A method for preparing chiral secondary alcohol by alternating electrocatalytic asymmetric electrophilic cross-coupling reaction

Abstract

The application discloses a method for preparing chiral secondary alcohol through alternating current catalytic asymmetric electrophilic cross-coupling reaction. The method comprises the following steps: mixing azafused aryl triflate, aldehyde, electrolyte, nickel catalyst, ligand and sacrificial agent in a solvent in a protective atmosphere, and then carrying out asymmetric electrophilic cross-coupling reaction under alternating current condition, and then carrying out post-treatment to obtain the chiral secondary alcohol compound. The asymmetric cross-coupling reaction of azafused aryl triflate and aldehyde substrate is catalyzed by alternating current, and the asymmetric cross-coupling of various aryl (class) halides and aldehydes can be realized; the alternating current is used to improve the mass transfer efficiency, reduce the electrode corrosion and inhibit the reduction hydrogenation. In addition, the synthesis product can be used as a chiral ligand, and the practicability of the product in asymmetric catalysis is proved, and the product has wide development prospect. The electrochemical synthesis method has the characteristics of mild reaction condition, cleanness and greenness and simple reaction operation.

Description

Technical Field

[0001] This invention relates to the technical field of organic electrochemical synthesis, and more specifically, to a method for preparing chiral secondary alcohols by alternating current electrocatalytic asymmetric electrophilic cross-coupling reaction, the chiral secondary alcohols, and their applications. Background Technology

[0002] Organic electrosynthesis offers significant advantages in achieving redox transformations through precise tuning of applied current and electrode potential. The synergistic combination of electrochemistry and asymmetric catalysis is a key strategy for efficiently constructing high-value chiral molecules and has become a powerful tool for achieving high stereoselectivity under mild conditions. Furthermore, significant progress has been made in the synergistic effects of electrochemical systems with complementary stereocontrollers, such as electro-transition metal catalysis, electro-organocatalysis, and electro-biocatalysis. However, current research focuses on direct current electrolysis, where the persistently stable electrical double layer leads to the deposition of chiral metal catalysts and passivation or corrosion of the electrodes. Moreover, the spatial separation of the anode and cathode significantly hinders mass transfer, thus preventing the efficient diffusion of intermediates and the asymmetric induction process. For the nickel-catalyzed asymmetric reduction cross-coupling of nitrogen-heteroaryl trifluoromethanesulfonates and aldehyde substrates, the yield of the target alcohol is low under direct current electrolysis due to the dominant hydrogenation and self-coupling pathways. Therefore, the development of new electrochemical strategies to achieve precise asymmetric control remains urgent. Summary of the Invention

[0003] To address the problems in existing technologies, this invention proposes a method for preparing chiral secondary alcohols via AC electrocatalytic asymmetric electrophilic cross-coupling reaction, along with the chiral secondary alcohols and their applications. This invention successfully achieves asymmetric cross-coupling of various nitrogen-heteroaryl trifluoromethanesulfonates and aldehyde substrates via AC electrocatalysis, yielding the corresponding chiral secondary alcohol products. This method effectively suppresses the reductive hydrogenation of nitrogen-heteroaryl trifluoromethanesulfonates by periodically reversing electrode polarity, while also mitigating electrode corrosion and passivation. Furthermore, this electrochemical synthesis method features mild reaction conditions, clean and environmentally friendly operation, and simple reaction procedures.

[0004] One objective of this invention is to provide a method for preparing chiral secondary alcohols via an alternating current catalytic asymmetric electrophilic cross-coupling reaction, comprising the following steps: in a protective atmosphere, mixing nitrogen-heteroaryl trifluoromethanesulfonate, aldehyde, electrolyte, nickel catalyst, ligand and sacrificial agent in a solvent, followed by an asymmetric electrophilic cross-coupling reaction under alternating current conditions, and then post-processing to obtain the chiral secondary alcohol compound.

[0005] In a preferred embodiment, the nitrogen-heteroaryl trifluoromethanesulfonate has at least one of the compounds in the general formula shown in Formula 1 or Formula 2:

[0006] or ;

[0007] In Formula 1, R1 is hydrogen, a C1-C10 alkoxy group, or a C1-C10 alkyl group; R2 is hydrogen, a C1-C10 alkoxy group, a cyano group, or a C1-C10 ester group.

[0008] X1 and X2 are each halogen atoms independently, and X1 and X2 do not exist simultaneously;

[0009] In Formula 2, R1 is hydrogen, a C1-C10 alkyl group, or a C1-C10 haloalkyl group;

[0010] In Formulas 1 and 2, OTf represents trifluoromethanesulfonate group (CF3SO3). - );

[0011] Preferably,

[0012] In Formula 1, R1 is hydrogen, a C1-C5 alkoxy group, or a C1-C5 alkyl group; R2 is hydrogen, a C1-C5 alkoxy group, a cyano group, or a C1-C5 ester group; and / or,

[0013] X1 and X2 are each independently selected from chlorine or bromine; and / or,

[0014] In Formula 2, R1 is hydrogen, a C1-C5 alkyl group, or a C1-C5 haloalkyl group; and / or,

[0015] More preferably,

[0016] In Formula 1, R1 is hydrogen, a C1-C3 alkoxy group, or a C1-C3 alkyl group; R2 is hydrogen, a C1-C3 alkoxy group, a cyano group, or a C1-C3 ester group; and / or,

[0017] In Formula 2, R1 is hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; the halogen in the C1-C3 haloalkyl group is selected from fluorine.

[0018] As a preferred implementation method,

[0019] The nitrogen-heteroaryl trifluoromethanesulfonate corresponding to Formula 1 is selected from at least one of the following compounds:

[0020] .

[0021] As a preferred implementation method,

[0022] The nitrogen-heteroaryl trifluoromethanesulfonate corresponding to Formula 2 is selected from at least one of the following compounds:

[0023] .

[0024] In a preferred embodiment, the aldehyde has the following general structural formula:

[0025] In Equation 3, R3 is C1-C10 alkyl groups, C7-C20 benzoalkyl groups, C1-C10 halogen-substituted alkyl groups, and C7-C20 benzoenyl groups;

[0026] In this context, Ar represents phenyl, heteroaryl, or fused-ring aryl; R4 represents C1-C10 alkoxy, C1-C10 alkyl, phenyl, halogen atom, C7-C20 benzyloxy, C1-C10 haloalkyl, C1-C10 acyloxy, C1-C10 alkylthio, cyano, C2-C20 ester, or C1-C15 sulfonamide.

[0027] Preferably,

[0028] In Equation 3, R3 is C1-C5 alkyl groups, C7-C15 benzoalkyl groups, C1-C5 halogen-substituted alkyl groups, C7-C15 benzoenyl groups; and / or,

[0029] In this context, Ar represents phenyl, ; and / or,

[0030] R4 is a C1-C5 alkoxy group, a C1-C5 alkyl group, a phenyl group, a halogen atom, a C7-C15 benzyloxy group, a C1-C5 haloalkyl group, a C1-C5 acyloxy group, a C1-C5 alkylthio group, a C2-C15 ester group, or a C1-C10 sulfonamide group.

[0031] More preferably, the aldehyde corresponding to Formula 3 is selected from at least one of the following compounds:

[0032]

[0033] .

[0034] As a preferred implementation method,

[0035] The electrolyte is selected from at least one alkyl salt; preferably, the alkyl salt is selected from at least one tetraalkylammonium salt; more preferably, the tetraalkylammonium salt is selected from at least one tetrabutylammonium hexafluorophosphate, tetrabutylammonium bromide, tetrabutylammonium perchlorate, and tetrabutylammonium tetrafluoroborate; and / or,

[0036] Based on 100% of nitrogen-based aryltrifluoromethanesulfonate, the amount of electrolyte added is 50 mol% to 200 mol% (i.e., the molar ratio of the electrolyte to nitrogen-based aryltrifluoromethanesulfonate is (0.5~2):1); and / or,

[0037] The nickel catalyst is selected from at least one of ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, nickel chloride, nickel bromide, or nickel iodide; and / or,

[0038] Based on 100% nitrogen-based aryl trifluoromethanesulfonate, the amount of nickel catalyst added is 10 mol% to 15 mol%; and / or,

[0039] The ligand is selected from at least one of (S)-4-tert-butyl-2-(2-azaphenyl)oxazoline, (S)-4-(tert-butyl)-2-(isoquinoline-1-yl)-4,5-dihydrooxazol, and (S)-2-(4-isopropyl-4,5-dihydro-oxazol-2-yl)pyridine; and / or,

[0040] The amount of the ligand added is 15 mol% to 20 mol, based on 100% of nitrogen-based aryl trifluoromethanesulfonate.

[0041] As a preferred implementation method,

[0042] The sacrificial agent is selected from at least one of triethylamine, N,N-diisopropylethylamine, triethylenediamine, Hantzschester ester, and N,N-diethylmethylamine; and / or,

[0043] Based on 100% of nitrogen-based aryl trifluoromethanesulfonate, the amount of the sacrificial agent added is 100 mol% to 400 mol%; and / or,

[0044] The molar ratio of the aldehyde to the nitrogen-heteroaryl trifluoromethanesulfonate is (1.2~2):1; and / or,

[0045] The solvent is selected from at least one of amide solvents, nitrile solvents, and sulfoxide solvents; preferably, the solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethyl sulfoxide, and acetonitrile; and / or,

[0046] The concentration of the nitrogen-heteroaryl trifluoromethanesulfonate in the solvent is 0.015~0.4 mol / L.

[0047] As a preferred implementation method,

[0048] During the reaction, an alternating current is passed through, preferably...

[0049] The alternating current voltage is 1~5 V; and / or,

[0050] The alternating current frequency is 0.01~50 Hz; and / or,

[0051] The alternating current bias is -0.5 to 1.0 V; and / or,

[0052] The alternating current duty cycle is 10%~99%; and / or,

[0053] The energizing reaction time is 1~20 h; and / or,

[0054] The energized reaction temperature is 0~40℃; and / or,

[0055] More preferably, the alternating current voltage is 2~4 V; and / or,

[0056] The alternating current frequency is 0.5~10 Hz; and / or,

[0057] The alternating current bias is -0.5~0.5 V; and / or,

[0058] The alternating current duty cycle is 50%~75%; and / or,

[0059] The energizing reaction time is 3-8 hours; and / or,

[0060] The energized reaction temperature is 10~30℃; and / or,

[0061] In the reaction, the cathode material is selected from graphite felt, nickel foam, or platinum sheet; the anode material is selected from graphite felt, nickel foam, or platinum sheet; and / or,

[0062] The post-processing includes extraction and column chromatography.

[0063] A second objective of this invention is to prepare chiral secondary alcohols by means of a method according to one objective of this invention, wherein the chiral secondary alcohols have the following general structural formula:

[0064] or ;

[0065] In Formula 4, R1, R2, R3, X1, and X2 correspond to the same R1, R2, R3, X1, and X2 described in Formula 1, one of the objectives of this invention;

[0066] In Formula 5, R1 and R3 correspond to the same R1 and R3 as described in any one of Formula 2, which is one of the objectives of this invention;

[0067] Preferably, the chiral secondary alcohol is selected from the following compounds:

[0068] ;

[0069] ;

[0070] .

[0071] A third objective of this invention is to provide an application of a chiral secondary alcohol prepared by the method described in one objective of this invention, or a chiral secondary alcohol as described in another objective of this invention, as a ligand in the catalytic asymmetric addition reaction of diethylzinc with benzaldehyde; preferably, the method includes the following steps: adding a chiral secondary alcohol to a dry reaction tube under a protective atmosphere, followed by adding a solvent and an additive; cooling and stirring the reaction tube; subsequently, adding a hexane solution of diethylzinc and benzaldehyde dropwise in sequence, followed by post-treatment to obtain the product shown in Formula 6; ;

[0072] More preferably, the chiral secondary alcohol is selected from at least one of the following compounds:

[0073] ;

[0074] Cool the reaction tube to -78°C and stir for 15-20 minutes; and / or,

[0075] The concentration of the diethylzinc n-hexane solution is 1.0~1.5 mol / L; and / or,

[0076] The additive is selected from at least one of tetraisopropyl titanate, tetratert-butyl titanate, and titanium triisopropoxychloride; and / or

[0077] Based on 100% benzaldehyde, the amount of the additive added is 30 mol% to 70 mol%; and / or,

[0078] Based on 100% benzaldehyde, the amount of chiral secondary alcohol added is 10 mol%~30 mol%; and / or,

[0079] The molar ratio of diethylzinc to benzaldehyde is (1.2~2.5):1; and / or,

[0080] The solvent is selected from at least one of amide solvents, nitrile solvents, and ether solvents; preferably, the solvent is selected from at least one of N,N-dimethylformamide, acetonitrile, and tetrahydrofuran; and / or,

[0081] The concentration of benzaldehyde in the solvent is 0.1~0.2 mol / L; and / or,

[0082] The reaction time is 10-15 h; and / or,

[0083] The reaction temperature is -60 ~ -40 ℃; and / or,

[0084] The post-processing includes acidification, extraction, and column chromatography.

[0085] The reaction mechanism of this invention is as follows:

[0086] Ni(II) precatalyst A is electrochemically reduced to Ni(O) substance B. Nitrogen-heteroaryl trifluoromethanesulfonate oxidatively adds to B to give the diastereomeric Ni(II) complex C, which rapidly epimerizes. Complex C undergoes electrochemical single-electron reduction to generate Ni(I) intermediate D. The aldehyde coordinates with D and then undergoes asymmetric nucleophilic addition via transition state E to produce intermediate F. F is protonated to release the chiral alcohol product and regenerate the active Ni catalyst, completing the catalytic cycle.

[0087]

[0088] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values; these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. In the following, various technical solutions can, in principle, be combined with each other to obtain new technical solutions, which should also be considered as specifically disclosed herein.

[0089] The present invention has the following advantages:

[0090] This invention utilizes alternating current to effectively suppress the reductive hydrogenation of nitrogen-based aryl trifluoromethanesulfonate by periodically reversing electrode polarity, while also reducing electrode corrosion and passivation.

[0091] This invention enables selective electrolysis of reaction substrates by adjusting the parameters of the alternating current and the materials of the anode and cathode. It is applicable to both nitrogen-based heteroaryl trifluoromethanesulfonates with different substituents and aromatic aldehydes and alkyl aldehydes with different substituents, and is compatible with sensitive functional groups such as halogen atoms, ester groups, and cyano groups, obtaining chiral secondary alcohols with high yields and high enantiomeric selectivity.

[0092] In summary, this invention a) achieves asymmetric electrophilic cross-coupling using alternating current; b) improves mass transfer efficiency, reduces electrode corrosion and passivation, and inhibits reductive hydrogenation of substrates by using alternating current; c) has a broad substrate range, covering various nitrogen-based heteroaryl trifluoromethanesulfonates and aldehydes with different substituents, and exhibits good tolerance to sensitive functional groups; d) the chiral secondary alcohols prepared by this invention can be used as chiral ligands to catalyze asymmetric reactions, showing broad application prospects. Detailed Implementation

[0093] The present invention will now be described in detail with reference to specific embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the content of the present invention are still within the scope of protection of the present invention.

[0094] It should also be noted that the various specific technical features described in the following embodiments can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the various possible combinations will not be described separately in this invention.

[0095] Furthermore, various embodiments of the present invention can be combined in any way, as long as they do not violate the spirit of the present invention. The resulting technical solutions are part of the original disclosure of this specification and also fall within the protection scope of the present invention.

[0096] Unless otherwise specified, the raw materials used in the examples and comparative examples are all disclosed in the prior art, such as those that can be directly purchased or prepared according to the preparation methods disclosed in the prior art.

[0097] Example 1

[0098] A preferred embodiment of the present invention provides a method for preparing chiral secondary alcohols via an alternating current electrocatalytic asymmetric electrophilic cross-coupling reaction, the specific steps of which are as follows:

[0099] In an argon-filled glove box, Ni(DME)Br2 (10 mol% of aziridine trifluoromethanesulfonate) and ligand L5 (15 mol% of aziridine trifluoromethanesulfonate) were added to a dry 10 mL sample vial. Then, anhydrous DMF (6.0 mL) was added, and the mixture was stirred for at least 20 minutes. Subsequently, aziridine trifluoromethanesulfonate (0.1 mmol), aldehyde (0.2 mmol, 2.0 eq.), TBABF4 (0.2 mmol, 65.9 mg, 2.0 eq.), and DIPEA (0.2 mmol, 25.9 mg, 34.8 μL, 2.0 eq.) were added sequentially. The sample vial was sealed with a rubber stopper pre-loaded with graphite felt electrodes (anode and cathode, 15 mm × 10 mm × 3 mm). The two electrodes were connected to a titanium wire and separated by a Teflon membrane. A Teflon wire was attached to both electrodes. The reaction tube was removed from the glove box and electrolyzed for 5 h under AC signal A (frequency: 1.0 Hz, voltage: 2.5 V, bias: 0 V, duty cycle: 50%). After the reaction was complete, the reaction mixture was diluted with H2O (30 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (3 mL × 30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The desired product was obtained by rapid column chromatography purification. The enantiomeric excess (%, ee) of the corresponding product was determined by HPLC analysis using a chiral stationary phase.

[0100] The nitrogen-based aryl trifluoromethanesulfonate substrate in Example 1 is as follows:

[0101]

[0102] The aldehyde substrates in Example 1 are as follows:

[0103]

[0104]

[0105] The ligand L5 in Example 1 is as follows:

[0106] The results for the chiral secondary alcohols in Example 1 are as follows:

[0107]

[0108]

[0109] This method is applicable to benzaldehyde and its substituted derivatives with electron-donating or electron-withdrawing groups at the para, meta, and ortho positions (1–12, 15–18). Compatible functional groups include alkoxy (1, 9, 10, 17, 18), alkyl (3, 4), and phenyl (5). Substrates containing halogen substituents also exhibit good tolerance (6–8, 16). Notably, substrates containing sensitive functional groups such as acetoxy, methylthio, and ester (11–12, 15) also show high reaction efficiency. Multisubstituted benzaldehydes perform well as coupling partners (19–23). Heterocyclic benzaldehydes (containing N / O / S heterocycles) can also be successfully transformed, including naphthalene (24), thiophene (25), furan (26), pyridine (27), benzothiophene (28), quinoline (29), and indole (30) derivatives, to obtain chiral secondary alcohols in high yields. Aliphatic aldehydes (33–37) reacted smoothly with high enantioselectivity, while sterically hindered secondary aldehyde substrates (36, 37) provided the target product in moderate yields (44–57%) while maintaining high ee (95–96%). Furthermore, aryl aldehydes derived from natural products—geraniol (38), citronellol (39), menthol (40)—and the drug probenecid (41) underwent efficient asymmetric transformations with excellent yields and enantioselectivity (78–92%, 94–96%, respectively).

[0110] This method is also applicable to aziridine trifluoromethanesulfonates containing various substituents. Substrates with bromine, chlorine, alkyl, or alkoxy groups at the 3–, 4–, or 5– positions of the isoquinoline ring (42–45) can undergo efficient reductive coupling, yielding products in high yields and with enantioselectivity (75–88%, 91–95%). The method can also accommodate aziridine trifluoromethanesulfonates with 4- or 6-position substitution at the naphthyl group (46–50), providing the target chiral secondary alcohol in moderate to very high yields. Disubstituted aziridine trifluoromethanesulfonates have also been successfully converted (51). Pyridine derivatives (52–54) yield the target product in moderate to very good yields (67–89%) and considerable ee (85–96%).

[0111] Example 2

[0112] A preferred embodiment of the present invention provides a method for preparing chiral secondary alcohols via an alternating current electrocatalytic asymmetric electrophilic cross-coupling reaction, the specific steps of which are as follows:

[0113] In an argon-filled glove box, Ni(DME)Br2 (10 mol% of aziridine trifluoromethanesulfonate) and ligand L5 (15 mol% of aziridine trifluoromethanesulfonate) were added to a dry 10 mL sample vial. Then, anhydrous DMF (6.0 mL) was added, and the mixture was stirred for at least 20 minutes. Subsequently, aziridine trifluoromethanesulfonate (0.1 mmol), aldehyde (0.2 mmol, 2.0 eq.), TBABF4 (0.2 mmol, 65.9 mg, 2.0 eq.), and DIPEA (0.2 mmol, 25.9 mg, 34.8 μL, 2.0 eq.) were added sequentially. The sample vial was sealed with a rubber stopper pre-loaded with graphite felt electrodes (anode and cathode, 15 mm × 10 mm × 3 mm). The two electrodes were connected to a titanium wire and separated by a Teflon membrane. A Teflon wire was attached to both electrodes. The reaction tube was removed from the glove box and electrolyzed for 5 h under AC signal B (frequency: 2.0 Hz, voltage: 2.5 V, bias: 0.5 V, duty cycle: 75%). After the reaction was complete, the reaction mixture was diluted with H₂O (30 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (3 mL × 30 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The desired product was obtained by rapid column chromatography purification. The enantiomeric excess (%, ee) of the corresponding product was determined by HPLC analysis using a chiral stationary phase.

[0114] The aldehyde substrates in Example 2 are as follows:

[0115]

[0116] The ligand L5 in Example 2 is as follows:

[0117]

[0118] The results of the chiral secondary alcohols in Example 2 are as follows:

[0119]

[0120] This method is applicable to benzaldehyde (13–14) containing trifluoromethyl and cyano groups at the para position, and can also accommodate cinnamaldehyde and analogs (31, 32), yielding the corresponding products in good yields and with excellent ee.

[0121] Examples 3–17

[0122] The reaction conditions were changed, and the yields were compared.

[0123] Reaction conditions: In an argon-filled glove box, Ni(DME)Cl2 (10 mol% of aziridine trifluoromethanesulfonate) and ligand L1 (15 mol% of aziridine trifluoromethanesulfonate) were added to a dry 10 mL sample vial. Then, anhydrous DMF (6.0 mL) was added, and the mixture was stirred for at least 20 minutes. Subsequently, aziridine trifluoromethanesulfonate (0.1 mmol), aldehyde (0.2 mmol, 2.0 eq.), NaI (0.2 mmol, 29.9 mg, 2.0 eq.), and DIPEA (0.2 mmol, 25.9 mg, 34.8 μL, 2.0 eq.) were added sequentially. The sample vial was sealed with a rubber stopper pre-loaded with graphite felt electrodes (anode and cathode, 15 mm × 10 mm × 3 mm). The two electrodes were connected to a titanium wire and separated by a Teflon membrane. A Teflon wire was attached to both electrodes. The reaction tube was removed from the glove box and electrolyzed for 5 h under an AC signal (frequency: 0.5 Hz, voltage: 2.5 V, bias: 0 V, duty cycle: 50%).

[0124]

[0125] The changes in reaction conditions and their yields are shown in the table below:

[0126] Table 1

[0127] The yields in Table 1 above are the separation yields, and the ee values ​​were determined by HPLC analysis using a chiral stationary phase. The structures of the L2–L5 ligands mentioned in the table are as follows:

[0128]

[0129] As shown in Table 1 above, under the reaction conditions of this invention, the yield of the corresponding chiral secondary alcohol is as high as 85%, and the ee value is as high as 97%. A series of control experiments show that using Ni(DME)Cl2 or other nickel catalysts instead of Ni(DME)Br2 significantly reduces the yield. Using LiClO4 as the electrolyte does not yield good results. Increasing or decreasing the 2.5 V voltage leads to a decrease in yield, as does increasing or decreasing the 1.0 Hz frequency. Through screening chiral ligands, it was found that using the L5 ligand in this reaction yields the best yield and ee value.

[0130] The parameters of some of the products synthesized in this invention are as follows:

[0131]

[0132]

[0133]

[0134]

[0135] Product 12, Appearance: Colorless solid;

[0136]

[0137]

[0138]

[0139]

[0140]

[0141] Product 21, Appearance: Colorless solid;

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] Product 30, Appearance: Deep yellow oily liquid;

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158] Product 42, Appearance: Colorless solid;

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] Example 18

[0167] The chiral secondary alcohol prepared by this invention can be used as a ligand to catalyze an asymmetric reaction. Specifically, the prepared chiral secondary alcohol acts as a ligand to catalyze the asymmetric addition reaction between diethylzinc and aromatic aldehydes, and the reaction equation is as follows:

[0168]

[0169] Note: L=1 represents a chiral secondary alcohol compound with ligand number 1; L=19 represents a chiral secondary alcohol compound with ligand number 19; L=50 represents a chiral secondary alcohol compound with ligand number 50.

[0170] The specific steps are as follows:

[0171] In an argon-filled glove box, recrystallized ligand L (a chiral secondary alcohol product, 15 mol% of benzaldehyde) was added to a dry 10 mL reaction tube. Then anhydrous THF (4.0 mL) and Ti(O) were added. i Pr)4 (50 mol% of benzaldehyde). The reaction tube was cooled to -78°C and stirred for 15 min. Subsequently, ZnEt2 (2.1 equivalences, 1.0 M n-hexane solution) and freshly prepared benzaldehyde (0.5 mmol, 1.0 equivalences) were added dropwise. The mixture was heated to -50°C and stirred for 12 h. After the reaction was complete, the reaction mixture was diluted with HCl (1 M) and extracted with EtOAc (2 × 20 mL). The organic layers were combined and washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by column chromatography yielded the desired product. The enantiomeric excess (%, ee) of the corresponding product was determined by HPLC analysis using a chiral stationary phase.

[0172] Several recrystallization products successfully catalyzed the reaction, achieving yields as high as 58% and enantiomeric excess of 72% using compound 50 as a ligand. The use of chiral secondary alcohol products as ligands in this reaction expands the ligand library and has broad prospects for development and application.

[0173] The present invention has been described in detail above with reference to specific embodiments and exemplary examples; however, these descriptions should not be construed as limiting the present invention. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and embodiments of the present invention without departing from the spirit and scope of the invention, and all such modifications and improvements fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims.

[0174] All publications, patent applications, patents, and other references mentioned in this specification are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the art. In case of conflict, the definitions in this specification shall prevail.

[0175] When this specification uses the prefixes “known to those skilled in the art,” “prior art,” or similar terms to derive materials, substances, methods, steps, apparatus, or components, the objects derived from such prefixes cover those commonly used in the art at the time of this application, but also include those that are not currently commonly used but will become generally recognized in the art as suitable for similar purposes.

[0176] In the context of this specification, except where expressly stated otherwise, any matters or issues not mentioned shall apply directly to those known in the art without any modification.

Claims

1. A method for preparing chiral secondary alcohols via an alternating current electrocatalytic asymmetric electrophilic cross-coupling reaction, characterized in that, Includes the following steps: In a protective atmosphere, nitrogen-heteroaryl trifluoromethanesulfonate, aldehyde, electrolyte, nickel catalyst, ligand and sacrificial agent are mixed in a solvent and subjected to an asymmetric electrophilic cross-coupling reaction under alternating current conditions. After post-treatment, the chiral secondary alcohol compound is obtained.

2. The method according to claim 1, characterized in that: The nitrogen-heteroaryl trifluoromethanesulfonate has at least one of the compounds in the general formula shown in Formula 1 or Formula 2: or ; In Formula 1, R1 is hydrogen, a C1-C10 alkoxy group, or a C1-C10 alkyl group; R2 is hydrogen, a C1-C10 alkoxy group, a cyano group, or a C1-C10 ester group. X1 and X2 are each halogen atoms independently, and X1 and X2 do not exist simultaneously; In Formula 2, R1 is hydrogen, a C1-C10 alkyl group, or a C1-C10 haloalkyl group; In Formulas 1 and 2, OTf represents a trifluoromethanesulfonate group; Preferably, In Formula 1, R1 is hydrogen, a C1-C5 alkoxy group, or a C1-C5 alkyl group; R2 is hydrogen, a C1-C5 alkoxy group, a cyano group, or a C1-C5 ester group; and / or, X1 and X2 are each independently selected from chlorine or bromine; and / or, In Formula 2, R1 is hydrogen, a C1-C5 alkyl group, or a C1-C5 haloalkyl group; and / or, More preferably, In Formula 1, R1 is hydrogen, a C1-C3 alkoxy group, or a C1-C3 alkyl group; R2 is hydrogen, a C1-C3 alkoxy group, a cyano group, or a C1-C3 ester group; and / or, In Formula 2, R1 is hydrogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group; the halogen in the C1-C3 haloalkyl group is selected from fluorine.

3. The method according to claim 1 or 2, characterized in that: The nitrogen-heteroaryl trifluoromethanesulfonate corresponding to Formula 1 is selected from at least one of the following compounds: 。 4. The method according to claim 1 or 2, characterized in that: The nitrogen-heteroaryl trifluoromethanesulfonate corresponding to Formula 2 is selected from at least one of the following compounds: 。 5. The method according to claim 1, characterized in that: The aldehyde has the following general structural formula: ; In Equation 3, R3 is C1-C10 alkyl groups, C7-C20 benzoalkyl groups, C1-C10 halogen-substituted alkyl groups, and C7-C20 benzoenyl groups; In this context, Ar represents phenyl, heteroaryl, or fused-ring aryl; R4 represents C1-C10 alkoxy, C1-C10 alkyl, phenyl, halogen atom, C7-C20 benzyloxy, C1-C10 haloalkyl, C1-C10 acyloxy, C1-C10 alkylthio, cyano, C2-C20 ester, or C1-C15 sulfonamide. Preferably, In Equation 3, R3 is C1-C5 alkyl groups, C7-C15 benzoalkyl groups, C1-C5 halogen-substituted alkyl groups, C7-C15 benzoenyl groups; and / or, In this context, Ar represents phenyl, ; and / or, R4 is a C1-C5 alkoxy group, a C1-C5 alkyl group, a phenyl group, a halogen atom, a C7-C15 benzyloxy group, a C1-C5 haloalkyl group, a C1-C5 acyloxy group, a C1-C5 alkylthio group, a C2-C15 ester group, or a C1-C10 sulfonamide group. More preferably, the aldehyde corresponding to Formula 3 is selected from at least one of the following compounds: 。 6. The method according to claim 1, characterized in that: The electrolyte is selected from at least one alkyl salt; preferably, the alkyl salt is selected from at least one tetraalkylammonium salt; more preferably, the tetraalkylammonium salt is selected from at least one tetrabutylammonium hexafluorophosphate, tetrabutylammonium bromide, tetrabutylammonium perchlorate, and tetrabutylammonium tetrafluoroborate; and / or, Based on 100% nitrogen-based aryl trifluoromethanesulfonate, the amount of electrolyte added is 50 mol% to 200 mol%; and / or, The nickel catalyst is selected from at least one of ethylene glycol dimethyl ether nickel bromide, ethylene glycol dimethyl ether nickel chloride, nickel chloride, nickel bromide, or nickel iodide; and / or, Based on 100% nitrogen-based aryl trifluoromethanesulfonate, the amount of nickel catalyst added is 10 mol% to 15 mol%; and / or, The ligand is selected from at least one of (S)-4-tert-butyl-2-(2-azaphenyl)oxazoline, (S)-4-(tert-butyl)-2-(isoquinolin-1-yl)-4,5-dihydrooxazol, and (S)-2-(4-isopropyl-4,5-dihydro-oxazol-2-yl)pyridine; and / or, The amount of the ligand added is 15 mol% to 20 mol, based on 100% of nitrogen-based aryl trifluoromethanesulfonate.

7. The method according to claim 1, characterized in that: The sacrificial agent is selected from at least one of triethylamine, N,N-diisopropylethylamine, triethylenediamine, hesperidin, and N,N-diethylmethylamine; and / or, Based on 100% of nitrogen-based aryl trifluoromethanesulfonate, the amount of the sacrificial agent added is 100 mol% to 400 mol%; and / or, The molar ratio of the aldehyde to the nitrogen-heteroaryl trifluoromethanesulfonate is (1.2~2):1; and / or, The solvent is selected from at least one of amide solvents, nitrile solvents, and sulfoxide solvents; preferably, the solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethyl sulfoxide, and acetonitrile; and / or, The concentration of the nitrogen-heteroaryl trifluoromethanesulfonate in the solvent is 0.015~0.4 mol / L.

8. The method according to claim 1, characterized in that: During the reaction, an alternating current is passed through, preferably... The alternating current voltage is 1~5 V; and / or, The alternating current frequency is 0.01~50 Hz; and / or, The alternating current bias is -0.5 to 1.0 V; and / or, The alternating current duty cycle is 10%~99%; and / or, The energizing reaction time is 1~20 h; and / or, The energized reaction temperature is 0~40℃; and / or, More preferably, the alternating current voltage is 2~4 V; and / or, The alternating current frequency is 0.5~10 Hz; and / or, The alternating current bias is -0.5~0.5 V; and / or, The alternating current duty cycle is 50%~75%; and / or, The energizing reaction time is 3-8 hours; and / or, The energized reaction temperature is 10~30℃; and / or, In the reaction, the cathode material is selected from graphite felt, nickel foam, or platinum sheet; the anode material is selected from graphite felt, nickel foam, or platinum sheet; and / or, The post-processing includes extraction and column chromatography.

9. The chiral secondary alcohol prepared by the method according to any one of claims 1–8, characterized in that: The chiral secondary alcohol has the following general structural formula: or ; In Formula 4, R1, R2, R3, X1, X2 correspond to the same R1, R2, R3, X1, X2 as in any one of Formula 1 in claims 1-7; In Formula 5, R1 and R3 correspond to the same R1 and R3 as in any one of Formula 2 of claims 1-7; Preferably, the chiral secondary alcohol is selected from the following compounds: ； ； 。 10. The application of a chiral secondary alcohol prepared by the method of any one of claims 1-8 or the chiral secondary alcohol as described in claim 9 as a ligand in catalyzing the asymmetric addition reaction of diethylzinc with benzaldehyde; preferably, comprising the following steps: In a protective atmosphere, a chiral secondary alcohol was added to a dry reaction tube, followed by a solvent and an additive; the reaction tube was cooled and stirred; then, a hexane solution of diethylzinc and benzaldehyde were added dropwise in sequence, followed by reaction and post-treatment to obtain the product shown in Formula 6. ； More preferably, the chiral secondary alcohol is selected from at least one of the following compounds: ； Cool the reaction tube to -78°C and stir for 15-20 minutes; and / or, The concentration of the diethylzinc n-hexane solution is 1.0~1.5 mol / L; and / or, The additive is selected from at least one of tetraisopropyl titanate, tetratert-butyl titanate, and titanium triisopropoxychloride; and / or Based on 100% benzaldehyde, the amount of the additive added is 30 mol% to 70 mol%; and / or, Based on 100% benzaldehyde, the amount of chiral secondary alcohol added is 10 mol%~30 mol%; and / or, The molar ratio of diethylzinc to benzaldehyde is (1.2~2.5):1; and / or, The solvent is selected from at least one of amide solvents, nitrile solvents, and ether solvents; preferably, the solvent is selected from at least one of N,N-dimethylformamide, acetonitrile, and tetrahydrofuran; and / or, The concentration of benzaldehyde in the solvent is 0.1~0.2 mol / L; and / or, The reaction time is 10-15 h; and / or, The reaction temperature is -60 ~ -40 ℃; and / or, The post-processing includes acidification, extraction, and column chromatography.

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