Phosphine compound, ligand, metal complex, and synthesis catalyst

Abstract

To provide a synthesis catalyst that avoids loss of reactivity and suppresses cyclization, even in the synthesis of biaryl compounds having three or four substituents at the ortho position.SOLUTION: The present invention provides a phosphine compound represented by formula (1).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel phosphine compound, a ligand composed of the phosphine compound, a metal complex containing the phosphine compound as a ligand, and a synthetic catalyst containing the phosphine compound as a ligand. [Background technology]

[0002] Many pharmaceuticals, liquid crystal materials, and organic materials contain biaryl skeletons in which carbon atoms on two aromatic rings (aryl groups) are bonded to each other. The Suzuki-Miyaura coupling (SMC) method and other techniques are used to synthesize such biaryl compounds. The catalysts used in this process include those that are composed of a metal complex that combines a central metal (Pd, Rh, Ir, Pt, Au, etc.) with a ligand that does not directly participate in the reaction.

[0003] Many biaryl compounds used in medicines have a substituent at the ortho position. Examples include those shown in the following formulas (2), (3), and (4).

[0004] [ka]

[0005] [ka]

[0006] [ka]

[0007] The compound shown in formula (2) contains one substituent at the ortho position, the compound shown in formula (3) contains three substituents at the ortho position, and the compound shown in formula (4) contains four substituents at the ortho position.

[0008] The catalysts used in the synthesis of biaryl compounds promote the bonding reaction between carbon atoms on two aromatic rings (aryl groups). Therefore, there was a problem in that the reaction activity was significantly reduced when there were many substituents around the carbon atom involved in the bonding (ortho position). Non-Patent Document 1 discloses that when a biaryl compound was synthesized using a catalyst that uses an SPhos ligand, which is one of the Buchwald ligands, the amount of Pd required for the synthesis was 0.0005 mol % Pd for the synthesis of formula (2), 0.1 mol % Pd for the synthesis of formula (3), and 3 mol % Pd for the synthesis of formula (4). In other words, 200 times the catalyst was required for ortho trisubstitution compared to monosubstitution, and 6000 times the catalyst was required for ortho tetrasubstitution compared to monosubstitution, indicating that the reaction activity was insufficient for the synthesis of ortho trisubstitution and tetrasubstitution compounds.

[0009] In addition, when the ligand of the phosphine compound has a biaryl structure such as a Buchwald ligand, there has been a problem that, depending on the ligand structure, an unwanted cyclization reaction occurs during the synthesis of biaryl compounds such as pharmaceuticals (Non-Patent Document 2). [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Timothy E. Barder, Shawn D. Walker, Joseph R. Martinelli, and, Stephen L. Buchwald, J. AM. CHEM. SOC. 2005, 127, 4685-4696 [Non-Patent Document 2] Espinet, P. et al Chem.Commun. 2021, 57, 5458. Summary of the Invention [Problem to be solved by the invention]

[0011] The main object of the present invention is to provide a synthesis catalyst that does not lose reaction activity even in the synthesis of a biaryl compound having three or four substituents at the ortho positions and can suppress cyclization.

[0012] Means for Solving the Problems The present inventors have conducted intensive research in light of the above circumstances and have found a biaryl synthesis catalyst, a metal complex, a ligand for use in the catalyst, and a phosphine compound that do not lose reaction activity and can suppress cyclization even in the synthesis of a biaryl compound having three or four substituents at the ortho positions.

[0013] That is, the phosphine compound of the present invention is represented by the following formula (1).

[0014] [ka]

[0015] In the formula, R 1 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, and [2,6-bis(trifluoromethyl)]-4-pyridyl functional groups; R 2 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, and alkoxy functional groups; R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxy functional groups; X 1 , X 2 , X 3 , X 4 , X 5 are each independently selected from the halogens.

[0016] The ligand of the present invention is composed of the above-mentioned phosphine compound.

[0017] The metal complex of the present invention contains the above-mentioned phosphine compound as a ligand.

[0018] The metal of the metal complex is preferably palladium.

[0019] The synthesis catalyst of the present invention contains the above-mentioned phosphine compound as a ligand.

[0020] The biaryl synthesis catalyst of the present invention is obtained by applying the above synthesis catalyst to biaryl synthesis.

[0021] The biaryl to which the biaryl synthesis catalyst is applied may be a biaryl having tri- or tetra-substituted carbons at the ortho positions. Effect of the Invention

[0022] According to the phosphine compound of the present invention, a ligand composed of the phosphine compound, a metal complex containing the phosphine compound as a ligand, and a synthetic catalyst containing the phosphine compound as a ligand, the reaction activity is not decreased even in the synthesis of a biaryl compound having three or four substituents at the ortho positions, and cyclization can be suppressed. [Brief description of the drawings]

[0023] [Figure 1] Examples of Pd catalyst precursors that have been reported to have high activity are shown below. [Diagram 2] (a) is a 31P-NMR spectrum of an example of the synthetic catalyst of the present invention when stirred in a toluene solution for 24 hours, and (b) is a 31P-NMR spectrum of a comparative compound when stirred in a toluene solution for 24 hours. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The embodiments of the present invention will be specifically described below.

[0025] The phosphine compound of the present invention is represented by the following formula (1).

[0026] [ka]

[0027] In the formula, R 1is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, and [2,6-bis(trifluoromethyl)]-4-pyridyl functional groups. Among these, cyclohexyl is more preferred from the viewpoints of electron donating ability to P and bulkiness.

[0028] In the formula, R 2 is appropriately selected from functional groups other than hydrogen, and is preferably selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, and alkoxy functional groups, and more preferably alkoxy and methoxy. R 2 By introducing a functional group other than hydrogen into the aryl group, it is possible to suppress the cyclization reaction described below.

[0029] In the formula, R 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxy functional groups, with hydrogen and alkoxy being more preferred.

[0030] In the formula, X 1 , X 2 , X 3 , X 4 , X 5 are each independently selected from halogens (F, Cl, Br, I, etc.). Among them, F, which has a high electronegativity, is more preferable from the viewpoint of electron-withdrawing property.

[0031] Furthermore, by introducing a trifluoromethyl group, which has higher electron-withdrawing power, into the 4'-position of the lower aromatic ring that does not contain P, the electron density of the lower aromatic ring can be further reduced compared to the case where a fluoro group is introduced, and attack by bases can also be prevented.

[0032] That is, a preferred example of the phosphine compound of the present invention is represented by the following formula (5).

[0033] [ka]

[0034] The ligand of the present invention is composed of the above-mentioned phosphine compound.

[0035] The metal complex of the present invention contains the above-mentioned phosphine compound as a ligand. The metal complex contains a phosphine compound as a ligand and a central metal such as Pd, Rh, Ir, Pt, Au, etc. Among them, the central metal is preferably Pd because it shows a significantly high activity in Suzuki-Miyaura coupling.

[0036] Furthermore, in the metal complex of the present invention, the central metal may have a precursor structure. Figure 1 shows examples of Pd catalyst precursors that are known to be highly active. Palladacycle precatalysts are available in 1st, 2nd, 3rd, 4th, 5th, and 6th generation. Precursors from the 3rd generation onwards are more preferred, as they are versatile, dissolve well in many solvents, and can accommodate extremely bulky ligand groups.

[0037] The synthetic catalyst of the present invention contains the above-mentioned phosphine compound as a ligand. The synthesis catalyst is applicable to the synthesis of biaryls, arylamines, anilines, and the like.

[0038] The biaryl synthesis catalyst of the present invention is the above-mentioned synthesis catalyst applied to the synthesis of biaryls. The biaryl to which the biaryl synthesis catalyst is applied may be fully substituted, partially substituted, or unsubstituted at the ortho carbons. As described later, the biaryl synthesis catalyst of the present invention has a significantly higher reaction activity in biaryls in which the ortho carbons are tri- or tetra-substituted, as compared with conventional synthesis catalysts.

[0039] One of the reasons why the synthesis catalyst of the present invention has high activity is believed to be that the lower aromatic ring (aromatic ring not containing P) of the ligand of the present invention undergoes secondary interaction with Pd, stabilizing the catalyst. At this time, the lower aromatic ring substituted with a functional group having strong electron-withdrawing properties promotes reductive elimination of Pd. Therefore, even if the ortho-position of the synthesized biaryl has three or four bulky substituents, the coupling reaction is promoted. A conceptual diagram of the synthesis reaction is shown in the following formula (6).

[0040] [ka]

[0041] An example of a method for synthesizing the ligand of the present invention is the scheme shown in formula (7) below.

[0042] [ka]

[0043] The details of one example of the synthesis method are as follows. Diethyl [6-methoxy-2',3',5',6'-tetrafluoro-4'-trifluoromethyl-(1,1'-biphenyl)-2-yl] phosphonate (referred to as "diethyl phosphonate" in this paragraph) was prepared using the previous method. A Schlenk flask (50 mL) was heated and dried, and the atmosphere was replaced with argon. Lithium aluminum hydride (217 mg, 5.73 mmol) was added thereto, and THF (4.4 mL) and chlorotrimethylsilane (740 μL, 5.73 mmol) were added dropwise at -78 °C, and the mixture was stirred for 15 minutes. After 15 minutes, the mixture was returned to room temperature and stirred for 90 minutes. Then, diethylphosphonate (880 mg, 1.91 mmol) dissolved in THF (6.0 mL) was cooled to -50 °C and added dropwise. After the addition was completed, the mixture was stirred overnight at -30 °C. Under an argon gas atmosphere, degassed water (1.0 mL) was added dropwise to quench the reaction, and the mixture was stirred until no hydrogen generation was observed. Degassed water and 30% NaOH aqueous solution (2.9 mL) were added, and the mixture was stirred until the solid turned white. THF was added, and the supernatant was transferred to another Schlenk flask using a cannula. The white precipitate was extracted with THF, and Et2O was added to the supernatant transferred to the above tube. The aqueous layer was removed using a cannula, and the organic layer was washed with brine and dried with Na2SO4. The solution was transferred to another dried Schlenk tube using a cannula, and the solvent was removed under vacuum to obtain the crude product of the primary phosphine compound. In an argon gas atmosphere, phosphorus pentachloride (516 mg, 1.91 mmol) and toluene (6.8 mL) were added to the primary phosphine (680 mg, 1.91 mmol) in a 50 mL Schlenk flask, and the mixture was stirred at room temperature for 45 minutes. The mixture was then concentrated in vacuum to give the crude product of the dichlorophosphine. An oven-dried 50 mL three-neck round-bottom flask was equipped with a magnetic stirrer, magnesium (117 mg, 4.81 mmol), a reflux condenser, and a rubber septum, and the addition funnel and apparatus were flushed with argon gas. Diethyl ether (1.0 mL) was transferred to the flask along with a single crystal of iodine. The addition funnel was charged with chlorocyclohexane (480 μL, 4.85 mmol) and anhydrous diethyl ether (4.0 mL). Approximately 300 μL of this chlorocyclohexane solution was added to the flask and gently warmed to initiate the reaction, observing the disappearance of the iodine color and the gentle bubbling of ether. Once initiated, the chlorohexane solution was added (1-2 drops per second) to maintain a gentle reflux without external heating. After the addition of the chlorohexane solution was complete, the mixture was heated to reflux for 1 h, then the flask was cooled to -30°C, and a solution of the dichlorophosphine derivative (812 mg, 1.91 mmol) in 4.0 mL of diethyl ether was added dropwise with vigorous stirring. The solution was then allowed to warm to room temperature and stirred for 1 h. Saturated aqueous ammonium chloride was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was then concentrated under reduced pressure to give the crude product. The crude material was purified by silica gel chromatography (hexane / ethyl acetate = 30 / 1) to give 738 mg of 2-dicyclohexylphosphino-6-methoxy-2',3',5',6'-tetrafluoro-4'-trifluoromethyl-1,1'-biphenyl (51% yield) as a white solid.

[0044] The physical property data of the obtained 2-dicyclohexylphosphino-6-methoxy-2',3',5',6'-tetrafluoro-4'-trifluoromethyl-1,1'-biphenyl are as follows: Mp 124 °C 1H NMR (500 MHz, CDCl3) δ 7.47 (t, J = 8.0 Hz, 1H), 7.26–7.24 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.76 (s, 3H), 1.85–1.62 (m, 10H), 1.51 (d,J = 13 Hz, 2H), 1.27-1.00 (m, 10H) 13 C NMR (126 MHz, CDCl3) δ 156.8 (d, J = 9.7 Hz), 145.1–144.7 (m), 143.3–142.6 (m), 138.2 (d, J = 21.5 Hz), 130.2 (s), 125.1 (d, J = 2.4 Hz), 123.4 (d, J = 34.9 Hz), 122.7 (ddd, J = 8.3, 19.2 Hz), 121.2 (q, J = 275.2 Hz), 111.2(s), 108.7–108.2(m), 55.7(s), 34.3, 34.2, 30.3,000. 30.1, 28.8, 28.7, 27.3, 27.2, 27.1, 27.0, 26.3 19 F NMR (471 MHz, CDCl3) δ-55.9(s,3F),-135.9(s,2F),-142.4(s,2F) 31 P NMR (202 MHz, CDCl3) δ 6.0 (s); IR (KBr,cm-1) 3853 , 3672 , 3539 , 2925 , 2849 , 1334 , 1257 , 1144 , 1054 , 636 HRMS (FAB) m / z calcd 26 H 28 F 7O P ([M + H] + ): 520.1766, found:

[0045] -The New Year's Eve Review(1)- The activity of the catalyst was evaluated for the synthesis of a biaryl compound with four ortho-substituted groups. The structure of the ortho-tetrasubstituted biaryl used in the evaluation is shown in formula (8) below. In this evaluation, the biaryl of formula (8) was synthesized by reacting 1-bromo-2,6-dimethoxybenzene and 2,6-dimethoxyphenylboronic acid in toluene with Pd-ligand catalyst (0.5 mol%) and tripotassium phosphate (1.0 equiv.) at 60°C for 2 hours.

[0046] [ka]

[0047] The ligand of the phosphine compound of the formula (5) of the present invention was used at 0.5 mol% in combination with 0.5 mol of palladium acetate to prepare a biaryl synthesis catalyst. For comparison, the yield of the compound of the formula (8) was confirmed for the Buchwald ligands XPhos, tBuXPhos, BrettPhos, AlPhos, DavePhos, SPhos, and RuPhos, as well as the non-Buchwald ligands PhenCarPhos and BFPySphos.

[0048] The yield of formula (8) was as follows: Example of the present invention: Formula (5) 37% XPhos 2% tBuXPhos <1% BrettPhos <1% AlPhos <1% DavePhos 7% SPhos 18% RuPhos 9% PhenCarPhos 8% BFPySphos 14%

[0049] - Activity evaluation of the ligand of the present invention (2) - * After examining conditions (third generation (G3) catalyst) The activity of the catalyst was evaluated for the synthesis of a biaryl compound with four ortho-substituted groups. The structure of the ortho-tetrasubstituted biaryl used in the evaluation is shown in formula (8). In this evaluation, the biaryl of formula (8) was synthesized by reacting 1-bromo-2,6-dimethoxybenzene and 2,6-dimethoxyphenylboronic acid in a 1:3 mixture of isopropyl alcohol and water with a Pd-ligand catalyst (0.05 mol%) and tripotassium phosphate (2.0 equiv.) at 60°C for 6 hours.

[0050] The ligand of the phosphine compound of the formula (5) of the present invention was complexed with a precursor of the third generation Pd catalyst (3rd generation in FIG. 1) to obtain a biaryl synthesis catalyst. For comparison, the yield of the Buchwald ligand XPhos of the formula (8) was confirmed.

[0051] The yield of formula (8) was as follows: Inventive Example Formula (5) 90% XPhos 14%

[0052] From the above results, it was found that the catalyst containing the ligand of the present invention is more active than the catalyst containing the conventional ligand even in the synthesis of biaryls substituted with four carbons at the ortho positions.

[0053] -Activity evaluation of the ligand of the present invention (3)- ※After examining the conditions (third generation (G3) catalyst) The activity of the catalyst was evaluated for the synthesis of a biaryl compound with four ortho-substituted groups. The structure of the ortho-tetrasubstituted biaryl used in the evaluation is shown in formula (8). In this evaluation, the biaryl of formula (8) was synthesized by reacting 1-bromo-2,6-dimethoxybenzene and 2,6-dimethoxyphenylboronic acid in a 1:5 mixture of isopropyl alcohol and water with a Pd-ligand catalyst (0.025 mol%) and potassium carbonate (2.0 equiv.) at 60°C for 12 hours.

[0054] The ligand of the phosphine compound of the formula (5) of the present invention was complexed with a precursor of the third generation Pd catalyst (3rd generation in FIG. 1) to obtain a biaryl synthesis catalyst. For comparison, the yield of the Buchwald ligand XPhos of the formula (8) was confirmed.

[0055] The yield of formula (8) was as follows: Example of the present invention (5) 93% XPhos 5%

[0056] From the above results, it was found that the catalyst containing the ligand of the present invention has higher activity than the catalyst containing the conventional ligand even in the synthesis of biaryls substituted with four carbons at the ortho positions. It was also found that the yield was improved even if the amount of catalyst was reduced by changing the reaction conditions in the above-mentioned evaluation of the activity of the ligand of the present invention (2).

[0057] -Evaluation of the cyclization reaction suppression effect of the ligand of the present invention- R in Equation (1) 2 is appropriately selected from functional groups other than hydrogen. 2 This is because by introducing a functional group other than hydrogen into the ligand, it is possible to suppress damage to the ligand itself due to a cyclization reaction.

[0058] In one of the examples, the two aromatic rings in formula (5) are twisted and not on the same plane, but the ease of rotation of the carbon bond axis is thought to depend on the presence or absence and size of the substituents. The rotation part is shown in equation (9).

[0059] [ka]

[0060] As a comparative example, the compound represented by the following formula (10) was synthesized, in which the methoxy group at the 6-position was replaced with hydrogen.

[0061] [ka]

[0062] The example of formula (9) and the comparative example of formula (10) were dissolved in toluene and stirred at 30° C. for 24 hours to confirm whether a cyclization reaction occurred. After the reaction, 31 P-NMR spectra were measured. FIG. 2(a) shows the spectrum of the example of formula (9), and FIG. 2(b) shows the spectrum of the comparative example of formula (10). In the spectrum of the comparative example, a peak was observed at -57.9 ppm indicating a cyclization reaction, whereas in the spectrum of the example, no peak indicating a cyclization reaction was observed.

[0063] From the above evaluation results, it is believed that the absence of a substituent at the 6-position leads to a more planar conformation, making it easier for phosphorus to attack the other aromatic ring, resulting in a cyclization reaction.

Claims

1. A phosphine compound represented by the following formula (1): 【Chemistry 1】 [In the formula, R 1 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, and [2,6-bis(trifluoromethyl)]-4-pyridyl functional groups; R 2 is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, and alkoxy functional groups, 3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxy functional groups; X 1 , X 2 , X 3 , X 4 , X 5 are each independently selected from the halogens.

2. A ligand comprising the phosphine compound according to claim 1.

3. A metal complex comprising the phosphine compound according to claim 1 as a ligand.

4. The metal complex of claim 3 , wherein the metal of the metal complex is palladium.

5. A synthesis catalyst comprising the phosphine compound of claim 1 as a ligand.

6. A biaryl synthesis catalyst, in which the synthesis catalyst according to claim 5 is applied to biaryl synthesis.

7. The biaryl synthesis catalyst according to claim 6, wherein the biaryl to which the biaryl synthesis catalyst is applied is a biaryl having a tri- or tetra-substituted carbon atom at the ortho position.

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