A method for synthesizing chiral β-nitrogen aromatic tertiary carbon center compounds

Abstract

The present invention relates to a method for synthesizing a chiral β-azaaromatic tertiary carbon center compound, and belongs to the technical field of organic synthesis. Under an argon atmosphere, N-aryl substituted glycine (I) and (E)-2-aryl / alkyl vinyl azaaromatic (II) are reacted at room temperature in a toluene solvent under visible light irradiation with sodium dihydrogen phosphate and anthracene as additives in the presence of a visible light catalyst dinitrile pyrazine derivative DPZ and a chiral spirocyclic phosphonic acid catalyst CPA, and separated and purified to obtain a chiral β-azaaromatic tertiary carbon center compound (III). In the reaction, a strategy of assisting the chiral classical hydrogen bonding action with the weak interaction of non-classical hydrogen bonds is used, a metal-free DPZ photocatalyst is used, the catalyst dosage is extremely small, the catalytic efficiency is high, and the reaction conditions are mild, stable and efficient, simple to operate, environmentally friendly, and the substrate range is wide (not only aryl azaaromatics but also alkyl azaaromatics), the product conversion rate is high, and the enantioselectivity is good.

Description

Technical Field

[0001] The invention specifically relates to a method for synthesizing chiral β-azaaromatic tertiary carbon center compounds, and belongs to the technical field of photocatalysis in organic synthesis. Background Art

[0002] Free radicals are usually highly reactive, which provides valuable opportunities for the direct use of inert raw materials and the easy realization of non-traditional bond cleavage and formation under mild reaction conditions. However, this unique property of free radicals in turn poses a huge challenge to asymmetric catalysis. Although catalytic strategies in ground state reactions have been widely used in enantioselective free radical reactions, the latter are much less successful than the former, especially the classic chiral hydrogen bond catalytic 1,4-conjugate addition of active olefins to directly construct a chiral stereocenter at the β-position of the olefin remains unsolved. In 2016, Melchiorre pioneered the use of chiral phosphoric acid (CPA) to catalyze the conjugate addition of α-amino radicals derived from dimethylaniline by photoredox catalysis to (E)-2-(p-methylphenyl)pyridine. Despite a lot of condition optimization, only 35% ee was obtained in the end. In terms of strategy, the single hydrogen bond interaction between CPA and olefin pyridine was used to provide an enantiostatic control environment. Due to the high reactivity of free radicals and the weak activation energy of hydrogen bonds, non-catalytic racemic background reactions are easily caused, resulting in poor enantioselectivity.

[0003] In asymmetric organocatalysis, although non-classical hydrogen bonding is very weak (<4 kcal / mol), it has been widely used to assist mainstream catalytic strategies to achieve high enantioselectivity. In general, the presence and pattern in the catalytic system is unpredictable, but some empirical strategies have been established. For example, the introduction of strong electron-withdrawing substituents can allow the aromatic group to form some specific carbon-hydrogen bonds as non-classical H-bond donors. The present invention uses this method to create non-classical hydrogen bonding interaction sites on α-amino radicals, which can solve this attractive but elusive conjugate addition reaction and realize the visible light asymmetric catalytic synthesis of chiral β-nitrogen aromatic tertiary carbon center compounds. Summary of the invention

[0004] The purpose of the present invention is to overcome the defects of the prior art and provide a method for synthesizing a tertiary carbon center compound of chiral β-azaaromatic hydrocarbons catalyzed by visible light. In the reaction, the strategy of using the weak interaction of non-classical hydrogen bonds to assist the chiral classical hydrogen bonding is used, a metal-free DPZ photocatalyst is used, the catalyst dosage is extremely small, the catalytic efficiency is high, the reaction conditions are mild, stable and efficient, the operation is simple, the environment is friendly, the substrate range is wide (not only aryl azaaromatic hydrocarbons but also alkyl azaaromatic hydrocarbons), the product conversion rate is high, and the enantioselectivity is good.

[0005] A method for synthesizing a chiral β-azaaromatic tertiary carbon center compound comprises the following steps: N-aryl substituted glycine (I) and (E)-2-aryl / alkyl vinyl azaaromatic (II) react in the presence of a chiral spirocyclic phosphonic acid catalyst CPA and a visible light catalyst dinitrile pyrazine derivative DPZ, with sodium dihydrogen phosphate and anthracene as additives, under visible light irradiation to obtain a chiral β-azaaromatic tertiary carbon center compound (III); the reaction equation is as follows:

[0006]

[0007] Wherein: R is C1-C6 alkyl, C1-C6 cycloalkyl, 1-butylene, 1-methylthioethyl, adamantyl, tetrahydropyranyl, phenyl, substituted phenyl, naphthyl, furanyl or benzyl; the substituent in the substituted phenyl is C1-C4 alkyl, C1-C4 alkoxy or halogen; Ar 2 It is a nitrogen-containing heterocyclic ring, including pyridine, substituted pyridine, thiazole, and N-methylbenzimidazole; the substituent in the substituted pyridine is one or more of halogen, C1-C4 alkyl, and phenyl.

[0008] Furthermore, in the above technical solution, the molar ratio of N-aryl substituted glycine (I) to (E)-2-aryl / alkyl vinyl azaarene (II) is 1:1-1.2.

[0009] Furthermore, in the above technical solution, the molar ratio of the visible light catalyst DPZ to the N-aryl substituted glycine (I) is 0.001-0.01:1.

[0010] Furthermore, in the above technical solution, the molar ratio of the chiral spirocyclic phosphonic acid catalyst to the N-aryl substituted glycine (I) is 0.1-0.2:1.

[0011] Furthermore, in the above technical solution, the molar ratio of disodium hydrogen phosphate to N-aryl substituted glycine (I) is 0.1-0.2:1.

[0012] Furthermore, in the above technical solution, the molar ratio of anthracene to N-aryl substituted glycine (I) is 0.5-0.6:1.

[0013] Furthermore, in the above technical solution, the reaction is carried out in toluene solvent under the protection of inert gas.

[0014] Furthermore, in the above technical solution, the wavelength of visible light is 450-455nm.

[0015] Furthermore, in the above technical solution, the reaction temperature is 0-30°C; preferably 25°C.

[0016] Beneficial effects of the present invention

[0017] Compared with the existing synthesis methods, the method of the present invention uses a metal-free DPZ photocatalyst, uses a small amount of catalyst, and has mild reaction conditions. It uses non-classical hydrogen bonds to assist classical hydrogen bonds to quickly, efficiently, and with high yield and high enantioselectivity to synthesize chiral β-nitrogen aromatic tertiary carbon center compounds. It is green and environmentally friendly and has great value for promotion and application. DETAILED DESCRIPTION

[0018] The technical solution of the present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.

[0019] In the following examples, the organic photocatalyst DPZ can be prepared according to the literature (Yu Zhao, Chenhao Zhang, Kek FooChin, Oldrich Pytela, Guo Wei, Hongjun Liu, Filip Bures, Zhiyong Jiang. RSC Adv., 2014, 4, 30062). Chiral spirocyclic phosphonic acid CPA was purchased from Daicel.

[0020] Optimization of experimental conditions

[0021]

[0022]

[0023]

[0024] a 0.05 mmol scale. b Irradiation distance. c Determined by TLC analysis of the UV(254 nm) and KMnO4 solution-staining signals between 2a and3ka. d Determined by HPLC analysis on a chiral stationary phase. e 2 x 3W blueLEDs were used. f Yield = 60%. g Yield = 55.6%. h Yield = 62%. i 3 x 3W blue LEDs were used. j Yield = 52.1%. k Yield = 73%.

[0025] Example 1

[0026]

[0027] Dissolve 1 mg / mL of organic photocatalyst DPZ in 200 μL of toluene, extract 35.5 μL (0.0005 mmol, 0.005 eq) into a 25 mL Schlenk tube, and blow dry the toluene with an air pump. Then add 28.7 mg (0.1 mmol) of [3,5-bis(trifluoromethyl)phenyl]glycine, 18.1 mg (0.1 mmol) of (E)-2-phenylphenylpyridine, 14.3 mg (0.02 mmol) of chiral spirocyclic phosphonic acid, 2.8 mg (0.02 mmol) of disodium hydrogen phosphate, and 10.7 mg (0.06 mmol) of anthracene, and then add 2 mL of purified and dried toluene. After three times of vacuuming, liquid nitrogen freezing, room temperature, and argon protection, the reaction bottle was placed in a 25 ° C thermostat and irradiated with a 3W blue LED lamp at a distance of 3 cm and stirred for 60 hours. After the reaction was completed, toluene was evaporated by rotary evaporator, and column chromatography (n-hexane / ethyl acetate 100-5:1) was used to obtain 28.8 mg of (S)-N-[2-phenyl-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 68% and 93% ee. 1 H NMR (300MHz, CDCl3) δ8.71(d,J=4.1Hz,1H),7.69(td,J=7.7,1.8Hz,1H),7.48-7.41(m,2H),7.40-7.37(m,1H),7.33(m,2H),7.35 7.30(m,1H),7.19(s,1H),7.13(d,J=7.8Hz,1H),6.92(s,2H),4.61(s,1H),3.70-3.57(m,2H),3.53-3.44(m,1H),3.42-3.23(m,2H); 13 C NMR (75MHz, CDCl3) δ159.3, 149.1, 148.6, 142.2, 136.7, 132.3 (q, J = 32.6Hz), 128.9, 127.6, 127. 2,123.8,123.7(q,J=254.2Hz),121.6,111.9(q,J=7.8Hz),109.9(q,J=7.3Hz),48.3,44.8,42.6; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z425.1447 (M+H + ),calc.for C 22 H 19F6N2 + 425.1443.

[0028] Example 2

[0029]

[0030] The (E)-2-vinylpyridine in Example 1 was replaced by (E)-2-(2-fluorophenyl)vinylpyridine, and the other steps were the same as in Example 1 to obtain 26.5 mg of (S)-N-[2-(2-fluorophenyl)-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 60% and 92% ee. 1 H NMR(300MHz, CDCl3)δ8.66(d,J=4.3Hz,1H),7.64(td,J=7.7,1.9Hz,1H),7.33-7.20(m,3H),7.22-7.10(m,3H),7.12-7.07(m,1H),6 .89(s,2H),4.68(t,J=6.0Hz,1H),3.96-3.84(m,1H),3.67-3.47(m,2H),3.41(dd,J=14.0,8.2Hz,1H),3.27(dd,J=14.0,6.1Hz,1H); 13 C NMR (75MHz, CDCl3) δ161.0 (d, J = 245.3Hz), 159.3, 149.2, 148.6, 136.8, 132.2 (q, J = 32.7Hz), 129.2q, J = 5.0Hz), 128.7 (q, J = 8.4Hz) ,124.5(q,J=3.5Hz),123.7,123.6(q,J=272.6Hz),121.7,116.1,115.7,111.8(q,J=3.2Hz),109.9(q,J=7.9Hz),47.3,41.1,39.1; 19 F NMR (376MHz, CDCl3) δ-63.2,-117.2; HRMS (ESI) m / z 443.1353 (M+H + ),calc.for C 22 H 18 F7N2 + 443.1345.

[0031] Example 3

[0032]

[0033] The (E)-2-phenylvinylpyridine in Example 1 was replaced by (E)-2-(3-chlorophenyl)vinylpyridine, and the other steps were the same as in Example 1 to obtain 27.5 mg of (S)-N-[2-(3-chlorophenyl)-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 60% and 94% ee. 1 H NMR (300MHz, CDCl3) δ8.71(d,J=4.8Hz,1H),7.69(td,J=7.7,1.7Hz,1H),7.72-7.29(m,4H),7.19(d,J=6.8Hz,2H),7.13(d,J=7.8Hz,1H ),6.93(s,2H),4.61(t,J=5.7Hz,1H),3.72-3.56(m,2H),3.49-3.46(m,1H),3.33(dd,J=14.1,7.5Hz,1H),3.24(dd,J=14.1,5.8Hz,1H); 13 C NMR (75MHz, CDCl3) δ158.9, 149.4, 148.5, 144.5, 136.7, 134.7, 132.3 (q, J = 32.6Hz), 130.2, 127. 8,127.4,126.0,125.4,123.8,121.8,111.9(q,J=3.0Hz),110.1(q,J=7.8,Hz),48.2,44.5,42.4; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z 459.1057 (M+H + ),calc.for C 22 H 18 ClF6N2 + 459.1047.

[0034] Example 4

[0035]

[0036] The (E)-2-vinylpyridine in Example 1 was replaced by (E)-2-(4-bromophenyl)vinylpyridine, and the other steps were the same as in Example 1 to obtain 36.6 mg of (S)-N-[2-(4-bromophenyl)-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 73% and 94% ee. 1H NMR (300MHz, CDCl3) δ8.59(d,J=4.7Hz,1H),7.59(td,J=7.7,1.8Hz,1H),7.44(d,J=8.4Hz,2H),7.18(dd,J=7.1,4.9Hz,1H),7.07(d,J=8.5Hz ,3H),7.00(d,J=7.8Hz,1H),6.82(s,2H),4.54(s,1H),3.58-3.46(m,2 H),3.38-3.30(m,1H),3.29-3.22(m,1H),3.11(dd,J=14.0,6.0Hz,1H); 13 C NMR (75MHz, CDCl3) δ158.8,149.9,149.0,148.5,141.2,137.0,132.0,132.3(q,J=32.7Hz),131.5,129.4,1 28.7,124.0,123.6(q,J=272.7Hz),121.9,121.0,111.9(q,J=3.3Hz),110.0(q,J=7.8Hz),48.2,44.3,42.2; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z 503.0 552 (M+H + ),calc.for C 22 H 18 BrF6N2 + 503.0544.

[0037] Example 5

[0038]

[0039] The (E)-2-phenylvinylpyridine in Example 1 was replaced by (E)-2-(2-toluene)vinylpyridine, and the other steps were the same as in Example 1 to obtain 31.5 mg of (S)-N-[2-(2-methylphenyl)-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 72% and 90% ee. 1H NMR (300MHz, CDCl3) δ8.67 (d, J=4.1Hz, 1H), 7.63 (td, J=7.7, 1.8Hz, 1H), 7.38-7.3 1(m,2H),7.27-7.19(m,3H),7.16(s,1H),7.03(d,J=7.8Hz,1H),6.90(s,2H),4.72 (s,1H),4.03-3.82(m,1H),3.62(dt,J=13.1,6.6Hz,1H),3.47(ddd,J=12.6,7.7,4 .8Hz,1H),3.33(dd,J=13.9,7.7Hz,1H),3.19(dd,J=13.9,6.1Hz,1H),2.26(s,3H); 13 C NMR (75MHz, CDCl3) δ159.6,149.0,148.7,140.4,136.6,136.5,132.2(q,J=32.6Hz),130.7,126.7,126.6,1 25.9,123.8,123.6(q,J=272.6Hz),121.6,111.8(q,J=2.9Hz),109.7(q,J=8.0Hz),48.1,42.8,39.5,19.6; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z 439.1603 (M+H + ),calc.for C 23 H 21 F6N2 + 439.1598.

[0040] Example 6

[0041]

[0042] The (E)-2-phenylvinylpyridine in Example 1 was replaced by (E)-2-(4-methoxyphenyl)vinylpyridine, and the other steps were the same as in Example 1 to obtain 24.1 mg of (S)-N-[2-(4-methoxyphenyl)-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 53% and 98% ee. 1H NMR (300MHz, CDCl3) δ8.59(d,J=4.2Hz,1H),7.57(td,J=7.7,1.7Hz,1H),7.21-7.04(m,4H),7.00(d,J=7.8Hz,1H) ,6.94-6.72(m,4H),4.52(s,1H),3.79(s,3H),3.54-3.39(m,2H),3.34-3.17(m,2H),3.13(dd,J=13.9,6.1Hz,1H); 13 C NMR (75MHz, CDCl3) δ159.4, 158.6, 148.8, 148.7, 136.9, 133.9, 132.2 (q, J = 32.6Hz), 128.6, 124. 0,123.6(q,J=272.7Hz),121.7,111.8(q,J=2.8Hz),109.8(q,J=7.9Hz),55.2,48.4,44.1,42.6; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z455.1553 (M+H + ),calc.for C 23 H 21 F6N2O + 455.1546.

[0043] Example 7

[0044]

[0045] The (E)-2-phenylvinylpyridine in Example 1 was replaced by (E)-2-(2-(naphthalene-2-yl)vinyl)pyridine, and the other steps were the same as in Example 1 to obtain 23.7 mg of (S)-N-[2-(2-fluorophenyl)-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 50% and 90% ee. 1H NMR (300MHz, CDCl3) δ8.61(d,J=3.5Hz,1H),7.84(d,J=8.1Hz,2H),7.77(d,J=5.2Hz,1H),7.6 3(d,J=1.7Hz,1H),7.62-7.50(m,1H),7.53-7.42(m,2H),7.38(dd,J=8.5,1.8Hz,1H),7.18(dd ,J=7.5,5.0Hz,1H),7.09(s,1H),7.02(d,J=7.8Hz,1H),6.84(s,2H),4.59(s,1H),3.80-3.64( m,1H),3.70-3.55(m,1H),3.53-3.41(m,1H),3.46-3.33(m,1H),3.27(dd,J=14.0,6.5Hz,1H); 13 C NMR (75MHz, CDCl3) δ159.1,148.7,148.6,139.3,137.1,133.5,132.6,132.2(q,J=32.6Hz),128.8,127.7,1 27.6,126.6,126.4,125.9,125.4,124.0,121.8,111.9(q,J=3.1Hz),109.8(q,J=7.8Hz),48.2,45.0,42.3; 19 F NMR (376MHz, CDCl3) δ-63.1; HRMS (ESI) m / z 475.1603 (M+H + ),calc.for C 26 H 21 F6N2 + 475.1596.

[0046] Example 8

[0047]

[0048] The (E)-2-phenylvinylpyridine in Example 1 was replaced with (E)-2-(furan-2-yl)vinylpyridine, and the other steps were the same as in Example 1 to obtain 21.5 mg of (S)-N-[2-(furan-2-yl)-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 52% and 98% ee. 1H NMR (300MHz, CDCl3) δ8.58 (d, J=4.8Hz, 1H), 7.60 (td, J=7.7, 1.9Hz, 1H), 7.37 (dd ,J=1.9,0.8Hz,1H),7.18(ddd,J=7.6,4.9,1.1Hz,1H),7.10-7.00(m,2H),6.85(s ,3H),6.28(dd,J=3.2,1.9Hz,1H),6.04(d,J=3.2Hz,1H),4.73(t,J=6.1Hz,1H),3 .72-3.59(m,1H),3.53-3.34(m,2H),3.24(d,J=1.9Hz,1H),3.21(d,J=3.1Hz,1H); 13 C NMR(75MHz, CDCl3)δ158.77,155.11,148.95,148.62,141.80,136.89,132.23(q,J=32.6Hz),123.85,123.5 8(q,J=272.2Hz),121.77,111.80(q,J=2.9Hz),110.23,109.82(q,J=8.1Hz),106.63,45.90,39.50,38.52; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z 415.1240 (M+H + ),calc.for C 20 H 17 F6N2O + 415.1232.

[0049] Example 9

[0050]

[0051] The (E)-2-phenylvinylpyridine in Example 1 was replaced by (E)-2-phenylvinyl-3-chloropyridine, and the other steps were the same as in Example 1 to obtain 27.9 mg of (S)-N-[2-(2-fluorophenyl)-3-(3-chloropyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 61% and 92% ee. 1H NMR (300MHz, CDCl3) δ8.50 (dd, J=4.8, 1.5Hz, 1H), 7.66 (dd, J=8.0, 1.5Hz, 1H), 7.39-7.32 (m, 2H), 7.31-7. 22(m,3H),7.18-7.11(m,1H),7.09(s,1H),6.84(s,2H),4.26(s,1H),3.75-3.55(m,2H),3.43-3.32(m,3H); 13 CNMR (75MHz, CDCl3) δ156.7, 148.5, 147.1, 142.2, 137.1, 132.3 (q, J = 32.6Hz), 131.6, 128.9, 127. 7,127.2,123.6(q,J=272.5Hz),122.7,112.0(q,J=3.9Hz),109.9(q,J=8.0Hz),48.1,42.8,39.4; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z 459.1057 (M+H + ),calc.for C 22 H 18 ClF6N2 + 459.1049.

[0052] Example 10

[0053]

[0054] The (E)-2-phenylvinylpyridine in Example 1 was replaced by (E)-2-phenylvinyl-4-methoxypyridine, and the other steps were the same as in Example 1 to obtain 22.7 mg of (S)-N-(2-phenyl-3-(4-methoxypyridin-2-yl)propyl)-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 50% and >99% ee. 1H NMR(300MHz, CDCl3)δ8.38(d,J=5.8Hz,1H),7.22-7.17(m,2H),7.24(t,J=5.0Hz,1 H),7.20(m,2H),7.05(s,1H),6.79(s,2H),6.67(dd,J=5.8,2.5Hz,1H),6.47(d,J= 2.4Hz,1H),4.65(d,J=5.9Hz,1H),3.73(s,3H),3.48(dd,J=12.9,8.0Hz,2H),3.34 (dd,J=9.3,4.9Hz,1H),3.20(dd,J=13.8,7.5Hz,1H),3.08(dd,J=13.8,5.8Hz,1H); 13 C NMR (75MHz, CDCl3) δ166.1, 161.0, 150.2, 148.7, 142.3, δ 132.2 (q, J = 32.6Hz), 128.8, 127.6, 127.1, 123.6(q,J=272.7Hz),111.7(q,J=3.1Hz),109.8,109.6(q,J=7.9Hz),107.9,55.0,48.3,44.7,42.7; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z 455.1553 (M+H + ),calc.for C 23 H 21 F6N2O + 455.1545.

[0055] Embodiment 11

[0056]

[0057] The (E)-2-phenylvinylpyridine in Example 1 was replaced with (E)-2-methyl-4-phenyl-6-phenylvinylpyridine, and the other steps were the same as in Example 1 to obtain 29.8 mg of (S)-N-[2-phenyl-3-(4-phenyl-6-methylpyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 58% and 93% ee. 1H NMR (300MHz, CDCl3) δ7.53-7.47(m,2H),7.46-7.38(m,3H),7.53-7.47(m,2H),7.31-7.27(m,1H),7.27-7.22(m,3H ),7.08(s,1H),6.99(s,1H),6.81(s,2H),4.84(t,J=5.4Hz,1H),3.63-3.36(m,3H),3.33-3.13(m,2H),2.65(s,3H); 13 C NMR (75MHz, CDCl3) δ159.3, 158.4, 149.2, 148.7, 142.4, 138.3, 132.2 (q, J = 32.6Hz), 128.9, 128.9, 127. 7,127.1,127.0,123.6(q,J=272.8Hz),119.2,119.0,111.7,109.6(q,J=3.9Hz),48.5,45.1,43.0,24.5; 19 F NMR (565MHz, CDCl3) δ-63.2; HRMS (ESI) m / z 515.1916 (M+H + ),calc.for C 29 H 25 F6N2 + 515.1912.

[0058] Example 12

[0059]

[0060] The (E)-2-phenylvinylpyridine in Example 1 was replaced with (E)-2-(3-phenylpropyl-1-enyl-1-yl)pyridine, and the other steps were the same as in Example 1 to obtain 31.1 mg of (R)-N-[2-benzyl-3-(pyridin-2-yl)propyl]-3,5-di(trifluoromethyl)aniline as a yellow oil with a yield of 71% and 95% ee. 1 H NMR (300MHz, CDCl3) δ8.61(d,J=4.3Hz,1H),7.71-7.56(m,1H),7.41-7.27(m,3H),7.22(dd,J=7.4,6.0Hz,3H),7.15-7.00( m,2H),6.74(s,2H),5.04(s,1H),3.16(d,J=4.6Hz,2H),3.03-2.88(m,2H),2.86-2.72(m,2H),2.67(dd,J=11.8,5.2Hz,2H); 13C NMR (75MHz, CDCl3) δ159.8,148.8,148.5,139.6,137.2,132.1(q,J=32.6Hz),129.0,128 .6,126.4,124.1,121.6,111.6(q,J=3.3Hz),109.4(q,J=7.7Hz),46.7,40.7,39.8,39.5; 19 F NMR (376MHz, CDCl3) δ-63.2; HRMS (ESI) m / z 439.1603 (M+H + ),calc.for C 23 H 21 F6N2 + 439.1597.

[0061] Embodiment 13

[0062]

[0063] The (3,5-bis(trifluoromethyl)phenyl)glycine in Example 1 was replaced with [(4-trifluoromethyl)phenyl]glycine, and the (E)-2-phenylvinylpyridine was replaced with (E)-2-(pent-1-en-1-yl)pyridine. The other steps were the same as in Example 12 to obtain 24.8 mg of (R)-N-[2-(pyridin-2-ylmethyl)pentyl]-4-trifluoromethylaniline as a yellow oil with a yield of 77% and 94% ee. 1 H NMR (300MHz, CDCl3) δ8.56 (dd, J=5.1, 1.8Hz, 1H), 7.60 (td, J=7.7, 1.9Hz, 1H), 7.34 (d,J=8.4Hz,2H),7.19-7.09(m,2H),6.52(d,J=8.5Hz,2H),4.76(s,1H),3.13(dd,J= 12.8,5.4Hz,1H),3.01(dd,J=12.8,7.3Hz,1H),2.89(dd,J=13.8,5.9Hz,1H),2.82( dd,J=13.8,7.1Hz,1H),2.31-2.16(m,1H),1.50-1.35(m,4H),0.91(t,J=6.8Hz,3H); 13 C NMR (75MHz, CDCl3) δ160.5, 151.0, 148.8, 136.6, 126.5 (q, J = 3.8Hz), 125.1 (q, J = 270. 2Hz), 123.9, 121.3, 118.0 (q, J = 32.5Hz), 111.5, 46.9, 41.0, 38.1, 34.9, 20.1, 14.3.;19 F NMR (565MHz, CDCl3) δ-60.9; HRMS (ESI) m / z 323.1730 (M+H + ),calc.for C 18 H 22 F3N2 + 323.1725.

[0064] Embodiment 14

[0065]

[0066] The (E)-2-(pent-1-en-1-yl)pyridine in Example 13 was replaced with (E)-2-(4-(methylthio)but-1-en-1-yl)pyridine, and the other steps were the same as in Example 12 to obtain 30.9 mg of (S)-N-[4-methylthio-2-(pyridin-2-ylmethyl)butyl]-4-(trifluoromethyl)aniline as a yellow oil with a yield of 87% and 92% ee. 1 H NMR (300MHz, CDCl3) δ8.55 (d, J=3.9Hz, 1H), 7.60 (td, J=7.7, 1.9Hz, 1H), 7.34 (d,J=8.5Hz,2H),7.15(dd,J=7.6,4.4Hz,2H),6.53(d,J=8.5Hz,2H),4.76(s,1 H),3.14(dd,J=12.8,5.8Hz,1H),3.05(dd,J=12.8,7.0Hz,1H),2.88-2.85(m, 1H),2.56(t,J=7.6Hz,2H),2.42-2.28(m,1H),2.05(s,3H),1.74-1.62(m,2H); 13 C NMR (75MHz, CDCl3) δ159.8,150.8,148.9,136.6,126.4(q,J=3.8Hz),125.0(q,J=270 .1Hz),123.8,121.4,118.1(q,J=32.5Hz),111.6,46.7,40.6,37.4,31.8,31.7,15.4; 19 F NMR (376MHz, CDCl3) δ-60.9; HRMS (ESI) m / z 355.1450 (M+H + ),calc.for C 18 H 22 F3N2S + 355.1445.

[0067] Embodiment 15

[0068]

[0069] The (E)-2-(pent-1-en-1-yl)pyridine in Example 13 was replaced with (E)-2-(hex-1-en-5-yn-1-yl)pyridine, and the other steps were the same as Example 13 to obtain 23.6 mg of (R)-N-[2-(pyridin-2-ylmethyl)hex-5-yn-1-yl]-4-(trifluoromethyl)aniline as a white solid with a melting point of 107.2-108.3°C and a yield of 71%, 92% ee. 1 H NMR (300MHz, CDCl3) δ8.59(d,J=1.7Hz,1H),7.62(td,J=7.7,1.9Hz,1H),7.31(d,J =8.5Hz,2H),7.22-7.12(m,2H),6.42(d,J=8.5Hz,2H),5.05(d,J=2.3Hz,1H),4.64( s,1H),4.57(d,J=2.4Hz,1H),3.55(d,J=9.5Hz,1H),3.30-3.20(m,1H),2.19-3.09( m,1H),2.73-2.63(m,1H),2.62-2.52(m,2H),2.20-2.05(m,1H),1.62-1.42(m,1H); 13 C NMR (75MHz, CDCl3) δ163.2,154.4,150.8,149.4,136.7,126.4(q,J=3.8Hz),125.1(q,J=2 70.0Hz), 122.9, 121.6, 118.1 (q, J = 32.5Hz), 111.5, 108.7, 57.7, 47.9, 46.6, 32.9, 30.1; 19 F NMR (376MHz, CDCl3) δ-60.9; HRMS (ESI) m / z 333.1572 (M+H + ),calc.for C 18 H 18 F3N2 + 333.1567.

[0070] Example 16

[0071]

[0072] The (E)-2-(pent-1-en-1-yl)pyridine in Example 13 was replaced by (E)-2-[2-(tetrahydro-2H-pyran-4-yl)enyl]pyridine, and the other steps were the same as Example 13 to obtain 26.2 mg of (S)-N-3-(pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)propyl-4-(trifluoromethyl)aniline as a white solid with a melting point of 67.0-68.6°C and a yield of 72%, >99% ee. 1 H NMR (300MHz, CDCl3) δ8.56 (d, J = 4.7Hz, 1H), 7.59 (td, J = 7.7, 1.9Hz, 1H), 7.33 (d, J = 8. 4Hz,2H),7.19-7.08(m,2H),6.47(d,J=8.4Hz,2H),4.89(s,1H),4.07-3.90(m,2H),6.5 3-6.40(m,2H),3.18(dd,J=12.5,5.2Hz,1H),3.06(dd,J=12.6,7.5Hz,1H),2.98(dd,J =14.2,4.7Hz,1H),2.79(dd,J=14.2,8.2Hz,1H),2.22-2.06(m,1H),1.79-1.50(m,5H); 13 CNMR(75MHz, CDCl3)δ160.6,150.8,149.0,136.6,126.4(q,J=3.8Hz),125.0(q,J=270.1Hz) ,123.7,121.3,118.0(q,J=32.5Hz),111.5,77.0,68.2,44.5,43.0,38.2,37.3,30.1,29.9; 19 F NMR (376MHz, CDCl3) δ-60.9; HRMS (ESI) m / z 365.1835 (M+H + ),calc.forC 20 H 24 F3N2O + 365.1833.

[0073] Embodiment 17

[0074]

[0075] The (E)-2-(pent-1-en-1-yl)pyridine in Example 13 was replaced with 2-((E)-2-((3r,5r,7r)-adamantane-1-yl)enyl)pyridine, and the other steps were the same as in Example 13 to obtain 29.8 mg of N-(S)-2-[(3S,5S,7S)-adamantane-1-yl]-3-(pyridin-2-yl)propyl-4-(trifluoromethyl)aniline as a white solid with a melting point of 105.3-106.4°C and a yield of 72%, >99% ee. 1 H NMR(300MHz, CDCl3) δ8.56(d,J=4.2Hz,1H),7.56(td,J=7.7,1.9Hz,1H),7.30( d,J=8.5Hz,2H),7.17-7.08(m,2H),6.41(d,J=8.5Hz,2H),5.40(s,1H),3.38(d ,J=11.5Hz,1H),3.14(dd,J=14.5,3.4Hz,1H),2.98(t,J=10.3Hz,1H),2.65(dd ,J=14.5,7.7Hz,1H),2.07-1.99(m,3H),1.86-1.76(m,2H),1.75-1.57(m,12H); 13 C NMR (75MHz, CDCl3) δ162.6,151.1,148.8,136.7,126.3(q,J=3.8Hz),125.2(q,J=270.1H z),123.5,121.0,117.4(q,J=32.5Hz),111.2,49.0,43.7,39.9,37.1,36.91,35.5,28.6; 19 F NMR (376MHz, CDCl3) δ-60.7; HRMS (ESI) m / z 415.2356 (M+H + ),calc.for C 25 H 30 F3N2 + 415.2354.

[0076] Embodiment 18

[0077]

[0078] The (E)-2-(pent-1-en-1-yl)pyridine in Example 13 was replaced with (E)-4-chloro-2-(2-cyclohexylenyl)pyridine, and the other steps were the same as Example 13 to obtain 33.3 mg of (S)-N-[3-(4-chloropyridin-2-yl)-2-cyclohexylpropyl]-4-(trifluoromethyl)aniline as a yellow solid with a melting point of 115.6-116.8°C and a yield of 84%, 98% ee. 1 H NMR (300MHz, CDCl3) δ8.44(d,J=6.1Hz,1H),7.34(d,J=8.4Hz,2H),7.18-7.08(m,2H),6.47(d,J=8.4Hz,2H),4.68(s,1H),3.26-3.12(m,1H),3.09-2 .97(m,1H),2.92(dd,J=14.2,4.8Hz,1H),2.74(dd,J=14.2,8.2Hz,1H),2. 16-2.03(m,1H),1.83-1.63(m,5H),1.54-1.38(m,1H),1.28-1.06(m,5H); 13 C NMR (75MHz, CDCl3) δ163.2, 150.8, 149.9, 144.3, 126.5 (q, J = 3.8Hz), 125.1 (q, J = 270.2Hz), 12 3.8,121.6,118.0(q,J=32.5Hz),111.4,44.8,43.6,40.0,38.5,30.0,29.7,26.6,26.6,26.5; 19 F NMR (376MHz, CDCl3) δ-60.9; HRMS (ESI) m / z397.1653 (M+H + ),calc.for C 21 H 25 ClF3N2 + 397.1648.

[0079] Embodiment 19

[0080]

[0081] The (E)-2-(pent-1-en-1-yl)pyridine in Example 13 was replaced by (E)-2-(2-cyclohexylenyl)-1-methyl-1H-benzo[d]imidazole, and the other steps were the same as Example 13 to obtain 22.8 mg of (S)-N-[2-cyclohexyl-3-(pyridin-4-yl)propyl]-4-(trifluoromethyl)aniline as a white solid with a melting point of 154.6-155.8°C and a yield of 55%, 91% ee. 1H NMR (300MHz, CDCl3) δ7.78-7.70(m,1H),7.32-7.25(m,3H),7.25-7.20(m,2 H),6.31(d,J=8.4Hz,2H),4.90(s,1H),3.56(s,3H),3.34-3.24(m,1H),3.2 3-3.12(m,1H),2.99(dd,J=15.5,4.2Hz,1H),2.86(dd,J=15.5,9.3Hz,1H), 2.43-2.29(m,1H),1.88-1.70(m,5H),1.62-1.52(m,1H),1.31-1.16(m,5H); 13 C NMR (75MHz, CDCl3) δ154.8, 150.6, 142.1, 135.7, 126.3 (q, J = 3.8Hz), 125.0 (q, J = 270.0Hz), 122.2, 122. 0,119.6,118.4,117.8(q,J=32.5Hz),109.0,45.7,41.4,40.8,30.0,29.7,29.6,28.8,26.6,26.6,26.5; 19 F NMR (376MHz, CDCl3) δ-60.8; HRMS (ESI) m / z 416.2308 (M+H + ),calc.for C 24 H 29 F3N3 + 416.2302.

[0082] Embodiment 20

[0083]

[0084] The (E)-2-(pent-1-en-1-yl)pyridine in Example 13 was replaced by (E)-2-(2-cyclohexanedyl)thiazole, and the other steps were the same as Example 13 to obtain 22.8 mg of (S)-N-[2-cyclohexyl-3-(thiazol-2-yl)propyl]-4-(trifluoromethyl)aniline as a white solid with a melting point of 80.1-81.6°C and a yield of 82%, 90% ee. 1H NMR (300MHz, CDCl3) δ7.71(d,J=3.4Hz,1H),7.35(d,J=8.5Hz,2H),7.21(d,J=3.4Hz,1H),6.51(d,J=8.5Hz,2H),4.49(s,1H),3.26(dd,J=12.8,5.4H z,1H),3.17(dd,J=15.1,4.9Hz,1H),3.13-2.98(m,2H),2.20-2.03(tq,J= 7.9,5.0Hz,1H),1.87-1.68(m,9H),1.56-1.43(m,1H),1.34-1.14(m,5H); 13 C NMR (75MHz, CDCl3) δ170.1, 150.7, 142.2, 126.4 (q, J = 3.8Hz), 125.0 (q, J = 270.2Hz), 11 8.4,118.1(q,J=32.5Hz),111.2,44.7,44.1,39.6,33.5,30.0,29.8,26.6,26.5,26.5; 19 F NMR (376MHz, CDCl3) δ-61.0; HRMS (ESI) m / z 369.1607 (M+H + ),calc.forC 19 H 24 F3N2S + 369.1603.

[0085] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing a chiral β-azaarene tertiary carbon center compound, characterized in that: The method comprises the following steps: N-aryl substituted glycine (I) and (E)-2-aryl / alkyl vinyl azaaromatic hydrocarbon (II) are reacted in the presence of a chiral spirocyclic phosphonic acid catalyst CPA and a visible light catalyst dinitrile pyrazine derivative DPZ, with sodium dihydrogen phosphate and anthracene as additives, under visible light irradiation to obtain a chiral β-azaaromatic hydrocarbon tertiary carbon center compound (III); the reaction equation is as follows: Wherein: R is C1-C6 alkyl, C1-C6 cycloalkyl, 1-methylthioethyl, adamantyl, tetrahydropyranyl, phenyl, substituted phenyl, naphthyl, furanyl or benzyl; the substituent in the substituted phenyl is C1-C4 alkyl, C1-C4 alkoxy or halogen; Ar 2 The method comprises the following steps: the first step is to prepare a reaction mixture comprising pyridine, substituted pyridine, thiazole, and N-methylbenzimidazole; the substituent in the substituted pyridine is one or more of halogen, C1-C4 alkyl, and phenyl; the molar ratio of the N-aryl substituted glycine (I) to the (E)-2-aryl / alkyl vinyl nitrogen heteroaromatic hydrocarbon (II) is 1:1-1.2; the molar ratio of disodium hydrogen phosphate to the N-aryl substituted glycine (I) is 0.1-0.2:1; the molar ratio of anthracene to the N-aryl substituted glycine (I) is 0.5-0.6:1; the reaction is carried out in a toluene solvent under the protection of an inert gas; and the reaction temperature is 0-30°C.

2. The method for synthesizing the chiral β-azaarene tertiary carbon center compound according to claim 1, characterized in that: The molar ratio of the visible light photocatalyst DPZ to the N-aryl substituted glycine (I) is 0.001-0.01:

1.

3. The method for synthesizing chiral β-azaarene tertiary carbon center compounds according to claim 1, characterized in that: The molar ratio of the chiral spirocyclic phosphonic acid catalyst to the N-aryl substituted glycine (I) is 0.1-0.2:

1.

4. The method for synthesizing a chiral β-azaarene tertiary carbon center compound according to any one of claims 1 to 3, characterized in that: The wavelength of visible light is 450-455nm.

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