Patent Grant
11530175
The invention discloses a method for the preparation of fluoro alkylated compounds by homogeneous Ni catalyzed fluoro alkylation with fluoro alkyl halides in the presence of a base.
Organofluorine chemistry plays an important role in medicinal, agricultural, and material sciences and fields. Fluoroalkyl groups have strong effects such as high stability and lipophilicity, in addition, longer fluoroalkyl groups have high water and oil resistance and low friction.
According to Table 1 entry 10 the coupling of C6F13I provided 81% yield.
But a repetition of this experiment with the bromide instead of the iodide provided less than 1% yield, see Comparative Example herein.
There was a need fora homogenous catalyzed method for the preparation of fluoro alkylated compounds by direct C—H fluoro methylation, which provides high yields but does not need the assistance of a directing group or of electron rich aromatic compounds. The method should be applicable to a wide variety of substrates and should be compatible with a wide variety of functional groups. Furthermore the method should not be restricted to iodides as alkylating agents only, but should also work with bromides.
Unexpectedly a reaction with homogenous Ni catalysis was found that meets these requirements. No dialkylated products are observed. Only small exchange of the halide against H in the fluoro alkylated halide is observed.
In this text, the following meanings are used, if not otherwise stated:
Subject of the invention is a method for the preparation of a fluoro alkylated compound FACOMPSUBST by a reaction of a compound COMPSUBST with a fluoro alkyl halide FAHALIDE by homogeneous catalysis using a Ni catalyst NICAT in the presence of a base BAS;
Preferably, when LIG is Ph3P then NISALT is Ni(NO3)2.
Preferably, when LIG is compound of formula (dppb) then NISALT is NiCl2.
Preferably, LIG is compound of formula (DPEPhos) or Ph3P.
Preferably, Ni(NO3)2 is used in form of its hydrate Ni(NO3)2 6H2O.
Preferably, BAS is selected from the group consisting of Cs2CO3, K3PO4, NaH and NaOtBu; more preferably,
Preferably, m and n are identical or different and independently from each other 0, 1, 2, 3 or 4; more preferably, m and n are identical or different and independently from each other 0 or 4.
Preferably, COMPSUBST is selected from the group consisting of compound COMPSUBST-I, ethene, cyclohexene, ethine, and polystyrene;
More preferably, COMPSUBST-I is unsubstituted or substituted
Especially, COMPSUBST is selected from the group consisting of
ethene, cyclohexene, ethine, and polystyrene;
Preferably, Y is methyl or ethyl;
Embodiments of the substituted ethene are propene, ethene-1,1-diyldibenzene and 3,3-dimethylbut-1-ene:
An embodiment of substituted cyclohexene is 4-(cyclohex-1-en-1-yl)morpholine.
An embodiment of the substituted ethine is 1-octyne.
An embodiment of COMPSUBST is compound of formula (PYRAZ)
Preferably, R3 is CMS alkylen, wherein in the alkylen chain at least one of the hydrogens is substituted by F;
Especially, FAHALIDE is selected from the group consisting of perfluoro C1-20 alkyl-X1, Br—(CF2)n3—Br, and F2HC—X1;
In particular, FAHALIDE is selected from the group consisting of F21C10—I, F21C10—Br, F17C8—I, F17C8—Br, F13C6—I, F13C6—Br, F9C4—I, F9C4—Br, F7C3—I, F7C3—Br, F3C—I, F3C—Br, Br—(CF2)4—Br, F2HC—I, and F2HC—Br;
In one embodiment,
In one embodiment,
Preferably, from 0.1 to 20 mol %, more preferably from 0.5 to 15 mol %, even more preferably from 0.5 to 10 mol %, especially from 0.5 to 7.5 mol %, more especially from 0.5 to 6 mol %, even more especially from 0.75 to 5.5 mol %, of NICAT are used in the reaction, the mol % are based on the molar amount of FAHALIDE.
Preferably, from 0.1 to 20 mol %, more preferably from 0.5 to 15 mol %, even more preferably from 1 to 12.5 mol %, especially from 2 to 12.5 mol %, of LIG are used in the reaction, the mol % are based on the molar amount of FAHALIDE.
In case of FAHALIDE being in gaseous form at ambient temperature, then preferably FAHALIDE is used in the reaction in an amount which corresponds to a pressure of from 1 to 20 bar, more preferably from 1 to 15 bar, even more preferably from 1 to 10 bar, especially from 2 to 10 bar, more especially from 3 to 8 bar, even more especially from 4 to 8 bar, at ambient temperature.
Preferably, from 1 to 20 mol equivalents, more preferably 1 to 15 mol equivalents, even more preferably from 2 to 15 mol equivalents, especially from 2 to 12.5 mol equivalents, more especially from 2 to 11 mol equivalents, even more especially from 2.5 to 11 mol equivalents, of COMPSUBST are used in the reaction, the mol equivalents are based on the molar amount of FAHALIDE.
Preferably, from 0.1 to 10 mol equivalents, more preferably from 0.5 to 5 mol equivalents, even more preferably from 0.75 to 5 mol equivalents, especially from 0.85 to 5 mol equivalents, more especially from 0.95 to 5 mol equivalents, even more especially from 0.95 to 4 mol equivalents, in particular from 0.95 to 3 mol equivalents, of BAS are used in the reaction, the mol equivalents are based on the molar amount of FAHALIDE.
The reaction temperature of the reaction is preferably from 20 to 200° C., more preferably from 30 to 175° C., even more preferably from 40 to 175° C., especially from 40 to 150° C.
The reaction time of the reaction is preferably from 1 to 96 h, more preferably from 2 to 84 h, even more preferably from 3 to 80 h, especially from 4 to 76 h.
Preferably, the reaction is done under inert atmosphere. Preferably, the inert atmosphere is achieved by the use if an inert gas preferably selected from the group consisting of argon, another noble gas, lower boiling alkane, nitrogen, more preferably nitrogen.
The lower boiling alkane is preferably a C1-3 alkane, i.e. methane, ethane or propane.
The reaction can be done in a closed system, it can be done at a pressure caused by the reaction mixture at the chosen temperature in a closed system, and/or caused by the pressure applied by COMPSUBST, in case that COMPSUBST is in gaseous form. It is also possible to apply pressure with said inert gas. It is also possible to carry out the reaction at ambient pressure.
The reaction can be done in the presence of a an additive ADD;
Preferably, from 1 to 40 mol %, more preferably from 1 to 30 mol %, even more preferably from 1.5 to 30 mol %, especially from 1.5 to 25 mol %, more especially from 2 to 25 mol %, of ADD are used in the reaction, the mol % are based on the molar amount of FAHALIDE.
The reaction can be done in the presence of a an drying agent DRYAG;
The molecular sieve is preferably a Na12[(AlO2)12(SiO2)12]×H2O.
Preferably, the amount of DRYAG used in the reaction is from 0.1 to 2 fold, more preferably from 0.1 to 1.5 fold, even more preferably from 0.1 to 1 fold, especially from 0.1 to 0.75 fold, more especially from 0.1 to 0.5 fold, based on the weight of FAHALIDE.
Preferably, the reaction can be done in the presence of DRYAG when NICAT is Ni-cat1.
The reaction can be done neat or in a solvent SOL, SOL is preferably selected from the group consisting of alkanes, chlorinated alkanes, ketones, ethers, esters, aliphatic nitrils, aliphatic amides, sulfoxides, C6F6, and mixtures thereof;
It is also possible to use COMPSUBST and/or FAHALIDE simultaneously as solvent, meaning that the reaction is done neat.
Preferably, the reaction is done neat or in C6F6 as SOL.
The amount of SOL is preferably from 0.1 to 100 fold, more preferably from 1 to 50 fold, even more preferably from 1 to 25 fold, especially from 1 to 12.5 fold, more especially from 1 to 10 fold, even more especially from 3 to 10 fold, of the weight of FAHALIDE.
After the reaction, FACOMPSUBST can be isolated by standard methods such as evaporation of volatile components, extraction, washing, drying, concentration, crystallization, chromatography and any combination thereof, which are known per se to the person skilled in the art.
A mixture of COMPSUBST, FAHALIDE, NICAT, LIG, BAS, ADD, DRYAG, solvent (all equivalents and amounts are specified in the experimental table) were placed in a thick-walled pressure tube (Ace pressure tube, Sigma-Adrich Art. Nr. Z564575). The gas atmosphere in the pressure tube was flushed with nitrogen, the tube was closed with a screw cap and heated (reaction temperature and reaction time are specified in Table 3). The resulting mixture was cooled to room temperature and diluted with dichloromethane (4 ml). The solids were removed by centrifugation (3000 rpm, 15 min). The obtained product solution was analyzed by quantitative GC analysis (internal standard hexadecane), 19F-NMR analysis using the internal standards 1,2-difluorobenzene or 1,4-difluorobenzene, or GC-MS.
Isolation of the products was conducted by pipette column chromatography using FluoroFlash® reverse phase silica gel (Sigma Aldrich No.: 00866) and a gradient solvent elution (1. MeOH:H2O (4:1. 10 mL) 2. MeOH (100%, 10 mL) 3. acetone (100%, 10 mL) for long chains perfluoroalkyl chains (alkyl chain containing 10 or more carbon atoms) or by normal phase silical gel chromatography using silicagel (Sigma Aldrich No.: 236802) and a gradient solvent elution (1. Pentane Ether (100%) 2. Pentane:Diethylether (50%:50%, 10 ml) for perfluoroalkyl chains containing less than 10 carbon atoms.
Preformation of Ni-cat2 was done according to Standley, E. A. et al., A Broadly Applicable Strategy for Entry into Homogeneous Nickel(0) Catalysts from Air-Stable Nickel(II) Complexes, Organometallics 2014, 33, 2012:
NiCl2.6H2O (8.5 mmol, 2.02 g) and EtOH (25 mL) were placed in an argon flushed round bottom flask equipped with a septum and a reflux condenser (Schlenk-flask). Then dppf (8.5 mmol, 4.712 g) was added and the resulting reaction mixture refluxed for 30 min (temperature ca. 80° C.), before cooled to 0° C. for 10 min. The so formed solid was collected by filtration and washed twice with EtOH (2 times with 10 mL) and with diethylether (2 times with 10 mL). After drying of the solid under vacuum (ca. 20 mbar, room temperature) 4.98 g intermediate Ni-int1, (dppf)NiCl2, corresponding to 85% yield was obtained as a deep green powder.
This Ni-int1 (6.81 mmol, 4.658 g) and 180 mL CH2Cl2 were placed in an argon flushed round bottom flask. The resulting solution was cooled to 0° C., then o-tolylmagnesium chloride (6.81 mmol, 0.945 M in THF, 7.21 mL) was added dropwise with vigorous stirring. Near the end of the addition, the color of the solution changed from green to orange. This solution was stirred for an additional 15 min at 0° C. after addition, then the solvent was evaporated under vacuum at room temperature. Then 25 ml MeOH were added and the reaction mixture was stirred for 5 min at room temperature. After cooling this mixture to 0° C., the solid was collected by filtration, the residue was washed with MeOH (2 times with 5 ml) and dried under vacuum (ca. 5 mbar) at room temperature to yield 4.63 g Ni-cat2, (dppf)Ni(o-tol)Cl, corresponding to 92% yield as a fine, bright yellow powder.
1H NMR (400 MHz, CD2Cl2): delta=8.23-8.12 (m, 4H), 8.02-7.93 (m, 2H), 7.51-7.38 (m, 7H), 7.27 (td, J=8.3, 2.0 Hz, 2H), 7.21-7.15 (m, 1H), 6.99 (t, J=7.4 Hz, 1H), 6.76 (td, J=8.2, 2.6 Hz, 2H), 6.66-6.54 (t, 2H), 6.43 (t, J=7.4 Hz, 1H), 6.30 (t, J=6.8 Hz, 1H), 6.10 (d, J=7.1 Hz, 1H), 5.15 (s, 1H), 4.54 (m, 1H), 4.25 (s, 1H), 4.19 (s, 1H), 4.02 (d, J=10.1 Hz, 2H), 3.52 (m, 1H), 3.33 (m, 1H), 2.44 (s, 3H).
31P NMR (162 MHz, CD2Cl2): delta=29.51 (d, J=25.9 Hz, 1P), 12.12 (d, J=25.9 Hz, 1P).
A mixture of FAHALIDE (1 eq, 0.2 mmol), Ni-cat2 (5 mol %, 0.01 mmol, 7.40 mg, prepared according to the procedure “Preformation of Ni-cat2”), COMPSUBST (10 eq, 2 mmol,) and BAS were placed in a thick-walled Ace pressure tube (Sigma-Aldrich Art. Nr. Z564575). The gas atmosphere in the pressure tube was flushed with nitrogen, the tube was closed with a screw cap and heated for the reaction time and at the reaction temperature specified in the tables. The resulting reaction mixture was cooled to room temperature and diluted with dichloromethane (4 ml).
The solids were removed by centrifugation (3000 rpm, 15 min). The obtained product solution was analyzed by quantitative 19F-NMR analysis using 1,4-difluorobenzene or 1,2-difluorobenzene as internal standard, quantitative GC analysis using hexadecane as internal standard, or GC-MS.
Isolation of the products was conducted by pipette column chromatography using FluoroFlash® reverse phase silica gel (Sigma Aldrich No.: 00866) and a gradient solvent elution (1. MeOH:H2O (4:1. 10 mL) 2. MeOH (100%, 10 mL) 3. acetone (100%, 10 mL) for long chains perfluoroalkyl chains (alkyl chain containing 10 or more carbon atoms) or by normal phase silical gel chromatography using silicagel (Sigma Aldrich No.: 236802) and a gradient solvent elution (1. Pentane Ether (100%) 2. Pentane:Diethylether (50%:50%, 10 ml) for perfluoroalkyl chains containing less than 10 carbon atoms.
Details of the examples are given in Tables 1, 2 and 3.
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
19F-NMR
The entry 10 in Table 1 of Loy, R. N., et al., Organic Letters 2011, 13, 2548-2551, was repeated according to the detailed procedure given in the Supporting Information for said article, which is described under “Optimization procedure” on page S3 in connection with entry 9 in Table S4 on page S5.
The phosphine was BINAP.
[Pd] was Pd2dba3.
The base was Cs2CO3.
The alkylhalogenid was perfluorohexyl bromide instead of perfluorohexyl iodide.
To a screw cap 1 dram vial was added base (0.4 mmol, 2 equiv), [Pd] (0.02 mmol, 10 mol %) and phosphine (0.04-0.08 mmol, 20-40 mol %). Benzene (1 mL) and perfluorohexyl bromide (43 microL, 0.2 mmol, 1 equiv) were added, and the resulting mixture was sealed with a Teflon-lined cap and heated in an aluminum reaction block with vigorous stirring for 15 h at 80° C. The reaction mixture was cooled to 23° C. and chlorobenzene (20 microL) was added as a GC internal standard. An aliquot (ca. 100 microL) was removed from the crude reaction mixture and passed through a plug of Celite, eluting with EtOAc (2 mL). This sample was then analyzed by GC, and the yield was determined by comparison to a calibration against the chlorobenzene internal standard.
Result:
A yield of less than 1% was measured.
| Number | Date | Country | Kind |
|---|---|---|---|
| 19158332 | Feb 2019 | EP | regional |
This application is the U.S. National Stage entry of International Application Number PCT/EP2020/054542 filed under the Patent Cooperation Treaty having a filing date of Feb. 20, 2020, which claims priority to U.S. Provisional Patent Application No. 62/807,899 having a filing date of Feb. 20, 2019, and European Patent Application No. 19158332.7 having a filing date of Feb. 20, 2019, which are incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/054542 | 2/20/2020 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2020/169768 | 8/27/2020 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 10968187 | Taeschler | Apr 2021 | B2 |
| Entry |
|---|
| Butcher, Angew. Chem. Int. Ed.2021, 60, 2-27. |
| Zhang, Chem. Commun., 2020, 56, 15157-15160. |
| International Search Report and Written Opinion for PCT/EP2020/054542 dated Apr. 9, 2020, 12 pages. |
| Loy et al, “Palladium-Catalyzed C—H Perfluoroalkylation of Arenes,” Organic Letters, vol. 13, May 1, 2024, pp. 2548-2551. |
| Standley et al., “A Broadly Applicable Strategy for Entry into Homogeneous Nickel(0) Catalysts from Air-Stable Nickel(II) Complexes,” Organometallics, Apr. 16, 2014, pp. 2012-2018. |
| Number | Date | Country | |
|---|---|---|---|
| 20220041530 A1 | Feb 2022 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62807899 | Feb 2019 | US |
