阅读说明：本技术 一种铜催化不对称烯丙基烷基化反应方法及手性化合物 (Copper-catalyzed asymmetric allyl alkylation reaction method and chiral compound ) 是由 游恒志 宋晓 金剑 陈芬儿 于 2021-09-17 设计创作，主要内容包括：本发明提供了一种铜催化不对称烯丙基烷基化反应方法及制备的手性化合物,所述反应方法包括：在-78℃-0℃条件下,以铜盐和手性配体作为催化剂,在溶剂中使有机锂试剂与环状底物进行烷基化反应,其中,所述环状底物、所述铜盐和所述手性配体的摩尔比为1:0.05:(0.055-0.06)。本发明以有机锂试剂作为不对称烯丙基烷基化反应的亲核试剂,不仅能够实现良好的反应收率及对映选择性,且所用催化剂用量较低。(The invention provides a copper-catalyzed asymmetric allyl alkylation reaction method and a prepared chiral compound, wherein the reaction method comprises the following steps: carrying out alkylation reaction on an organic lithium reagent and a cyclic substrate in a solvent by using a copper salt and a chiral ligand as catalysts at the temperature of-78-0 ℃, wherein the molar ratio of the cyclic substrate to the copper salt to the chiral ligand is 1:0.05 (0.055-0.06). The invention takes the organic lithium reagent as the nucleophilic reagent of the asymmetric allylic alkylation reaction, which not only can realize good reaction yield and enantioselectivity, but also has lower dosage of the used catalyst.)

1. A copper-catalyzed asymmetric allyl alkylation reaction method is characterized by comprising the following steps:

carrying out alkylation reaction on an organic lithium reagent and a cyclic substrate in a solvent by using a copper salt and a chiral ligand as catalysts at the temperature of-78-0 ℃, wherein the molar ratio of the cyclic substrate to the copper salt to the chiral ligand is 1:0.05 (0.055-0.06).

2. The method of claim 1, wherein the molar ratio of the cyclic substrate, the copper salt, and the chiral ligand is 1:0.05: 0.06.

3. The copper-catalyzed asymmetric allylic alkylation reaction process of claim 1, wherein the organolithium reagent comprises one of methyllithium, ethyllithium, butyllithium, isobutyllithium, trimethylsilyllithium, tert-butyllithium, and n-hexyllithium.

4. The method of claim 1, wherein the copper salt comprises one of cuprous dimethyl sulfide bromide, copper (I) thiophene-2-carboxylate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, and copper (II) trifluoromethanesulfonate.

5. The copper-catalyzed asymmetric allylic alkylation reaction process of claim 1, wherein the chiral ligand comprises one of (R, R) -L1 ligand, (S, S, S) -L2 ligand, (S, S, S) -L3 ligand, and (S, R, R) -L4 ligand;

wherein the structural formula of the (R, R) -L1 ligand is as follows:

the structural formula of the (S, S, S) -L2 ligand is as follows:

the structural formula of the (S, S, S) -L3 ligand is as follows:

the structural formula of the (S, R, R) -L4 ligand is as follows:

6. the method of claim 1, wherein the copper salt is cuprous dimethyl sulfide bromide, the cuprous dimethyl sulfide is used in an amount of 5 mol%, the chiral ligand is (S, S, S) -L2 ligand, and the (S, S, S) -L2 ligand is used in an amount of 6 mol%.

7. The method of claim 1, wherein the cyclic substrate comprises:

andone kind of (1).

8. The method of claim 1, comprising the steps of:

dissolving the copper salt and the chiral ligand in anhydrous dichloromethane, and stirring at room temperature to obtain a reaction solution;

dropwise adding the annular substrate into the reaction solution, adding an internal standard substance, and cooling at a set temperature for a set time;

and (3) diluting the organic lithium reagent, dropwise adding the diluted organic lithium reagent into the reaction solution within 2h, and continuing to react for 1-2h after the dropwise adding is finished.

9. The method of claim 1, comprising the steps of:

adding dry magnetons into a dry tube, weighing equivalent copper salt and chiral ligand, exhausting air and exchanging air for multiple times, using nitrogen for protection, adding an anhydrous dichloromethane solvent, stirring at room temperature for 10-20min, and fully coordinating the chiral ligand and the copper salt to obtain a reaction solution;

and then dropwise adding the cyclic substrate into the reaction liquid, adding 1 equivalent of an internal standard substance, transferring the internal standard substance into a low-temperature circulating stirrer at the temperature of-78 ℃, cooling for 10-15min, diluting 1.5 equivalents of the organic lithium reagent, dropwise adding the organic lithium reagent into the reaction liquid within 2 hours, continuing to react for 1 hour after dropwise adding, slowly dropwise adding 1M dilute hydrochloric acid for quenching after the reaction is finished, and measuring the separation yield and the enantioselectivity.

10. A chiral compound prepared by the copper-catalyzed asymmetric allylic alkylation reaction process of any of claims 1 to 9.

Technical Field

The invention relates to the technical field of chemical industry, and particularly relates to a copper-catalyzed asymmetric allyl alkylation reaction method and a chiral compound.

Background

Chirality means that molecules can be like the left and right hands of a human being and mirror images of each other, but cannot be superposed with each other, molecules with such properties are chiral molecules, a pair of chiral molecules in mirror image relationship with each other are enantiomers, and chiral molecules with different configurations have different functions. Asymmetric Allylation (AAA) reaction is an effective method for constructing chiral compounds, allylation reaction is a reaction formed by carbon-carbon bond, the reaction process is nucleophilic substitution reaction, so nucleophilic reagent is needed in the reaction process, Grignard reagent is usually used as nucleophilic reagent in the prior art, but the obtained product has poor enantioselectivity and low yield.

Disclosure of Invention

The invention solves the problems that the yield of the asymmetric allyl alkylation reaction which takes the Grignard reagent as the nucleophilic reagent in the prior art is lower, and the enantioselectivity of the product is poorer.

In order to solve the above problems, the present invention provides a copper-catalyzed asymmetric allyl alkylation reaction method, comprising:

carrying out alkylation reaction on an organic lithium reagent and a cyclic substrate in a solvent by using a copper salt and a chiral ligand as catalysts at the temperature of-78-0 ℃, wherein the molar ratio of the cyclic substrate to the copper salt to the chiral ligand is 1:0.05 (0.055-0.06).

Preferably, the molar ratio of the cyclic substrate, the copper salt and the chiral ligand is 1:0.05: 0.06.

Preferably, the organolithium reagent comprises one of methyllithium, ethyllithium, butyllithium, isobutyllithium, trimethylsilyllithium, tert-butyllithium and n-hexyllithium.

Preferably, the copper salt comprises one of cuprous bromide dimethyl sulfide, copper (I) thiophene-2-carboxylate, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, and copper (II) trifluoromethanesulfonate.

Preferably, the chiral ligand comprises one of (R, R) -L1 ligand, (S, S) -L2 ligand, (S, S) -L3 ligand, and (S, R) -L4 ligand;

wherein the structural formula of the (R, R) -L1 ligand is as follows:

the structural formula of the (S, S, S) -L2 ligand is as follows:

the structural formula of the (S, S, S) -L3 ligand is as follows:

the structural formula of the (S, R, R) -L4 ligand is as follows:

preferably, the copper salt is cuprous bromide dimethyl sulfide, the dosage of the cuprous bromide dimethyl sulfide is 5 mol%, the chiral ligand is (S, S, S) -L2 ligand, and the dosage of the (S, S, S) -L2 ligand is 6 mol%.

Preferably, the cyclic substrate comprises:

andone kind of (1).

Preferably, the copper-catalyzed asymmetric allylic alkylation reaction method comprises the following steps:

dissolving the copper salt and the chiral ligand in anhydrous dichloromethane, and stirring at room temperature to obtain a reaction solution;

dropwise adding the annular substrate into the reaction solution, adding an internal standard substance, and cooling at a set temperature for a set time;

and (3) diluting the organic lithium reagent, dropwise adding the diluted organic lithium reagent into the reaction solution within 2h, and continuing to react for 1-2h after the dropwise adding is finished.

Preferably, the copper-catalyzed asymmetric allylic alkylation reaction method comprises the following steps:

adding dry magnetons into a dry tube, weighing equivalent copper salt and chiral ligand, exhausting air and exchanging air for multiple times, using nitrogen for protection, adding an anhydrous dichloromethane solvent, stirring at room temperature for 10-20min, and fully coordinating the chiral ligand and the copper salt to obtain a reaction solution;

and then dropwise adding the annular substrate into the reaction liquid, adding 1 equivalent of an internal standard substance, transferring the internal standard substance into a low-temperature circulating stirrer at the temperature of-78 ℃, cooling for 10-15min, diluting 1.5 equivalents of the organic lithium reagent, dropwise adding the organic lithium reagent into the reaction liquid within 2 hours, continuing to react for 1 hour after dropwise adding, slowly dropwise adding 1M dilute hydrochloric acid for quenching after the reaction is finished, and measuring the separation yield and the enantioselectivity.

The invention also provides a chiral compound prepared by the copper-catalyzed asymmetric allyl alkylation reaction method.

Compared with the prior art, the invention has the following beneficial effects:

the invention takes the organic lithium reagent as the nucleophilic reagent of the asymmetric allyl alkylation reaction, which not only can realize good reaction yield and enantioselectivity, but also uses lower dosage of the expensive chiral ligand catalyst.

Drawings

FIG. 1 is a flow diagram of a copper catalyzed asymmetric allylic alkylation reaction according to an embodiment of the present invention;

FIG. 2 is a schematic diagram of a copper catalyzed asymmetric allylic alkylation template reaction according to an embodiment of the present disclosure;

FIG. 3 is a schematic diagram of the copper-catalyzed asymmetric allyl alkylation reaction process in the embodiment of the present invention.

Detailed Description

In the prior art, asymmetric allyl alkylation reaction of racemic cyclic substrate is carried out at-78 ℃ by using Grignard reagent as nucleophilic reagent, DFT calculation shows that the reaction is a direct enantiomer convergence conversion, i.e. two enantiomers in racemic substrate generate products with the same configuration through different reaction paths. However, the enantioselectivity and the yield of the product obtained by adopting the method have larger promotion space.

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below.

The embodiment of the invention provides a copper-catalyzed asymmetric allyl alkylation reaction method, which comprises the following steps:

and (2) carrying out alkylation reaction on the organic lithium reagent and the cyclic substrate in a solvent at the temperature of-78-0 ℃ by using a copper salt and a chiral ligand as catalysts, wherein the molar ratio of the cyclic substrate, the copper salt and the chiral ligand is 1:0.05 (0.055-0.06), preferably 1:0.05:0.06, and the molar ratio of the copper salt to the chiral ligand is 1:1.2, namely the molar ratio of the copper salt to the chiral ligand is 1 (1.1-1.2) in the embodiment.

In the embodiment, an organolithium reagent is used as a nucleophilic reagent for asymmetric allylic alkylation (AAA for short) reaction, and is catalyzed by a copper catalyst together to realize asymmetric allylic alkylation of a cyclic substrate.

As shown in fig. 1, the specific steps of this embodiment are as follows:

dissolving copper salt and chiral ligand in anhydrous dichloromethane, and stirring at room temperature to obtain a reaction solution; wherein, the stirring time is preferably 10-20 min;

dropwise adding a ring-shaped substrate into the reaction solution, adding an internal standard substance, and cooling at a set temperature for a set time; wherein the set temperature is-78-0 ℃, and the set time is preferably 10-15 min;

and (3) diluting the organic lithium reagent, dropwise adding the diluted organic lithium reagent into the reaction solution within 2h, and continuing to react for 1-2h after the dropwise adding is finished.

Specifically, according to the present invention, firstly, a suitable template reaction is selected, 3-bromocyclohexene is used as a template substrate, methyllithium is used as a nucleophile, and the optimization of the experimental conditions of the template reaction (as shown in fig. 2) including the screening and optimization of chiral ligand, copper salt, temperature and catalyst loading is performed, wherein the experimental results are shown in table 1. Wherein the copper salt comprises cuprous dimethyl sulfide (CuBr. SMe)₂) And copper (I) thiophene-2-carboxylate (CuTc), cuprous chloride (CuCl), cuprous bromide, cuprous iodide (CuI), cuprous cyanide, and copper (II) trifluoromethanesulfonate.

In fig. 2, the left side of the dotted line represents the reaction process of the template reaction, the reactant is 3-bromocyclohexene, and the reaction process of the 3-methylcyclohexene product is schematically represented by asymmetric allylic alkylation reaction at-78 ℃ under the action of methyl lithium, a copper catalyst, a chiral ligand (represented by L), and a solvent, and the right side of the dotted line represents that the chiral ligand L includes four ligands, namely (R, R) -L1 ligand, (S, S) -L2 ligand, (S, S) -L3 ligand, and (S, R) -L4 ligand (referred to as L1, L2, L3, and L4, respectively); wherein the structural formula of each ligand is shown as follows:

the organolithium reagent comprises one of methyl lithium, ethyl lithium, butyl lithium, isobutyl lithium, trimethyl silyl lithium, tert-butyl lithium and n-hexyl lithium.

The cyclic substrates include cyclic substrates having different carbon numbers such as six-membered rings, seven-membered rings, etc., and cyclic substrates having a modifying group such as 3-bromocycloheptene having seven-membered rings and 6-bromo-1-phenylcyclohexene having a phenyl substituent at the ortho-position. Illustratively, the structural formulae of several cyclic substrates are shown below:

in addition, the usage of each reactant is also shown in fig. 2, wherein the usage of methyllithium is 1.5 equivalents, the usage of copper catalyst (copper salt) is expressed by X in mol%, the usage of chiral ligand L is 1.1X, and the usage of chiral ligand L is in mol%, that is, the usage of chiral ligand is 1.1 times of the usage of copper catalyst, or the molar ratio of copper salt to chiral ligand is 1:1.1, hereinafter, only the usage of copper salt is limited, and it should be understood that the usage of chiral ligand in the template reaction is 1.1 times of the usage of copper salt.

Wherein in the header of table 1, the entry represents the entry number for each set of tests; l represents a chiral ligand, including L1, L2, L3 and L4; cu salt represents a copper salt; x represents the amount of copper catalyst, i.e. the amount of copper salt, mol% represents the mole percentage; temp represents temperature in units of; yield (y)^aRepresents the nuclear magnetic yield in%; ee^bRepresenting the enantioselectivity in%, where b represents the enantioselectivity measured directly from a gas phase chiral column.

Firstly, screening copper salt by using L3 ligand, respectively selecting CuTc, CuCl, CuI, CuBr & SMe₂As the copper salt, experiments of items 1 to 4 were conducted, wherein in the four experiments, the amount of the copper catalyst was 5 mol% and the reaction temperature was controlled at-78 ℃. The results show that different kinds of copper salts have a very large influence on the reaction, among which the best performing one is a complex of cuprous dimethyl sulfide bromide, and that the enantioselectivity of the reaction at-78 c can reach 91% when the amount of copper catalyst is 5 mol%, as shown in entry 4 in table 1.

The cuprous bromide dimethyl sulfide complex is selected as a copper catalyst, different chiral ligands suitable for the reaction are screened, and four ligands L1, L2, L3 and L4 are respectively subjected to experiments, as shown in items 4-7 in Table 1. The results show that octahydronaphthol chiral monophosphoryl ligand L2 performed best, and that 98% ee and 99% yield were achieved under the same experimental conditions, as shown in Table 1, entry 6.

On the basis, the reaction temperature is optimized, and the reaction temperature is the same as other experimental conditions (including the type of the used chiral ligand, the type of the copper salt, the dosage of the copper catalyst and the like) shown in item 6 in table 1, and only two groups of experiments of item 9 and item 10 are designed by changing the reaction temperature. The experiment showed that the enantioselectivity of the reaction decreased significantly when the reaction temperature was increased, and that the ee values were 77% and 70% when the temperature was increased to-40 ℃ (table 1, entry 9) and 0 ℃ (table 1, entry 10), respectively.

The equivalent weight of the copper catalyst was optimized to be the same as other experimental conditions shown in item 6 of table 1 (including the chiral ligand used, the kind of copper salt, the reaction temperature, etc.), and only the equivalent weight of the copper catalyst was changed to design the experiment of item 8. Experiments show that when the equivalent weight of the copper catalyst is reduced to 1 mol%, the catalytic combination of the copper salt and the ligand still shows higher activity, and the ee value of the reaction can reach 93%, as shown in entry 8 in table 1.

TABLE 1 screening of different ligands, copper salts, temperatures, catalyst equivalents

^aNuclear magnetic yield, dibromomethane as internal standard;^bdirectly measured by a gas-phase chiral column

The reaction mechanism is shown in FIG. 3, and is represented by cuprous bromide dimethyl sulfide complex (CuBr. SMe)₂) The copper catalyst and chiral ligand (represented by L) are used together as the catalyst of the reaction, methyllithium (MeLi) is used as a nucleophilic reagent, 3-bromocyclohexene is used as a cyclic substrate and comprises an R type and an S type, and the catalyst is represented by (R) -1a and (S) -1a in figure 3 respectively. Under the action of a catalyst, (R) -1a forms an Int-1a intermediate through oxidation and addition of trans-SN 2 '(anti-SN 2'), (S) -1a forms an Int-1a intermediate through oxidation and addition of trans-SN 2(anti-SN2), and then the Int-1a intermediate is rapidly reduced and eliminated to form a target product (R) -2a with a single configuration.

Through the condition optimization experiment, the optimal experimental conditions for obtaining the racemization annular substrate AAA reaction in which the organic lithium participates are as follows: under the condition of-78 ℃, 5 mol% of cuprous bromide dimethyl sulfide complex is used as a copper salt catalyst, 6 mol% (S, S, S) -L2 octahydro chiral binaphthol is used as a chiral ligand, anhydrous dichloromethane is used as a solvent, organic lithium is used as a nucleophilic reagent, and the chiral compound and a racemic bromo-cyclic substrate are subjected to asymmetric allyl alkylation reaction for 1h, so that the chiral compound with high yield and enantioselectivity can be obtained.

Illustratively, the specific reaction process is as follows: adding dried magneton into a dry 10ml Schlenk tube, weighing equivalent copper salt and ligand, evacuating and ventilating for three times, adding anhydrous dichloromethane solvent 2ml under protection of nitrogen, stirring at room temperature for 10-20min, preferably 15min to make ligand and copper salt fully coordinate, then 0.5mmol of brominated cyclic substrate is taken by a microliter needle and is dripped into the reaction solution, 1 equivalent of internal standard substance (dibromomethane) is added, the mixture is transferred into a low-temperature circulating stirrer at-78 ℃, the mixture is cooled for 10-15min, 1.5 equivalents of methyllithium reagent is diluted to 1ml by anhydrous toluene (other organic lithium reagents are diluted by normal hexane), dropwise adding the mixture into the reaction solution within 2 hours, continuing to react for 1 hour after the dropwise adding is finished, slowly dropwise adding 1M dilute hydrochloric acid to quench after the reaction is finished, and measuring the separation yield and the ee value.

The ee value is measured by performing epoxy derivatization on the purified product, then testing the ee value by using a gas-phase chiral column, exemplarily separating and purifying the product by column chromatography, then oxidizing a double bond into epoxy by using disodium hydrogen phosphate and an oxidant m-chloroperoxybenzoic acid (m-CPBA), and measuring the ee value by using the gas-phase chiral column, except that 3-methyl-1-cyclohexene, 3-ethyl-1-cyclohexene and 6-bromo-1-phenylcyclohexene are directly measured by using the gas-phase chiral column.

Another embodiment of the invention provides a chiral compound prepared by the above copper-catalyzed asymmetric allylic alkylation reaction method.

Example 1

5 mol% of cuprous bromide dimethyl sulfide copper salt and 6 mol% of chiral ligand L2 are used as catalysts, a solvent is Dichloromethane (DCM), and asymmetric allylalkylation reaction is carried out on methyl lithium and 3-bromocyclohexene under the condition of the temperature of-78 ℃.

In this example, the enantioselectivity of the reaction was 97% and the nuclear magnetic yield was 99%.

Example 2

The difference from example 1 is that the nucleophile is ethyllithium and the product is

In this example, the enantioselectivity of the reaction was 94% and the nuclear magnetic yield was 99%.

Example 3

The difference from example 1 is that the nucleophile is butyllithium and the product is

In this example, the enantioselectivity of the reaction was 90% and the isolated yield was 82%.

Example 4

The difference from example 1 is that the nucleophile is lithium isobutyrate and the product is

In this example, the enantioselectivity of the reaction was 70% and the isolated yield was 74%.

Example 5

The difference from example 1 is that the nucleophile is trimethylsilyllithium, the product is

In this example, the enantioselectivity of the reaction was 80% and the isolated yield was 60%.

Example 6

The difference from example 1 is that the nucleophile is tert-butyllithium and the product is

In this example, the enantioselectivity of the reaction was 50% and the isolated yield was 76%.

Example 7

The difference from example 1 is that the nucleophile is hexyllithium and the product is

In this example, the enantioselectivity of the reaction was 80% and the isolated yield was 99%.

Example 8

The difference from example 1 is that the racemic substrate is 3-bromocycloheptene and the product is

In this example, the enantioselectivity of the reaction was 62% and the isolated yield was 92%.

Example 9

The difference from example 1 is that the racemic substrate is 6-bromo-1-phenylcyclohexene and the product is

In this example, the enantioselectivity of the reaction was 80% and the yield was 98%.

In the above examples, when the nucleophilic reagent is an organolithium reagent containing methyl and ethyl groups, the isolated yield is not obtained because the product is strongly volatile, whereas the nuclear magnetic yield is determined and the isolated yield is obtained in the case of the remaining organolithium reagents.

Although the present disclosure has been described above, the scope of the present disclosure is not limited thereto. Various changes and modifications may be effected therein by one of ordinary skill in the pertinent art without departing from the spirit and scope of the present disclosure, and these changes and modifications are intended to be within the scope of the present disclosure.