CN110128341B - Chiral 2, 2' -bipyridyl ligand, preparation method thereof and application thereof in preparation of chiral cyclopropane derivative - Google Patents

Chiral 2, 2' -bipyridyl ligand, preparation method thereof and application thereof in preparation of chiral cyclopropane derivative Download PDF

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CN110128341B
CN110128341B CN201910394448.9A CN201910394448A CN110128341B CN 110128341 B CN110128341 B CN 110128341B CN 201910394448 A CN201910394448 A CN 201910394448A CN 110128341 B CN110128341 B CN 110128341B
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李鹏飞
欧阳彝钊
占苗
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Xian Jiaotong University
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Abstract

The invention provides a chiral 2,2 ' -bipyridyl ligand and a preparation method and application thereof, the chiral 2,2 ' -bipyridyl ligand is shown as a formula (1) or a formula (1 '),

Description

Chiral 2, 2' -bipyridyl ligand, preparation method thereof and application thereof in preparation of chiral cyclopropane derivative
Technical Field
The invention belongs to the technical field of fine chemical engineering, and relates to a chiral 2, 2' -bipyridyl ligand, a preparation method thereof and application thereof in preparation of chiral cyclopropane derivatives.
Background
Cyclopropane structures are common in natural products, drugs, pesticides and other functional molecules, and their unique bonding mode and high-tension ring structure make it easy to synthesize other molecules through ring-opening or ring-expansion reactions. The academic world has been actively researching the synthesis of cyclopropane, and a large number of high-efficiency chiral catalysts, such as metal complexes of copper, rhodium, ruthenium, cobalt and the like, are developedThus, the research on the synthesis of the cyclopropane is greatly advanced. Among them, transition metals catalyze asymmetric cyclopropane reaction of olefins and diazo compounds, which is a widely used strategy for synthesizing chiral cyclopropane derivatives. For example, in 2000, the Gregory C.Fu group developed a C2Symmetrical surface chiral bipyridine ligands and are used in the synthesis of cyclopropane compounds from olefins and tert-butyl diazoacetate with good results (Ramon, R.; Jack, L.; Michael, M.C.L.; Gregory, C.F.Chem.Comm.2000, 377-378.).
However, most of diazo compounds used at present are reagents having a large steric hindrance group such as t-butyl diazoacetate and benzyl diazoacetate, and these reagents are difficult to synthesize and expensive. It is difficult to obtain a high yield while obtaining a specific stereoselectivity by using cheap and easily available ethyl diazoacetate as a raw material. Therefore, the improvement of the yield and the enantioselectivity of the chiral cyclopropane product when ethyl diazoacetate is used as a raw material has important research significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a chiral 2, 2' -bipyridyl ligand, a preparation method thereof and application thereof in preparing chiral cyclopropane derivatives, wherein the yield and enantioselectivity of chiral cyclopropane products can be kept at higher levels when ethyl diazoacetate is used as a raw material.
The invention is realized by the following technical scheme:
a chiral 2,2 '-bipyridine ligand has a structural formula shown as formula (1) or formula (1'):
Figure BDA0002057706890000021
the preparation method of the chiral 2, 2' -bipyridyl ligand comprises the following steps:
(1) reacting anthracene and 2-cyclopentenone under the catalysis of Lewis acid to obtain a pair of enantiomers;
(2) reacting the obtained enantiomer with (R) -tert-butyl sulfinamide and tetraethyl titanate, then separating and purifying the product by using a silica gel chromatographic column to obtain sulfinylimine, and then hydrolyzing by using hydrochloric acid to obtain chiral ketone shown in formula (2) or formula (2');
Figure BDA0002057706890000022
(3) placing chiral ketone shown in a formula (2) and hydroxylamine into ethanol for reaction to obtain oxime shown in a formula (3);
or, placing the chiral ketone shown in the formula (2 ') and hydroxylamine into ethanol for reaction to obtain oxime shown in the formula (3');
Figure BDA0002057706890000023
(4) adding oxime shown in a formula (3) into toluene, and then adding iron powder, acetic anhydride and acetic acid to react to obtain amide shown in a formula (4);
or adding the oxime shown in the formula (3 ') into toluene, and then adding iron powder, acetic anhydride and acetic acid to react to obtain the amide shown in the formula (4');
Figure BDA0002057706890000031
(5) dissolving amide shown in a formula (4) in N, N-dimethylformamide, then dropwise adding phosphorus oxychloride, and reacting to obtain a chloropyridine derivative shown in a formula (5);
or dissolving the amide shown in the formula (4 ') in N, N-dimethylformamide, and then dropwise adding phosphorus oxychloride to react to obtain the chloropyridine derivative shown in the formula (5');
Figure BDA0002057706890000032
(6) adding zinc powder, nickel chloride hexahydrate and triphenylphosphine into N, N-dimethylformamide, heating and stirring for 2 hours, then adding a chloropyridine derivative shown in a formula (5) or a formula (5 ') dissolved in the N, N-dimethylformamide, and reacting to obtain the chiral 2, 2' -bipyridine ligand.
Preferably, the specific process of step (1) is as follows: under the protection of nitrogen, anthracene, 2-cyclopentenone and aluminum trichloride are reacted in dichloromethane at 30-50 ℃ for 48-72 hours, after the reaction, water washing and dichloromethane extraction are carried out, organic phases are combined and dried by anhydrous magnesium sulfate, filtering and reduced pressure evaporation of dichloromethane are carried out, and the obtained crude product is subjected to one-step recrystallization to obtain a pair of racemic enantiomers.
Preferably, in the step (2), the reaction temperature is 50-60 ℃ and the reaction time is 12-20 hours.
Preferably, the specific process of step (3) is as follows: placing chiral ketone and hydroxylamine into an ethanol solution, heating, refluxing and stirring for 18-24 hours, then washing with water, extracting with dichloromethane, drying the obtained organic phase with anhydrous sodium sulfate, and removing the solvent to obtain oxime.
Preferably, the specific process of step (4) is as follows: adding oxime into toluene, cooling to 0 ℃, adding iron powder, adding a mixture of acetic anhydride and acetic acid, heating to room temperature for reaction, stirring for 18-24 hours, filtering out the iron powder, adding an ammonium chloride aqueous solution, extracting by using ethyl acetate, and performing silica gel column chromatography separation to obtain amide.
Preferably, the specific process of step (5) is as follows: dissolving amide in N, N-dimethylformamide, dropwise adding phosphorus oxychloride in an ice bath, stirring at 80-100 ℃ for 18-24 hours, and separating the mixture by using column chromatography to obtain the chloropyridine derivative.
Preferably, the specific process of step (6) is as follows: adding zinc powder, nickel chloride hexahydrate and triphenylphosphine into N, N-dimethylformamide, heating to 70-80 ℃, stirring, observing that the color is changed to green, adding a chloropyridine derivative dissolved in the N, N-dimethylformamide, stirring for 24-36 hours, washing with ammonia water, extracting with dichloromethane, combining organic phases, drying with anhydrous magnesium sulfate, filtering, decompressing and evaporating to dryness to obtain a crude product, and separating and purifying the crude product by column chromatography to obtain the chiral 2, 2' -bipyridine ligand.
The chiral 2, 2' -bipyridyl ligand is used as a catalyst ligand in the preparation of chiral cyclopropane derivatives.
Preferably, the method comprises the following steps:
under the condition of argon, uniformly stirring a chiral 2, 2' -bipyridyl ligand and a cuprous trifluoromethanesulfonate toluene complex in dichloromethane, then adding olefin, adding ethyl diazoacetate dissolved in dichloromethane, reacting, filtering, decompressing and evaporating dichloromethane to dryness, and separating and purifying an obtained crude product by using column chromatography to obtain the chiral cyclopropane derivative.
Compared with the prior art, the invention has the following beneficial technical effects:
when the ligand is used for preparing the chiral cyclopropane derivative, the ligand is a bipyridyl dinitrogen bidentate ligand, has a relatively rigid and stable chiral space, forms a stable complex after being coordinated with metal, does not change the chiral environment in the reaction process, and can improve the enantioselectivity of a chiral cyclopropane product when ethyl diazoacetate is used as a raw material while obtaining high yield.
The raw materials for synthesizing the ligand have low cost, are simple and easy to obtain, and are convenient to synthesize.
The ligand of the invention is adopted to prepare the cyclopropane derivative, cheap ethyl diazoacetate can be adopted as a raw material, a catalyst is cheap metal copper, and the product has good stereoselectivity, high yield and easy purification.
Drawings
FIG. 1 shows chiral 2, 2' -bipyridine ligands of formula (1) in an example of the present invention1H NMR spectrum.
Detailed Description
The present invention will now be described in further detail with reference to specific examples, which are intended to be illustrative, but not limiting, of the invention.
A chiral 2,2 '-bipyridine ligand has a structural formula shown as formula (1) or formula (1'):
Figure BDA0002057706890000051
a process for preparing a chiral 2, 2' -bipyridine ligand comprising the steps of:
the first step is as follows: under the protection of nitrogen, anthracene and 2-cyclopentenone and aluminum trichloride are reacted in dichloromethane at 40 ℃ for 48-72 hours. After the reaction, washing with water, extracting with dichloromethane, combining organic phases, drying with anhydrous magnesium sulfate, filtering, decompressing and evaporating the solvent to dryness, and performing one-step recrystallization on the obtained crude product to obtain a pair of racemic diastereoisomers.
The second step is that: stirring the obtained diastereoisomer, the (R) -tert-butyl sulfinamide and a certain amount of tetraethyl titanate in an organic solvent at 60 ℃ overnight, and then separating and purifying the product by using a silica gel chromatographic column to obtain the optically pure sulfinyl imine. Followed by hydrolysis with aqueous hydrochloric acid to give the chiral ketone of formula (2) or formula (2').
Figure BDA0002057706890000061
The third step: placing the chiral ketone shown in the formula (2) or the formula (2') and excess hydroxylamine into an ethanol solution, refluxing and stirring for 18-24 hours, then washing with water, and extracting with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain an oxime represented by the formula (3) or (3') in which the ketone was converted.
Figure BDA0002057706890000062
The fourth step: the oxime of formula (3) or formula (3') is added to an appropriate amount of toluene. The toluene solution was then cooled to 0 ℃ and excess iron powder was added. Then a mixture of the appropriate acetic anhydride and acetic acid is slowly added to the solution and allowed to warm to room temperature. Filtering the iron powder after the reaction, adding a proper amount of ammonium chloride aqueous solution into the filtrate, extracting by using ethyl acetate, and then carrying out silica gel column chromatography separation to obtain the corresponding amide product shown in the formula (4) or the formula (4').
Figure BDA0002057706890000063
The fifth step: an amide represented by the formula (4) or (4') is dissolved in N, N-dimethylformamide. Then dropping phosphorus oxychloride into the ice bath. After stirring at 80-100 ℃ for 24 hours, the mixture is separated by column chromatography to obtain the chloropyridine derivative represented by formula (5) or (5') which is an important intermediate.
Figure BDA0002057706890000071
And a sixth step: adding a proper amount of zinc powder, nickel chloride hexahydrate and triphenylphosphine into a certain amount of N, N-dimethylformamide solvent, heating to 70-80 ℃, and stirring for 2 hours. After the color was observed to turn green, the chloropyridine derivative of formula (5) or (5') was dissolved in N, N-dimethylformamide and added dropwise to the system. The reactant is stirred for 24 to 36 hours, washed by ammonia water and extracted by dichloromethane, organic phases are combined and dried by anhydrous magnesium sulfate, filtered, and the solvent is evaporated by decompression, and the obtained crude product is separated and purified by column chromatography to obtain the chiral 2,2 '-bipyridine ligand of the formula (1) or the formula (1').
The application of the chiral 2, 2' -bipyridyl ligand as a catalyst ligand in the synthesis of cyclopropane derivatives comprises the following steps:
stirring the chiral 2,2 '-bipyridyl ligand of the formula (1) or the formula (1') and cuprous trifluoromethanesulfonate toluene complex in dichloromethane for 30-60 minutes under the argon condition, then adding olefin, dissolving ethyl diazoacetate in dichloromethane, and slowly dropwise adding the ethyl diazoacetate into the reaction system. Filtering, decompressing and evaporating the solvent, and separating and purifying the obtained crude product by column chromatography to obtain the chiral cyclopropane derivative.
The structure of the chiral cyclopropane compound is shown as the formula (6):
Figure BDA0002057706890000072
wherein R is1Represents a benzene ring or a hydrogen atom, R2Represents an aromatic ring, a substituted aromatic ring or a naphthalene ring.
Example 1
Synthesis of chiral 2, 2' -bipyridine ligand:
1.1
Figure BDA0002057706890000081
anthracene (8.9g, 50mmol) and 2-cyclopentenone (8.2g, 100mmol) were added to a three-necked round bottom flask, and the system atmosphere was replaced with nitrogen after addition of a reflux condenser. Then 75mL of dichloromethane was added and anhydrous aluminum trichloride (10g, 41mmol) was slowly added in portions to the flask and the temperature was raised to 40 ℃. After stirring for about 72 hours, cooling to 0 ℃ and quenching with 20mL of distilled water, followed by extraction with 20-30mL of dichloromethane 3 times each, combining the organic phases and drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure, the crude product obtained is purified by recrystallization from ethanol to give a pair of enantiomers (9S,10S,11R,12R) -9, 10-dihydro-9, 10- [1,2] cyclopentylanthracene-13-one and (9R,10R,11S,12S) -9, 10-dihydro-9, 10- [1,2] cyclopentylanthracene-13-one in a ratio of 1: 1.
1.2
Figure BDA0002057706890000082
the above enantiomer (3.9g, 15mmol) was taken and reacted with (R) - (+) -tert-butylsulfinamide (1.81g, 15mmol) and tetraethyltitanate (6.8g, 30mmol) in tetrahydrofuran (75mL) at 60 ℃ for 20 hours. And (3) cooling the materials to room temperature, adding saturated ammonium chloride aqueous solution (20mL) to quench the materials for reaction, extracting the materials for 3 times by using 20-30mL ethyl acetate each time, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, concentrating the organic phases under reduced pressure, and separating and purifying the obtained crude product by using column chromatography to obtain optically pure sulfinylimine intermediates respectively. After the intermediate was hydrolyzed with aqueous hydrochloric acid (20mL), respectively, (9S,10S,11R,12R) -9, 10-dihydro-9, 10- [1,2] cyclopentylbenzoanthracen-13-one and (9R,10R,11S,12S) -9, 10-dihydro-9, 10- [1,2] cyclopentylbenzoanthracen-13-one were obtained.
1.3
Figure BDA0002057706890000091
(9S,10S,11R,12R) -9, 10-dihydro-9, 10- [1,2] cyclopenta-xanthen-13-one (3.9g, 15mmol) was dissolved in 20mL of ethanol, hydroxylamine (1.5g, 45mmol) was added thereto, and the mixture was heated to 80 ℃ and stirred under reflux overnight. After cooling to room temperature, 20mL of water was added and the mixture was extracted 3 times with 20-30mL of dichloromethane each time, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product (9S,10S,11R,12R E) -9, 10-dihydro-9, 10- [1,2] cyclopentylanthracene-13-oxime.
1.4
Figure BDA0002057706890000092
The oxime (2.7g, 10mmol) obtained in the previous step was dissolved in toluene (20mL) and iron powder (3.35g, 60mmol) was added and cooled to 0 ℃. A mixture of acetic anhydride (3.1g, 30mmol) and acetic acid (1.8g, 30mmol) was then slowly added to the system and allowed to return to room temperature. Stirring for 18-24 hr, adding saturated ammonium chloride solution (20mL) to quench reaction, extracting with 20-30mL ethyl acetate for 3 times, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying the crude product by column chromatography to obtain N-13- ((9S,10S,11R,12R) -9, 10-dihydro-9, 10- [1,2] cyclopentylanthracene-13-ene) yl-acetamide.
1.5
Figure BDA0002057706890000101
N-13- ((9S,10S,11R,12R) -9, 10-dihydro-9, 10- [1,2] cyclopentacanthracen-13-en) yl-acetamide (1g, 3.3mL) obtained in the previous step and N, N-dimethylformamide (0.8g, 12mmol) were taken in a round-bottomed flask, and after replacement of nitrogen gas, phosphorus oxychloride (3.8g, 25mmol) was added dropwise. After the completion of the dropwise addition, the mixture was heated to 100 ℃ and stirred for 24 hours. Cooling to room temperature, and directly separating and purifying by column chromatography to obtain the chloropyridine derivative shown in formula (5).
1.6
Figure BDA0002057706890000102
Collecting zinc powder (214.5mg, 3.3mmol) and chlorine hexahydrateNickel oxide (643mg, 2.7mmol) and triphenylphosphine (2.8g, 10.7mmol) were added to N, N-dimethylformamide (15mL) and heated to 70 ℃ with stirring for 2 hours. After the color was observed to turn green, the chloropyridine derivative of formula (5) (658mg, 2mmol) was dissolved in N, N-dimethylformamide (3mL), and the chloropyridine derivative solution was dropwise added to the reaction system, followed by stirring for 36 hours. After the reaction, the temperature was reduced to room temperature, and the reaction mixture was quenched with 10% by mass aqueous ammonia (10 mL). Then extracting with 20-30mL of dichloromethane for 3 times, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying the obtained crude product by column chromatography to obtain the chiral 2, 2' -bipyridine ligand of the formula (1). Preparation of the resulting chiral 2, 2' -bipyridine ligand1The H NMR spectrum is shown in FIG. 1.
Example 2
Synthesis of chiral 2, 2' -bipyridine ligand:
2.1
Figure BDA0002057706890000111
the reaction temperature of 1.1 in example 1 was adjusted to 50 ℃ and the reaction time was shortened to 48 hours, and the reaction results were the same under the same conditions.
2.2
Figure BDA0002057706890000112
The reaction temperature of 1.2 in example 1 was lowered to 50 ℃ and the stirring time was shortened to 12 hours, and the reaction results were the same under the same conditions.
2.3
Figure BDA0002057706890000113
The reaction time of (9S,10S,11R,12R) -9, 10-dihydro-9, 10- [1,2] cyclopentylanthracene-13-one in the reaction 1.3 of example 1 was replaced with (9R,10R,11S,12S) -9, 10-dihydro-9, 10- [1,2] cyclopentylanthracene-13-one, f was shortened to 18 hours, and the same conditions were followed to obtain a crude product (9R,10R,11S,12S, E) -9, 10-dihydro-9, 10- [1,2] cyclopentylanthracene-13-oxime).
2.4
Figure BDA0002057706890000121
The oxime from the 1.4 reaction in example 1 was replaced with the oxime from the 2.3 step, stirring for 18 hours, and the conditions were the same to give N-13- ((9R,10R,11S,12S, E) -9, 10-dihydro-9, 10- [1,2] cyclopentylanthracen-13-en) yl-acetamide.
2.5
Figure BDA0002057706890000122
N-13- ((9R,10R,11S,12S, E) -9, 10-dihydro-9, 10- [1,2] cyclopentylbenzo-13-en) yl-acetamide (1g, 3.3mL) obtained in the previous step and N, N-dimethylformamide (0.8g, 12mmol) were taken in a round-bottomed flask, and after replacement of nitrogen gas, phosphorus oxychloride (3.8g, 25mmol) was added dropwise. After the completion of the dropwise addition, the mixture was heated to 90 ℃ and stirred for 18 hours. Cooling to room temperature, and directly separating and purifying by column chromatography to obtain the chloropyridine derivative formula (5').
2.6
Figure BDA0002057706890000123
The formula (5) in the reaction of 1.6 in example 1 was replaced with the formula (5 '), the heating temperature was adjusted to 80 ℃ and the stirring time was adjusted to 30 hours, and the remaining conditions were the same as those of 1.6 in example 1, whereby the formula (1') was obtained.
Example 3
Synthesis of chiral 2, 2' -bipyridine ligand:
3.1
Figure BDA0002057706890000131
the reaction temperature of 1.1 in example 1 was adjusted to 30 ℃ and the reaction time was shortened to 60 hours, and the other conditions were the same as those of 1.1 in example 1.
3.2
Figure BDA0002057706890000132
The reaction temperature of 1.2 in example 1 was lowered to 55 ℃ and the stirring time was shortened to 18 hours, and the other conditions were the same as those of 1.2 in example 1.
3.3
Figure BDA0002057706890000133
The reaction time in 1.3 in example 1 was shortened to 20 hours, and the remaining conditions were the same as in 1.3 in example 1.
3.4
Figure BDA0002057706890000141
The stirring time was adjusted to 20 hours in 1.4 of example 1, and the other conditions were the same as in 1.4 of example 1.
3.5
Figure BDA0002057706890000142
The solution 1.4 of example 1 was heated to 80 ℃ after completion of the dropwise addition, and stirred for 20 hours under the same conditions as 1.5 of example 1.
3.6
Figure BDA0002057706890000143
The heating temperature in 1.6 in example 1 was adjusted to 75 ℃ and the stirring time was adjusted to 24 hours, and the conditions were the same as in 1.6 in example 1, whereby formula (1) was obtained.
The following examples further illustrate the use of the invention and do not therefore limit the scope of the invention described.
Preparation of chiral cyclopropane derivatives
Preparation of example 1
This example is a preparation of ethyl (1R, 2R) -phenylcyclopropanecarboxylate, comprising in particular the following steps: under argon, first, cuprous trifluoromethanesulfonate-toluene complex (1.3mg, 0.005mmol) and chiral 2, 2' -bipyridyl ligand (3.3mg, 0.0055mmol, formula (1)) and dichloromethane (1mL) were added to the reaction tube and stirred at room temperature for one hour. Styrene (72mg, 0.5mmol) was then added, ethyl diazoacetate (125.4mg, 1.1mmol) was dissolved in dichloromethane (1mL), and the solution was added dropwise to the system using a syringe pump over a period of 5 hours. After the reaction is finished, the solvent (dichloromethane) is removed by a rotary evaporator, and the product is purified by a silica gel column chromatography method (200-300 mesh silica gel is used, the mass ratio of the silica gel to the substance to be purified is 50-100: 1, the eluent is petroleum ether and ethyl acetate, and the volume ratio is 10-20: 1) to obtain the (1R, 2R) -phenyl cyclopropane carboxylic acid ethyl ester (97% yield, 10: 1dr, 97% ee).1H NMR(400MHz,CDCl3)7.22–7.18(m,2H),7.14–7.11(m,1H),7.03–7.02(m,2H),4.10(q,J＝7.0Hz,2H),2.47–2.42(m,1H),1.84–1.82(m,1H),1.55–1.51(m,1H),1.26–1.21(m,1H),1.19(t,J＝7.0Hz,3H)；13C NMR(100MHz,CDCl3)175.7,141.1,134.6,131.1,130.1,63.3,28.0,26.7,19.6,16.8。
Preparation of example 2
The reaction was carried out under the same conditions but using 4-methoxystyrene instead of styrene in preparation example 1 to give ethyl (1R, 2R) - (4-methoxyphenyl) -cyclopropanecarboxylate (96% yield, 10: 1dr, 96% ee).1H NMR(400MHz,CDCl3)7.03(d,J＝8.2Hz,2H),6.82(d,J＝8.2Hz,2H),4.16(q,J＝7.1Hz,2H),3.78(s,3H),2.50–2.45(m,1H),1.84–1.81(m,1H),1.57–1.54(m,1H),1.29–1.27(m,4H)；13C NMR(100MHz,CDCl3)173.1,158.3,132.6,127.6,113.5,60.8,55.4,25.5,24.1,17.0,14.2。
Preparation of example 3
The reaction was carried out under the same conditions except for using 4-tert-butylstyrene instead of styrene in production example 1 to give ethyl (1R, 2R) - (4-tert-butylphenyl) -cyclopropanecarboxylate (90% yield, 10: 1dr, 96% ee).1H NMR(400MHz,CDCl3)7.31(d,J＝8.4Hz,2H),7.04(d,J＝8.3Hz,2H),4.16(q,J＝7.1Hz,2H),2.51-2.48(m,1H),1.90-1.86(m,1H),1.60–1.56(m,1H),1.30–1.27(m,13H)；13C NMR(100MHz,CDCl3)174.1,148.4,139.6,129.5,128.6,61.9,33.5.,31.4,26.5,25.1,18.0,15.2。
Preparation of example 4
The reaction was carried out under the same conditions except for using 4-chlorostyrene instead of the styrene used in preparation example 1 to obtain (1R, 2R) - (4-chlorophenyl) -cyclopropanecarboxylic acid ethyl ester (94% yield, 9: 1dr, 94% ee).1H NMR(400MHz,CDCl3)7.24(d,J＝8.4Hz,2H),7.03(d,J＝8.4Hz,2H),4.17(q,J＝7.1Hz,2H),2.51–2.47(m,1H),1.88–1.84(m,1H),1.62–1.57(m,1H),1.30–1.26(m,4H)；13C NMR(100MHz,CDCl3)171.9,137.4,130.1,127.3,126.3,59.6 24.2,22.9,15.8,13.0。
Preparation of example 5
The reaction was carried out under the same conditions but using 2-bromostyrene instead of styrene as in preparation example 1 to give (1R, 2R) - (2-bromophenyl) -cyclopropanecarboxylic acid ethyl ester (94% yield, 8: 1dr, 93% ee).1H NMR(400MHz,CDCl3)7.39(d,J＝8.4Hz,2H),6.97(d,J＝8.4Hz,2H),4.17(q,J＝7.1Hz,2H),2.49–2.44(m,1H),1.88–1.84(m,1H),1.62–1.57(m,1H),1.30–1.26(m,4H)；13C NMR(100MHz,CDCl3)173.5,138.7,132.1,127.5,120.6,60.8,25.9,24.6,17.4,14.7。
Preparation of example 6
The substitution of 1, 1-stilbene for the styrene in preparation example 1 specifically included the following steps: under argon, first, cuprous trifluoromethanesulfonate-toluene complex (2.6mg, 0.01mmol) and chiral 2, 2' -bipyridine ligand (6.6mg, 0.011mmol, formula (1)) and dichloromethane (2mL) were added to the reaction tube and pre-stirred at room temperature for one hour. Styrene (72mg, 0.5mmol) was then added, ethyl diazoacetate (125.4mg, 1.1mmol) was dissolved in dichloromethane (1mL), and the solution was added dropwise to the system using a syringe pump over 10 hours. The reaction was carried out under the same conditions to give ethyl (R) -2, 2-diphenylcyclopropane-1-carboxylate (99% yield, 87% ee).1H NMR(400MHz,CDCl3)7.30(dd,J＝5.2,3.3Hz,2H),7.18–7.06(m,8H),3.84–3.79(m,2H),2.44(dd,J＝8.1,5.9Hz,1H),2.08(dd,J＝5.8,4.9Hz,1H),1.58(dd,J＝8.1,4.8Hz,1H),0.91(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)171.1,137.9,125.3,125.0,124.7,120.4,118.0,60.8,41.4,38.7,20.2,12.5。
The chiral cyclopropyl derivative obtained by the preparation method has higher yield and stereoselectivity. The product can be used for synthesizing intermediates of medicines/pesticides, and the preparation method can be used for preparing a plurality of similar products and has industrial application value.

Claims (10)

1. A chiral 2,2 '-bipyridine ligand is characterized in that the structural formula is shown as a formula (1) or a formula (1'):
Figure FDA0002478825770000011
2. a process for the preparation of chiral 2, 2' -bipyridine ligands of claim 1, comprising the steps of:
(1) reacting anthracene and 2-cyclopentenone under the catalysis of Lewis acid to obtain a pair of enantiomers;
(2) reacting the obtained enantiomer with (R) -tert-butyl sulfinamide and tetraethyl titanate, then separating and purifying the product by using a silica gel chromatographic column to obtain sulfinylimine, and then hydrolyzing by using hydrochloric acid to obtain chiral ketone shown in formula (2) or formula (2');
Figure FDA0002478825770000012
(3) placing chiral ketone shown in a formula (2) and hydroxylamine into ethanol for reaction to obtain oxime shown in a formula (3);
or, placing the chiral ketone shown in the formula (2 ') and hydroxylamine into ethanol for reaction to obtain oxime shown in the formula (3');
Figure FDA0002478825770000013
(4) adding oxime shown in a formula (3) into toluene, and then adding iron powder, acetic anhydride and acetic acid to react to obtain amide shown in a formula (4);
or adding the oxime shown in the formula (3 ') into toluene, and then adding iron powder, acetic anhydride and acetic acid to react to obtain the amide shown in the formula (4');
Figure FDA0002478825770000021
(5) dissolving amide shown in a formula (4) in N, N-dimethylformamide, then dropwise adding phosphorus oxychloride, and reacting to obtain a chloropyridine derivative shown in a formula (5);
or dissolving the amide shown in the formula (4 ') in N, N-dimethylformamide, and then dropwise adding phosphorus oxychloride to react to obtain the chloropyridine derivative shown in the formula (5');
Figure FDA0002478825770000022
(6) adding zinc powder, nickel chloride hexahydrate and triphenylphosphine into N, N-dimethylformamide, heating and stirring for 2 hours, then adding a chloropyridine derivative shown in a formula (5) or a formula (5 ') dissolved in the N, N-dimethylformamide, and reacting to obtain the chiral 2, 2' -bipyridine ligand.
3. The method for preparing chiral 2, 2' -bipyridine ligand according to claim 2, wherein the specific process of step (1) is as follows: under the protection of nitrogen, anthracene, 2-cyclopentenone and aluminum trichloride are reacted in dichloromethane at 30-50 ℃ for 48-72 hours, after the reaction, water washing and dichloromethane extraction are carried out, organic phases are combined and dried by anhydrous magnesium sulfate, filtering and reduced pressure evaporation of dichloromethane are carried out, and the obtained crude product is subjected to one-step recrystallization to obtain a pair of racemic enantiomers.
4. The method for preparing chiral 2, 2' -bipyridine ligand according to claim 2, wherein in the step (2), the reaction temperature is 50-60 ℃ and the reaction time is 12-20 hours.
5. The method for preparing chiral 2, 2' -bipyridine ligand according to claim 2, wherein the step (3) comprises the following steps: placing chiral ketone and hydroxylamine into an ethanol solution, heating, refluxing and stirring for 18-24 hours, then washing with water, extracting with dichloromethane, drying the obtained organic phase with anhydrous sodium sulfate, and removing the solvent to obtain oxime.
6. The method for preparing chiral 2, 2' -bipyridine ligand according to claim 2, wherein the step (4) comprises the following steps: adding oxime into toluene, cooling to 0 ℃, adding iron powder, adding a mixture of acetic anhydride and acetic acid, heating to room temperature for reaction, stirring for 18-24 hours, filtering out the iron powder, adding an ammonium chloride aqueous solution, extracting by using ethyl acetate, and performing silica gel column chromatography separation to obtain amide.
7. The method for preparing chiral 2, 2' -bipyridine ligand according to claim 2, wherein the step (5) comprises the following steps: dissolving amide in N, N-dimethylformamide, dropwise adding phosphorus oxychloride in an ice bath, stirring at 80-100 ℃ for 18-24 hours, and separating the mixture by using column chromatography to obtain the chloropyridine derivative.
8. The method for preparing chiral 2, 2' -bipyridine ligand according to claim 2, wherein the step (6) comprises the following steps: adding zinc powder, nickel chloride hexahydrate and triphenylphosphine into N, N-dimethylformamide, heating to 70-80 ℃, stirring, observing that the color is changed to green, adding a chloropyridine derivative dissolved in the N, N-dimethylformamide, stirring for 24-36 hours, washing with ammonia water, extracting with dichloromethane, combining organic phases, drying with anhydrous magnesium sulfate, filtering, decompressing and evaporating to dryness to obtain a crude product, and separating and purifying the crude product by column chromatography to obtain the chiral 2, 2' -bipyridine ligand.
9. The use of the chiral 2, 2' -bipyridine ligand of claim 1 as a catalyst ligand in the preparation of chiral cyclopropane derivatives by reacting a styrenic compound with ethyl diazoacetate.
10. Use according to claim 9, characterized in that it comprises the following steps:
under the condition of argon, uniformly stirring a chiral 2, 2' -bipyridyl ligand and a cuprous trifluoromethanesulfonate toluene complex in dichloromethane, then adding olefin, adding ethyl diazoacetate dissolved in dichloromethane, reacting, filtering, decompressing and evaporating dichloromethane to dryness, and separating and purifying an obtained crude product by using column chromatography to obtain the chiral cyclopropane derivative.
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