Chiral alpha-aryl alkyne compound and synthesis method thereof

Abstract

The invention relates to the technical field of organic chemical synthesis, and discloses a chiral alpha-aryl alkyne compound and a synthesis method thereof. The compound has the following structure: # imgabs0 #, R1 is H, Cl or MeO, R2 is H, F, Cl, CF3, CO2Me, Ac or Bpin, and Alkyl is alkyl or an alkyl substituent with a functional group. The preparation method of the chiral alpha-aryl alkyne compound provided by the invention is simple, the raw material source is wide, the reaction condition is mild, and the product is easy to separate and purify.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a chiral α-aryl acetylene compound and a synthesis method thereof. Background Art

[0002] The chiral carbon center structure containing propargyl has special structural characteristics and metabolic properties, and is widely present in various natural products or active pharmaceutical molecules, such as the special anti-AIDS drug Efavirenz, Staphylococcus aureus antibiotics (PLA inhibitor) and blood sugar regulating drugs (GPR40 agonist and GPR40 Activator). In addition, the alkynyl triple bond is an important active functional group in organic synthesis and can undergo a variety of subsequent transformations. Therefore, the asymmetric synthesis method of the propargyl chiral center has always been the object of research and development by organic chemists.

[0003] In the past few decades, the construction of propargyl C(sp3)-C(sp2) bonds by transition metal asymmetric catalysis has become one of the most effective methods for synthesizing chiral α-aryl acetylenes. Among them, the nickel-catalyzed enantioconvergent redox-neutral cross-coupling reaction has developed rapidly. However, the limitation of this traditional coupling strategy is that it requires the pre-preparation of organometallic reagents. On the one hand, the additional pre-activation step does not conform to the principle of atom economy; on the other hand, the extremely sensitive properties of organometallic reagents are not conducive to their industrial application. Therefore, it is urgent to develop a coupling reaction with readily available raw materials and mild conditions to synthesize chiral α-aryl acetylenes.

[0004] Alcohol compounds are widely present in nature, and their quantity is second only to amine compounds in commercially available chemical raw materials. Using free alcohol as substrate, constructing CC bonds through direct activation of carbon-oxygen bonds is a very attractive research field. However, the carbon-oxygen bonds in alcohols have high dissociation energy, which greatly limits the direct application of free alcohols in coupling reactions.

[0005] In 2021, the MacMillan group (reference DOI number: org / 10.1038 / s41586-021-03920-6) achieved the deoxyarylation of alkyl alcohols by in situ activation of the carbon-oxygen bond with NHC (N-arylbenzoxazolium salts), which has good versatility for primary, secondary and tertiary alcohols. This scheme provides a good strategy for the direct dehydroxylation functionalization of alcohol compounds.

[0006] Based on the above background, the present invention uses propargyl alcohol as a coupling reagent, directly cuts the carbon-oxygen bond with the help of NHC activation strategy, and realizes the stereoselective deoxygenation reduction coupling reaction of propargyl alcohol and aryl bromide through photo-nickel synergistic catalysis, providing an efficient and convenient method for synthesizing chiral α-aryl acetylenic compounds with diverse structures. Summary of the invention

[0007] The purpose of the present invention is to provide a chiral α-aryl acetylene compound and a synthesis method thereof based on the above technical problem.

[0008] In order to achieve the above object, the first aspect of the present invention provides a chiral α-aryl acetylene compound having the structure shown below:

[0009] Among them, R 1 is H, Cl or MeO, R 2 It is H, F, Cl, CF3, CO2Me, Ac or Bpin, and Alkyl is an alkyl group or an alkyl substituent having a functional group.

[0010] Preferably, the Alkyl is ethyl, isobutyl, n-hexyl or an alkyl substituent with a functional group, wherein the functional group is Ph, Cl, OMe, CO2Me, OPh, CF3 or OTBS.

[0011] The second aspect of the present invention provides a method for preparing the chiral α-aryl acetylenic compound according to the first aspect of the present invention, the method comprising the following steps:

[0012] (1) In the presence of THF, compound I, a hexane solution of n-butyl lithium, and an electrophilic reagent are subjected to a first reaction. After the reaction is completed, the reaction is quenched with a saturated NH4Cl solution, and then extracted with ethyl acetate. The organic phase is collected, dried with Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain compound II with a purity of >97% in the form of a colorless transparent liquid;

[0013] (2) In a glove box, under sealed conditions, NiBr2·DME, ligand, Ir[dF(CF3)(ppy]2(dtbbpy)PF6, and anhydrous 1,4-dioxane are first stirred to obtain solution I; compound II, NHC, and anhydrous methyl tert-butyl ether are second stirred, and pyridine is added dropwise, and third stirred to obtain a suspension, which is filtered to obtain solution II;

[0014] (3) In a glove box, aryl bromide, quinuclidine and N,N'-dimethylacetamide are mixed, and then injected into the solution I and the solution II, sealed, and transferred to an EtOH cooling bath at a temperature of 15°C for a fourth stirring, irradiated with a blue LED light, and a second reaction is carried out. After the reaction is completed, the silica gel column is filtered, the filtrate is taken, and the vial III, the bottle cap, and the silica gel column are rinsed with ethyl acetate, the eluent and the filtrate are combined, concentrated, and the concentrate is taken. Separation and purification on a silica gel column to obtain a chiral α-aryl acetylene compound.

[0015] Preferably, in step (1), the compound I has the structure shown below:

[0016] Among them, R 1 The definitions are the same as those described in the first aspect of the present invention.

[0017] Further preferably, in step (1), relative to 20 mmol of the compound I, the amount of THF used is 80 mL.

[0018] Preferably, in step (1), the amount of the hexane solution of n-butyl lithium used is 22 mmol relative to 20 mmol of the compound I.

[0019] More preferably, in step (1), the electrophilic reagent is n-propionaldehyde or 3-(tert-butyldimethylsilyloxy)propionaldehyde, and the amount of the electrophilic reagent used is 30 mmol relative to 20 mmol of the compound I.

[0020] Preferably, in step (1), the first reaction is to first add the compound I and THF, and cool the THF to -78°C, then slowly add the hexane solution of n-butyl lithium, and stir for 30 to 60 minutes while maintaining the temperature at -78°C, and then slowly add the electrophilic reagent, and stir for 30 to 120 minutes while maintaining the temperature at -78°C.

[0021] Preferably, in step (2), the ligand has the structure shown below:

[0022]

[0023] Preferably, in step (2), the compound II has the structure shown below:

[0024] Among them, R 1 The definition of is the same as that in the first aspect of the present invention, and the definition of Alkyl is the same as that in the first aspect of the present invention.

[0025] Further preferably, in step (3), the aryl bromide has the structure shown below:

[0026] Among them, R 2 The definitions are the same as those described in the first aspect of the present invention.

[0027] Preferably, relative to 0.5 mmol of aryl bromide, the amount of NiBr2·DME used is 0.025 mmol.

[0028] More preferably, the amount of the ligand used is 0.03 mmol relative to 0.5 mmol of aryl bromide.

[0029] Preferably, the amount of Ir[dF(CF3)ppy]2(dtbbpy)PF6 used is 0.0075 mmol relative to 0.5 mmol of aryl bromide.

[0030] More preferably, the amount of anhydrous 1,4-dioxane used is 3.0 mL relative to 0.5 mmol of aryl bromide.

[0031] Preferably, relative to 0.5 mmol of aryl bromide, the amount of the compound II used is 0.8 mmol.

[0032] Preferably, the amount of NHC used is 0.8 mmol relative to 0.5 mmol of aryl bromide.

[0033] Preferably, the volume ratio of the anhydrous methyl tert-butyl ether to the anhydrous 1,4-dioxane is 1:1.5.

[0034] Preferably, the amount of pyridine used is 0.8 mmol relative to 0.5 mmol of aryl bromide.

[0035] Preferably, in step (3), the aryl bromide is p-bromotrifluorotoluene or m-bromoacetophenone.

[0036] More preferably, in step (3), the amount of quinuclidine used is 0.75 mmol relative to 0.5 mmol of aryl bromide.

[0037] Preferably, in step (3), the amount of N,N'-dimethylacetamide used is 0.5 mmol relative to 0.5 mmol of aryl bromide.

[0038] Preferably, in step (3), the amount of the solution I used is 3.0 mL relative to 0.5 mmol of aryl bromide, and the volume ratio of the solution I to the solution II is 1.5:1.

[0039] Preferably, in step (3), the conditions of the second reaction at least meet the following requirements: the reaction is carried out under irradiation of a blue LED light, at a temperature of 15° C., and for 20 h.

[0040] The third aspect of the present invention provides a chiral α-aryl alkyne compound prepared by the method described in the second aspect of the present invention.

[0041] The preparation method of the chiral α-aryl acetylene compound provided by the invention is simple, has a wide source of raw materials, mild reaction conditions, and the product is easy to separate and purify. DETAILED DESCRIPTION

[0042] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0043] In the present invention, "Bpin" represents a boric acid pinacol ester group.

[0044] As mentioned above, the first aspect of the present invention provides a chiral α-aryl acetylene compound having the structure shown below:

[0045] Among them, R 1 is H, Cl or MeO, R 2 It is H, F, Cl, CF3, CO2Me, Ac or Bpin, and Alkyl is an alkyl group or an alkyl substituent having a functional group.

[0046] Preferably, the Alkyl is ethyl, isobutyl, n-hexyl or an alkyl substituent with a functional group, wherein the functional group is Ph, Cl, OMe, CO2Me, OPh, CF3 or OTBS.

[0047] As mentioned above, the second aspect of the present invention provides a method for preparing the chiral α-aryl acetylenic compound as described in the first aspect of the present invention, the method comprising the following steps:

[0048] (1) In the presence of THF, compound I, a hexane solution of n-butyl lithium, and an electrophilic reagent are subjected to a first reaction. After the reaction is completed, the reaction is quenched with a saturated NH4Cl solution, and then extracted with ethyl acetate. The organic phase is collected, dried with Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain compound II with a purity of >97% in the form of a colorless transparent liquid;

[0049] (2) In a glove box, under sealed conditions, NiBr2·DME, ligand, Ir[dF(CF3)(ppy]2(dtbbpy)PF6, and anhydrous 1,4-dioxane are first stirred to obtain solution I; compound II, NHC, and anhydrous methyl tert-butyl ether are second stirred, and pyridine is added dropwise, and third stirred to obtain a suspension, which is filtered to obtain solution II;

[0050] (3) In a glove box, aryl bromide, quinuclidine and N,N'-dimethylacetamide are mixed, and then injected into the solution I and the solution II, sealed, and transferred to an EtOH cooling bath at a temperature of 15°C for a fourth stirring, irradiated with a blue LED light, and a second reaction is carried out. After the reaction is completed, the silica gel column is filtered, the filtrate is taken, and the vial III, the bottle cap, and the silica gel column are rinsed with ethyl acetate, the eluent and the filtrate are combined, concentrated, and the concentrate is taken. Separation and purification on a silica gel column to obtain a chiral α-aryl acetylene compound.

[0051] According to a particularly preferred embodiment, the method for preparing the chiral α-aryl acetylenic compound comprises the following steps:

[0052] (1) Take a round-bottom flask with a magnetic stirring bar, seal it with a rubber stopper, and use a double-row tube to evacuate and vent it three times to replace the atmosphere in the round-bottom flask with nitrogen, then add compound I and THF, and cool THF to -78°C, slowly add a hexane solution of n-butyl lithium, and stir for 30 minutes while keeping the temperature at -78°C, then slowly add an electrophilic reagent, and stir for 30 minutes while keeping the temperature at -78°C. After the reaction is completed, quench the reaction with a saturated NH4Cl solution, extract with ethyl acetate, collect the organic phase, dry it with Na2SO4, filter, and concentrate, and purify the residue by silica gel column chromatography to obtain compound II with a purity of >97% and a colorless transparent liquid.

[0053] (2) In a glove box, NiBr2·DME, ligand, and Ir[dF(CF3)ppy]2(dtbbpy)PF6 were added to a vial I equipped with a stirring bar, and anhydrous 1,4-dioxane was added. The cap of the vial I was sealed and stirred at room temperature for 30 min to obtain a slightly red solution, which was recorded as solution I.

[0054] The compound II and NHC were added to vial II, and then anhydrous methyl tert-butyl ether was added, and the mixture was stirred at room temperature for 5 min. Then, pyridine was slowly added dropwise and stirred at room temperature for 30 min. During this period, a white solid was precipitated to obtain a suspension. The suspension was filtered and a uniform red solution was taken, which was recorded as solution II.

[0055] (3) In a glove box, aryl bromide, quinuclidine and N,N'-dimethylacetamide are added to vial III, and then the solution I and the solution II are added to the vial III with a syringe, the cap of the vial III is sealed, and the vial is transferred to a 15°C EtOH cooling bath and stirred for 5 minutes, and then irradiated with a blue LED light, and stirred for 24 hours at 15°C under the irradiation condition, filtered through a silica gel column, and the filtrate is taken, and the vial III, the cap and the silica gel column are rinsed with ethyl acetate, the eluent and the filtrate are combined, concentrated, and the concentrate is separated and purified on a silica gel column, wherein the eluent is ethyl acetate and petroleum ether in a volume ratio of 1:20, to obtain a chiral α-aryl acetylene compound.

[0056] Preferably, in step (1), the compound I has the structure shown below:

[0057] Among them, R 1 The definitions are the same as those described in the first aspect of the present invention.

[0058] Further preferably, in step (1), relative to 20 mmol of the compound I, the amount of THF used is 80 mL.

[0059] Preferably, in step (1), the amount of the hexane solution of n-butyl lithium used is 22 mmol relative to 20 mmol of the compound I.

[0060] More preferably, in step (1), the electrophilic reagent is n-propionaldehyde or 3-(tert-butyldimethylsilyloxy)propionaldehyde, and the amount of the electrophilic reagent used is 30 mmol relative to 20 mmol of the compound I.

[0061] Preferably, in step (1), the first reaction is to first add the compound I and THF, and cool the THF to -78°C, then slowly add the hexane solution of n-butyl lithium, and stir for 30 to 60 minutes while maintaining the temperature at -78°C, and then slowly add the electrophilic reagent, and stir for 30 to 120 minutes while maintaining the temperature at -78°C.

[0062] Preferably, in step (2), the ligand has the structure shown below:

[0063]

[0064] Preferably, in step (2), the compound II has the structure shown below:

[0065] Among them, R 1The definition of is the same as that in the first aspect of the present invention, and the definition of Alkyl is the same as that in the first aspect of the present invention.

[0066] Further preferably, in step (3), the aryl bromide has the structure shown below:

[0067] Among them, R 2 The definitions are the same as those described in the first aspect of the present invention.

[0068] Preferably, relative to 0.5 mmol of aryl bromide, the amount of NiBr2·DME used is 0.025 mmol.

[0069] More preferably, the amount of the ligand used is 0.03 mmol relative to 0.5 mmol of aryl bromide.

[0070] Preferably, the amount of Ir[dF(CF3)ppy]2(dtbbpy)PF6 used is 0.0075 mmol relative to 0.5 mmol of aryl bromide.

[0071] More preferably, the amount of anhydrous 1,4-dioxane used is 3.0 mL relative to 0.5 mmol of aryl bromide.

[0072] Preferably, relative to 0.5 mmol of aryl bromide, the amount of the compound II used is 0.8 mmol.

[0073] Preferably, the amount of NHC used is 0.8 mmol relative to 0.5 mmol of aryl bromide.

[0074] Preferably, the volume ratio of the anhydrous methyl tert-butyl ether to the anhydrous 1,4-dioxane is 1:1.5.

[0075] Preferably, the amount of pyridine used is 0.8 mmol relative to 0.5 mmol of aryl bromide.

[0076] Preferably, in step (3), the aryl bromide is p-bromotrifluorotoluene or m-bromoacetophenone.

[0077] More preferably, in step (3), the amount of quinuclidine used is 0.75 mmol relative to 0.5 mmol of aryl bromide.

[0078] Preferably, in step (3), the amount of N,N'-dimethylacetamide used is 0.5 mmol relative to 0.5 mmol of aryl bromide.

[0079] Preferably, in step (3), the amount of the solution I used is 3.0 mL relative to 0.5 mmol of aryl bromide, and the volume ratio of the solution I to the solution II is 1.5:1.

[0080] Preferably, in step (3), the conditions of the second reaction at least meet the following requirements: the reaction is carried out under irradiation of a blue LED light, at a temperature of 15° C., and for 20 h.

[0081] The third aspect of the present invention provides a chiral α-aryl acetylene compound prepared by the method described in the second aspect of the present invention.

[0082] The present invention will be described in detail below by way of examples. In the following examples, unless otherwise specified, the raw materials are all commercially available.

[0083] In the following examples, unless otherwise specified, the yield of the chiral α-aryl acetylenic compounds is obtained by nuclear magnetic resonance spectrometer results, and the model of the nuclear magnetic resonance spectrometer is Bruker 400 MHz.

[0084] In the following examples, unless otherwise specified, the room temperature is 25±2°C.

[0085] As mentioned above, in step (1), the compound I has the following structure:

[0086]

[0087] In the following examples, in the compound I, when R 1 is H, the compound I is denoted as 1a; when R 1 is MeO, and the compound I is recorded as 1b.

[0088] As mentioned above, in step (2), the compound II has the following structure:

[0089]

[0090] In the following examples, in the compound II, when R 1 is H, Alkyl is Et, and the compound II is denoted as 2a; when R 1 is H, Alkyl is CH2CH2OTBS, and the compound II is denoted as 2b; when R 1 is OMe, Alkyl is Et, and the compound II is recorded as 2c.

[0091] Example 1

[0092]

[0093] (1) Take a 250 mL round-bottom flask with a magnetic stirring bar, seal it with a rubber stopper, and use a double-row tube to evacuate and vent it three times to replace the atmosphere in the round-bottom flask with nitrogen. Then add 20 mmol 1a (2.04 g) and 80 mL THF (0.25 mol / L), and cool the THF to -78°C. Slowly add 22 mmol n-butyl lithium hexane solution (8.8 mL), stir for 30 min while keeping the temperature at -78°C, then slowly add 30 mmol n-propanal (1.74 g), stir for 30 min while keeping the temperature at -78°C. After the reaction is completed, quench the reaction with saturated NH4Cl solution, extract with 50 mL ethyl acetate, collect the organic phase, dry with Na2SO4, filter, concentrate, and purify the residue by silica gel column chromatography to obtain a colorless transparent liquid with a purity of >97%, which is recorded as 2a.

[0094] (2) In a glove box, 0.025 mmol NiBr2·DME (7.8 mg), 0.030 mmol ligand (17.9 mg), and 0.0075 mmol Ir[dF(CF3)ppy]2(dtbbpy)PF6 (9.0 mg) were added to a vial I equipped with a stirring bar, and then 3.0 mL of anhydrous 1,4-dioxane was added. The cap of the vial I was sealed and stirred at room temperature for 30 min to obtain a slightly red solution, which was recorded as solution I.

[0095] 0.8 mmol 2a (128.0 mg) and 0.8 mmol NHC (316.5 mg) were added to vial II, and then 2.0 mL anhydrous methyl tert-butyl ether was added, and the mixture was stirred at room temperature for 5 min. Then 0.8 mmol pyridine (63.2 mg) was slowly added dropwise, and the mixture was stirred at room temperature for 30 min (during which a white solid was precipitated) to obtain a suspension, which was filtered to obtain a uniform red solution, which was recorded as solution II.

[0096] (3) In a glove box, 0.50 mmol of p-bromotrifluorotoluene (112.5 mg), 0.75 mmol of quinuclidine (83.5 mg) and 0.50 mmol of N,N'-dimethylacetamide (43.5 mg) were added to vial III, and then 3.0 mL of the solution I and 2.0 mL of the solution II were added to the vial III using a syringe. The cap of the vial III was sealed and the mixture was transferred to a 15°C EtOH cooling bath and stirred for 5 min. The mixture was then irradiated with a blue LED light and stirred for 24 h under irradiation conditions at 15°C. The mixture was filtered through a silica gel column and the filtrate was taken. The vial III, the cap and the silica gel column were rinsed with ethyl acetate. The eluent and the filtrate were combined and concentrated. The concentrate was separated and purified on a silica gel column (ethyl acetate and petroleum ether in a volume ratio of 1:20) to obtain a chiral α-aryl acetylene compound, which was designated as Alkyne-A.

[0097] Alkyne-A, yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ7.62 (d, J=8.2

[0098] Hz,2H),7.55(d,J=8.2Hz,2H),7.51-7.43(m,2H),7.36-7.27(m,3H),3.87(dd,J=7.7,6.2Hz,1H),1.96-1.83(m,2H),1.08(t,J=7.4Hz,3H); 13 C NMR (101MHz, Chloroform-d) δ146.1,131.6,129.1,128.3,128.0,127.9,125.4,124.5,123.5,90.3,84.0,39.8,31.5,11.7; 19 F NMR(376MHz,Chloroform-d)δ-62.4; HRMS(EI)calcd for C 18 H 15 F3[M] + :288.1126; Found: 288.1120; FT-IR (film): 2971, 2022, 1320, 1171, 1116, 1067, 1018, 845, 753, 690, 603, 537; [α] 26 D=-10.2(c 0.32, CHCl3); 91%ee, from (S)-L.

[0099] Example 2

[0100]

[0101] (1) Take a 250 mL round-bottom flask with a magnetic stirring bar, seal it with a rubber stopper, and use a double-row tube to evacuate and vent it three times to replace the atmosphere in the round-bottom flask with nitrogen. Then add 20 mmol 1a (2.04 g) and 80 mL THF (0.25 mol / L), and cool the THF to -78°C. Slowly add 22 mmol n-butyl lithium hexane solution (8.8 mL), stir for 30 min while keeping the temperature at -78°C, then slowly add 30 mmol n-propanal (1.74 g), stir for 1 h while keeping the temperature at -78°C. After the reaction is completed, quench the reaction with saturated NH4Cl solution, extract with 50 mL ethyl acetate, collect the organic phase, dry with Na2SO4, filter, concentrate, and purify the residue by silica gel column chromatography to obtain a colorless transparent liquid with a purity of >97%, which is recorded as 2a.

[0102] (2) In a glove box, 0.025 mmol NiBr2·DME (7.8 mg), 0.030 mmol ligand (17.9 mg), and 0.0075 mmol Ir[dF(CF3)ppy]2(dtbbpy)PF6 (9.0 mg) were added to a vial I equipped with a stirring bar, and then 3.0 mL of anhydrous 1,4-dioxane was added. The cap of the vial I was sealed and stirred at room temperature for 30 min to obtain a slightly red solution, which was recorded as solution I.

[0103] 0.8 mmol 2a (128.0 mg) and 0.8 mmol NHC (316.5 mg) were added to vial II, and then 2.0 mL anhydrous methyl tert-butyl ether was added, and the mixture was stirred at room temperature for 5 min. Then 0.8 mmol pyridine (63.2 mg) was slowly added dropwise, and the mixture was stirred at room temperature for 30 min (during which a white solid was precipitated) to obtain a suspension, which was filtered to obtain a uniform red solution, which was recorded as solution II.

[0104] (3) In a glove box, 0.50 mmol of m-bromoacetophenone (99.5 mg), 0.75 mmol of quinuclidine (83.5 mg) and 0.50 mmol of N,N'-dimethylacetamide (43.5 mg) were added to vial III, and then 3.0 mL of the solution I and 2.0 mL of the solution II were added to the vial III using a syringe. The cap of the vial III was sealed and the vial was transferred to a 15°C EtOH cooling bath and stirred for 5 min. The vial was then irradiated with a blue LED light and stirred for 24 h at 15°C. The vial was filtered through a silica gel column and the filtrate was taken. The vial III, the cap and the silica gel column were rinsed with ethyl acetate. The eluent and the filtrate were combined and concentrated. The concentrate was separated and purified on a silica gel column (ethyl acetate and petroleum ether in a volume ratio of 1:20) to obtain a chiral α-aryl acetylene compound, which was designated as Alkyne-B.

[0105] Alkyne-B, yellow liquid. 1 H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.85(d,J=7.8,1.4Hz,1H),7.66(d,J=7.7,1.5Hz,1H),7.50-7.41( m,3H),7.36-7.27(m,3H),3.87(dd,J=7.7,6.3Hz,1H),2.62(s,3H),1.94-1.84(m,2H),1.07(t,J=7.3Hz,3H); 13 C NMR(101MHz,Chloroform-d)δ198.1,142.7,137.4,132.3,131.6,128.7,128.2, 127.9,127.4,126.8,123.5,90.7,83.9,39.8,31.5,26.7,11.8; HRMS(ESI)calcd for C 19 H 19 O[M+H] + :263.1430; Found:263.1423; FT-IR(film):2969,2023,1681,1272,753,690,585;[α] 26 D =-5.9(c0.32,CHCl3);89%ee,from(S)-L.

[0106] Example 3

[0107]

[0108] (1) Take a 250 mL round-bottom flask with a magnetic stirring bar, seal it with a rubber stopper, and use a double-row tube to evacuate and vent it three times to replace the atmosphere in the round-bottom flask with nitrogen. Then add 20 mmol 1a (2.04 g) and 80 mL THF (0.25 mol / L), and cool the THF to -78°C. Slowly add 22 mmol n-butyl lithium hexane solution (8.8 mL), and stir for 30 min while keeping the temperature at -78°C. Then slowly add 30 mmol 3-(tert-butyldimethylsilyloxy)propanal (5.64 g), and stir for 2 h while keeping the temperature at -78°C. After the reaction is completed, quench the reaction with saturated NH4Cl solution, and then extract with 50 mL ethyl acetate. Collect the organic phase, dry it with Na2SO4, filter it, and concentrate it. Purify the residue by silica gel column chromatography to obtain a colorless transparent liquid with a purity of >97%, which is recorded as 2b.

[0109] (2) In a glove box, 0.025 mmol NiBr2·DME (7.8 mg), 0.030 mmol ligand (17.9 mg), and 0.0075 mmol Ir[dF(CF3)ppy]2(dtbbpy)PF6 (9.0 mg) were added to a vial I equipped with a stirring bar, and 3.0 mL of anhydrous 1,4-dioxane was added. The cap of the vial I was sealed and stirred at room temperature for 30 min to obtain a slightly red solution, which was recorded as solution I. 0.8 mmol 2b (232.0 mg) and 0.8 mmol NHC (316.5 mg) were added to a vial II, and 2.0 mL of anhydrous methyl tert-butyl ether was added. The mixture was stirred at room temperature for 5 min, and then 0.8 mmol pyridine (63.2 mg) was slowly added dropwise. The mixture was stirred at room temperature for 30 min (a white solid was precipitated during this period) to obtain a suspension. The suspension was filtered and a uniform red solution was taken, which was recorded as solution II.

[0110] (3) In a glove box, 0.50 mmol of p-bromotrifluorotoluene (112.5 mg), 0.75 mmol of quinuclidine (83.5 mg) and 0.50 mmol of N,N'-dimethylacetamide (43.5 mg) were added to vial III, and then 3.0 mL of the solution I and 2.0 mL of the solution II were added to the vial III using a syringe. The cap of the vial III was sealed and the mixture was transferred to a 15°C EtOH cooling bath and stirred for 5 min. The mixture was then irradiated with a blue LED light and stirred for 24 h at 15°C. The mixture was filtered through a silica gel column and the filtrate was taken. The vial III, the cap and the silica gel column were rinsed with ethyl acetate. The eluent and the filtrate were combined and concentrated. The concentrate was separated and purified on a silica gel column (ethyl acetate and petroleum ether in a volume ratio of 1:20) to obtain a chiral α-aryl acetylene compound, which was designated as Alkyne-C.

[0111] Alkyne-C, yellow liquid. 1 H NMR (400MHz, Chloroform-d) δ7.63 (d, J=8.2

[0112] Hz,2H),7.59(d,J=8.0Hz,2H),7.50-7.41(m,2H),7.35-7.30(m,3H),4.19(t,J=7.5Hz,1H),3. 96-3.89(m,1H),3.77-3.69(m,1H),2.09-2.00(m,2H),0.96(s,9H),0.13(s,3H),0.11(s,3H); 13 C NMR (101MHz, Chloroform-d) δ146.1,131.6,129.1,128.3,128.0,125.5,124.3,123.4,90.2,83.9,60.3,41.4,34.5,26.0,25.9,18.3,-5.3,-5.4; 19 F NMR(376MHz,Chloroform-d)δ-62.3; HRMS(EI)calcd for C 24 H 29 ClF3OSi[M] + :418.1940; Found: 418.1942; FT-IR (film): 2966, 2881, 1619, 1322, 1165, 1111, 1065, 1016, 841, 816, 744, 598, 472; [α] 26D =-7.5 (c 0.32, CHCl3); 91%ee, from (S)-L.

[0113] Example 4

[0114]

[0115] (1) Take a 250 mL round-bottom flask with a magnetic stirring bar, seal it with a rubber stopper, and use a double-row tube to evacuate and vent it three times to replace the atmosphere in the round-bottom flask with nitrogen. Then add 20 mmol 1b (2.64 g) and 80 mL THF (0.25 mol / L), and cool the THF to -78°C. Slowly add 22 mmol n-butyl lithium hexane solution (8.8 mL), stir for 1 h while keeping the temperature at -78°C, then slowly add 30 mmol n-propanal (1.74 g), stir for 2 h while keeping the temperature at -78°C. After the reaction is completed, quench the reaction with saturated NH4Cl solution, extract with 50 mL ethyl acetate, collect the organic phase, dry with Na2SO4, filter, concentrate, and purify the residue by silica gel column chromatography to obtain a colorless transparent liquid with a purity of >97%, which is recorded as 2c.

[0116] (2) In a glove box, 0.025 mmol NiBr2·DME (7.8 mg), 0.030 mmol ligand (17.9 mg), and 0.0075 mmol Ir[dF(CF3)ppy]2(dtbbpy)PF6 (9.0 mg) were added to a vial I equipped with a stirring bar, and 3.0 mL of anhydrous 1,4-dioxane was added. The cap of the vial I was sealed and stirred at room temperature for 30 min to obtain a slightly red solution, which was recorded as solution I. 0.8 mmol 2c (152.0 mg) and 0.8 mmol NHC (316.5 mg) were added to a vial II, and 2.0 mL of anhydrous methyl tert-butyl ether was added. The mixture was stirred at room temperature for 5 min, and then 0.8 mmol pyridine (63.2 mg) was slowly added dropwise. The mixture was stirred at room temperature for 30 min (a white solid was precipitated during this period) to obtain a suspension. The suspension was filtered and a uniform red solution was taken, which was recorded as solution II.

[0117] (3) In a glove box, 0.50 mmol of p-bromotrifluorotoluene (112.5 mg), 0.75 mmol of quinuclidine (83.5 mg) and 0.50 mmol of N,N'-dimethylacetamide (43.5 mg) were added to vial III, and then 3.0 mL of the solution I and 2.0 mL of the solution II were added to the vial III using a syringe. The cap of the vial III was sealed and the mixture was transferred to a 15°C EtOH cooling bath and stirred for 5 min. The mixture was then irradiated with a blue LED light and stirred for 24 h at 15°C. The mixture was filtered through a silica gel column and the filtrate was taken. The vial III, the cap and the silica gel column were rinsed with ethyl acetate. The eluent and the filtrate were combined and concentrated. The concentrate was separated and purified on a silica gel column (ethyl acetate and petroleum ether in a volume ratio of 1:20) to obtain a chiral α-aryl acetylene compound, which was designated as Alkyne-D.

[0118] Alkyne-D, yellow liquid. 1 H NMR(600MHz,Chloroform-d)δ7.51(d,J=7.8

[0119] Hz,2H),7.45(d,J=8.0Hz,2H),7.31(d,2H),6.76(d,2H),3.76(t,J=7.1Hz,1H),3.74-3.69(m,3H),1.84-1.71(m,2H),0.98(t,J=7.1Hz,3H); 13 C NMR (151MHz, Chloroform-d) δ159.4,146.3,133.0,128.9,127.9,125.3,124.3,115.6,113.9,88.7,83.8,55.2,39.8,31.5,11.7; 19 F NMR(376MHz,Chloroform-d)δ-62.4; HRMS(ESI)calcd for C 19 H 18 F3O[M+H] + :319.1304; Found: 319.1311; FT-IR(film):2963,1604,1510,1321,1243,1168,1109,1066,1017,827,531;[α] 26 D=-13.4 (c 0.32, CHCl3); 90%ee, from (S)-L.

[0120] Comparative Example 1

[0121] Chiral α-aryl acetylene compounds were prepared according to the method of Example 1, except that in step (2), in vial I, the anhydrous 1,4-dioxane was replaced by the same volume of 1,4-dioxane; in vial II, the anhydrous methyl tert-butyl ether was replaced by the same volume of 1,4-dioxane, and the remaining steps and parameters were the same as in Example 1.

[0122] The obtained chiral α-aryl acetylene compound is denoted as Alkyne-A-1 and is a yellow liquid.

[0123] Comparative Example 2

[0124] Chiral α-aryl acetylene compounds were prepared according to the method of Example 1, except that in step (2), 4-methylpyridine was used in the same molar ratio to replace the pyridine, and the remaining steps and parameters were the same as in Example 1.

[0125] The obtained chiral α-aryl alkyne compound is denoted as Alkyne-A-2 and is a yellow liquid.

[0126] Comparative Example 3

[0127] Chiral α-aryl acetylene compounds were prepared according to the method of Example 1, except that in step (3), sodium acetate was used in the same molar ratio to replace the quinuclidine, and the remaining steps and parameters were the same as in Example 1.

[0128] The obtained chiral α-aryl alkyne compound is denoted as Alkyne-A-3 and is a yellow liquid.

[0129] The yields of the chiral α-aryl acetylenes obtained in the above examples and comparative examples were calculated, and the results are shown in Table 1.

[0130] Table 1

[0131] Example No. Yield, % Example 1 80 Example 2 77 Example 3 71 Example 4 73 Comparative Example 1 56 Comparative Example 2 33 Comparative Example 3 4

[0132] It can be seen from the results in Table 1 that the chiral α-aryl acetylenic compounds prepared by the embodiments of the present invention have a higher yield.

[0133] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A chiral α-aryl acetylenic compound, characterized in that: This compound has the structure shown below: Among them, R 1 is H, Cl or MeO, R 2 It is H, F, Cl, CF3, CO2Me, Ac or Bpin, and Alkyl is an alkyl group or an alkyl substituent having a functional group.

2. The chiral α-aryl acetylenic compound according to claim 1, wherein The Alkyl is ethyl, isobutyl, n-hexyl or an alkyl substituent with a functional group, wherein the functional group is Ph, Cl, OMe, CO2Me, OPh, CF3 or OTBS.

3. A method for preparing a chiral α-aryl acetylenic compound as claimed in claim 1 or 2, characterized in that: The method comprises the following steps: (1) In the presence of THF, compound I, a hexane solution of n-butyl lithium, and an electrophilic reagent are subjected to a first reaction. After the reaction is completed, the reaction is quenched with a saturated NH4Cl solution, and then extracted with ethyl acetate. The organic phase is collected, dried with Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain compound II with a purity of >97% in the form of a colorless transparent liquid; (2) In a glove box, under sealed conditions, NiBr2·DME, ligand, Ir[dF(CF3)(ppy]2(dtbbpy)PF6, and anhydrous 1,4-dioxane are first stirred to obtain solution I; compound II, NHC, and anhydrous methyl tert-butyl ether are second stirred, and pyridine is added dropwise, and third stirred to obtain a suspension, which is filtered to obtain solution II; (3) In a glove box, aryl bromide, quinuclidine and N,N'-dimethylacetamide are mixed, and then injected into the solution I and the solution II, sealed, and transferred to an EtOH cooling bath at a temperature of 15°C for a fourth stirring, irradiated with a blue LED light, and a second reaction is carried out. After the reaction is completed, the silica gel column is filtered, the filtrate is taken, and the vial III, the bottle cap, and the silica gel column are rinsed with ethyl acetate, the eluent and the filtrate are combined, concentrated, and the concentrate is taken. It is separated and purified on a silica gel column to obtain a chiral α-aryl acetylene compound.

4. The method according to claim 3, wherein: In step (1), the compound I has the structure shown below: Among them, R 1 The definition is the same as that in claim 1.

5. The method according to claim 3 or 4, wherein: In step (1), the amount of THF used is 80 mL relative to 20 mmol of the compound I; and / or, in step (1), the amount of the hexane solution of n-butyl lithium used is 22 mmol relative to 20 mmol of the compound I; and / or, in step (1), the electrophilic reagent is n-propionaldehyde or 3-(tert-butyldimethylsilyloxy)propionaldehyde, and the amount of the electrophilic reagent used is 30 mmol relative to 20 mmol of the compound I; And / or, in step (1), the first reaction is to first add the compound I and THF, and cool the THF to -78°C, then slowly add the hexane solution of n-butyl lithium, and stir for 30 to 60 minutes while keeping the temperature at -78°C, and then slowly add the electrophilic reagent, and stir for 30 to 120 minutes while keeping the temperature at -78°C.

6. The method according to claim 3 or 4, wherein: In step (2), the ligand has the structure shown below: And / or, in step (2), the compound II has the structure shown below: Among them, R 1 The definition of is the same as that in claim 1 or 2, and the definition of Alkyl is the same as that in claim 1 or 2.

7. The method according to claim 3 or 4, wherein: In step (3), the aryl bromide has the structure shown below: Among them, R 2 The definition of is the same as that in claim 1; and / or, relative to 0.5 mmol of aryl bromide, the amount of NiBr2·DME used is 0.025 mmol; and / or, relative to 0.5 mmol of aryl bromide, the amount of the ligand used is 0.03 mmol; and / or, relative to 0.5 mmol of aryl bromide, the amount of Ir[dF(CF3)ppy]2(dtbbpy)PF6 used is 0.0075 mmol; and / or, relative to 0.5 mmol of aryl bromide, the amount of anhydrous 1,4-dioxane used is 3.0 mL; and / or, relative to 0.5 mmol of aryl bromide, the amount of the compound II is 0.8 mmol; and / or, relative to 0.5 mmol of aryl bromide, the amount of NHC used is 0.8 mmol; And / or, the volume ratio of the anhydrous methyl tert-butyl ether to the anhydrous 1,4-dioxane is 1:1.5; And / or, relative to 0.5 mmol of aryl bromide, the amount of pyridine used is 0.8 mmol.

8. The method according to claim 3 or 4, wherein: In step (3), the aryl bromide is p-bromotrifluorotoluene or m-bromoacetophenone; and / or, in step (3), the amount of quinuclidine used is 0.75 mmol relative to 0.5 mmol of aryl bromide; and / or, in step (3), the amount of N,N'-dimethylacetamide used is 0.5 mmol relative to 0.5 mmol of aryl bromide; And / or, in step (3), the amount of the solution I used is 3.0 mL relative to 0.5 mmol of aryl bromide, and the volume ratio of the solution I to the solution II is 1.5:

1.

9. The method according to claim 3 or 4, wherein: In step (3), the conditions of the second reaction at least meet the following requirements: being carried out under irradiation of a blue LED light, at a temperature of 15° C., and for a period of 20 h.

10. A chiral α-aryl alkyne compound prepared by the method according to any one of claims 3 to 9.

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