mechanical stirrer, thermometer and Dean- Stark apparatus, under nitrogen atmosphere, cyclohexyl chloride (94 g, 0.8 mol, 7.3 eq) is added, followed by sodium hydride 90% (2.9 g, 0.11 mol, 1.0 eq). The mixture is heated at 70 °C with an oil bath and diethyl 2-isopentylmalonate 98% (25 g, 0.11 mol, 1.0 eq) is added dropwise and left in isotherm for 1.5 hours. Then oil temperature is raised to 145 °C to achieve an internal temperature of 135°C, and the mixture is heated at the same temperature for 5.5 hours. Successively, the mixture is cooled to 70°C and sodium hydride 90% (0.4 g, 0.02 mol, 0.15 eq) added. Again, the slurry is heated at 70°C for 1.5 hours and then at 135°C for 4 hours. At the end, the mixture is added of 50 mL of hydrochloric acid 0.8 M and extracted with 50 mL of iso-hexanes. The aqueous phase is discharged and the organic one washed twice with 50 mL of water. The organic phase is evaporated at 140°C / 20 mbar for 2 hours, to obtain diethyl 2-cyclohexyl-2-isopentylmalonate as an orange oil, 32 g, purity 83% (based on GC area).

[0050] Example 4: Synthesis of diethyl 2-cvclopentyl-2-isopentylmalonate

[0051] Same procedure of Example 1, reaction conducted in a 250 mL round bottom flask using cyclopentyl chloride 73 g (0.7 mol, 8.0 eq), potassium ethoxide 95% (7.7 g, 0.09 mol, 1.0 eq) and diethyl 2-isopentylmalonate 98% (20 g, 0.09 mol, 1.0 eq), first isotherm at 130°C for 3 hours. Second isotherm at 130°C for 3 hours with additional potassium ethoxide 95% (1.1 g, 0.01 mol, 0.15 eq). Diethyl 2-cyclopentyl-2-isopentylmalonate is obtained as an orange oil, 24.4 g, purity 93% (based on GC area).

[0052] Example 5: Synthesis of diethyl 2-cyclohexyl-2-isopentylmalonate

[0053] To a 3 L round bottom flask equipped with mechanical stirrer, thermometer and Dean- Stark apparatus, under nitrogen atmosphere, chlorobenzene (610 mL) is added, followed by cyclohexyl chloride (597 g, 14.0 mol, 2.8 eq) is added, followed by potassium ethoxide 95% (163 g, 1.8 mol, 1.0 eq). The mixture is heated at 70°C with an oil bath and diethyl 2-isopentylmalonate 92% (450 g, 1.8 mol, 1.0 eq) is added dropwise heated at the same temperature for 1.5 hours. Then oil temperature is raised to 145°C to achieve an internal temperature of 130°C, removing condensate at T= 110-120°C. The mixture is allowed to react at the same temperature for 12 hours. Successively, the mixture is cooled to 70°C and potassium ethoxide 95% (25 g, 0.27 mol, 0.15 eq). Again, the slurry is heated at 70°C for 1.5 hours and then at 130°C for 6 hours, removing additional condensate at T= 110-120°C. At the end, the mixture is siphoned in a 6 L flask containing 1 L of7FE7699-WO-01hydrochloric acid 0.8 M and 0.5 L of iso-hexanes. The aqueous phase is discharged and the organic one washed twice with 300 mL of water. The organic phase is evaporated at 140°C / 20 mbar for 2 hours, to obtain diethyl 2-cyclohexyl-2-isopentylmalonate as an orange oil, 535 g, purity 87.5% (based on GC area).

[0054] Example 6: Synthesis of diethyl 2-cyclohexyl-2-isopentylmalonate

[0055] Same procedure of Example 5, using o-xylene instead of chlorobenzene. Diethyl 2-cyclohexyl-2-isopentylmalonate is obtained as an orange oil, 494 g, purity 88.0% (based on GC area).

[0056] Example 7: Reduction of diethyl 2-cyclohexyl-2-isopentylmal onate to 2-cyclohexyl-2-isopentyl-l,3-propandiol

[0057] According to the procedure reported in W02024008862 Al , diethyl 2-cyclohexyl-2-isopentylmalonate 86.4% (20 g, 0.06 mol) is reduced to 2-cyclohexyl-2-isopentyl-l,3-propandiol obtained as colorless viscous oil, 12.6 g, purity 98% (based on GC area).

[0058] Example 8: Methylation of 2-cvclohexyl-2-isopentyl-l,3-propandiol to 2-cvclohexyl-2-isopentyl-1.3-dimethoxypropane

[0059] According to the procedure reported in W02024 / 008862 Al, 2-cyclohexyl-2-isopentyl-l,3-propandiol 98% (10 g, 0.04 mol) is methylated to 2-cyclohexyl-2-isopentyl-l,3-dimethoxypropane obtained as colorless, 11.2 g, purity 98% (based on GC area).

[0060] Comparative example 1: Synthesis of diethyl 2-cyclohexyl-2-isopentylmalonate

[0061] To a 250 mL round bottom flask equipped with mechanical stirrer and thermometer, under nitrogen atmosphere, DMF (40 mL) is added, followed by diethyl 2-isopentylmalonate 92% (10.8 g, 0.04 mol, 1.0 eq) and potassium ethoxide 95% (3.6 g, 0.04 mol, 1.0 eq). The mixture is heated at 40°C for 30 minutes, and complete enolate salt formation is verified via1H-NMR (quenching of the salt with D2O). Then cyclohexyl chloride (7.7 g, 0.06 mol, 1.5 eq) is added, and the reaction is heated to 130°C for 9 hours. Product is not isolated due to low conversion of starting material (22%).

[0062] Comparative example 2; Synthesis of diethyl 2-cyclohexyl-2-isopentylmalonateSame procedure of Example 1, reaction conducted in a 500 mL round bottom flask using cyclohexyl bromide 330 g (2.0 mol, 8.0 eq), potassium ethoxide 95% (25 g, 0.28 mol, 1.0 eq) and8FE7699-WO-01diethyl 2-isopentylmalonate 94% (68 g, 0.28 mol, 1.0 eq), first isotherm at 130°C for 5.5 hours. Second isotherm at 130°C for 4 hours with additional potassium ethoxide (3.3 g, 0.04 mol, 0.15 eq). Product is not isolated due to low conversion of starting material (29%).

[0063] CHARACTERIZATION

[0064] The characterization of the products obtained in the following examples has been carried out via1H-NMR. Conversion of the starting substrate having an active beta-methylene has been determined via GC. Yield represented is corrected by the purity (as % GCArea) of the final alkylated product.Table 1DMF= N,N-dimethylformamide; KOEt = potassium ethoxide; NaH = sodium hydride; CHC = cyclohexyl chloride; CPC= cyclopentyl chloride; CHB= cyclohexyl bromide9FE7699-WO-01

Claims

CLAIMSWhat is claimed is:A process for the alkylation of a substrate of formula (I)where:-R1group is hydrogen or a C1-C15 hydrocarbon group;-R2groups, equal or different to each other, are selected from the groups of formula (II) to (VIII) below- in which Ar is a Ce-Cis aryl group, R3groups, equal or different to each other, are selected from C1-C10 hydrocarbon groups or aryl, and R4are, same or different, H or R3; said process comprising reacting at a temperature of at least 100°C, said substrate (I) with a compound of formula AX where A is a secondary C3-C15 alkyl or a C3-C10 cycloalkyl and X is Cl or F, in the presence of (i) a reaction media having a dielectric constant lower than 30 and (ii) a base with the proviso that when both R2groups have formula (III), R1group is not hydrogen.

2. A process according to claim 1 wherein R1group is a primary C1-C10 alkyl group, more preferably Ci-Cs, especially Ci-Ce linear or branched alkyl or cycloalkyl group.

3. A process according to claim 1 or 2 wherein R2groups are selected from groups of formula (II) or (III), more preferably from groups of formula (III).

4. A process according to any of the preceding claims wherein R3is selected from Ci-Cs, preferably Ci-Ce linear or branched alkyl groups.10FE7699-WO-015. A process according to any of the preceding claims wherein the reaction temperature is above 110°C, more preferably above 120°C and in particular above 130°C, especially in the range 120-160°C.

6. A process according to any of the preceding claims wherein in the compound of formula AX, A is a secondary C3-C10 alkyl or a C3-C10 cycloalkyl, preferably a Cs-Ce cycloalkyl, and X is Cl or F.

7. A process according to claim 6 wherein A is selected from isopropyl, sec-butyl, 2-pentyl, cyclopentyl and cyclohexyl group, with cyclohexyl being the most preferred, and X is chlorine.

8. A process according to any of the preceding claims wherein the reaction media or diluent has a boiling point higher than 100°C preferably above 110°C, more preferably above 120°C, in particular in the range 130-150°C.

9. A process according to any of the preceding claims wherein the dielectric constant of the reaction media or diluent is lower than 25, preferably lower than 20, especially lower than 10 and most preferably in the range from 3 to 10.

10. A process according to claim 9 wherein the reaction media or diluent 1 is selected from the group consisting of anisole, chlorobenzene, dibutyl ether, xylenes and mixtures of two or more thereof.

11. A process according to claim 9 wherein the reaction media or diluent also acts as alkylating agent AX.

12. A process according to any of the preceding claims wherein the base is selected among metal alkoxides, metal hydrides and metal amides and in particular from (i) alkoxides of formula R50M where R5is a C1-C10 hydrocarbon group, preferably alkyl, and M is Na or K and (ii) metal hydrides MHz where M is a metal belonging to group I-II of the periodic table of elements and z is the valence of the metal.

13. A process according to any of the preceding claims wherein the total amount of compound AX, expressed in equivalents per equivalent of substrate, is at least 3, preferably at least 4 and especially in the range 5-8.

14. A process according to any of the preceding claims wherein both R2groups are selected from formula (III), and the deriving alkylated substrate is a malonate derivative of formula (IX)11FE7699-WO-01where A, R1and R3are as defined in claim 1.A process according to claim 14 further comprising the reduction and methylation of the malonate derivative of formula (IX) thereby obtaining 2,2-dialkyl substituted 1,3- diethers.12FE7699-WO-01

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