CN116041253A - Method for synthesizing diphenyl-2-pyridylmethane derivative - Google Patents
Method for synthesizing diphenyl-2-pyridylmethane derivative Download PDFInfo
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Abstract
The invention provides a method for synthesizing diphenyl-2-pyridylmethane derivatives. Mixing and stirring a compound D, butyl boric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1, reacting, and separating and purifying to obtain a diphenyl-2-pyridylmethane derivative E, wherein the chemical reaction formula is as follows:
wherein R is 1 、R 2 Each independently selected from one of hydrogen, alkyl, alkoxy, aryl, heteroaryl. The invention has high selectivity and high yield, high reaction catalysis efficiency, low catalyst consumption, simple post-treatment and no byproduct generation in the system.
Description
Technical Field
The invention relates to the technical field of synthesis of carbocyclic compounds, in particular to a method for synthesizing diphenyl-2-pyridylmethane derivatives.
Background
Chiral compounds are extremely important in fine chemical production as precursors, intermediates or end products of medicines, pesticides, fragrances and functional materials. Research into methods for obtaining single enantiomer compounds remains one of the primary tasks of contemporary chemists. Carbon heteroatom bonds (C-X) are commonly found in biological molecules in nature, are one of the most active parts of the molecular structure of organic compounds, and are also one of the basic framework raw materials for synthesizing the enantiomer products, so the construction of C-X bonds is a hot spot for organic chemists to study.
The C-H bond insertion reaction catalyzed by the transition metal has the characteristics of high efficiency and economy, and provides a simple method for constructing various molecules with complex structures from simple and easily obtained raw materials. Over the past several decades, an increasing number of transition metal catalysts have been developed and successfully applied to the activation of various C-H bonds, providing a new and efficient method for the construction of C-X bonds.
However, there are few effective methods for activating C-H bonds, and the regulation of the activity and selectivity is difficult. Thus, the development of various transition metal catalysts, efficient C-H bond activation, is a significant challenge currently faced. The main obstacle in Pd-catalyzed C-H bond activation reactions is the need for a ligand that binds Pd, controlling its chemical, regional and stereoselectivity of the inserted C-H bond.
Therefore, there is a need to develop a Pd-catalyzed asymmetric C-H activation/C-C coupling reaction with high yields and high selectivity, differentiating chiral C-H bonds by metal insertion.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a method for synthesizing diphenyl-2-pyridylmethane derivatives by palladium-catalyzed hydrocarbon living reaction, which solves the problems of low yield and low selectivity existing in the prior art.
The invention provides a method for synthesizing diphenyl-2-pyridylmethane derivatives, which comprises the steps of mixing and stirring a compound D, butyl boric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1, reacting, separating and purifying to obtain the diphenyl-2-pyridylmethane derivatives E, wherein the chemical reaction formula is as follows:
wherein R is 1 、R 2 Each independently selected from one of hydrogen, alkyl, alkoxy, aryl, heteroaryl.
Further, the catalyst is Pd (OAc) 2 The ligand is
/>
Wherein R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
Further, the oxidant is terephthalquinone, and the additive is silver oxide.
Further, the organic solvent 1 is tetrahydrofuran.
Further, the molar ratio of the compound D, the butyl boric acid, the catalyst, the ligand and the oxidant to the additive is 1:1:0.1:0.2:0.5:1.0.
Further, the reaction temperature is 50-60 ℃ and the reaction time is 20-24h.
Further, the preparation method of the ligand comprises the following steps: in the presence of an organic solvent 2, an acylating agent, a catalyst and an organic base, a 7-carboxyl-1, 1' -spiroindane compound shown in a formula B reacts with a compound shown in a formula C to prepare a compound shown in a formula A, wherein the reaction formula is as follows:
wherein R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
Further, the acylating agent is oxalyl chloride, the catalyst is N, N-dimethylformamide, the organic base is triethylamine, and the organic solvent 2 is dichloromethane.
Further, the molar ratio of the 7-carboxyl-1, 1' -spiroindane compound shown in the formula B to the compound shown in the formula C to the acylating agent to the organic base is 0.9-1:1-1.1:1.3-1.5:3;
the 7-carboxyl-1, 1' -spiroindane compound shown in the formula A and the catalyst are 1:0.01 in mol/L.
Further, the reaction time is 5-7 hours, and the reaction temperature is 0-room temperature.
In one embodiment of the invention, the preparation method of the 7-carboxyl-1, 1' -spiroindane compound shown in the formula B comprises the following steps:
1,1 '-spiroindan-7, 7' -diol is used as an initiator, and is obtained through methylation reaction, first sulfonation reaction, first substitution reaction, demethylation reaction, second sulfonation reaction, second substitution reaction and hydrolysis reaction; the reaction process is as follows:
the method specifically comprises the following steps: (1) Adding 1,1 '-spiroindan-7, 7' -diol into an organic solvent 1, and generating a compound 2 under the action of a methylating reagent and a first base;
(2) Mixing the compound 2 with an organic solvent 2, and adding a first sulfonating reagent and a second base to generate a compound 3;
(3) Adding the compound 3 into an organic solvent 3, and adding a first catalyst, a first reaction substrate and a third base in the presence of CO to perform a first substitution reaction to generate a compound 4;
(4) Adding an organic solvent 4 into the compound 4, and carrying out a demethylation reaction under the action of a demethylating reagent to generate a compound 5;
(5) Adding an organic solvent 5 into the compound 5, and adding a second sulfonation reagent and a fourth base to generate a compound 6;
(6) Adding the compound 6 into an organic solvent 6, adding a second catalyst and a second reaction substrate in the presence of nitrogen, and performing a second substitution reaction to generate a compound 7;
(7) And adding an organic solvent 7 into the compound 7, and hydrolyzing in the presence of a fifth base to obtain the 7-carboxyl-1, 1' -spiroindane compound shown in the formula B.
Preferably, in the step (1), the organic solvent 1 is tetrahydrofuran, the methylating agent is methyl iodide, and the first base is sodium hydride; the reaction temperature is 0-10 ℃ and the reaction time is 6-12h;
in the step (2), the organic solvent 2 is methylene dichloride, the first sulfonating agent is trifluoro methanesulfonic anhydride, and the second base is pyridine; the reaction temperature is 0-10 ℃ and the reaction time is 6-12h;
in the step (3), the organic solvent 3 is acetonitrile and methanol; the third base is triethylamine; the first catalyst is PdCl 2 (dppf); the first reaction substrate is methanol; the reaction temperature is 80 ℃ and the reaction time is 16-24 hours;
in the step (4), the organic solvent 4 is DCM, and the demethylating agent is BBr 3 The reaction temperature is between 20 ℃ below zero and 10 ℃ below zero, and the reaction time is between 6 and 8 hours;
in the step (5), the organic solvent 5 is dichloromethane, the second sulfonation reagent is trifluoromethanesulfonic anhydride, the fourth base is pyridine, the reaction temperature is-0-10 ℃, and the reaction time is 6-12h;
in the step (6), the organic solvent 6 is methanol; the second catalyst is PdCl 2 (dppf); the second reaction substrate is HCOONa;
in the step (7), the organic solvent 7 is DMSO; the fifth alkali is potassium hydroxide; the reaction temperature is 150 ℃ and the reaction time is 16-24 hours.
Preferably, in step (1), 1 '-spiroindan-7, 7' -diol in molar ratio: methylating agent: first base = 2:1:1;
in the step (2), the first sulfonating agent is compound 2, and the second base=10:13:15;
in the step (3), the compound 3 comprises a first catalyst, a first reaction substrate and a third base=10:0.5:100:30 in terms of mole ratio;
in step (4), compound 4: first demethylating agent = 1:3 in molar ratio;
in the step (5), the compound 5 comprises a second sulfonating agent and a fourth base=10:13:15 according to the mole ratio;
in the step (6), the compound 6 is a second catalyst and a second reaction substrate=10:0.5:30 in terms of molar ratio;
in step (7), compound 7: fifth base=1:10 in terms of molar ratio.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, palladium acetate and chiral spiro ligand are used as catalysts for the first time, and a series of diphenyl-2-pyridylmethane derivatives are synthesized through the C-C bond coupling reaction of the substituted diphenyl-2-pyridylmethane and butyl boric acid with excellent enantioselectivity and high yield, so that more choices are provided for the development of organic synthesis and biological medicine;
2. the chiral spiro ligand synthesized for the first time has the advantages of high reaction catalysis efficiency, low catalyst consumption, simple post-treatment and no byproduct generation in the system.
3. The method is simple and convenient to operate, mild in reaction conditions and suitable for large-scale industrial production.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
EXAMPLE 1 Synthesis of ligands
Compound B1 (10 mmol), N-dimethylformamide (DMF, 100. Mu.L) and dichloromethane (DCM, 10 mL) were added to the reaction flask under nitrogen protection, oxalyl chloride (15 mmol) was added dropwise to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. After the dripping is finished, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of B1, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with C1 (11 mmol), triethylamine (Et) 3 N,30 mmol) and dichloromethane (30 mL), slowly dropwise adding the acyl chloride solution of B1 obtained in the previous step into C1 and triethylamine, stirring at room temperature for 3-4 hours, and carrying out quenching column chromatography to obtain a product A1 with a yield of 95%;
the preparation method of the compound B1 comprises the following steps:
compound 1 (10 mmol) and tetrahydrofuran (200 mL) were added to the reaction flask under nitrogen protection, naH (5 mmol) was added to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. Then, THF solution (5mmol MeI in 60mL THF) of methyl iodide is added into the system dropwise, the temperature is controlled to be 0-10 ℃, the reaction is carried out for 6-12 hours after the completion of the addition, and the reaction liquid is subjected to quenching column chromatography to obtain a product 2, wherein the yield is 77%.
Compound 2 (10 mmol) and methylene chloride (100 mL) were added to a reaction flask under nitrogen protection, and pyridine (15 mmol) was added to the reaction system. Subsequently, a methylene chloride solution of trifluoromethanesulfonic anhydride (13 mmol Tf) was added dropwise to the system 2 O in 60mL DCM), controlling the temperature to be 0-10 ℃, and reacting for 6-12 hours after dripping, wherein the reaction liquid is subjected to quenching column chromatography to obtain the product 3 with the yield of 91%.
Compound 3 (10 mmol) and methanol (100 mmol), acetonitrile (100 mL), triethylamine (30 mmol) were added to the reaction flask under nitrogen. Subsequently add PdCl to the system 2 (dppf) (0.5 mmol), CO was replaced three times after the addition, the reaction was carried out under pressure of 2.5MPa at 80℃for 16-24 hours, and the reaction mixture was subjected to quenching column chromatography to give product 4 in 80% yield.
Compound 4 (10 mmol) and DCM (500 mL) were added to the reaction flask under nitrogen. Subsequently, BBr is added into the system in a dropwise manner 3 (30 mmol) and controlling the temperature to-20-10 ℃. After the addition, the reaction is carried out for 6 to 8 hours, and the reaction liquid is subjected to quenching column chromatography to obtain the compound 5 with the yield of 65 percent.
Compound 5 (10 mmol) and methylene chloride (100 mL) were added to a reaction flask under nitrogen protection, and pyridine (15 mmol) was added to the reaction system. Subsequently, a methylene chloride solution of trifluoromethanesulfonic anhydride (13 mmol Tf) was added dropwise to the system 2 O in 60mL DCM), controlling the temperature to be 0-10 ℃, reacting for 6-12 hours after dripping, and obtaining the compound 6 by quenching column chromatography of the reaction liquid, wherein the yield is 88%.
Compound 6 (10 mmol) and methanol (100 mmol), HCOONa (30 mmol) were added to the reaction flask under nitrogen. Subsequently add PdCl to the system 2 (dppf) (0.5 mmol), after the addition, the nitrogen was replaced three times and reacted at 80℃for 16-24 hours, the reaction solution is subjected to quenching column chromatography to obtain the compound 7 with the yield of 84%.
Compound 7 (10 mmol) and DMSO (500 mL) were added to the reaction flask under nitrogen. Then 60% aqueous potassium hydroxide solution (100 mmol) is added into the system, the temperature is raised to 150 ℃ after the addition, the reaction is carried out for 16-24 hours, and the product B1 is obtained through quenching column chromatography, and the yield is 80%.
EXAMPLE 2 Synthesis of ligands
Compound B2 (9 mmol), N-dimethylformamide (DMF, 90. Mu.L) and dichloromethane (DCM, 10 mL) were added to the reaction flask under nitrogen protection, oxalyl chloride (13 mmol) was added dropwise, and the temperature was controlled between 0℃and 10℃during the addition. After the dripping is finished, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of B2, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with C2 (10 mmol), triethylamine (Et) 3 N,27 mmol) and dichloromethane (30 mL), the acid chloride solution of B2 obtained in the previous step was slowly added dropwise to C2 and triethylamine, stirred at room temperature for 3-4 hours, and the product A2 was obtained by quench column chromatography in 91% yield.
EXAMPLE 3 Synthesis of ligands
Compound B3 (10 mmol), N-dimethylformamide (DMF, 100. Mu.L) and dichloromethane (DCM, 10 mL) were added to the reaction flask under nitrogen protection, oxalyl chloride (15 mmol) was added dropwise to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. After the dripping is finished, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of B3, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with C3 (11 mmol), triethylamine (Et) 3 N,30 mmol) and dichloromethane (30 mL), the acyl chloride solution of B3 obtained in the previous step is slowly dripped into C3 and triethylamine, stirred for 3-4 hours at room temperature, and the product A3 is obtained by quenching column chromatography, and the yield is93%.
Example 4
To the reaction vessel was added 0.25mmol of compound D1,0.25mmol (1.0 eq) of butylboronic acid, 25. Mu. Mol (10 mol%) of catalyst Pd (OAc) under nitrogen protection 2 50. Mu. Mol (20 mol%) of the ligand prepared in example 1, 0.125mmol (0.5 eq) of BQ (terephthalquinone), 0.25mmol (1.0 eq) of Ag 2 O,1ml Tetrahydrofuran (THF), at 60 ℃ for 20 hours, concentrating, filtering and purifying to obtain the target product E1. 1 H NMR:δ0.88(3H,t,J＝6.5Hz),1.25-1.37(2H,1.31(h,J＝6.5Hz),1.31(h,J＝6.5Hz)),1.50-1.64(2H,1.57(tt,J＝7.3,6.5Hz),1.57(tt,J＝7.3,6.5Hz)),2.18-2.30(6H,2.23(s),2.25(s)),2.61-2.73(2H,2.67(t,J＝7.3Hz),2.67(t,J＝7.3Hz)),5.66(1H,s),6.98-7.34(9H,7.05(ddd,J＝8.0,7.8,2.1Hz),7.06(ddd,J＝8.0,1.5,0.6Hz),7.08(dd,J＝8.1,1.5Hz),7.09(ddd,J＝8.0,7.8,1.5Hz),7.09(t,J＝8.1Hz),7.09(dd,J＝8.1,1.5Hz),7.17(ddd,J＝8.0,2.1,0.6Hz),7.21(ddd,J＝7.4,5.1,1.5Hz),7.28(ddd,J＝7.9,1.5,0.6Hz)),7.69(1H,ddd,J＝7.9,7.4,1.9Hz),8.53(1H,ddd,J＝5.1,1.9,0.6Hz)。
The yield of the reaction was 93% and the ee value of the enantioselectivity was 90% as measured.
Example 2
In a reaction vessel under nitrogen, 0.25mmol of compound D2, 0.25mmol (1.0 eq) of butylboronic acid, 25. Mu. Mol (10 mol%) of Pd (OAc) were introduced 2 Catalyst, 50. Mu. Mol (20 mol%) of the ligand prepared in example 2, 0.125mmol (0.5 eq) of BQ,0.25mmol (1.0 eq) of Ag 2 O,1ml of THF was reacted at 50℃for 24 hours, concentrated, filtered and purified to give the target product E2. 1 H NMR:δ0.88(3H,t,J＝6.5Hz),1.25-1.37(2H,1.31(h,J＝6.5Hz),1.31(h,J＝6.5Hz)),1.49-1.63(2H,1.56(tt,J＝7.3,6.5Hz),1.56(tt,J＝7.3,6.5Hz)),2.61-2.73(2H,2.67(t,J＝7.3Hz),2.67(t,J＝7.3Hz)),5.68(1H,s),6.99-7.39(11H,7.05(ddd,J＝7.8,1.6,0.6Hz),7.17(td,J＝7.8,2.0Hz),7.19(ddd,J＝8.1,7.8,1.6Hz),7.18(ddd,J＝8.1,2.0,0.6Hz),7.20(tt,J＝7.7,1.3Hz),7.21(ddd,J＝7.4,5.1,1.5Hz),7.28(ddd,J＝7.9,1.5,0.6Hz),7.28(dtd,J＝7.6,1.3,0.5Hz),7.33(tdd,J＝7.7,1.9,0.5Hz)),7.69(1H,ddd,J＝7.9,7.4,1.9Hz),8.53(1H,ddd,J＝5.1,1.9,0.6Hz)。
The yield of the reaction was 94% and the ee value of the enantioselectivity was 92% as determined.
Example 3
To the reaction vessel was added 0.25mmol of compound D3,0.25mmol (1.0 eq) of butylboronic acid, 25. Mu. Mol (10 mol%) of Pd (OAc) under nitrogen protection 2 50. Mu. Mol (20 mol%) of the ligand prepared in example 3, 0.125mmol (0.5 eq) of BQ,0.25mmol (1.0 eq) of Ag 2 O,1ml of THF was reacted at 60℃for 20 hours, concentrated, filtered and purified to give the target product E3. 1 H NMR:δ0.88(3H,t,J＝6.5Hz),1.25-1.37(2H,1.31(h,J＝6.5Hz),1.31(h,J＝6.5Hz)),1.44-1.57(2H,1.50(tt,J＝7.4,6.5Hz),1.50(tt,J＝7.4,6.5Hz)),2.51-2.63(2H,2.57(t,J＝7.4Hz),2.57(t,J＝7.4Hz)),3.67-3.80(6H,3.72(s),3.75(s)),5.67(1H,s),6.59-6.79(2H,6.65(dd,J＝2.9,0.5Hz),6.72(dd,J＝8.1,2.9Hz)),6.81-7.06(4H,6.88(ddd,J＝8.2,2.7,2.5Hz),6.90(td,J＝2.7,0.5Hz),6.99(ddd,J＝7.9,2.7,2.5Hz),7.00(dd,J＝8.1,0.5Hz)),7.14-7.34(3H,7.21(ddd,J＝7.4,5.1,1.5Hz),7.22(ddd,J＝8.2,7.9,0.5Hz),7.28(ddd,J＝7.9,1.5,0.6Hz)),7.69(1H,ddd,J＝7.9,7.4,1.9Hz),8.53(1H,ddd,J＝5.1,1.9,0.6Hz)。
The yield of the reaction was 92% and the ee value of the enantioselectivity was 91%.
Comparative example
Similar to example 4, the difference is that: the ligand is replaced with a ligand of the formula.
The yield of the reaction was 45% and the ee value of the enantioselectivity was 46% as measured.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (10)
1. A method for synthesizing diphenyl-2-pyridylmethane derivatives, characterized by: mixing and stirring a compound D, butyl boric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1, reacting, and separating and purifying to obtain a diphenyl-2-pyridylmethane derivative E, wherein the chemical reaction formula is as follows:
wherein R is 1 、R 2 Each independently selected from one of hydrogen, alkyl, alkoxy, aryl, heteroaryl.
2. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the catalyst is Pd (OAc) 2 The ligand is
Wherein R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
3. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the oxidant is terephthalquinone, and the additive is silver oxide.
4. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the organic solvent 1 is tetrahydrofuran.
5. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the molar ratio of the compound D to the butyl boric acid to the catalyst to the ligand to the oxidant to the additive is 1:1:0.1:0.2:0.5:1.0.
6. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the reaction temperature is 50-60 ℃ and the reaction time is 20-24h.
7. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the preparation method of the ligand comprises the following steps: in the presence of an organic solvent 2, an acylating agent, a catalyst and an organic base, a 7-carboxyl-1, 1' -spiroindane compound shown in a formula B reacts with a compound shown in a formula C to prepare a compound shown in a formula A, wherein the reaction formula is as follows:
wherein R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
8. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 7, wherein: the acylating agent is oxalyl chloride, the catalyst is N, N-dimethylformamide, the organic base is triethylamine, and the organic solvent 2 is dichloromethane.
9. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 7, wherein: the molar ratio of the 7-carboxyl-1, 1' -spiroindane compound shown in the formula B to the acylating agent to the organic base is 0.9-1:1-1.1:1.3-1.5:3;
the 7-carboxyl-1, 1' -spiroindane compound shown in the formula A and the catalyst are 1:0.01 in mol/L.
10. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 7, wherein: the reaction time is 5-7 hours, and the reaction temperature is 0-room temperature.
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