Novel chiral ferrocenyl-bridged binaphthyl backbone phosphine ligands and uses thereof

Abstract

The application provides a novel chiral ferrocene-bridged binaphthyl skeleton phosphine ligand and application thereof. The ligand has multiple advantages such as low cost, simple synthesis and air stability. The ligand has good catalytic activity and enantioselectivity in an asymmetric hydrogenation reaction of a ketone, and has certain industrial application prospect in synthesis of a drug molecule.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of chemical industry, and particularly relates to a novel chiral ferrocene-bridged binaphthyl skeleton phosphine ligand and application thereof. BACKGROUND

[0002] The asymmetric hydrogenation of prochiral ketone compounds is a direct and efficient synthesis method for synthesizing chiral alcohol compounds, and the core lies in developing stable, efficient and broad-spectrum chiral phosphine ligands to realize the accurate recognition of prochiral ketones. Since the ligands developed by Professors Noyori, Zhang Xumu, Zhou Qilin and Zhang Wanbin, the field has developed rapidly. However, the existing ligands are still insufficient for the chiral recognition of some prochiral ketone compounds, thereby limiting the wide application of the field. Therefore, it is still of great value to develop novel chiral phosphine ligands and catalytic systems. SUMMARY

[0003] In order to achieve the technical purpose of the application, the technical scheme of the application is as follows:

[0004] Firstly, the application provides a novel chiral ferrocene-bridged binaphthyl skeleton phosphine ligand, specifically a chiral ferrocene-bridged binaphthyl skeleton phosphine ligand shown in formula I:

[0005] ,

[0006] A chiral ferrocene-bridged binaphthyl skeleton phosphine ligand shown in formula II is provided:

[0007] ,

[0008] A chiral ferrocene-bridged binaphthyl skeleton phosphine ligand shown in formula III is provided:

[0009] ,

[0010] A chiral ferrocene-bridged binaphthyl skeleton phosphine ligand shown in formula IV is provided:

[0011] ,

[0012] Among them:

[0013] The Ar in the chiral ferrocene-bridged binaphthyl skeleton phosphine ligand shown in formula I-IV is aryl or substituted aryl;

[0014] R in formula I-IV is independently selected from one of hydrogen, aryl, alkyl, fluorine, chlorine, bromine, iodine and alkoxy; 1

[0015] R in formula I-IV is independently selected from one of hydrogen, aryl, alkyl, fluorine, chlorine, bromine, iodine and alkoxy; 2 ​is independently selected from the group consisting of NH2, NHMe, NMe2, NHAc, NHCOAr, NHSO2Me, NHSO2CF3, NHSO2Ar, wherein Ar is aryl or substituted aryl.

[0016] The Ar is more preferably phenyl, and the R 1 is more preferably hydrogen, and the R 2 is more preferably NH2, NMe2, NHSO2Ar, wherein Ar is substituted aryl.

[0017] Most preferably, the chiral ferrocenyl bridged binaphthyl backbone phosphine ligand has the structure:

[0018] ,

[0019] ,

[0020] .

[0021] In a second aspect, the present application provides a method for preparing the chiral ferrocenyl bridged binaphthyl backbone phosphine ligand of formula III, according to the following reaction scheme:

[0022] ,

[0023] wherein Ar, R 1 , R 2 are defined as above.

[0024] wherein, （S) -DI-NH2 and (S c ,R Fc ) The solvent for the first addition reaction is an organic solvent, and more preferably methanol.

[0025] wherein, （S) -DI-NH2 and (S c ,R Fc ) The temperature for the first addition reaction is in the range of 50-70°C, and more preferably 60°C.

[0026] More preferably, the chiral ferrocenyl bridged binaphthyl backbone phosphine ligand (S c ,S ax ,R Fc ) The method for preparing L1 is as follows:

[0027] .

[0028] In a third aspect, the present application provides a catalyst for asymmetric hydrogenation reaction, which is prepared by complexing the chiral ferrocenyl bridged naphthalene skeleton phosphine ligand with transition metal and its salt. The transition metal is one of Ru (ruthenium), Rh (rhodium), Pd (palladium), Ir (iridium), Fe (iron), Co (cobalt), Ni (nickel), Cu (copper), Sc (scandium), Ti (titanium), Cr (chromium), Mn (manganese), Re (rhenium), Os (osmium), Pt (platinum).

[0029] The transition metal salt is RuX3 (trivalent ruthenium salt), RuHX(L)2 (diphosphine ruthenium hydrogen complex), RuX2(L)2 (diphosphine divalent ruthenium complex), Ru(arene)X2 (diphosphine divalent ruthenium complex), Ru(aryl group)X2 (disubstituted aryl divalent ruthenium complex), Ru(RCOO)2 (diphosphine disubstituted carboxyl divalent ruthenium complex), Ru(methallyl)2 (diphosphine bis (methylallyl) ruthenium complex), Ru(aryl group)X2(PPh3)3 (substituted aryl tris (triphenylphosphine) ruthenium complex), Ru(COD)(COT) (1,5-cyclopentadiene) (1,3,5-cyclooctatriene) ruthenium), Ru(COD)(COT)X (1,5-cyclopentadiene) (1,3,5-cyclooctatriene) ruthenium salt), RuX2(Cymene) (p-cymene divalent ruthenium complex), RuCl(COD) nRu(ArH)Cl2 (dichloroaryl ruthenium complex), Ru(COD)(methallyl)2 (bis(methallyl)(l,5-cyclooctadiene)ruthenium), Rh(CO)2Cl2 (dicarbonyl rhodium dichloride), [Rh(NBD)2]BF4 (dibenzorbornadiene rhodium tetrafluoroborate), [Rh(NBD)Cl]2 (benzorbornadiene rhodium chloride dimer), [Rh(COD)Cl]2 ((l,5-cyclooctadiene)rhodium chloride dimer), [Rh(COD)2]X ((l,5-cyclooctadiene)rhodium salt), Rh(acac)(CO)2 (dicarbonyl acetylacetonato rhodium), Rh(ethylene)2(acac) (acetylacetonato di(ethylene)rhodium), [Rh(ethylene)2Cl]2 (di(ethylene)rhodium chloride dimer), RhCl(PPh3)3 (tris(triphenylphosphine)rhodium chloride), PdX2 (divalent palladium salt), Pd(PPh3)4 (tetra(triphenylphosphine)palladium), Pd(allyl)Cl (allyl palladium chloride), IrX3 (trivalent iridium salt), [Ir(NBD)2)Cl]2 (dibenzorbornadiene iridium chloride dimer), [Ir(COD)Cl]2 ((l,5-cyclooctadiene)iridium chloride), Ir(COD)X ((l,5-cyclooctadiene)iridium salt), FeX2 (divalent iron salt), FeX3 (trivalent iron salt), Ni(acac)2 (acetylacetonato nickel(II)), NiX2 (divalent nickel salt), [Ni(allyl)X]2 (allyl nickel dimer), Ni(COD)2 (bis-(l,5-cyclooctadiene)nickel), CuX (monovalent copper salt), CuX2 (divalent copper salt), MoO2(acac)2 (acetylacetonato molybdenum), ScX2 (divalent scandium salt), Ti(O i Pr)4 (tetraisopropyl titanate), CrX2 (divalent chromium salt), CrX3 (trivalent chromium salt), MnBr(CO)5 (penta-carbonyl manganese bromide), Mn2(CO) 10one of Mn10 (Chinese expression: decacarbonyldimanganese), MnX2 (Chinese expression: divalent manganese salt), Mn(acac)2 (Chinese expression: acetylacetonatomanganese (II)) or MeReO3 (Chinese expression: methyltrioxorhenium). Wherein, X is independently selected from one of Cl-, Br-, I-, ClO4-, BF4-, Sb6-, PF6-, CF3SO3-, RCOO-, BAr4-; L is MeCN, DMSO and the like solvent molecules; R is independently selected from one of alkyl, alkoxy or substituted alkyl. Wherein, the above Ru represents metal ruthenium, Diphosphine represents a diphosphine ligand, arene and ArH represent aryl, aryl group represents a substituted aryl group, methallyl represents a methallyl group, PPh3 represents triphenylphosphine, COD represents 1,5-cyclooctadiene, COT represents 1,3,5-cyclooctatriene, Cymene represents p-cymene, Rh represents metal rhodium, CO represents carbonyl, NBD represents norbornadiene, acac represents acetylacetone, ethylene represents ethylene, Pd represents metal palladium, allyl represents an allyl group, Ir represents metal iridium, Fe represents metal iron, Ni represents metal nickel, Cu represents metal copper, Mo represents metal molybdenum, Sc represents metal scandium, Ti represents metal titanium, Cr represents metal chromium, Mn represents metal manganese, Me represents methyl, and Re represents metal rhenium.

[0030] More preferably, the catalyst is an Ir complex formed by complexing a chiral ferrocenyl bridged binaphthyl skeleton phosphine ligand with an Ir metal salt.

[0031] The application provides the use of the above chiral ferrocenyl bridged binaphthyl skeleton phosphine ligand in the asymmetric hydrogenation of prochiral ketone compounds, thereby synthesizing chiral alcohol compounds. Specifically, under a nitrogen atmosphere, a metal salt, the ligand and a solvent are added, stirred to form a clear solution, then a base, a prochiral ketone compound and a solvent are added to the reaction solution, and the reaction is carried out under hydrogen.

[0032] Wherein, the definition of the metal salt is the same as described above. The definition of the ligand is the same as described above.

[0033] Wherein, the solvent is an organic solvent, and more preferably anhydrous tetrahydrofuran.

[0034] Wherein, the base is a strong base, and more preferably potassium tert-butoxide.

[0035] Wherein, the reaction temperature of the asymmetric hydrogenation reaction is 10-60°C, and more preferably 20-30°C.

[0036] Wherein, the reaction time of the asymmetric hydrogenation reaction is 30-60h, and more preferably 48h.

[0037] More preferably, the application is the use of chiral ferrocene-bridged binaphthyl backbone phosphine ligand in the asymmetric hydrogenation of acetophenone, thereby synthesizing 1-phenylethanol.

[0038]

[0039] The application has the advantages that the ligand is simple to synthesize, low in price and easy to scale up, the metal complex of the ligand has good catalytic activity and better enantioselectivity in the process of asymmetric hydrogenation of prochiral ketone compounds to synthesize chiral alcohol, and has certain industrial application potential in asymmetric hydrogenation reaction. DETAILED DESCRIPTION

[0040] In order to further understand the application, the novel chiral ferrocene-bridged binaphthyl backbone phosphine ligand and its application provided by the application are described in detail below in combination with examples. It should be understood that these examples are only for further detailed description of the features of the application, and are not a limitation on the scope of the application or the scope of claims of the application.

[0041] The reagents used in the application can be purchased from the market.

[0042] In the application, mmol represents millimole, h represents hour, g represents gram, L represents liter, and ml represents milliliter.

[0043] Example 1: Synthesis of ligand L1

[0044]

[0045] （S) Synthesis of -DI-NH2:

[0046] A 250 ml flask was charged with （S ax ） BINOL (5.00 g, 17.4 mmol), 2-bromopropionamide (7.96 g, 52.2 mmol), potassium carbonate (7.21 g, 52.2 mmol) and potassium iodide (33 mg, 0.20 mmol), followed by dimethyl sulfoxide (30 mL) and stirring was started. The reaction was heated to 50-55℃ and stirred until the raw material was completely converted (TLC detection, generally 24 h). The temperature was lowered to 20-30℃, potassium hydroxide (15.3 g, 217.5 mmol, 80%) was added, and then the reaction was heated to 145-150℃ and stirred for 4 h. The reaction was lowered to 0℃, water 100 mL was added to quench the reaction, the reaction was extracted with ethyl acetate (100 mL x 3), dried with sodium sulfate, filtered, concentrated and subjected to column chromatography, followed by eluent concentration and drying to obtain (S ax) DI-NH2 was light brown solid, total 3.96 g, molar yield 80%.

[0047] 1 H-NMR (400 MHz, CDCl3) δ 7.84-7.78 (m, 4H),7.27-7.18 (m, 4H),7.15 (d, J = 8.8 Hz, 2H),7.09 (d, J = 8.1 Hz, 2H),3.69 (brs, 4H).

[0048] (S c ,R Fc ) - Synthesis of 1:

[0049] 100ml flask was added （S c ） -1(2.57 g, 10 mmol) and anhydrous ether (100 mL) was replaced by nitrogen three times, then cooled to 0-5℃, and the internal temperature was controlled at 0-5℃. A solution of sec -butyl lithium (8.5 m, 11 mmol, 1.3 M) was added dropwise, and after the dropwise addition was completed, it was stirred at 0-5℃ for 0.5 hours, and then warmed to 20-30℃ for 1.5 hours. The reaction solution was cooled to 0-5℃, and the internal temperature was controlled at 0-5℃. Diphenyl phosphorus chloride (2.65 g, 12 mmol) was added dropwise, and after the dropwise addition was completed, it was stirred at 20-30℃ for 16 hours. The reaction solution was added to 200 mL of water to quench the reaction, extracted with ethyl acetate (200 mL ×3), dried with sodium sulfate, filtered, concentrated, and then separated by column chromatography. After the eluent was concentrated and dried, 1.5 g of 1 was obtained as a yellow solid, with a molar yield of 60%. (S c ,R Fc ) -1 was orange solid, total 3.08 g, molar yield 70%.

[0050] 1 H-NMR (400 MHz, CDCl3) δ 7.59 (dq, J = 7.5, 3.0, 2.0 Hz, 2H), 7.40-7.31(m, 3H), 7.23-7.12 (m, 5H), 4.36 (q, J = 2.0 Hz, 1H), 4.24 (t, J = 2.4 Hz, 1H),4.15 (dd, J =6.8, 2.8 Hz, 1H), 3.94 (s, 5H), 3.85 (dt, J = 2.4, 1.2 Hz, 1H),1.77 (s, 6H), 1.25(d, J = 6.8 Hz, 3H).

[0051] (S c ,S ax ,R Fc ) Synthesis of L1:

[0052] 10 ml flask was added (S c ,R Fc ) -1 (441 mg, 1 mmol) and acetic anhydride (3 mL) was replaced with nitrogen three times, and then the internal temperature was raised to 100-105 °C for 4-5 hours (TLC detection reaction to raw material point disappeared). After the reaction was completed, the reaction liquid was cooled to 20-30 °C, the solvent was spin-dried, 10 mL of toluene was added three times and evaporated three times, and the residue was added (S) -DI-NH2 (284 mg, 1 mmol) and methanol 10 mL, stirred at 60 °C for 16-24 hours. The reaction liquid was filtered, the filter cake was dissolved with 50 mL of dichloromethane, concentrated and then column chromatography was separated, and then the eluent was concentrated and dried to obtain (S c ,S ax ,R Fc ) L1 is a light yellow solid, a total of 448 mg, the molar yield is 63%.

[0053] 1 H-NMR (400 MHz, DMSO- d 6) δ 7.91-7.84 (m, 3H), 7.81-7.75 (m, 1H),7.43-7.28 (m, 5H), 7.24-7.15 (m, 4H), 7.14-7.08 (m, 3H), 7.07-7.00 (m, 4H),6.86-6.75 (m, 2H), 5.07 (dd, J = 10.1, 7.2 Hz, 1H), 4.71-4.57 (m, 3H), 4.35 (q, J = 1.9 Hz, 1H), 4.19 (t,J = 2.5 Hz, 1H), 3.57 (s, 5H), 3.54 (s, 1H), 1.21 (d, J = 6.4 Hz, 3H).

[0054] 31 P-NMR (162 MHz, DMSO- d 6) δ -25.03.

[0055] Example 2: (S c ,S ax ,R Fc ) Synthesis of -L2

[0056]

[0057] 10 ml flask was added (S c ,S ax ,R Fc ) -L1 (712 mg, 1 mmol), triethylamine (202 mg, 2 mmol), 4-dimethylaminopyridine (12 mg, 10 mol%) and dichloromethane (5 mL), stirring at 0-10 °C. Control internal temperature 0-10 °C dropwise added p-toluenesulfonyl chloride (380 mg, 2 mmol). Drop, to room temperature, reaction 24 h to the complete reaction of raw materials. The reaction solution was concentrated, followed by column chromatography separation, eluent concentration and drying, to get (S c ,S ax ,R Fc ) -L2 is a light yellow solid, a total of 493 mg, molar yield 57%.

[0058] 1 H-NMR (400 MHz, DMSO- d 6) δ 8.11 (d, J = 9.0 Hz, 1H), 8.05 (d, J = 8.2 Hz,1H), 8.00 -7.87 (m, 3H), 7.80 (d, J = 8.0 Hz, 1H), 7.49 (ddd, J= 8.1, 6.8, 1.2 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.41-7.29 (m, 4H), 7.27-7.09 (m, 7H), 7.08-6.97 (m, 4H), 6.91 (ddd, J = 8.1, 6.7, 1.3 Hz, 2H), 6.18 (d, J = 8.4 Hz, 1H), 4.91 (t, J = 8.2 Hz, 1H), 4.68 (dd, J = 9.1, 6.4 Hz, 1H), 4.35 (q, J = 1.9 Hz, 1H), 4.20 (t, J = 2.5 Hz, 1H), 3.58-3.46 (m, 6H), 2.31 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H).

[0059] 31 P-NMR (162 MHz, DMSO- d 6) δ -25.50.

[0060] Example 3: (S c ,S ax ,R Fc ) Synthesis of -L3

[0061]

[0062] 10 ml flask was added (S c ,S ax ,R Fc ) -L1(712 mg, 1 mmol), methyl iodide (426 mg, 3 mmol), potassium carbonate (691 mg, 5 mmol) and anhydrous acetonitrile (5 mL), stirred at 75-82 °C until the raw material was completely reacted. The reaction solution was concentrated, then column chromatography was carried out, the eluent was concentrated and dried to obtain (S c ,S ax ,R Fc )- L3 was a light yellow solid, 229.4 mg, 31% molar yield.

[0063] 1 H NMR (400 MHz, DMSO- d 6) δ 8.09 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 8.1 Hz,1H), 7.88 (d, J = 9.0 Hz, 1H), 7.80-7.74 (m, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.43-7.34 (m, 4H), 7.33-7.28 (m, 2H), 7.20-7.07 (m, 6H), 7.02 (d, J = 8.6 Hz, 1H),6.96-6.89 (m, 4H), 6.79 (dt, J = 6.3, 3.1 Hz, 1H), 5.33 (t, J = 9.5 Hz, 1H), 4.42(q, J = 1.9 Hz, 1H), 4.23 (dt, J = 7.8, 2.5 Hz, 1H), 3.74 (s, 1H), 3.55-3.42 (m,5H), 2.42 (s, 6H), 1.15 (d, J = 6.4 Hz, 3H).

[0064] 31 P-NMR (162 MHz, DMSO- d 6) δ -25.14.

[0065] Example 4: Asymmetric hydrogenation of acetophenone

[0066]

[0067] Under nitrogen atmosphere, 8 ml hydrogenation vial was added [Ir(COD)Cl]2(3.36 mg, 0.5 mmol%), the above ligand (1.02 mol%) and anhydrous tetrahydrofuran (1 mL), and stirred at 20-30 °C for 0.5-1.0 h to form a yellow clear solution, then added potassium tert-butoxide (2.8 mg, 2.5 mol%) to the reaction solution, phenylacetone (120 mg, 1 mmol) and anhydrous tetrahydrofuran (3 mL), and placed in a 250 mL hydrogenation autoclave, hydrogen was replaced for 4 times, then filled with hydrogen 5.0 Mpa, and reacted at 20-30 °C for 48 h. After the reaction was completed, the reaction solution was determined by HPLC for chiral purity.

[0068] The liquid phase conditions are as follows:

[0069] Chromatographic column: OD-H;

[0070] Mobile phase: n-hexane / isopropyl alcohol = 95 / 5, flow rate: 1.0 mL / min, isocratic elution;

[0071] Detection wavelength: 210 nm;

[0072] Retention time: 7.46 min ( S ), 9.02 min ( R ).

[0073] The screening results of some of the above ligands are shown in the following table:

[0074] No. Ligand Conversion rate (%) 1 2 3 4 5 6 7 (%) 1 <![CDATA[ (S c ,S ax ,R Fc ) -L9]]> 64 72 2 <![CDATA[ (S c ,S ax ,R Fc ) -L2]]> 75 93

[0075] Although the present application has been fully described in connection with the preferred embodiments, various modifications and changes thereto will be apparent to those skilled in the art. Such modifications and changes are intended to fall within the scope of the application as defined by the appended claims.

Claims

1. A chiral ferrocene-bridged naphthalene-skeletal phosphine ligand, characterized in that, The structural formula is: in: Ar in the chiral ferrocene-bridged naphthalene skeleton phosphine ligands shown in Formulas I-IV is phenyl or substituted phenyl; R in Equation I-IV 1 It is independently selected from one of hydrogen, phenyl, fluorine, chlorine, bromine, and iodine; R in Equation I-IV 2 It is independently selected from one of NH2, NHMe, NMe2, NHAc, NHCOAr, NHSO2Me, NHSO2CF3, and NHSO2Ar, wherein Ar is a phenyl or a substituted phenyl.

2. The chiral ferrocene-bridged naphthalene-skeletal phosphine ligand according to claim 1, characterized in that, Ar in the chiral ferrocene-bridged naphthyl phosphine ligands shown in Formulas I-IV is phenyl.

3. The chiral ferrocene-bridged naphthalene-skeletal phosphine ligand according to claim 1, characterized in that, R in formulas I-IV 1 It is hydrogen.

4. The chiral ferrocene-bridged naphthalene-skeletal phosphine ligand according to claim 1, characterized in that, R in formulas I-IV 2 The NH2, NMe2, and NHSO2Ar are used, where Ar is a substituted phenyl group.

5. The chiral ferrocene-bridged naphthalene-skeletal phosphine ligand according to any one of claims 1 to 4, characterized in that, The structural formula is:

6. A method for preparing a chiral ferrocene-bridged naphthalene skeletal phosphine ligand of formula III, characterized in that, The reaction formula is as follows: in, Ar is a phenyl or substituted phenyl; R 1 It is independently selected from one of hydrogen, phenyl, fluorine, chlorine, bromine, and iodine; R 2 It is independently selected from one of NH2, NHMe, NMe2, NHAc, NHCOAr, NHSO2Me, NHSO2CF3, and NHSO2Ar, wherein Ar is a phenyl or a substituted phenyl.

7. The method for preparing chiral ferrocene-bridged naphthalene skeletal phosphine ligand III according to claim 6, characterized in that, The (S)-DI-NH2 and (S) c ,R Fc The solvent for the addition reaction is an organic solvent.

8. The method for preparing chiral ferrocene-bridged naphthalene skeletal phosphine ligand III according to claim 6, characterized in that, The (S)-DI-NH2 and (S) c ,R Fc The temperature for the addition reaction is 50–70 °C.

9. A catalyst for use in asymmetric hydrogenation reactions, characterized in that, It is prepared by the chiral ferrocene-bridged naphthalene skeletal phosphine ligand as described in claim 1 and a transition metal and its salt; wherein the transition metal is one of ruthenium, rhodium, palladium, iridium, cobalt, and nickel.

10. The catalyst according to claim 9, characterized in that, The transition metal salt is one of the following: trivalent iridium salt, bisnorbornene iridium chloride dimer, (1,5-cyclooctadiene) iridium chloride, and (1,5-cyclooctadiene) iridium salt.

11. The use of the chiral ferrocene-bridged naphthalene skeletal phosphine ligand as described in claim 1 in the asymmetric hydrogenation synthesis of chiral alcohols from prochiral ketones.

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