Method for constructing aza-arene alpha-chiral center through asymmetric photooxidation reduction catalysis

Abstract

The invention discloses a method for constructing an aza-arene alpha-chiral center through asymmetric photooxidation reduction catalysis, and belongs to the field of organic synthesis.The preparation process specifically comprises the steps that under the protective atmosphere, cyano aza-arene shown in the formula I, Hanss ester 1, 4-dihydropyridine shown in the formula II and alpha-borate-alpha-substituted olefin shown in the formula III are subjected to a reaction at the temperature of 50-60 DEG C, and the aza-arene alpha-chiral center is obtained. In a solvent, DPZ is used as a visible light oxidation reduction catalyst, L-tertiary leucine-derived bisamide (C1) is used as a procedure catalyst, stirring reaction is performed completely at room temperature under visible light irradiation, and separation and purification are performed to obtain the target aza-arene alpha-chiral center derivative IV. According to the present invention, the high enantioselectivity is achieved, and the wide practicality in the efficient construction of the deuterium-labeled tertiary carbon stereo center with the pharmaceutical attraction is represented; in general, the method provides a simple, efficient and practical strategy for enantioselective synthesis of high-value aza-aromatic alpha-chiral center derivatives.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for constructing an α-chiral center of nitrogen heteroaromatics by asymmetric photooxidation-reduction catalysis. Background Art

[0002] In recent years, visible light-driven photocatalysis has been widely recognized as an important tool for chemical synthesis. This sustainable free radical chemistry platform can not only utilize simple and inert raw materials, but also exhibit excellent functional group tolerance under mild reaction conditions, which is mainly due to the inherent high reactivity and unique bond formation mode of free radicals. Chemists have developed many efficient methods to promote the generation of free radicals and improve chemical selectivity by regulating reaction parameters. In particular, significant progress has been made in the enantioselective synthesis based on the construction of stereocenters by free radical addition based on the use of external chiral catalysts. However, achieving precise enantioselective control through free radical coupling still faces major challenges.

[0003] Free radicals have extremely low flipping energy barriers, which significantly hinders the effective discrimination between R- and S-enantioplasms by chiral catalysts. At the same time, the free radical coupling process exhibits extremely high reactivity due to the almost zero activation energy, which leads to the appearance of racemic background reactions in the system, thus significantly weakening the enantioselectivity. Therefore, achieving precise enantioselectivity control through free radical coupling remains a rare achievement, usually relying on specific reaction conditions, substrates, and careful selection of additives. This approach inevitably consumes a lot of time and human resources, and the development of a general solution strategy is still extremely challenging.

[0004] In the field of asymmetric photocatalysis, enantioselective protonation has emerged as an alternative strategy to free radical addition and coupling for the construction of tertiary carbon stereocenters. Although the process involves a series of free radical transformations and the generation of anionic intermediates via single-electron reduction, the small size and high mobility of protons and the presence of racemic background reactions have not hindered the successful realization of many key asymmetric transformations. This is due to the fact that sp 2 Intermediate generation sp 3The endothermic process of the C-H bond highlights the key role of chiral Bronsted acids as relays in the proton transfer process (Xu, B.; Zhu, S.-F.; Xie, X.-L.; Shen, J.-J.; Zhou, Q.-L. Asymmetric NH insertion reaction cooperatively catalyzed by rhodium and chiral spiro phosphoricacids. Angew. Chem. Int. Ed. 2011, 50, 11483-11486). Based on this background, exploring the potential of enantioselective protonation in stereocenter assembly by regulating free radical coupling has become a key research direction.

[0005] As an important class of substrates, cyano-azaarene (Yin, Y.; Zhao, X.; Jiang, Z. Advances in the synthesis of imine-containing azaarene derivatives via photoredox catalysis. ChemCatChem 2020, 12, 4471-4489) has been widely used in the photoredox catalytic synthesis of pharmaceutically important azaarene derivatives. These chemicals are not only easy to obtain, but also have excellent reaction regioselectivity, showing attractive synthetic advantages. However, there are still relatively few successful cases in achieving enantioselectivity. Therefore, the present application develops a new method for asymmetric photoredox catalytic reduction of azaarene, using 4-substituted 1,4-dihydropyridine and α-boronate-α-substituted olefins as reaction ligands. This method provides a concise, efficient and practical new approach for the enantioselective preparation of high-value azaarene derivatives containing α-substituents. Summary of the invention

[0006] The object of the present invention is to provide a method for constructing an α-chiral center of nitrogen heteroaromatics by asymmetric photooxidation-reduction catalysis.

[0007] Based on the above purpose, the present invention adopts the following technical solutions:

[0008] A method for constructing an α-chiral center of nitrogen heteroaromatics by asymmetric photoredox catalysis, the synthetic route is as follows:

[0009]

[0010] The specific preparation process is as follows: under a protective atmosphere, cyano azaaromatic hydrocarbon represented by formula I, Hans ester 1,4-dihydropyridine represented by formula II, and α-boronic acid ester-α-substituted olefin represented by formula III are reacted completely at room temperature under visible light irradiation with DPZ as a visible light redox catalyst and C1 as a chiral catalyst, and the target azaaromatic hydrocarbon α-chiral center derivative IV is obtained by separation and purification; wherein R 1 is H, F, Cl, Br, C1-C4 alkyl, methoxy, R 2 is a C4-C6 alkyl group, a C4-C6 cycloalkyl group,

[0011]

[0012] n=1、2、3、4、5,G 1 represents 1 to 3 identical or different substituents, and each G 1 independently selected from H, F, Cl, Br, C1-C4 alkyl, methoxy, Ar is G 2 represents 1 to 3 identical or different substituents, and each G 2 Independently selected from H, F, Cl, Br, C1-C4 alkyl, and methoxy.

[0013] Furthermore, the molar ratio of the cyano azo aromatic hydrocarbon shown in formula I, the Hans ester 1,4-dihydropyridine shown in formula II, the α-boronate-α-substituted olefin shown in formula III, DPZ and the chiral catalyst C1 is 1:(1-1.5):(1-1.5):(0.001-0.005):(0.1-0.3).

[0014] Furthermore, the wavelength of the visible light is λ=450-455 nm, and the visible light is provided by 1-2 3W blue LED lamps.

[0015] Furthermore, the organic solvent is dichloromethane, 1,2-dichloroethane, 2-chloropropane, chloroform or 1-chloropropane.

[0016] Furthermore, it also includes adding D2O, wherein the amount of D2O added is 100 to 200 times the molar amount of the cyano azaaromatic hydrocarbon shown in formula I.

[0017] The above method can prepare the azaarene α-chiral center derivative.

[0018] Specifically, the present application synthesized the following compounds:

[0019]

[0020]

[0021] Under the optimized conditions (0.3 mol% DPZ and 20 mol% of bisamide catalyst (C1) derived from L-tert-leucine, at 25°C, 2-chloropropane as solvent), various isoquinolines with different substituents on the aromatic ring can be efficiently converted into the corresponding products (4-12, 20, 21) with a yield of 56-90% and excellent enantioselectivity (ee of 87-92%). The study also found that phenanthridine is also applicable, and the generated product 13 achieves a yield of 83% and an enantiomeric excess of 97%.

[0022] Further studies have shown that different substituents on the olefin aromatic ring have little effect on the reaction activity and enantioselectivity. This was verified by the high yields and high enantioselectivities (ee values) of products 14-17. It is worth mentioning that this method is not only applicable to condensed rings (such as product 18), but can also introduce electron-rich heteroaryl groups (such as product 19) into the stereocenter, thereby constructing a tertiary carbon stereocenter with two heteroaryl groups of different structures.

[0023] In addition, when testing different alkyl-substituted 1,4-dihydropyridines (with various alkyl substituents at the 4-position), the generated products 20–35 showed good generality with yields ranging from 54% to 99% and enantiomeric excesses (ee values) ranging from 90% to 97%.

[0024] Notably, a variety of drug molecules, including 2,4-D (31), adapalene (32), probenecid (33), gabapentin (34), and indomethacin (35), can be efficiently introduced into the corresponding nitrogen-arene derivatives via this method, further highlighting the practicality of this method in drug development.

[0025] In addition, a variety of α-deuterium-labeled azaaromatic derivatives were successfully synthesized through asymmetric photoredox-catalyzed three-component reaction. The results showed that products D-4, D-9, D-13, D-14 and D-23 all achieved satisfactory yields and enantioselectivities.

[0026] This method synthesized a series of nitrogen heteroaromatic derivatives containing α-tertiary carbon stereocenters with high yields and excellent enantioselectivity. DETAILED DESCRIPTION

[0027] The present invention is further described in detail below in conjunction with the examples. It should be understood that the examples described in this specification are only for explaining the present invention, not for limiting the present invention, and the parameters, proportions, etc. of the examples can be selected according to local conditions without substantial impact on the results.

[0028] Example 1

[0029] Synthesis of compound 4:

[0030]

[0031] 21 μL of DPZ solution (5 mg DPZ dissolved in 1.0 mL toluene, 0.0003 mmol, 0.003 equiv) was added to a 25 mL Schlenk tube, and then the solvent was removed by decompression. 1-Cyanoisoquinoline 1 (0.1 mmol, 1.0 equiv), Hans ester derivative 2 (DHP) (0.12 mmol, 1.2 equiv), 4,4,6-trimethyl-1,3,2-dioxaborane 3 (0.11 mmol, 1.1 equiv), C1 (0.02 mmol, 0.2 equiv) and 2-chloropropane (3.0 mL) were added in sequence, and then degassed three times by freeze-vacuum-thaw method. The reaction mixture was stirred in an argon atmosphere at 25 ° C and reacted for 48 hours under irradiation of a 3W blue LED lamp (λ = 450-455 nm) at a distance of 4.0 cm. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1 ratio) to obtain the target compound 4 as a colorless oil with a yield of 76%, 91% ee.

[0032] The NMR data of compound 4 are: 1 H NMR (300MHz, CDCl3) δ8.58(d,J=5.6Hz,1H),8.30(d,J=8.5Hz,1H),7.78(d,J=7 .9Hz,1H),7.66–7.49(m,3H),7.41(d,J=7.6Hz,2H),7.31–7.20(m,2H),7.13(t, J=7.2Hz,1H),5.07(t,J=7.5Hz,1H),2.40(dt,J=14.0,7.2Hz,1H),2.11(dt,J= 13.7,7.0Hz,1H),1.92(d,J=12.0Hz,1H),1.82–1.48(m,4H),1.36–0.82(m,6H); 13 CNMR (75MHz, CDCl3) δ162.6,144.3,141.6,136.6,129.6,128.4,128.1,12 7.6,127.2,126.2,125.0,119.4,45.2,43.6,35.2,33.7,33.5,26.7,26.3.

[0033] Example 2

[0034] Synthesis of compound 13:

[0035] Same as Example 1, compound 13 was a white solid, Mp 103.3-105.2°C, yield 83%, 97% ee.

[0036] The NMR data of compound 13 are: 1 H NMR (300MHz, CDCl3) δ8.61(d,J=8.2Hz,1H),8.54(d,J=8.0Hz,1H),8.36(d,J=8.0Hz,1H),8.27 (d,J=7.8Hz,1H),7.75(t,J=6.6Hz,2H),7.68–7.53(m,2H),7.46(d,J=7.3Hz,2H),7.35–7.19( m,2H),7.18–7.05(m,1H),5.10(t,J=7.4Hz,1H),2.62(dt,J=14.1,7.3Hz,1H),2.10(dd,J=13. 3,6.7Hz,1H),1.96(d,J=12.4Hz,1H),1.85–1.48(m,4H),1.40–1.24(m,1H),1.22–0.80(m,5H); 13 C NMR (75MHz, CDCl3) δ161.7,144.5,143.6,133.1,130.3,129.8,128.4,128.1,127.1,126 .4,126.1,125.9,125.5,123.5,122.4,121.8,45.8,43.8,35.2,33.6,26.6,26.3,26.2.

[0037] Example 3

[0038] Synthesis of compound 18:

[0039] Same as Example 1, compound 18 was a white solid, Mp 117.7-119.2°C, yield 60%, 94% ee.

[0040] The NMR data of compound 18 are: 1H NMR (300MHz, CDCl3) δ8.61(d,J=8.2Hz,1H),8.55(d,J=7.9Hz,1H),8.42(d,J= 8.1Hz,1H),8.32(d,J=8.0Hz,1H),7.91–7.53(m,9H),7.49–7.31(m,2H),5.27( t,J=7.3Hz,1H),2.69(dt,J=14.1,7.2Hz,1H),2.20(dt,J=13.6,6.7Hz,1H),2. 03(d,J=12.4Hz,1H),1.90–1.51(m,4H),1.49–1.31(m,1H),1.25–0.97(m,5H); 13 CNMR (75MHz, CDCl3) δ161.7,143.7,142.1,133.5,133.2,132.2,130.4,129.8,128.4,128.0,127.7,127.5,127.2,12 6.7,126.5,126.4,126.0,125.7,125.6,125.2,123.5,122.4,121.8,46.1,43.7,35.3,33.7,33.6,26.7,26.3,26.2.

[0041] Example 4

[0042] Synthesis of compound 19:

[0043] Same as Example 1, compound 19 was a colorless oil with a yield of 44% and 92% ee.

[0044] The NMR data of compound 19 are: 1 H NMR (300MHz, CDCl3) δ8.64(d,J=8.2Hz,1H),8.55(d,J=7.8Hz,1H),8.37(d,J=8.1Hz ,1H),8.23(d,J=7.8Hz,1H),7.86–7.70(m,2H),7.64(t,J=7.6Hz,2H),7.26–7.05(m, 3H),5.25(t,J=7.3Hz,1H),2.55(dt,J=14.1,7.3Hz,1H),2.15(dt,J=13.6,6.9Hz,1 H),1.92(d,J=12.1Hz,1H),1.87–1.52(m,4H),1.39–1.26(m,1H),1.22–0.93(m,5H); 13C NMR (75MHz, CDCl3) δ161.9,144.9,143.7,133.1,130.2,129.9,128.3,127.8,127.1,126.4, 125.7,125.3,125.0,123.4,122.5,121.8,120.7,43.2,41.4,35.3,33.6,26.6,26.2,26.2.

[0045] The synthesis of compounds 5-12, 14-17, 20-30 is the same as in Example 1.

[0046] Example 5

[0047] Synthesis of compound 31:

[0048] Same as Example 1, except that the reaction time was 72 h, compound 31 was a colorless oil with a yield of 73% and 92% ee. The NMR data of compound 31 were: 1 H NMR (300MHz, CDCl3) δ8.61(d,J=8.3Hz,1H),8.54(d,J=8.1Hz,1H),8.30(d,J=8.4Hz,1H),8.25(d ,J=8.0Hz,1H),7.86–7.53(m,4H),7.40(dd,J=16.2,4.9Hz,3H),7.29–7.19(m,2H),7.18–7.08(m, 2H),6.73(d,J=8.8Hz,1H),4.88(t,J=6.7Hz,1H),4.63(s,2H),4.17(t,J=6.5Hz,2H),2.63(ddd,J =12.9,7.9,4.4Hz,1H),2.20(ddd,J=16.2,8.8,2.8Hz,1H),1.74–1.54(m,2H),1.50–1.29(m,3H); 13 C NMR (75 MHz, CDCl3) δ 168.1, 161.4, 152.4, 144.1, 143.6, 133.1, 130.3, 129.9, 128.4, 128.0, 127.5, 127.2, 127.0, 126.5, 126.3, 126.0, 125.5, 124.2, 123.5, 122.4, 121.8, 114.6, 66.3, 65.6, 49.3, 35.8, 28.3, 27.6, 25.9. The synthesis of compounds 32 to 35 was the same as in Example 5.

[0049] Example 6

[0050] Synthesis of compound D-4:

[0051] Same as Example 1, except that 10 mmol to 20 mmol D2O is further added to obtain the target compound.

[0052] Compound D-4 is a colorless oil with a yield of 82%, 91% ee, and D=90%.

[0053] The NMR data of compound D-4 are: 1 H NMR (300MHz, CDCl3) δ8.58(d,J=5.6Hz,1H),8.30(d,J=8.3Hz,1H),7.78(d,J=8. 0Hz,1H),7.66–7.47(m,3H),7.42(d,J=7.5Hz,2H),7.33–7.19(m,2H),7.13(t,J =7.2Hz,1H),5.07(t,J=7.4Hz,0.1H),2.39(dd,J=13.5,7.1Hz,1H),2.11(dd,J= 13.5,6.2Hz,1H),1.92(d,J=12.2Hz,1H),1.78–1.49(m,4H),1.42–0.77(m,6H); 13 C NMR (75MHz, CDCl3) δ162.5,144.3,141.8,136.5,129.4,128.3,128.1,127.5, 127.1,127.0,126.1,124.9,119.2,45.1,43.5,35.1,33.6,33.4,26.6,26.2.

[0054] Example 7

[0055] Synthesis of compound D-13:

[0056] Same as Example 6, compound D-13 is a white solid, Mp 106.1-107.9°C, yield 79%, 95% ee, D=92%.

[0057] The NMR data of compound D-13 are: 1H NMR (300MHz, CDCl3) δ8.62(d,J=8.2Hz,1H),8.55(d,J=8.1Hz,1H),8.36(d,J=8.2Hz,1H),8.27(d,J= 8.1Hz,1H),7.76(t,J=7.5Hz,2H),7.70–7.54(m,2H),7.47(d,J=7.7Hz,2H),7.34–7.19(m,2H),7.14( t,J=7.1Hz,1H),5.11(t,J=7.3Hz,0.08H),2.61(dd,J=13.5,6.7Hz,1H),2.09(dd,J=13.5,6.6Hz,1H) ,1.96(d,J=12.5Hz,1H),1.85–1.72(m,1H),1.73–1.49(m,3H),1.44–1.29(m,1H),1.22–0.90(m,5H); 13 CNMR (75MHz, CDCl3) δ161.7,144.4,143.6,133.1,130.3,129.8,128.4,128.1,127.1,12 6.3,126.1,125.9,125.5,123.5,122.4,121.8,45.8,43.7,35.2,33.6,26.7,26.3,26.2.

[0058] The synthesis of compounds D-9, D-14 and D-23 is the same as in Example 6.

[0059] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for constructing an α-chiral center of nitrogen aromatics by asymmetric photoredox catalysis, characterized in that: The synthetic route is as follows: The specific preparation process is as follows: under a protective atmosphere, cyano azaaromatic hydrocarbon represented by formula I, Hans ester 1,4-dihydropyridine represented by formula II, and α-boronic acid ester-α-substituted olefin represented by formula III are placed in a solvent, DPZ is used as a visible light redox catalyst, and C1 is used as a chiral catalyst. The reaction is completely stirred at room temperature under visible light irradiation, and the target azaaromatic hydrocarbon α-chiral center derivative IV is obtained by separation and purification; wherein R 1 is H, F, Cl, Br, C1-C4 alkyl, methoxy, R 2 is a C4-C6 alkyl group, a C4-C6 cycloalkyl group, n=1、2、3、4、5,G 1 represents 1 to 3 identical or different substituents, and each G 1 independently selected from H, F, Cl, Br, C1-C4 alkyl, methoxy, Ar is G 2 represents 1 to 3 identical or different substituents, and each G 2 Independently selected from H, F, Cl, Br, C1-C4 alkyl, and methoxy.

2. The method for constructing an α-chiral center of nitrogen aromatics by asymmetric photoredox catalysis according to claim 1, characterized in that: The molar ratio of cyano azaaromatic hydrocarbon shown in formula I, Hans ester 1,4-dihydropyridine shown in formula II, α-boronic acid ester-α-substituted olefin DPZ shown in formula III and chiral catalyst C1 is 1:(1-1.5):(1-1.5):(0.001-0.005):(0.1-0.3).

3. The method for constructing an α-chiral center of nitrogen aromatics by asymmetric photoredox catalysis according to claim 1, characterized in that: The wavelength of the visible light is λ=450-455 nm, and the visible light is provided by 1-2 3W blue LED lamps.

4. The method for constructing an α-chiral center of nitrogen aromatics by asymmetric photoredox catalysis according to claim 1, characterized in that: The organic solvent is dichloromethane, 1,2-dichloroethane, 2-chloropropane, chloroform or 1-chloropropane.

5. The method for constructing an α-chiral center of nitrogen aromatics by asymmetric photoredox catalysis according to claim 1, characterized in that: The method further comprises adding D2O, wherein the amount of D2O added is 100 to 200 times the molar amount of the cyano azaaromatic hydrocarbon shown in formula I.

6. A nitrogen heteroarene α-chiral center derivative obtained by the method according to any one of claims 1 to 5.

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