Method for asymmetric C-H bond arylation reaction of amide compounds

Abstract

The present invention provides a method for the asymmetric C-H arylation reaction of amide compounds. The method includes mixing and stirring a compound shown in Formula 2, arylboronic acid fluoride, a catalyst, a ligand, an additive, an oxidant, a base, water and a solvent under nitrogen conditions to carry out a cross-coupling reaction to generate a target compound 1, and the reaction equation is as follows: wherein, R 1 is one of an alkyl group, an alkoxy group, a phenyl group and a substituted phenyl group, and Ar is an aryl group or a substituted aryl group; Ar F is a fluorine-substituted aryl group. The chiral catalyst provided by the present invention provides a new reaction pathway for the asymmetric C-H activation of acyclic amides, has high selectivity and high yield, mild reaction conditions, a simple method, is green and environment-friendly, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of asymmetric catalysis, and particularly relates to a method for the asymmetric C-H arylation reaction of amide compounds. Background Art

[0002] Amide compounds are one of the most common compounds in natural bioactive molecules and synthetic organic compounds. Amide compounds play important roles in the fields of medicinal chemistry, biochemistry, and polymer synthesis. Research shows that more than a quarter of drugs are amide compounds. For example, acetanilide is an intermediate for preparing sulfonamide drugs. Moreover, many important natural products, such as proteins, polypeptides, and enzymes that maintain various daily lives of organisms, all contain a large number of amide bonds. In addition, widely used polymer materials, such as nylon, are also polyamide polymers composed of a large number of amide bonds.

[0003] Developing the selective arylation of the C(sp 3 )-H bond of amide compounds has always been an important research content in the late-stage functionalization of organic molecules. Zheng Jing et al. reported the selective coupling reaction of Rh(Ⅲ)-catalyzed d N-methoxy-1-indole-1-carboxamide and arylboronic acid. Through the transformation of different reaction conditions or substituents, three different reactions, namely arylation, [4+2] cyclization, and [4+1] cyclization, were successfully achieved. J. Wencel-Delord et al. developed a Rh(Ⅲ)-catalyzed selective dehydrogenative cross-coupling reaction, that is, benzamide and aryl halides form biaryl products through the dual C—H bond activation effect. Huang Yuming et al. reported the regioselective C—H bond activation cross-coupling reaction of [Rh(PPh 3 ) 3 Cl] catalyzing aromatic amine derivatives and various heteroarenes.

[0004] However, the current selective arylation reaction of the C(sp 3 )-H bond of amide compounds has disadvantages such as poor regioselectivity. Therefore, there is an urgent need for a method with high selectivity and high yield for constructing various aryl structures of amide compounds. Summary of the Invention

[0005] Aiming at the deficiencies in the prior art, the present invention provides a method for the asymmetric C-H arylation reaction of amide compounds, which solves the problems of low selectivity and low yield in the prior art.

[0006] On the one hand, the present invention provides a method for the asymmetric C-H bond arylation reaction of amide compounds, which includes mixing and stirring the compound shown in Formula 2, aryl fluoroborate, catalyst, ligand, additive, oxidant, base, water and solvent under nitrogen conditions to carry out a cross-coupling reaction to generate the target compound 1, and the reaction equation is as follows:

[0007]

[0008] Among them, R 1 is one of alkyl, alkoxy, phenyl, substituted phenyl, Ar is aryl or substituted aryl; Ar F is a fluorine-substituted aryl.

[0009] Furthermore, the aryl fluoroborate includes one of potassium phenylfluoroborate, potassium p-methoxyphenylfluoroborate, potassium p-methylphenylfluoroborate, potassium p-cyanophenylfluoroborate, potassium p-chlorophenylfluoroborate, potassium p-bromophenylfluoroborate.

[0010] Furthermore, the catalyst is Pd(OAc) 2 .

[0011] Furthermore, the chemical structure of the ligand is shown in Formula 3:

[0012]

[0013] Among them, R 2 is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, substituted benzyl.

[0014] Furthermore, the preparation method of the ligand is that in the presence of an organic solvent, an acylating agent, a catalyst, and an organic base, the 7-carboxy-1,1'-spirodihydroindene compound shown in Formula 4 reacts with the compound of Formula 5 to prepare the compound shown in Formula 3, and the reaction formula is as follows:

[0015]

[0016] Among them, R 2 is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, substituted benzyl.

[0017] Furthermore, the reaction includes at least one of the following conditions:

[0018] (1) The organic solvent is dichloromethane;

[0019] (2) The acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, and the organic base is triethylamine;

[0020] (3) The 7-carboxy-1,1'-spirobiindane compound shown in formula (4): the compound shown in formula (5): the molar ratio of the acylating agent: the organic base is 0.9 - 1:1 - 1.1:1.3 - 1.5:3; calculated by mol / L, the 7-carboxy-1,1'-spirobiindane compound shown in formula A: the catalyst is 1:0.01;

[0021] (4) The reaction time is 5 - 7 hours, and the reaction temperature is 0 °C - room temperature.

[0022] Further, the oxidizing agent is 1,4-benzoquinone, and the additive is Ag 2 CO 3 and the base is Na 2 CO 3 and the solvent is tert-amyl alcohol.

[0023] Further, the molar equivalent ratio of the compound of formula 2: aryl fluoroborate: catalyst: ligand: additive: oxidizing agent: base: water is 1:2:0.1:0.2:2:0.5:2.5:5.

[0024] Further, calculated by mol / L, the compound of formula 2: the solvent is 1:5.

[0025] Further, the reaction temperature is 40 - 50 °C, and the reaction time is 20 - 24 h.

[0026] Among them, the synthesis method of compound 4a includes the following steps:

[0027]

[0028] Under nitrogen protection, compound a (10 mmol) and tetrahydrofuran (200 mL) were added to a reaction flask, and NaH (5 mmol) was added to the reaction system, and the temperature was controlled at 0 - 10 °C during the addition process. Subsequently, a THF solution of methyl iodide (5 mmol MeI in 60 mL THF) was added dropwise to the system, and the temperature was controlled at 0 - 10 °C. After the addition was completed, the reaction was carried out for 6 - 12 hours, and the reaction solution was quenched and purified by column chromatography to obtain product b with a yield of 77%.

[0029] Under nitrogen protection, compound b (10 mmol) and dichloromethane (100 mL) were added to a reaction flask, and pyridine (15 mmol) was added to the reaction system. Subsequently, a dichloromethane solution of trifluoromethanesulfonic anhydride (13 mmol Tf 2 O in 60 mL DCM) was added dropwise to the system, and the temperature was controlled at 0 - 10 °C. After the addition was completed, the reaction was carried out for 6 - 12 hours, and the reaction solution was quenched and purified by column chromatography to obtain product c with a yield of 91%.

[0030] Under nitrogen protection, compound c (10 mmol), methanol (100 mmol), acetonitrile (100 mL), and triethylamine (30 mmol) were added to a reaction flask. Subsequently, PdCl 2 (dppf) (0.5 mmol) was added. After addition, CO was displaced three times, the pressure was increased to 2.5 MPa, and the reaction was carried out at 80 °C for 16 - 24 hours. The reaction solution was quenched and purified by column chromatography to obtain product d with a yield of 80%.

[0031] Under nitrogen protection, compound d (10 mmol) and DCM (500 mL) were added to a reaction flask. Subsequently, BBr 3 (30 mmol) was added dropwise to the system while controlling the temperature at -20 °C to 10 °C. After addition, the reaction was carried out for 6 - 8 hours. The reaction solution was quenched and purified by column chromatography to obtain compound e with a yield of 65%.

[0032] Under nitrogen protection, compound e (10 mmol) and dichloromethane (100 mL) were added to a reaction flask, and pyridine (15 mmol) was added to the reaction system. Subsequently, a dichloromethane solution of trifluoromethanesulfonic anhydride (13 mmol Tf 2 O in 60 mL DCM) was added dropwise while controlling the temperature at 0 - 10 °C. After the addition was complete, the reaction was carried out for 6 - 12 hours. The reaction solution was quenched and purified by column chromatography to obtain compound f with a yield of 88%.

[0033] Under nitrogen protection, compound f (10 mmol), methanol (100 mmol), and HCOONa (30 mmol) were added to a reaction flask. Subsequently, PdCl 2 (dppf) (0.5 mmol) was added. After addition, nitrogen was displaced three times, and the reaction was carried out at 80 °C for 16 - 24 hours. The reaction solution was quenched and purified by column chromatography to obtain compound g with a yield of 84%.

[0034] Under nitrogen protection, compound g (10 mmol) and DMSO (500 mL) were added to a reaction flask. Subsequently, 60% aqueous potassium hydroxide solution (100 mmol) was added. After addition, the temperature was raised to 150 °C, and the reaction was carried out for 16 - 24 hours. The reaction solution was quenched and purified by column chromatography to obtain product 4a with a yield of 80%.

[0035] The term "Ar F " is a fluorine - substituted aryl group, including but not limited to fluorobenzene, fluorine - substituted benzophenone, and fluorine - substituted diaryl sulfone, etc. In the examples of the present invention, Ar F is selected from the 2,3,5,6 - tetrafluorobenzonitrile group.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] (1) The chiral catalyst provided by the present invention offers a new reaction pathway for the asymmetric C-H activation of amides.

[0038] (2) The chiral catalyst provided by the present invention has high selectivity and high yield for the asymmetric C-H activation of amides.

[0039] (3) The reaction conditions of the present invention are mild, the method is simple, environmentally friendly, and suitable for large-scale industrial production. Detailed implementation manners

[0040] The technical solutions in the present invention will be further described below in conjunction with the embodiments.

[0041] Example 1 Synthesis of ligand

[0042]

[0043] Under nitrogen protection, compound 4a (10 mmol), N,N-dimethylformamide (DMF, 100 μL) and dichloromethane (DCM, 10 mL) were added to a reaction flask. Oxalyl chloride (15 mmol) was added dropwise to the reaction system, and the temperature was controlled at 0-10 °C during the addition. After the addition, the temperature was restored to room temperature, and the reaction was stirred for 2-3 hours. The reaction mixture was concentrated to dryness to obtain the acyl chloride of 4a, and 10 mL of dichloromethane was added for standby. Another reaction flask was charged with 5a (11 mmol), triethylamine (Et 3 N, 30 mmol) and dichloromethane (30 mL). The acyl chloride solution of 4a obtained in the previous step was slowly added dropwise to 5a and triethylamine. The mixture was stirred at room temperature for 3-4 hours, and the product 3a was obtained by quenching and column chromatography with a yield of 95%.

[0044] Among them, the synthesis method of compound 4a includes the following steps:

[0045]

[0046] Under nitrogen protection, compound a (10 mmol) and tetrahydrofuran (200 mL) were added to a reaction flask. NaH (5 mmol) was added to the reaction system, and the temperature was controlled at 0-10 °C during the addition. Subsequently, a THF solution of methyl iodide (5 mmol MeI in 60 mL THF) was added dropwise to the system, and the temperature was controlled at 0-10 °C. After the addition, the reaction was carried out for 6-12 hours. The reaction solution was quenched and column chromatographed to obtain the product b with a yield of 77%.

[0047] Under nitrogen protection, compound b (10 mmol) and dichloromethane (100 mL) were added to a reaction flask. Pyridine (15 mmol) was added to the reaction system. Subsequently, a dichloromethane solution of trifluoromethanesulfonic anhydride (13 mmol Tf 2Oin 60 mL of DCM), the temperature was controlled at 0 - 10 °C. After the addition was complete, the reaction was carried out for 6 - 12 hours. The reaction solution was quenched and purified by column chromatography to obtain product c with a yield of 91%.

[0048] Under nitrogen protection, compound c (10 mmol), methanol (100 mmol), acetonitrile (100 mL), and triethylamine (30 mmol) were added to a reaction flask. Subsequently, PdCl 2 (dppf) (0.5 mmol) was added to the system. After the addition was complete, CO was displaced three times, and the pressure was increased to 2.5 MPa. The reaction was carried out at 80 °C for 16 - 24 hours. The reaction solution was quenched and purified by column chromatography to obtain product d with a yield of 80%.

[0049] Under nitrogen protection, compound d (10 mmol) and DCM (500 mL) were added to a reaction flask. Subsequently, BBr 3 (30 mmol) was added dropwise to the system while controlling the temperature at -20 °C to 10 °C. After the addition was complete, the reaction was carried out for 6 - 8 hours. The reaction solution was quenched and purified by column chromatography to obtain compound e with a yield of 65%.

[0050] Under nitrogen protection, compound e (10 mmol) and dichloromethane (100 mL) were added to a reaction flask, and pyridine (15 mmol) was added to the reaction system. Subsequently, a dichloromethane solution of trifluoromethanesulfonic anhydride (13 mmol Tf 2 Oin 60 mL of DCM) was added dropwise while controlling the temperature at 0 - 10 °C. After the addition was complete, the reaction was carried out for 6 - 12 hours. The reaction solution was quenched and purified by column chromatography to obtain compound f with a yield of 88%.

[0051] Under nitrogen protection, compound f (10 mmol), methanol (100 mmol), and HCOONa (30 mmol) were added to a reaction flask. Subsequently, PdCl 2 (dppf) (0.5 mmol) was added to the system. After the addition was complete, nitrogen was displaced three times, and the reaction was carried out at 80 °C for 16 - 24 hours. The reaction solution was quenched and purified by column chromatography to obtain compound g with a yield of 84%.

[0052] Under nitrogen protection, compound g (10 mmol) and DMSO (500 mL) were added to a reaction flask. Subsequently, 60% aqueous potassium hydroxide solution (100 mmol) was added to the system. After the addition was complete, the temperature was raised to 150 °C, and the reaction was carried out for 16 - 24 hours. The reaction solution was quenched and purified by column chromatography to obtain product 4a with a yield of 80%.

[0053] Synthesis of the ligand in Example 2

[0054]

[0055] Under nitrogen protection, compound 4b (9 mmol), N,N-dimethylformamide (DMF, 90 μL), and dichloromethane (DCM, 10 mL) were added to a reaction flask. Oxalyl chloride (13 mmol) was added dropwise to the reaction system while controlling the temperature at 0 - 10 °C. After the addition, the mixture was restored to room temperature and stirred for 2 - 3 hours, then concentrated to dryness to obtain the acyl chloride of 4b. 10 mL of dichloromethane was added and kept for use. Another reaction flask was charged with 5b (10 mmol), triethylamine (Et 3 N, 27 mmol), and dichloromethane (30 mL). The acyl chloride solution of 4b obtained in the previous step was slowly added dropwise to 5b and triethylamine. The mixture was stirred at room temperature for 3 - 4 hours, quenched, and purified by column chromatography to obtain product 3b with a yield of 91%.

[0056] Synthesis of Ligand in Example 3

[0057]

[0058] Under nitrogen protection, compound 4c (10 mmol), N,N-dimethylformamide (DMF, 100 μL), and dichloromethane (DCM, 10 mL) were added to a reaction flask. Oxalyl chloride (15 mmol) was added dropwise to the reaction system while controlling the temperature at 0 - 10 °C. After the addition, the mixture was restored to room temperature and stirred for 2 - 3 hours, then concentrated to dryness to obtain the acyl chloride of 4c. 10 mL of dichloromethane was added and kept for use. Another reaction flask was charged with 5c (11 mmol), triethylamine (Et 3 N, 30 mmol), and dichloromethane (30 mL). The acyl chloride solution of 4c obtained in the previous step was slowly added dropwise to 5c and triethylamine. The mixture was stirred at room temperature for 3 - 4 hours, quenched, and purified by column chromatography to obtain product 3c with a yield of 93%.

[0059] Synthesis of N-(4-Cyano-2,3,5,6-tetrafluorophenyl)-2-(4-methoxybenzyl)-2,3,3-trimethylbutyramide in Example 4

[0060]

[0061] 0.1 mmol of compound 2-1 (1.0 equiv), 0.2 mmol of potassium phenylfluoroborate (Ar-BF 3 K, 2 equiv), 0.01 mmol of palladium acetate (Pd(OAc) 2 , 0.1 equiv), 0.02 mmol of the ligand prepared in Example 1 (0.2 equiv), 0.2 mmol of silver carbonate (Ag 2 CO 3 , 2 equiv), 0.05 mmol of 1,4-benzoquinone (BQ., 0.5 equiv), 0.25 mmol of Na 2CO 3 (2.5 equiv), 0.5 mmol H 2 O (5 equiv) and 0.5 mL tert-amyl alcohol ( t AmylOH) were mixed and stirred in a nitrogen atmosphere and heated to 50 °C, and the reaction was carried out for 20 h. After filtration, washing and concentration, the target compound 1-1 was obtained.

[0062] It was detected that the yield of the target compound 1-1 was 95% and the ee value was 99%.

[0063] Example 5 Synthesis of N-(4-cyano-2,3,5,6-tetrafluorophenyl)-2-(4-methoxybenzyl)-2-methylbutyramide

[0064]

[0065] 0.1 mmol of compound 2-2 (1.0 equiv), 0.2 mmol of Ar-BF 3 K (2 equiv), 0.01 mmol of Pd(OAc) 2 (0.1 equiv), 0.02 mmol of the ligand prepared in Example 2 (0.2 equiv), 0.2 mmol of Ag 2 CO 3 (2 equiv), 0.05 mmol of 1,4-benzoquinone (0.5 equiv), 0.25 mmol of Na 2 CO 3 (2.5 equiv), 0.5 mmol of H 2 O (5 equiv) and 0.5 mL of tert-amyl alcohol ( t AmylOH) were mixed and stirred in a nitrogen atmosphere and heated to 45 °C, and the reaction was carried out for 24 h. After filtration, washing and concentration, the target compound 1-2 was obtained.

[0066] It was detected that the yield of the target compound 1-2 was 90% and the ee value was 96%.

[0067] Example 6 Synthesis of N-(4-cyano-2,3,5,6-tetrafluorophenyl)-3-(4-methoxybenzyl)-2-methyl-2-phenylpropanamide

[0068]

[0069] 0.1 mmol of compound 2-3 (1.0 equiv), 0.2 mmol of Ar-BF 3 K (2 equiv), 0.01 mmol of Pd(OAc) 2(0.1 equiv), 0.02 mmol of the ligand prepared in Example 3 (0.2 equiv), 0.2 mmol of Ag 2 CO 3 (2 equiv), 0.05 mmol of 1,4-benzoquinone (0.5 equiv), 0.25 mmol of Na 2 CO 3 (2.5 equiv), 0.5 mmol of H 2 O (5 equiv) and 0.5 mL of tert-amyl alcohol ( t AmylOH) were mixed and stirred in a nitrogen atmosphere and heated to 50 °C, and the reaction was carried out for 20 h. After filtration, washing and concentration, the target compounds 1-3 were obtained.

[0070] It was detected that the yields of the target compounds 1-3 were 93% and the ee values were 95%.

[0071] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the purpose and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A method for the asymmetric C-H bond arylation reaction of an amide compound, characterized in that: it includes mixing and stirring a compound shown in Formula 2, an aryl fluoroborate, a catalyst, a ligand, an additive, an oxidant, a base, water and a solvent under nitrogen conditions to carry out a cross-coupling reaction to generate a target compound 1, and the reaction equation is as follows: ， wherein, R 1 is one of alkyl, alkoxy, phenyl, and substituted phenyl, and Ar is aryl or substituted aryl; Ar F is a fluorine-substituted aryl; The aryl fluoroborate is one of potassium phenylfluoroborate, potassium p-methoxyphenylfluoroborate, potassium p-methylphenylfluoroborate, potassium p-cyanophenylfluoroborate, potassium p-chlorophenylfluoroborate, potassium p-bromophenylfluoroborate; The catalyst is Pd(OAc) 2 ; The chemical structure of the ligand is shown in Formula 3: ， Among them, R 2 is alkyl or benzyl; The additive is silver carbonate; The oxidant is 1,4-benzoquinone; The base is Na 2 CO 3 ; The solvent is tert-amyl alcohol.

2. A method for the asymmetric C-H bond arylation reaction of an amide compound according to claim 1, characterized in that: The preparation method of the ligand is that in the presence of an organic solvent, an acylating agent, a catalyst, and an organic base, a 7-carboxy-1,1'-spirodihydroindene compound shown in Formula 4 reacts with a compound shown in Formula 5 to prepare a compound shown in Formula 3, and the reaction formula is as follows: ， Among them, R 2 is alkyl or benzyl.

3. A method for the asymmetric C-H bond arylation reaction of an amide compound according to claim 2, characterized in that: The reaction includes at least one of the following conditions: (1) The organic solvent is dichloromethane; (2) The acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, and the organic base is triethylamine; (3) The molar ratio of the 7-carboxy-1,1'-spirodihydroindene compound shown in Formula 4: the compound shown in Formula 5: the acylating agent: the organic base is 0.9-1:1-1.1:1.3-1.5:3; calculated by mol / L, the 7-carboxy-1,1'-spirodihydroindene compound shown in Formula A: the catalyst is 1:0.01; (4) The reaction time is 5-7 hours, and the reaction temperature is 0 °C - room temperature.

4. A method for the asymmetric C-H bond arylation reaction of an amide compound according to claim 1, characterized in that: The molar equivalent ratio of the compound shown in Formula 2: the aryl fluoroborate: the catalyst: the ligand: the additive: the oxidant: the base: water is 1:2:0.1:0.2:2:0.5:2.5:

5.

5. A method for the asymmetric C-H bond arylation reaction of an amide compound according to claim 1, characterized in that: Calculated by mol / L, the compound shown in Formula 2: the solvent is 1:

5.

6. A method for the asymmetric C-H bond arylation reaction of an amide compound according to claim 1, characterized in that: The reaction temperature is 40-50 °C, and the reaction time is 20-24 h.

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