Method for constructing axially chiral 2-aryl indole derivative

Abstract

The invention discloses a method for constructing an axially chiral 2-aryl indole derivative. According to the method, a chiral secondary amine catalyst is combined with a triethylamine additive, so that asymmetric Friedel-Crafts reaction of acrolein and indole binaphthol compounds is realized, and catalytic asymmetric synthesis of a series of axially chiral 2-aryl indole structures is realized in a dynamic kinetic resolution form.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for constructing axial chiral 2-aryl indole derivatives by utilizing the principle of dynamic kinetic resolution. Background Art

[0002] Axially chiral biaryl compounds are the core structural groups of various biologically active natural products, functional materials, organic catalysts and chiral ligands. Among them, indole biaryl isomers are widely present in natural products, drugs, and functional materials due to their unique biological activities and optoelectronic properties. In addition, they have unique properties such as abundant multi-nucleophilic sites and hydrogen bonding ability, making axially chiral indole biaryl compounds a promising compound for application. They can be used to prepare some potential lead compounds and chiral ligands / catalysts. Therefore, the development of a simple synthesis method for axially chiral indole biaryl compounds has become a research hotspot in recent years.

[0003] Modern common synthetic methods generally directly utilize the strong nucleophilicity of indole C3 / NH, which can undergo axially selective electrophilic arylation reactions with quinones, azoaromatics or nitroso-substituted aromatics under asymmetric catalysis to obtain C3- / N-arylindoles with axial chirality. However, compared with C3- / N-arylindoles, the asymmetric selective synthesis of 2-arylindoles has developed slowly, which may be due to its lower rotational barrier than C3- / N-arylindoles, making it easy to racemize, resulting in the asymmetric synthesis of 2-arylindoles being challenging. Here, we developed a catalytic method for the asymmetric Friedel-Crafts alkylation of 2-arylindoles with α,β-unsaturated aldehydes under the catalysis of chiral secondary amines through a dynamic kinetic resolution (DKR) process, thereby constructing a series of axially chiral 2-arylindoles. Summary of the invention

[0004] The existing technology for preparing 2-arylindole derivatives with axial chirality has the problems of transition metal participation in the reaction and easy racemization of the axial chirality of the product. In order to solve the above problems, the present invention provides a catalytic method for asymmetric Friedel-Crafts alkylation of 2-arylindole with α,β-unsaturated aldehyde by dynamic kinetic resolution (DKR) process under the catalysis of chiral secondary amine and base, which provides a more convenient and effective synthesis method for the application field of constructing axially chiral 2-arylindole derivatives.

[0005] Specifically, the present invention provides the following technical solutions:

[0006] A method for preparing 2-arylindole derivatives with axial chirality comprises the following steps: using 2-arylindole and α,β-unsaturated aldehyde as raw materials, reacting in the presence of a chiral catalyst and an acid or base additive to obtain the axially chiral 2-arylindole derivative:

[0007]

[0008] Compound 1, compound 2, a chiral catalyst, and an acid or a base react in a solvent at a temperature below 50° C. to obtain compound 3;

[0009] in,

[0010] R 1 , R 2 R are independently selected from H, halogen, C1-C5 alkyl, C1-C5 alkoxy; 3 An alkyl group selected from C1-C3; R 4 Selected from H, C1-C3 alkyl or benzyl;

[0011] The chiral catalyst is one or more of an imidazolidinone catalyst and a proline-derived secondary amine catalyst.

[0012] Furthermore, the alkyl group is selected from methyl and ethyl; the halogen group is selected from chlorine, bromine and iodine; and the alkoxy group is selected from methoxy and ethoxy.

[0013] “*” indicates that the chirality here is C.

[0014] Furthermore, in R 4 When R is H, the chiral catalyst is selected from a catalyst derived from proline; 4 When it is methyl, the chiral catalyst is selected from imidazolidinone chiral catalysts.

[0015] Wherein, the proline-derived catalyst is selected from the following structures: wherein R is selected from TMS, TBS or SiPh3;

[0016] The imidazolidinone chiral catalyst is selected from the following structures: Wherein, X is selected from O or S.

[0017] Further, the acid is one or more of p-toluenesulfonic acid, camphorsulfonic acid, and trifluoroacetic acid, and the base is one or more of Et3N, DIPEA, DABCO, Na2CO3, and K2CO3; further, in R 4 When H is present, the base is selected from Et3N; 4 When it is methyl, the acid is selected from D-camphorsulfonic acid.

[0018] Furthermore, the reaction is carried out in a solvent, and the solvent is one or more of dichloromethane, 1,2-dichloroethane, chloroform, dioxane, and toluene; further, the solvent is toluene or dichloromethane; more preferably, dichloromethane.

[0019] Further, the reaction temperature is -10°C to 40°C; further, the reaction temperature is 25°C to 40°C, preferably 40±2°C.

[0020] Furthermore, the molar ratio of 2-arylindole, α,β-unsaturated aldehyde, catalyst and acid or base is 1:(1.2-1.5):(0.1-0.2):(0.2-0.4); further, the molar ratio is 1:1.5:0.2:0.2.

[0021] The method for preparing a 2-arylindole structure product with axial chirality provided by the present invention has low cost, simple operation, less pollution and is environmentally friendly; the product is more stable and not easy to racemize, and the chiral catalyst used can be independently prepared; the reaction conditions are mild and the safety factor is high; the functional group compatibility is strong and the substrate range is wide. DETAILED DESCRIPTION

[0022] In order to more clearly understand the technical content of the present invention, the following embodiments are given in detail.

[0023] The raw materials involved in each embodiment of the present invention are either existing commercially available products or can be prepared according to existing methods. The specific preparation operations and characterization tests of the present invention are conventional techniques.

[0024] Example 1 Construction of 2-aryl indole structure products with axial chirality under different conditions

[0025] At room temperature, 2-arylindole 1a, α,β-unsaturated aldehyde 2a, chiral catalyst C and acid or base A were weighed into a 10 mL sealed tube, and a solvent was added and stirred to dissolve in the solvent, and the mixture was stirred at a specified temperature; after the reaction was complete, MeOH (0.5 mL) was added to the reaction solution, and then the reaction was placed at 0°C and NaBH4 was slowly added and stirred until the reaction was complete; ice water was added to quench the reaction solution, and then extracted with ethyl acetate three times, the organic phases were combined, washed with saturated NaCl, dried with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the solvent was spin-dried; purified by rapid column chromatography, and 2-arylindole product 3a with axial chirality was isolated. The reaction results under different operating conditions are shown in Table 1.

[0026] Through a series of screening conditions, including catalyst, additive, solvent, and temperature adjustment, it was found that the chiral secondary amine C4 combined with triethylamine as an additive, dichloromethane as a reaction solvent, and reaction at 40°C for about 30 hours can give the axial chiral 2-arylindole product with a total yield of 66% and an er value of 95:5. Therefore, this condition is used as the standard condition for substrate expansion. Other conditions can also give the target product, although the chirality control is not high.

[0027] Table 1. Results of the reaction of 2-arylindole with acrolein under different reaction conditions

[0028]

[0029]

[0030] a Unless otherwise stated, reactions were performed using 1a (0.05 mmol), 2a (0.075 mmol), C (20 mol%) and acid or base A (20 mol%) in solvent (1.0 mL). b Isolated yield. c Determined by high performance liquid chromatography using a chiral stationary phase.

[0031] Example 2 Optimal conditions for constructing 2-aryl indole structure products and their derivatives with axial chirality

[0032] At room temperature, 2-arylindole 1 (0.05mmol, 1.0equiv), acrolein 2a (0.075mmol, 1.5equiv), proline-derived chiral catalyst C4 (0.01mmol, 0.2equiv) and Et3N (0.01mmol, 0.2equiv) were weighed into a 10mL sealed tube, 1mL DCM was added and stirred to dissolve it in the solvent, and the mixture was stirred at 40°C; after the reaction was complete, MeOH (0.5mL) was added to the reaction solution, and then the reaction was placed at 0°C and NaBH4 (0.1mmol, 2equiv) was slowly added and stirred until the reaction was complete; ice water was added to quench the reaction solution, and then extracted with ethyl acetate three times, the organic phases were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the solvent was spin-dried; and the 2-arylindole product with axial chirality was isolated by rapid column chromatography.

[0033] Table 2 Different reaction substrates and 2-aryl indole derivatives with axial chirality

[0034]

[0035]

[0036] a Unless otherwise stated, reactions were performed at 40° C. with 1 (0.1 mmol), 2a (0.15 mmol), C4 (20 mol %) and Et 3 N (40 mol %) in DCM (1.0 mL). b The isolated yield and enantioselectivity were determined by HPLC. c The absolute configuration of 3a was determined by electron circular dichroism (ECD) analysis, and the others were assigned by analogy.

[0037] The above product data are characterized as follows:

[0038] 1-(3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)naphthalen-2-ol(3a).White solid 66% yield.Mp=76-78℃; [α] D 20 =-11.3 (c=1.0in CHCl3); 90%ee, determined by HPLC analysis [Daicel chiralpakv IB N-5, n-hexane / i-PrOH=80 / 20, 1.0mL / min, λ=254nm, t(minor)=17.78min, t(major)=5.43min]; 1 H NMR (400MHz, DMSO-d6): δ9.79(s,1H),7.92(d,J=8.9Hz,1H),7.87(d,J=7.7Hz,1H),7.62(d,J=7.8Hz,1H),7.44(d,J=8.1Hz,1H),7.36– 7.27(m,3H),7.21–7.04(m,3H),4.23(s,1H),3.34(s,3H),3.23(brs,2H),2.63–2.50(m,1H),2.40–2.30(m,1H),1.61–1.52(m,2H)ppm; 13 C NMR (100MHz, CDCl3): δ153.1,138.1,134.2,131.3,129.4,128.8,128.3,127.5,127.2,124.1,123 .6,122.2,119.3,119.3,117.6,115.9,110.4,109.7,62.7,32.7,30.2,21.4ppm; ESI-HRMS:calcd for C 22 H 21 NO2+Na+ 354.1465,found 354.1469.

[0039] 1-(3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)-6-methoxynaphthalen-2-ol(3b).Milky white solid,56%yield.M.p=72-74℃;[α]D 20 =+7.0(c=1.0 in CHCl3);88%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=20.56min,t(major)=6.16min]; 1 H NMR(400MHz,CDCl3):δ7.77(d,J=8.9Hz,1H),7.71(d,J=7.9Hz,1H),7.37(d,J=8.2Hz,1H),7.32–7.27(m,1H),7.23(d,J=5.9Hz,1H),7.20–7.09(m,3H),7.00(dd,J=9.1,2.6Hz,1H),3.88(s,3H),3.59–3.39(m,2H),3.34(s,3H),2.68(td,J=7.2,2.7Hz,2H),1.88–1.65(m,2H)ppm; 13 CNMR(100MHz,CDCl3):δ156.1,151.5,138.1,129.9,129.7,129.5,129.4,127.5,125.7,122.2,119.6,119.3,119.2,118.0,115.8,110.7,109.7,106.7,62.7,55.3,32.7,30.2,21.3ppm;ESI-HRMS:calcd for C 23 H 23 NO3+H + 362.1751,found 362.1747.

[0040] 1-(3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)-7-methoxynaphthalen-2-ol(3c).White solid,59%yield.M.p=74-76℃;[α]D 20 =-2.0(c=1.0 in CHCl3);86%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=20.95min,t(major)=5.98min]; 1 H NMR(400MHz,CDCl3):δ7.82(d,J=8.8Hz,1H),7.78–7.72(m,2H),7.43(d,J=8.2Hz,1H),7.37–7.31(m,1H),7.25–7.20(m,1H),7.15(d,J=8.8Hz,1H),7.03(dd,J=8.9,2.5Hz,1H),6.56(d,J=2.4Hz,1H),3.66(s,3H),3.58–3.45(m,2H),3.41(s,3H),2.73(t,J=7.3Hz,2H),1.90–1.74(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ159.1,153.7,138.2,135.7,131.1,129.9,129.5,127.7,124.2,122.2,119.3,119.3,115.8,115.7,114.9,109.8,109.7,103.2,62.7,55.4,32.9,30.2,21.3ppm;ESI-HRMS:calcd for C 23 H 23 NO3+H + 362.1751,found 362.1747.

[0041] 7-bromo-1-(3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)naphthalen-2-ol(3d).White solid,55%yield.M.p=91-92℃;[α] D 20=+2.6(c=1.0 in CHCl3);74%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=20.61min,t(major)=5.53min]; 1 H NMR(400MHz,CDCl3):δ7.87(d,J=8.9Hz,1H),7.77(d,J=7.9Hz,1H),7.71(d,J=8.6Hz,1H),7.46–7.41(m,2H),7.40–7.29(m,3H),7.26–7.21(m,1H),6.26(s,1H),3.63–3.47(m,2H),3.38(s,3H),2.81–2.61(m,2H),1.95–1.71(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ154.1,138.2,135.6,131.2,129.9,128.5,127.5,127.2,127.1,126.2,122.5,121.9,119.5,119.4,118.2,116.3,110.0,109.8,62.9,32.7,30.2,21.5ppm;ESI-HRMS:calcd for C 22 H 20 B r NO2+H + 410.0750,found 410.0753.

[0042] 6-bromo-1-(3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)naphthalen-2-ol(3e).White solid,51%yield.M.p=70-72℃;[α] D 20 =+7.0(c=1.0 in CHCl3);81%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=16.03min,t(major)=5.31min]; 1H NMR(400MHz,CDCl3):8.24(d,J=8.3Hz,1H),7.75(d,J=7.9Hz,1H),7.68(s,1H),7.49–7.30(m,4H),7.25–7.19(m,2H),3.64–3.43(m,2H),3.38(s,3H),2.80–2.61(m,2H),1.94–1.69(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ153.0,138.2,135.0,128.6,128.0,127.6,127.5,127.4,125.4,125.0,124.6,122.5,122.1,119.5,119.4,116.3,110.9,109.8,63.0,32.6,30.2,21.6ppm ppm;ESI-HRMS:calcd for C 22 H 20 B r NO2+H + 410.0750,found 410.0753.

[0043] 1-(3-(3-hydroxypropyl)-1,4-dimethyl-1H-indol-2-yl)naphthalen-2-ol(3f).White solid,53%yield.M.p=71-76℃;[α] D 20 =+1.0(c=1.0 in CHCl3);93%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=9.96min,t(major)=4.93min]; 1 H NMR(400MHz,CDCl3):δ7.81(d,J=8.9Hz,1H),7.78–7.72(m,1H),7.29–7.26(m,2H),7.22(d,J=8.9Hz,1H),7.19–7.15(m,2H),7.14–7.09(m,1H),6.88(d,J=6.8Hz,1H),5.89(s,1H),3.39–3.27(m,2H),3.26(s,3H),2.73–2.59(m,5H),1.74–1.49(m,2H)ppm; 13C NMR(100MHz,CDCl3):δ153.0,138.5,134.2,131.3,131.0,129.4,128.8,128.3,127.2,126.0,124.2,123.6,122.2,121.3,117.5,116.7,110.5,107.5,62.5,35.3,30.3,22.6,20.2ppm;ESI-HRMS:calcd forC 23 H 23 NO2+H + 346.1802,found 346.1798.

[0044] 1-(3-(3-hydroxypropyl)-1,5-dimethyl-1H-indol-2-yl)naphthalen-2-ol(3g).Milky white solid,55%yield.M.p=78-79℃;[α] D 20 =-4.0(c=1.0 in CHCl3);89%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=11.12min,t(major)=5.01min]; 1 H NMR(400MHz,CDCl3):δ7.90(d,J=8.9Hz,1H),7.87–7.82(m,1H),7.54(s,1H),7.38–7.33(m,2H),7.31(d,J=8.8Hz,2H),7.25–7.21(m,1H),7.17(dd,J=8.4,1.1Hz,1H),3.59–3.44(m,2H),3.35(s,3H),2.69(t,J=7.3Hz,2H),2.54(s,3H),1.91–1.70(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ153.1,136.6,134.3,131.2,129.4,128.8,128.7,128.2,127.7,127.2,124.2,123.9,123.6,118.9,117.6,115.4,110.6,109.4,62.8,32.8,30.2,21.5,21.4ppm;ESI-HRMS:calcd for C 23 H23 NO2+H + 346.1802,found 346.1798.

[0045] 1-(3-(3-hydroxypropyl)-1,6-dimethyl-1H-indol-2-yl)naphthalen-2-ol(3h).Milky white solid,50%yield.M.p=72-74℃;[α] D 20 =-15.4(c=1.0,CHCl3);81%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=6.49min,t(major)=5.12min]; 1 H NMR(400MHz,CDCl3):δ7.82(d,J=8.9Hz,1H),7.78–7.74(m,1H),7.56(d,J=8.1Hz,1H),7.30–7.21(m,3H),7.17–7.12(m,2H),6.98(dd,J=8.1,0.8Hz,1H),3.50–3.35(m,2H),3.26(s,3H),2.61(t,J=7.3Hz,2H),2.49(s,3H),1.83–1.63(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ153.1,138.6,134.3,132.3,131.2,128.8,128.6,128.2,127.2,125.4,124.2,123.6,121.1,119.0,117.6,115.8,110.6,109.7,62.7,32.8,30.1,21.9,21.4ppm;ESI-HRMS:calcd forC 23 H 23 NO2+H + 346.1802,found 346.1798.

[0046] 1-(3-(3-hydroxypropyl)-5-methoxy-1-methyl-1H-indol-2-yl)naphthalen-2-ol(3i).White soli,58%yield.M.p=71-72℃;[α] D20 =+12.368(c=1.0 in CHCl3);59%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=12.04min,t(major)=6.29min]; 1 H NMR(400MHz,CDCl3):7.90(d,J=8.9Hz,1H),7.87–7.82(m,1H),7.39–7.33(m,2H),7.31(d,J=8.9Hz,2H),7.25–7.21(m,1H),7.19(d,J=2.4Hz,1H),7.00(dd,J=8.8,2.4Hz,1H),3.93(s,3H),3.57–3.43(m,2H),3.35(s,3H),2.68(td,J=7.2,1.7Hz,2H),1.88–1.70(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ154.1,153.1,134.2,133.5,131.2,130.0,128.8,128.2,127.8,127.2,124.1,123.6,117.6,115.3,112.3,110.6,110.4,101.2,62.7,56.1,32.6,30.3,21.3ppm;ESI-HRMS:calcd for C 23 H 23 NO3+H + 362.1751,found 362.1747.

[0047] 1-(5-chloro-3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)naphthalen-2-ol(3j).Milky white solid,52%yield.M.p=85-87℃;[α] D 20 =-3.50(c=1.0 inCHCl3);87%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=7.17min,t(major)=5.35min];1 H NMR(400MHz,DMSO-d6):δ9.87(s,1H),7.94(d,J=8.9Hz,1H),7.90–7.85(m,1H),7.64(d,J=1.9Hz,1H),7.49(d,J=8.7Hz,1H),7.37–7.27(m,3H),7.16(dd,J=8.6,2.0Hz,1H),7.08(d,J=7.7Hz,1H),4.24(t,J=5.2Hz,1H),3.33(s,3H),3.25–3.16(m,2H),2.48–2.42(m,1H),2.36–2.25(m,1H),1.57–1.46(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ153.2,138.9,134.1,131.5,130.2,128.8,128.3,127.4,126.4,123.9,123.8,122.6,120.5,117.8,116.2,116.0,112.7,110.0,62.7,32.6,30.3,21.4ppm;ESI-HRMS:calcd for C 22 H 20 ClNO2+H + 366.1255,found 366.1250.

[0048] 1-(6-bromo-3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)naphthalen-2-ol(3k).White solid,51%yield.M.p=83-85℃;[α] D 20 =-21.6(c=1.0 in CHCl3);90%ee,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=7.18min,t(major)=5.97min]; 1H NMR(400MHz,CDCl3):δ7.91(d,J=8.9Hz,1H),7.88–7.83(m,1H),7.60(d,J=8.4Hz,1H),7.57(d,J=1.5Hz,1H),7.39–7.34(m,2H),7.32–7.28(m,2H),7.19–7.14(m,1H),6.16(s,1H),3.58–3.45(m,2H),3.33(s,3H),2.77–2.60(m,2H),1.88–1.70(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ153.2,138.9,134.1,131.5,130.2,128.8,128.3,127.4,126.4,123.9,123.7,122.6,120.5,117.8,116.2,115.9,112.7,110.0,62.7,32.6,30.3,21.4ppm;ESI-HRMS:calcd forC 22 H 21 B r NO2+H + 410.0750,found 410.0745.

[0049] 1-(3-(3-hydroxypropyl)-1,4-dimethyl-1H-indol-2-yl)-7-methoxynaphthalen-2-ol(3l).White solid,53%yield.M.p=78-79℃;[α] D 20 =+21.250(c=1.0 in CHCl3);94:6 er,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=10.04min,t(major)=5.46min]; 1H NMR(400MHz,DMSO-d6):δ9.69(s,1H),7.86–7.76(m,2H),7.25(d,J=8.1Hz,1H),7.15(d,J=8.8Hz,1H),7.05–6.95(m,2H),6.80(d,J=7.1Hz,1H),6.47(d,J=2.4Hz,1H),3.56(s,3H),3.30(s,3H),3.24–3.10(m,2H),2.69(s,3H),2.66–2.56(m,1H),2.47–2.37(m,1H),1.60–1.45(m,2H)ppm; 13 C NMR(100MHz,DMSO-d6):δ158.1,155.2,137.3,136.0,132.2,130.2,129.8,129.4,125.9,123.2,120.5,120.2,115.7,114.4,114.2,109.9,107.5,103.1,60.7,54.9,36.0,29.8,22.7,19.9ppm;ESI-HRMS:calcd for C 24 H 25 NO3+H + 375.1834,found 375.1832.

[0050] 6-bromo-1-(3-(3-hydroxypropyl)-1,4-dimethyl-1H-indol-2-yl)naphthalen-2-ol(3m).White solid,52%yield.M.p=98-100℃;[α] D 20 =+19.375(c=1.0 in CHCl3);88:12er,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=7.61min,t(major)=5.18min]; 1H NMR(400MHz,DMSO-d6):δ9.99(s,1H),8.15(d,J=2.0Hz,1H),7.93(d,J=9.0Hz,1H),7.44(dd,J=9.0,2.1Hz,1H),7.38(d,J=9.0Hz,1H),7.26(d,J=8.2Hz,1H),7.09–7.00(m,2H),6.81(d,J=7.1Hz,1H),3.28(s,3H),3.24–3.10(m,2H),2.68(s,3H),2.65–2.58(m,1H),2.41–2.31(m,1H),1.60–1.41(m,2H)ppm; 13 C NMR(100MHz,DMSO-d6):δ155.1,137.3,133.2,131.3,129.8,129.7,129.6,129.5,129.0,126.2,125.8,120.7,120.4,119.6,115.7,114.6,110.9,107.5,60.7,35.9,29.9,22.7,19.9ppm;ESI-HRMS:calcd for C 23 H 22 BrNO2+H + 446.0726,found 446.0668.

[0051] 1-(6-bromo-3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)naphthalen-2-ol(3n).White solid,55%yield.M.p=78-80℃;[α] D 20 =-5.0(c=1.0in CHCl3);91:9er,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=14.26min,t(major)=6.31min]; 1H NMR(400MHz,CDCl3):δ7.61(d,J=7.9Hz,1H),7.27(dd,J=16.0,7.9Hz,2H),7.23–7.20(m,1H),7.10–7.02(m,1H),6.64(d,J=8.3Hz,1H),6.52(d,J=8.3Hz,1H),3.68(s,3H),3.48–3.40(m,2H),3.39(d,J=6.3Hz,3H),2.82–2.67(m,1H),2.62–2.49(m,1H),1.83–1.71(m,2H)ppm; 13 C NMR(100MHz,CDCl3):δ157.9,154.4,137.0,130.2,126.9,126.4,121.0,118.2,118.0,113.4,108.6,107.4,105.7,101.6,61.2,54.7,31.6,29.0,20.0ppm;ESI-HRMS:calcd forC 19 H 21 NO3+H + 312.1589,found 312.1586.

[0052] 2-(6-bromo-3-(3-hydroxypropyl)-1-methyl-1H-indol-2-yl)-3-methoxyphenol(3o).White solid,52%yield.M.p=96-97℃;[α] D 20 =-16.0(c=1.0 inCHCl3);94:6er,determined by HPLC analysis[Daicel chiralpakv IB N-5,n-hexane / i-PrOH=80 / 20,1.0mL / min,λ=254nm,t(minor)=12.23min,t(major)=11.08min]; 1HNMR (400MHz, CDCl3): δ7.55–7.49(m,2H),7.34(t,J=8.3Hz,1H),7.24(dd,J=8.4,1.4Hz,1H),6.70(d,J=8.3Hz,1H),6.59(d,J=8 .3Hz,1H),5.58(s,1H),3.75(s,3H),3.57–3.45(m,2H),3.43(s,3H),2.83–2.73(m,1H),2.68–2.53(m,1H),1.88–1.74(m,2H)ppm; 13 C NMR (100MHz, CDCl3): δ158.4,155.3,139.0,132.1,131.2,126.6,123.0,121.9,115.7 ,112.7,108.4,107.0,102.6,102.3,62.2,55.7,32.5,30.2,21.0ppm; ESI-HRMS:calcd forC 19 H 20 BrNO3+H + 390.0627, found 390.0694.

[0053] Example 3 Construction of 2-aryl indole structure products with both axial chirality and central chirality under different conditions

[0054] At room temperature, 2-arylindole 1a, crotonaldehyde 2b, chiral catalyst C and acid or base A were weighed into a 10 mL sealed tube, and a solvent was added and stirred to dissolve them in the solvent, and the mixture was stirred at a specified temperature; after the reaction was complete, MeOH (0.5 mL) was added to the reaction solution, and then the reaction was placed at 0°C and NaBH4 was slowly added and stirred until the reaction was complete; ice water was added to quench the reaction solution, and then extracted three times with ethyl acetate, the organic phases were combined, washed with saturated NaCl, dried with anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the solvent was dried; and purified by rapid column chromatography to separate and obtain 2-arylindole product 4a with both axial chirality and central chirality. The reaction results under different operating conditions are shown in Table 3.

[0055] Through a series of screening conditions, including catalysts, additives, solvents, and temperature adjustments, it was found that the chiral secondary amine C1 combined with triethylamine as an additive, dry dichloromethane as a reaction solvent, and a reaction time of about 12 hours at 25 degrees can produce one of the isomers with good yield and enantioselectivity. Although the chirality of the other diastereoisomer is not ideal, the two isomers can be separated by silica gel column chromatography. Therefore, this condition is used as the standard condition for substrate expansion. Other conditions can also give the target product, although the stereoselectivity is not highly controlled.

[0056] Table 3 Results of the reaction of 2-arylindole with crotonaldehyde under different reaction conditions

[0057]

[0058]

[0059]

[0060] a Unless otherwise stated, reactions were performed at room temperature with 1a (0.05 mmol), 2b (0.075 mmol), C (20 mol%) and acid or base A (20 mol%) in solvent (1.0 mL). b Isolated yield. c Determined by high performance liquid chromatography using a chiral stationary phase. d C (30 mol%) and acid D-CSA (20 mol%).

[0061] Example 4 Optimal conditions for constructing C2-aryl indole structure products and their derivatives with both axial chirality and central chirality

[0062] At room temperature, 2-arylindole 1 (0.05mmol, 1.0equiv), crotonaldehyde 2b or 2-pentenal 2c (0.075mmol, 1.5equiv), C1 chiral catalyst (0.01mmol, 0.2equiv) and D-camphorsulfonic acid (0.02mmol, 0.2equiv) were weighed into a 10mL sealed tube, 1mL of dry DCM was added and stirred to dissolve in the solvent, and the reaction solution was stirred at room temperature; after the reaction was complete, MeOH (0.5mL) was added to the reaction solution, and then the reaction was placed at 0°C and NaBH4 (0.1mmol, 2equiv) was slowly added and stirred until the reaction was complete; ice water was added to quench the reaction solution, and then extracted three times with ethyl acetate, the organic phases were combined, washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the solvent was spin-dried; and purified by rapid column chromatography to separate and obtain 2-arylindole product 4 having both axial chirality and central chirality.

[0063] Table 4 Different reaction substrates and 2-aryl indole derivatives with both axial chirality and central chirality a

[0064]

[0065] aUnless otherwise stated, reactions were carried out with 1 (0.1 mmol), 2b (0.15 mmol), C1 (20 mol%) and D-CSA (20 mol%) in DCM (1.0 mL) at room temperature; the isolated yield and enantioselectivity of a single isomer were determined by HPLC. b The separation yield of the mixed isomers, dr value is given by 1 H-NMR was used to determine the ee value of a single isomer.

[0066] The above product data are characterized as follows:

[0067] [α] D 20 =+16.471(c=1.0 in CHCl3); 95:5er, determined by HPLC analysis [Daicel chiralpak AD-H, n-hexane / i-PrOH=90 / 10, 1.0mL / min, λ=254nm, t(minor)=7.94min, t(major)=11.15min; Product 4a″(minor) was obtained as awhitesolid (13.2 mg, 38% yield).70:30 er, determined by HPLC analysis [DaicelchiralpakAD-H, n-hexane / i-PrOH=90 / 10, 1.0mL / min, λ=254nm, t(minor)=14.44min, t(major)=12.17min]; 1H NMR(4a′,400MHz,CDCl3):δ7.83–7.71(m,3H),7.34(d,J=8.2Hz,1H),7.29–7.26(m,1H),7.25–7.24(m,1H),7.23–7.18(m,2H),7.11(d,J=7.0Hz,2H),3.67–3.52(m,2H),3.25(s,3H),2.83–2.74(m,1H),2.29–2.17(m,1H),1.86–1.77(m,1H),1.24(d,J=7.0Hz,3H)ppm; 13 C NMR(4a′,100MHz,CDCl3):δ153.5,138.3,134.9,131.1,129.8,128.8,128.1,126.9,125.8,124.4,123.5,121.7,120.3,119.6,118.9,118.4,111.5,109.9,62.8,38.5,30.1,29.9,22.6ppm;ESI-HRMS:calcd for C 23 H 23 NO2+H + 346.1802,found 346.1806.

[0068] 1-(3-(4-hydroxybutan-2-yl)-1-methyl-1H-indol-2-yl)-7-methoxynaphthalen-2-ol(4b).Upon workup,product 4b′(major)was obtained as awhite solid(15.0mg,42%yield).Mp=102–106℃;[α] D 20=-1.250(c=1.0 in CHCl3);1:1 dr,75:25 er,determined by HPLC analysis[Daicel chiralpak AD-H,n-hexane / i-PrOH=90 / 10,1.0mL / min,λ=254nm,t(minor)=7.64min,t(major)=8.49min;Product4b″(minor)was obtained as a white solid(15.0mg,42%yield).26:73 er,determinedby HPLCanalysis[Daicel chiralpak AD-H,n-hexane / i-PrOH=90 / 10,1.0mL / min,λ=254nm,t(minor)=13.11min,t(major)=9.86min]; 1 H NMR(4b′,400MHz,DMSO-d6):δ9.82(s,1H),7.96–7.83(m,2H),7.68(d,J=7.9Hz,1H),7.44(d,J=8.2Hz,1H),7.36–7.25(m,3H),7.19–7.11(m,2H),7.03(ddd,J=8.0,7.1,1.0Hz,1H),4.09(t,J=5.3Hz,1H),3.29(s,3H),3.22(ddd,J=19.6,9.0,4.8Hz,2H),2.26(qd,J=8.4,6.1Hz,1H),1.86(dtd,J=13.0,8.7,5.6Hz,1H),1.73(dq,J=13.0,8.0Hz,2H),1.63(d,J=6.9Hz,1H),0.59(t,J=7.4Hz,3H)ppm; 13 C NMR(4b′,100MHz,DMSO-d6):δ159.8,142.5,139.8,137.2,135.7,133.2,132.9,131.5,131.5,129.4,128.0,125.6,124.9,123.5,123.3,121.8,115.9,114.9,65.2,43.2,40.9,34.9,32.9,18.3ppm;ESI-HRMS:calcd for C 24 H 25 NO2+Na + 382.1778,found 382.1776.

[0069] 1-(5-chloro-3-(4-hydroxybutan-2-yl)-1-methyl-1H-indol-2-yl)naphthalen-2-ol(4c).Upon workup,product 4c′(major)was obtained as a paleyellow solid(20.4mg,56%yield).Mp=84–86℃;[α] D 20 =-10.625(c=1.0 in CHCl3);5:2 dr,92:8 er,determined by HPLC analysis[Daicel chiralpak AD-H,n-hexane / i-PrOH=90 / 10,1.0mL / min,λ=254nm,t(minor)=9.43min,t(major)=13.32min;Product4c″(minor)was obtained as a pale yellow solid(8.2mg,22%yield);76:24 er,determined by HPLC analysis[Daicel chiralpak AD-H,n-hexane / i-PrOH=90 / 10,1.0mL / min,λ=254nm,t(minor)=18.39min,t(major)=17.32min]; 1 H NMR(4c′,400MHz,CDCl3):δ7.85–7.76(m,2H),7.73(d,J=8.9Hz,1H),7.41(d,J=8.2Hz,1H),7.30(t,J=7.6Hz,1H),7.17(t,J=7.5Hz,1H),7.11(d,J=8.8Hz,1H),7.00(d,J=8.8Hz,1H),6.53(s,1H),3.71–3.56(m,5H),3.35(s,3H),2.90–2.80(m,1H),2.34–2.22(m,1H),1.93–1.82(m,1H),1.37(d,J=7.1Hz,3H)ppm; 13C NMR(4c′,100MHz,CDCl3):δ158.9,154.2,138.4,136.3,130.8,129.8,129.7,125.9,124.2,121.6,120.4,119.7,118.8,115.8,115.7,110.8,109.9,103.2,62.8,55.3,38.7,30.2,29.9,22.7ppm;ESI-HRMS:calcd for C 24 H 25 NO3+H + 376.1907,found 376.1902.

[0070] 1-(5-chloro-3-(4-hydroxybutan-2-yl)-1-methyl-1H-indol-2-yl)naphthalen-2-ol(4d):Upon workup,product 4d(mixture of 4d′and 4d″)was obtainedas a white solid(25.2mg,68%yield).Mp=70–72℃;3:2dr(determined by 1 H-NMR),95:5er(4d′,major isomer),determined by HPLC analysis[Daicel chiralpak IB N-5,n-hexane / i-PrOH=90 / 10,1.0mL / min,λ=254nm,t(minor)=10.94min,t(major)=5.81min;67:33er(4d″,minor isomer)was determined by HPLC analysis[Daicelchiralpak IB N-5,n-hexane / i-PrOH=90 / 10,1.0mL / min,λ=254nm,t(minor)=9.54min,t(major)=10.98min](singlediastereomer was obtained from TLC for the HPLCanalysis); 1H NMR(4d′,400MHz,DMSO-d6):δ9.90(s,1H),9.82(s,1H),7.93(d,J=8.9Hz,2H),7.87(d,J=7.7Hz,2H),7.70(s,2H),7.49(d,J=8.6Hz,2H),7.37–7.27(m,5H),7.17(d,J=8.7Hz,2H),7.12(d,J=8.0Hz,1H),7.04(d,J=8.1Hz,1H),4.11(d,J=5.1Hz,2H),3.32(s,2H),3.27(s,3H),3.23–3.13(m,2H),3.12–3.03(m,1H),2.62(dd,J=14.5,7.2Hz,1H),2.47(s,1H),1.95–1.77(m,2H),1.65(m,6.5Hz,2H),1.20(d,J=7.0Hz,2H),1.16(d,J=7.0Hz,3H)ppm; 13 C NMR(4d′,100MHz,DMSO-d6):δ155.1,155.0,136.3,136.2,134.9,134.9,133.7,133.6,131.1,128.6,128.5,128.2,128.1,127.5,127.3,124.2,124.1,123.3,123.3,120.7,118.9,118.8,118.7,118.5,118.1,111.8,110.7,110.7,60.4,60.2,30.4,30.3,28.7,28.6,21.5,21.1ppm;ESI-HRMS:calcd for C 23 H 22 ClNO2+H + 380.1412,found 380.1413.

[0071] In summary, the present invention discloses that 2-arylindole can react with acrolein or crotonaldehyde or 2-pentenal in α,β-unsaturated aldehyde compounds under the action of proline or imidazolidinone chiral catalyst and triethylamine or right-rotating camphorsulfonic acid to generate 2-arylindole derivatives with axial chirality or central chirality. The method is an effective method for preparing 2-arylindole derivatives with axial chirality and not easy to racemize by simple and readily available substrate raw materials and dynamic kinetic resolution (DKR) process. This method for constructing a 2-arylindole skeleton with axial chirality is different from C3- / N-arylindole, and can overcome the difficulty of preparing axial chirality of 2-arylindole. It also uses a relatively simple and economical chiral catalyst and the raw materials are cheap, easy to obtain and easy to prepare, and does not involve harsh conditions such as high temperature and high pressure, which provides a more convenient, effective and economical synthesis method for the application field of constructing C2-arylindole derivatives with axial chirality, and has important significance and value for the future development of drug synthesis.

[0072] The above shows and describes the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing a 2-aryl indole derivative having axial chirality, characterized in that: It includes the following: Compound 1, compound 2, a chiral catalyst, and an acid or a base react in a solvent at a temperature below 50° C. to obtain compound 3; in, R 1 , R 2 R are independently selected from H, halogen, C1-C5 alkyl, C1-C5 alkoxy; 3 An alkyl group selected from C1-C3; R 4 Selected from H, C1-C3 alkyl or benzyl; The chiral catalyst is one or more of an imidazolidinone catalyst and a proline-derived secondary amine catalyst.

2. The method for preparing the axially chiral 2-arylindole derivative according to claim 1, characterized in that: The alkyl group is selected from methyl and ethyl; the halogen group is selected from chlorine, bromine and iodine; and the alkoxy group is selected from methoxy and ethoxy.

3. The method for preparing the axially chiral 2-arylindole derivative according to claim 1, characterized in that: In R 4 When R is H, the chiral catalyst is selected from a catalyst derived from proline; 4 When it is methyl, the chiral catalyst is selected from imidazolidinone chiral catalysts.

4. The method for preparing an axially chiral 2-arylindole derivative according to any one of claims 1 to 3, wherein the proline-derived catalyst is selected from the following structures: wherein R is selected from TMS, TBS or SiPh3; The imidazolidinone chiral catalyst is selected from the following structures: in, X is selected from O or S.

5. The method for preparing the axially chiral 2-arylindole derivative according to claim 1, characterized in that: The acid is one or more of p-toluenesulfonic acid, camphorsulfonic acid, and trifluoroacetic acid; the base is one or more of Et3N, DIPEA, DABCO, Na2CO3, and K2CO3; further, in R 4 When H is present, the base is selected from Et3N; 4 When it is methyl, the acid is selected from D-camphorsulfonic acid.

6. The method for preparing axially chiral 2-arylindole derivatives according to claim 1, characterized in that: The reaction is carried out in a solvent, and the solvent is one or more of dichloromethane, 1,2-dichloroethane, chloroform, dioxane, and toluene; further, the solvent is toluene or dichloromethane; more preferably, dichloromethane.

7. The method for preparing axially chiral 2-arylindole derivatives according to claim 1, characterized in that: The reaction temperature is -10°C to 40°C; further, the reaction temperature is 25°C to 40°C, preferably 40±2°C.

8. The method for preparing axially chiral 2-arylindole derivatives according to claim 1, characterized in that: The molar ratio of 2-arylindole, α, β-unsaturated aldehyde, catalyst and acid or base is 1: (1.2-1.5): (0.1-0.2): (0.2-0.4); further, the molar ratio is 1: 1.5: 0.2: 0.2.

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