Method for synthesis of chiral nitrogen heteroarenes by visible light catalyzed three-component reaction

Abstract

The application discloses a method for synthesizing chiral nitrogen heteroarenes by a three-component reaction under visible light irradiation, and belongs to the technical field of organic synthesis. Under a nitrogen atmosphere, nitrogen-containing heterocycle I, high allyl alcohol II and halide III are reacted in an organic solvent under visible light irradiation in the presence of an organic photocatalyst DPZ, a chiral phosphoric acid catalyst (S-CPA) and an inorganic base to obtain chiral nitrogen heteroarenes. The method has wide substrate universality, the product has one or two chiral centers, and has a chiral or achiral tertiary alcohol structural unit. The reaction condition is mild, the enantioselectivity is high, and no metal is involved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing chiral nitrogen-containing aromatic compounds via visible light-catalyzed three-component reaction. Background Technology

[0002] Aromatic compounds have wide applications in pharmaceuticals, natural products, and materials (A. Abdildinova, Y. Gong, ACS Comb. Sci. 2018, 20, 309; (b) A. Taylor, R. Robinson, Y. M. Fobian, Org. Biomol. Chem. 2016, 14, 6611. (c) P. Silva Junior, C. LCD Rezende, J. P. Meines, et al. RSC Adv. 2016, 6, 22777). In the field of green organic synthesis, the construction of complex compounds with rich and diverse structures through the combination of various simple reaction substrates has significant theoretical research value and practical application value.

[0003] Currently, reported methods for synthesizing chiral aza-aromatic compounds can be divided into two categories. One category involves using pre-synthesized complex substrates containing aza-aromatic structural units for chiral functionalization modification (Yin, Y.; Li, Y. et al. J. Am. Chem. Soc. 2020, 142, 19451; RP Jumde, SR Harutyunyan. Science, 2016, 352, 433; S. Yu, HL Sang, S. Ge Angew. Chem. Int. Ed. 2017, 56, 15896; T. Shao, Y. Li, et al. iScience 2019, 16, 410; Y. Yin, Y. Dai, et al. J. Am. Chem. Soc. 2018, 140, 6083; K. Cao, SMTan, et al.). al. J. Am. Chem. Soc. 2019, 141, 5437); another type is based on the direct asymmetric addition of simple aza-aromatic structural units (i.e., the Minisci reaction) (RSJ Proctor, HJ Davis, RJP hipps, Science 2018, 360, 419; X. Liu, Y. Liu, G. Chai, B. Qiao, X. Zhao, Z. Jiang, Org. Lett. 2018, 20, 6298).

[0004] In June 2019, Studer's group reported the synthesis of aza-aromatic derivatives with a single chiral center under visible light irradiation using [Ir(dF(CF3)ppy)2(dtbpy)]PF6 as a photocatalyst, with aza-aromatics, alkenylamines, and bromoacetates as raw materials (D. Zheng, A. Studer, Angew. Chem. Int. Ed. 2019, 58, 15803). Of the above reports, only one concerns the asymmetric synthesis of aza-aromatics from three components, which has limited substrate types, a single product structure, and uses the transition metal iridium as a photosensitizer.

[0005] Therefore, it is necessary to develop methods that have a wider substrate adaptability and can avoid the synthesis of bipolar central nitrogen-containing aromatic compounds using transition metals. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing multi-chiral nitrogen-containing aromatic compounds by visible light catalytic three-component reaction. This method has simple substrates, mild reaction conditions, low catalyst dosage, high enantioselectivity, and no metal involvement.

[0007] To achieve the above objectives, the present invention employs the following technical solution: a method for synthesizing chiral nitrogen-containing aromatic compounds via a visible-light catalytic three-component reaction, comprising the following steps: reacting a nitrogen-containing heterocycle I, a homoallyl alcohol II, and a halide III in an organic solvent under visible light irradiation in the presence of an organic photocatalyst DPZ, a chiral phosphoric acid catalyst S-CPA, and an inorganic base to obtain a chiral nitrogen-containing aromatic compound; the reaction equation is as follows:

[0008]

[0009] Where: R 1 and R 2 Each is independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, R 3 The radical is selected from phenylacetyl, C1-C4 alkoxycarbonyl difluoromethyl, naphthylacetyl, cyclopropionyl butyryl, and diethyl malonate, and X is selected from Cl, Br, or I.

[0010] Furthermore, in the above technical solution, the aza-aromatic hydrocarbon I is selected from pyridine, quinoline, isoquinoline, or quinoxaline.

[0011] Furthermore, in the above technical solution, the molar ratio of the organic photocatalyst DPZ to the nitrogen-containing heterocyclic I is 0.002-0.005:1. The organic photocatalyst DPZ selected in this invention has a small relative molecular mass, is easy to synthesize, and possesses high catalytic efficiency.

[0012] Furthermore, in the above technical solution, the molar ratio of high allyl alcohol II, halogenated product III, and nitrogen-containing heterocyclic I is 2:2:1.

[0013] Furthermore, in the above technical solution, the molar ratio of the chiral phosphoric acid catalyst S-CPA to the nitrogen-containing heterocyclic I is 0.10-0.15:1.

[0014] Furthermore, in the above technical solution, the inorganic base is selected from NaHCO3, K2HPO4 or K2CO3, and the molar ratio of the inorganic base to the nitrogen-containing heterocyclic I is 1-2:1.

[0015] Furthermore, in the above technical solution, the organic solvent is selected from 1,2-dichloroethane or dichloromethane.

[0016] Furthermore, in the above technical solution, the reaction temperature is below -20℃ and the reaction time is not less than 10 hours.

[0017] Furthermore, in the above technical solution, the reaction is carried out under the protection of an inert gas.

[0018] Furthermore, in the above technical solution, the visible light is visible light with a wavelength of 450-455nm, such as irradiation by a 3-watt blue lamp.

[0019] The present invention further provides chiral nitrogen-containing aromatic compounds, the general structural formula of which is as follows:

[0020]

[0021] Where: R 1 and R 2 Each is independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, R 3 The hydrocarbon is selected from phenylacetyl, C1-C4 alkoxycarbonyl difluoromethyl, naphthylacetyl, cyclopropionyl butyryl, and diethyl malonate; X is selected from Cl, Br, or I; and the azo aromatic hydrocarbon I is selected from pyridine, quinoline, isoquinoline, or quinoxaline.

[0022] Furthermore, in the above technical solution, the anticancer agent is selected from anti-breast cancer MCF-7, cervical cancer HeLa, liver cancer HβG2, or malignant melanoma A-375.

[0023] The azo aromatic compounds constructed in this invention have bichiral centers and contain chiral tertiary alcohol units. The reaction uses a metal-free DPZ photocatalyst, which requires very little catalyst, has high catalytic efficiency, and the reaction conditions are mild, stable, efficient, simple to operate, environmentally friendly, and have high product conversion and good selectivity.

[0024] Compared with existing synthesis methods, the most significant feature of this invention is the synthesis of novel chiral nitrogen-containing aromatic hydrocarbon molecules. It requires less catalyst, operates under mild reaction conditions, is rapid and efficient, yields high efficiency, and is environmentally friendly. The synthesized product exhibits certain anticancer activity and has significant potential for widespread application.

[0025] This invention involves a wide range of substrates and produces diverse products; the bichiral central nitrogen-containing aromatic compounds constructed are currently unreported. Furthermore, this invention uses DPZ as a small organic molecule photocatalyst and chiral phosphoric acid as a small organic molecule catalyst, which offers advantages such as high catalytic efficiency and no metal residue in the reaction system. Detailed Implementation

[0026] The technical solution of the present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0027]

[0028] Organic photocatalyst DPZ and chiral phosphoric acid catalyst were prepared according to relevant literature (Y. Zhao, C. Zhang, et al. RSC Adv., 2014, 4, 30062; T. Shao, Y. Li, et al. iScience 2019, 16, 410). Inorganic base was purchased from Anaiji Reagent Company. The optimized conditions are as follows:

[0029]

[0030] [a]Reaction conditions:1a(0.15mmol,1.5equiv.),1'(0.15mmol,1.5equiv.),isoquinoline(0.1mmol,1.0equiv.),DPZ(0.2mol%),Cat.(10mol%)and base(0.2mmol,2.0equiv.)in solvent(1mL)underN2 atmosphere,irritationby a 3W blue LED for12h.[b]Yield of isolated product.[c]Enantiomeric excess determined by HPLC onchiral stationary phase.

[0031] The specific preparation steps of compound 4a (R configuration) in Example 1 are as follows:

[0032]

[0033] Accurately weigh 2-bromoacetophenone (0.2 mmol, 12.9 mg), DPZ (0.002 mmol, 0.071 mg), S-CPA (0.01 mmol, 5.8 mg), K₂HPO₄ (0.15 mmol, 34.8 mg), NaHCO₄ (0.15 mmol, 12.3 mg), and K₂CO₃ (0.1 mmol, 13.8 mg) and add them to a 10 mL Schlenk tube. Then add 2.0 mL of dichloromethane and stir thoroughly. Next, add isoquinoline (0.1 mmol, 12.9 mg) and compound 3a (0.2 mmol, 45.0 mg) sequentially. After weighing, seal the tube and remove air from the reaction flask using a double-row tube freezing-vacuum method. Repeat the degassing process three times. Then, freeze the reaction flask at -30°C for 20 minutes, irradiate it with a light source, and react for 24 hours. After the reaction was complete, 2 / 3 of the solution was evaporated using a rotary evaporator, and the solution was directly separated by column chromatography (n-hexane / ethyl acetate 60-10:1) to obtain 32.5 mg of white solid 4a, melting point 83.8-85.1℃; yield 69%, 94% ee; 1 H NMR(600MHz, CDCl3)δ8.44(d,J=5.7Hz,1H),7.80-7.69(m,4H),7.60(t,J=7.4Hz,1H),7.52-7 .44(m,2H),7.40(t,J=7.6Hz,1H),7.38-7.30(m,6H),7.23(t,J=7.6Hz,2H),7.16(t,J=7.3Hz, 1H),7.10(t,J=7.7Hz,2H),7.02(t,J=7.3Hz,1H),4.02-3.93(m,1H),3.51(brs,1H),3.21(br s,1H),2.86(dd,J=14.4,3.3Hz,1H),2.83-2.74(m,1H),2.74–2.65(m,1H),2.37-2.18(m,2H); 13 C NMR (151MHz, CDCl3) δ200.1,164.8,147.5,146.8,136.7,136.5,132.9,130.1,128.4,128.0,127.9,127.8, 127.2,127.1,127.1,126.6,126.4,126.0,126.0,125.1,119.5,78.2,45.5,36.5,35.8,31.6; HRMS(ESI)m / z 472.2263(M+H + ),calc.for C 33 H 30 NO2 +472.2271; Ee was determined by HPLC analysis: CHIRALPAK IA (4.6mm idx 250mm); hexane / 2-propanol=80 / 20; flow rate 1.0mL / min; 25℃; 230nm; retention time: 9.9min (minor), 12.0min (major).

[0034] Example 2 Synthesis of compound 4b

[0035]

[0036] In this embodiment, 3a in Example 1 was replaced with 3b, and the other steps were the same as in Example 1, yielding 30.7 mg of colorless oily liquid 4b, with a yield of 75%, dr > 19:1, and 96% ee. 1 H NMR (400MHz, CDCl3) δ8.49(d,J=5.7Hz,1H),7.84(d,J=8.6Hz,1H),7.79(d,J=8.3,1H ),7.76-7.70(m,2H),7.67-7.60(m,1H),7.55-7.40(m,3H),7.41-7.33(m,2H),7.29- 7.23(m,2H),7.23-7.10(m,2H),3.86-3.75(m,1H),3.14-2.98(m,1H),2.84-2.61(m, 2H),2.39(dd,J=14.5,3.5Hz,1H),2.24-2.11(m,1H),2.11-1.99(m,1H),1.51(s,3H); 13 C NMR (101MHz, CDCl3) δ199.9,164.5,147.6,141.0,136.7,136.5,132.8,130.0,128.4,127.9,127 .9,127.3,127.2,127.1,126.1,124.8,124.8,74.8,46.9,37.2,35.5,32.1,31.5; HRMS(ESI)m / z 410.2107(M+H + ), calc.forC 28 H 28 NO2 +410.2115; Ee was determined by HPLC analysis: FLM CHIRAL NX(2)(4.6mmi.dx 250mm); Hexane / 2-propanol=80 / 20; flow rate 1.0mL / min; 25℃; 230nm; retention time: 20.2min (minor) and 20.0min, 24.8min (major).

[0037] Example 2 Synthesis of compound 4c

[0038]

[0039] In Example 1, 3a was replaced with 3c, and the other steps were the same as in Example 1, yielding 30.0 mg of 4c, with a yield of 66% and a melting point of 109.5-110.8 °C. dr>19:1, 96% ee 1 H NMR (400MHz, CDCl3) δ8.48 (d, J = 5.7Hz, 1H), 7.80-7.61 (m, 6H), 7.59-7.28 (m, 10H), 7.28-7.16 (m, 1H), 3.83-3.72 (m,1H),3.23-3.12(m,1H),3.07(brs,OH),2.80-2.60(m,2H),2.52-2.43(m,1H),2.24-1.98(m,2H),1.59(s,3H); 13 C NMR (101MHz, CDCl3) δ199.9,164.4,144.8,140.7,136.7,136.4,133.0,132.8,132.0,130.1,128.4,128.0,127.8,127.7, 127.3,127.2,127.2,127.1,125.7,125.4,124.7,123.6,123.4,119.7,75.0,46.8,37.2,35.6,32.1,31.6; HRMS(ESI)m / z 460.2262(M+H + ),calc.for C 32 H 30 NO2 +460.2271; Ee was determined by HPLC analysis: FLM CHIRAL NQ (2) (4.6mm idx 250mm); Hexane / 2-propanol=70 / 30; flow rate 1.0mL / min; 25℃; 230nm; retention time: 20.6min (minor) and 17.5min (major).

[0040] Example 3 Synthesis of compound 4d

[0041]

[0042] In this embodiment, 1a in Example 1 was replaced with 1b, and the other steps were the same as in Example 1, resulting in 4d 23.3mg, yield 55%, dr>19:1, 92% ee; 1 H NMR (400MHz, CDCl3) δ8.09(d,J=8.4Hz,1H),7.94(dd,J=8.3,0.9Hz,1H),7.81-7.74(m,2H),7.73-7.66(m,1H),7.57-7.46(m,2H),7.45-7.34(m, 4H),7.29-7.22(m,2H),7.19-7.13(m,1H),7.08(s,1H),2.99-2.87(m,1H ),2.76-2.58(m,6H),2.32-2.14(m,2H),2.13-1.99(m,1H),1.56(s,3H); 13 C NMR (101MHz, CDCl3) δ199.8,164.7,148.3,146.4,145.6,136.7,133.0,129.5,128.8,128.4,127.9,127.9 ,126.9,126.1,125.2,123.6,121.0,74.3,47.3,42.7,35.6,32.3,30.1,18.9; HRMS(ESI)m / z424.2262(M+H + ),calc.for C 29 H 30 NO2 +424.2271; Ee was determined by HPLC analysis: CHIRALPAK ID*2 (4.6mm idx 250mm); Hexane / 2-propanol=80 / 20; flow rate 1.0mL / min; 25℃; 230nm; retention time: 34.7min (minor) and 29.4min (major).

[0043] Example 4: Synthesis of Compound 4e

[0044]

[0045] In this embodiment, 1a in Example 1 was replaced with 1c, and the other steps were the same as in Example 1, yielding 4e 22.0mg, yield 52%, dr>19:1, 90%ee. 1 H NMR(400MHz, CDCl3)δ8.06-7.95(m,1H),7.83-7.73(m,2H),7.71-7.64(m,2H), 7.56-7.47(m,1H),7.44-7.35(m,2H),7.31-7.21(m,4H),7.19-7.14(m,1H),3.3 1-3.19(m,1H),3.04-2.91(m,1H),2.88-2.77(m,2H),2.47(s,3H),2.38(dd,J= 14.5,3.2Hz,1H),2.18-2.07(m,1H),2.04-1.93(m,1H),1.47(d,J=22.6Hz,3H); 13 C NMR (101MHz, CDCl3) δ199.5,147.3,140.6,136.6,133.0,129.2,129.0,128.5,128.3 ,128.2,127.9,126.5,124.6,74.8,47.2,38.3,35.3,32.5,30.6,22.3; HRMS(ESI)m / z 425.2220(M+H + ),calc.for C 28 H 29 N2O2 +425.2224; Ee was determined by HPLC analysis: CHIRALPAK IE (4.6mm idx 250mm); Hexane / 2-propanol=80 / 20; flow rate 1.0mL / min; 25℃; 230nm; retention time: 15.8min (minor) and 12.1min (major).

[0046] Example 5: Synthesis of Compound 4f

[0047]

[0048] In this embodiment, 2a in Example 1 was replaced with 2b, and the other steps were the same as in Example 1, yielding 4f21.5 mg, yield 52%, dr>19:1, 92% ee. 1 H NMR (400MHz, CDCl3) δ8.47 (d, J = 5.7Hz, 1H), 7.85-7.75 (m, 2H), 7.74-7.69 (m, 2H) ,7.65-7.57(m,1H),7.53-7.45(m,2H),7.45-7.39(m,1H),7.39-7.32(m,2H),7.2 5-7.21(m,2H),7.20-7.08(m,3H),3.86-3.71(m,1H),3.11-2.97(m,1H),2.85-2. 58(m,3H),2.40-2.29(m,1H),2.22-1.94(m,3H),1.46(s,3H),1.35-1.17(m,3H); 13 C NMR (101MHz, CDCl3) δ200.0,164.5,147.7,136.8,136.5,132.8,130.0,128.4,127.9, 127.4,127.1,126.2,124.8,119.6,74.8,46.9,37.3,35.6,32.2,31.6; HRMS(ESI)m / z 414.1879(M+H + ),calc.for C 24 H 26 F2NO3 +414.1881; Ee was determined by HPLC analysis: CHIRALPAKIA (4.6mm idx 250mm); Hexane / 2-propanol=95 / 5; flow rate 1.0mL / min; 25℃; 230nm; retention time: 19.3, 20.6min (major) and 17.6, 22.0min (minor).

[0049] Substrate application scope:

[0050]

[0051] Example 6: Bioactivity Evaluation (Cellular Level)

[0052] Four cell lines—MCF-7 for breast cancer, HeLa for cervical cancer, HβG2 for liver cancer, and A-375 for malignant melanoma—were used. Logarithmically growing cells were seeded at 5000 cells per well in 96-well cell culture plates. 24 hours after spotting, the corresponding concentrations of compounds (Examples 1-5) were added. After 48 hours of incubation, the supernatant was discarded, and 50 μL of 1 mg / mL MTT solution was added to each well. After another 4 hours of incubation, 100 μL of dimethyl sulfoxide was added to each well. The plates were shaken for 30 minutes, and the OD value was measured at 490 nm using a full-wavelength microplate reader. The cell inhibition rate was calculated using the formula: Cell inhibition rate = (1 - Absorbance value of experimental group / Absorbance value of blank control group) × 100%. The statistics are as follows:

[0053]

[0054] As shown in the table above, the chiral aza-aromatic compounds prepared in Examples 1-5 of this invention exhibit certain inhibitory activity against four types of tumor cells: breast cancer MCF-7, cervical cancer HeLa, liver cancer HβG2, and malignant melanoma A-375. They are expected to be applied to the preparation of anticancer drugs.

Claims

1. A method for synthesizing chiral nitrogen-containing aromatic compounds via a visible-light catalytic three-component reaction, characterized in that, Includes the following steps: A nitrogen-containing heterocycle I, homoallyl alcohol II, and halide III are reacted in an organic solvent under visible light irradiation in the presence of an organic photocatalyst DPZ, a chiral phosphoric acid catalyst S-CPA, and an inorganic base to yield chiral nitrogen-containing aromatic compounds; wherein: the nitrogen-containing heterocycle I is selected from... The homolyl alcohol II is selected from The halogenated compound III is selected from The organic photocatalyst DPZ is selected from Chiral phosphoric acid catalyst S-CPA is selected from The organic solvent is dichloromethane; the reaction temperature is -30℃; the inorganic base is selected from either K₂HPO₄ or NaHCO₃, either NaHCO₃ or K₂CO₃, or a combination of K₂HPO₄, NaHCO₃, and K₂CO₃; the chiral nitrogen-containing aromatic compounds are selected from...

2. The method for synthesizing chiral nitrogen-containing aromatic compounds by a visible light-catalyzed three-component reaction according to claim 1, characterized in that: The molar ratio of the high-allyl alcohol II, the halogenated product III, and the nitrogen-containing heterocycle I is 2:2:

1.

3. The method for synthesizing chiral nitrogen-containing aromatic compounds by a three-component reaction catalyzed by visible light according to claim 1, characterized in that: The molar ratio of the organic photocatalyst DPZ to nitrogen-containing heterocyclic I is 0.002-0.005:

1.

4. The method for synthesizing chiral nitrogen-containing aromatic compounds by a three-component reaction catalyzed by visible light according to claim 1, characterized in that: The molar ratio of the chiral phosphoric acid catalyst S-CPA to nitrogen-containing heterocyclic I is 0.10-0.15:

1.

5. The method for synthesizing chiral nitrogen-containing aromatic compounds by a visible light-catalyzed three-component reaction according to claim 1, characterized in that: The molar ratio of inorganic base to nitrogen-containing heterocyclic I is 1-2:

1.

6. The method for synthesizing chiral nitrogen-containing aromatic compounds by a visible light-catalyzed three-component reaction according to claim 1, characterized in that: The visible light has a wavelength of 450–455 nm; the reaction time is not less than 10 hours.

7. The method for synthesizing chiral nitrogen-containing aromatic compounds by visible light catalytic three-component reaction according to any one of claims 1-6, characterized in that: The reaction is carried out under the protection of an inert gas.

8. A chiral aza-aromatic compound, characterized in that, The specific structural formula is as follows:

9. The application of the chiral aza-aromatic compounds as described in claim 8 in the preparation of anticancer drugs, characterized in that: The anticancer agents are selected from anti-breast cancer MCF-7, cervical cancer HeLa, liver cancer HβG2, or malignant melanoma A-375.

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