Method for preparing chiral 2-aza-arene amide through visible light catalysis asymmetric reaction

Abstract

The invention discloses a method for preparing chiral 2-aza-arene amide through a visible light catalysis asymmetric reaction, and belongs to the technical field of organic synthesis. The method comprises the following steps: in a nitrogen atmosphere, carrying out visible light irradiation reaction on racemic 2-bromo-amide I and aza-aromatic hydrocarbon II serving as raw materials in an organic solvent in the presence of a photosensitizer 3DPAFIPN, a chiral phosphoric acid catalyst and an inorganic base, so as to obtain chiral 2-aza-aromatic hydrocarbon amide III; the method is wide in substrate universality, high in atom economy and enantioselectivity and free of metal participation, and a new thought is provided for preparation of the compounds; meanwhile, the obtained product chiral 2-aza-aromatic amide shows good activity in resisting breast cancer MCF-7, resisting cervical cancer Hela and resisting malignant melanoma A-375.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing amide-substituted chiral nitrogen heteroaromatic hydrocarbons by Minisci reaction by generating amide free radicals under visible light irradiation with 2-bromoamide. Background Art

[0002] The free radical pathway Minisci reaction is one of the most important pathways for constructing functionalized nitrogen heteroaromatics (Tetrahedron 1971, 27, 3575; Angew. Chem. Int. Ed. 2015, 54, 2199; J. Am. Chem. Soc. 1988, 110, 8736). Traditional Minisci reactions require harsh reaction conditions such as stoichiometric oxidants, free radical initiators, and strong acids (RSCAdv. 2016, 6, 22777; Org. Biomol. Chem. 2016, 14, 6611). With the development of visible light catalysis, many new Minisci reactions with milder reaction conditions have been reported using photosensitizer redox pathways (Molecules 2014, 19, 16190; Nature 2015, 525, 87). Therefore, developing new free radical types and creating new Minisci products have important research significance and application value.

[0003] At present, the Minisci reaction catalyzed by visible light has been reported to include alkyl radicals, a-alkyl radicals with strong electron-rich α-amine, and a-oxygen atom-substituted radicals (Synthesis 2019, 51, AJ; Angew. Chem. Int. Ed. 2019, 58, 2). By using the mild system of photoredox in coordination with chiral Brønsted acid, i.e., "photocatalytic asymmetric Minisci reaction", a series of chiral azoaromatic compounds with important functional skeletons have been produced (Science 2018, 360, 419; Science 2019, 363, 1429; Org. Lett. 2018, 20, 6298; Angew. Chem. Int. Ed. 2019, 58, 15803; J. Am. Chem. Soc. 2021, 143, 4928). Despite this, existing asymmetric Minisci reactions are still limited to alkyl radicals and α-N / O substituted electron-rich radicals, and there have been no reports on Minisci reactions of weakly nucleophilic radicals such as amides.

[0004] Therefore, the present invention uses an amide radical precursor in an asymmetric Minisci reaction through a visible light asymmetric catalytic system to construct an amide-substituted nitrogen heteroaromatic compound with a novel structure and has good yield and enantioselectivity. Summary of the invention

[0005] The purpose of the present invention is to overcome the defects of the prior art. The present invention provides a method for the visible light catalytic asymmetric amidation of nitrogen heteroaromatic hydrocarbons. The substrate of the method is simple and easy to obtain, the reaction conditions are mild, the atom economy is high, the enantioselectivity is high and no metal participation is required.

[0006] To achieve the above object, the method for preparing chiral 2-azaaromatic amide by visible light catalytic asymmetric reaction of the present invention comprises the following steps: taking racemic 2-bromoamide I and azaaromatic II as raw materials, irradiating with visible light in an organic solvent in the presence of a photosensitizer 3DPAFIPN, a chiral phosphoric acid catalyst and an inorganic base to obtain chiral 2-azaaromatic amide III; the reaction equation is as follows:

[0007]

[0008] Where: R 1 is selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetyloxybenzyl or benzyl, which may contain sulfur or oxygen atoms; R 2 Selected from phenyl, substituted phenyl, thiophene, naphthalene; the substituted phenyl is substituted with at least one of C1-C4 alkyl, C1-C4 alkoxy, halogen, and trifluoromethyl.

[0009] Furthermore, in the above technical scheme, the azaaromatic hydrocarbon II is selected from isoquinoline, substituted isoquinoline, and phenanthridine; the substituted isoquinoline is substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, dimethylamino, and tert-butyl 1,4-diazacycloheptane-1-carboxylate.

[0010] Furthermore, in the above technical solution, the molar ratio of the photosensitizer 3DPAFIPN to the nitrogen heteroarene II is 0.001 to 0.01:1.

[0011] Furthermore, in the above technical scheme, the inorganic base is selected from NaHCO3, NaH2PO4, KH2PO4, K2HPO4, Na2CO3 or Li2CO3, and the molar ratio of the inorganic base to the nitrogen aromatic hydrocarbon II is 0.5 to 3.0:1.

[0012] Furthermore, in the above technical solution, the molar ratio of the chiral phosphoric acid catalyst to the nitrogen heteroaromatic hydrocarbon II is 0.05-0.2:1.

[0013] Furthermore, in the above technical solution, the organic solvent is selected from ethyl acetate, butyl acetate, dichloromethane, toluene and the like.

[0014] Furthermore, in the above technical solution, the reaction temperature is -30°C to 0°C, and the reaction time is not less than 10 hours.

[0015] Furthermore, in the above technical solution, the reaction is carried out under the protection of an inert gas.

[0016] Furthermore, in the above technical solution, the visible light is selected from visible light with a wavelength of 360-450nm, such as a 3-watt blue light.

[0017] The present invention further provides a chiral 2-azaarene amide, the general structural formula of which is as follows:

[0018]

[0019] Where: R 1 is selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetyloxybenzyl or benzyl, which may contain sulfur or oxygen atoms; R 2 is selected from phenyl, substituted phenyl, thiophene, and naphthalene; the substituted phenyl is substituted with at least one of C1-C4 alkyl, C1-C4 alkoxy, halogen, and trifluoromethyl. Selected from isoquinoline, substituted isoquinoline, phenanthridine; the substituted isoquinoline is substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, dimethylamino, tert-butyl 1,4-diazacycloheptane-1-carboxylate.

[0020] The present invention also provides application of chiral 2-azaaromatic amide in the preparation of anticancer drugs.

[0021] Furthermore, in the above technical solution, the anticancer is selected from anti-breast cancer MCF-7, anti-cervical cancer Hela, and anti-malignant melanoma A-375.

[0022] The nitrogen heteroaromatic compound constructed by the present invention has an amide functional group, no external oxidant is needed in the reaction, and the reaction conditions are mild, stable and efficient, the operation is simple, the environment is friendly, the atom economy is high, and the selectivity is good.

[0023] Compared with the existing synthesis methods, the biggest feature of the method of the present invention is that amide free radicals are introduced into nitrogen aromatics, organic small molecule catalysts are used, the reaction conditions are mild, rapid and efficient, the yield is high, and it is green and environmentally friendly. The synthesized product has certain anti-cancer activity and is of great value for promotion and application.

[0024] The present invention involves a wide range of substrate types and various product types, and the constructed amide-substituted chiral nitrogen heteroaromatic compounds have not been reported so far. In addition, the present invention does not require the use of an oxidant, and chiral phosphoric acid is used as an organic small molecule catalyst, which has the advantages of high catalytic efficiency and no metal residue in the reaction system. DETAILED DESCRIPTION

[0025] 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.

[0026]

[0027] 2-Bromoamide, photosensitizer 3DPAFIPN, and chiral phosphoric acid catalyst can all be prepared according to relevant literature (Nature, 2023, 618, 301-307; ACS Catal. 2016, 6, 873; T. Shao, Y. Li, et al. iScience 2019, 16, 410); organic solvents were purchased from Anergy Reagent Company; the reaction results are as follows:

[0028]

[0029]

[0030] [a]Reaction conditions:1a(0.02mmol)and irradiation distance=2.0cm.λ max =445nm;[b]Enantiomeric excesses(ee)were determined by HPLC analysis on astationary phase;[c]2*3WLEDs were used.

[0031] Example 1

[0032] The specific preparation steps of compound 3a are as follows:

[0033]

[0034] Compound 1a (0.15mmol, 40.0mg), compound 2a (0.1mmol, 12.9mg), 3DPA FIPN (0.001mmol, 0.65mg), and NaHCO3 (0.2mmol, 16.4mg) were accurately weighed and added to a 10mL Schlenk tube, and then 2.0mL of ethyl acetate was added. After sufficient stirring, the sealing stopper was covered, and the air in the reaction bottle was removed by double-row tube freezing-vacuuming. The degassing operation was repeated three times. Then the reaction bottle was placed in a -30℃ thermostat and stirred for 10 minutes away from light, and then the light source was turned on for irradiation. The reaction was stopped after 24 hours, quenched with water, and extracted with ethyl acetate. The solution was evaporated and concentrated by rotary evaporator, and directly separated by alkaline silica gel column chromatography (n-hexane / ethyl acetate 30~5:1) to obtain 22.9mg of white solid 3a. Melting point 167.4–168.2℃; 22.9mg, 83% yield, 90% ee; [α] 2 D 2 -9.1(c 1.0,CHCl3); 1 H NMR (400MHz, CDCl3) δ10.13(s,1H),8.53(d,J=5.8Hz,1H),8.43(d,J=8.5Hz,1H),7.89(d,J=8.1Hz,1H),7.77(t,J=7.4Hz,1H),7.70(d d,J=9.6,6.7Hz,2H),7.59(d,J=7.9Hz,2H),7.29(t,J=7.9Hz,2H),7.06(t,J=7.4Hz,1H),4.92(q,J=7.1Hz,1H),1.85(d,J=7.2Hz,3H); 13 C NMR (151MHz, CDCl3) δ171.4,160.4,141.0,138.4,136.9,130.8,129.0,128.2,12 7.8,126.8,124.7,124.1,120.6,119.9,45.6,21.2; HRMS(ESI)m / z299.1155(M+Na + ),calc.for C 18 H 16 N2O +299.1155; Ee was determined by HPLC analysis: CHIRALPAK IC (4.6mm idx 250mm); Hexane / 2-propanol=70 / 30; flow rate 1.0mL / min; 25℃; 254nm; retention time: 7.4min (major) and 8.2min (minor).

[0035] The specific preparation steps of compound 3b in Example 2 are as follows:

[0036]

[0037] In this example, 1a in Example 1 was replaced by 1b, and the other steps were the same as in Example 1 to obtain 24.9 mg of chiral product 3b, 82% yield, 90% ee; [α] 2 D 2 -36.3 (c 1.0, CHCl3); 1 H NMR (600MHz, CDCl3) δ10.09(s,1H),8.55(d,J=5.7Hz,1H),8.38(d,J=8.4Hz,1H),7.86(d,J=8.1Hz,1H),7.74(t,J=7.1Hz,1H),7.69–7.60(m,2H) ,7.57(d,J=7.6Hz,2H),7.33–7.26(m,2H),7.08–7.01(m,1H),4.75(t,J= 7.2Hz,1H),2.35–2.17(m,2H),1.48–1.23(m,2H),0.91(t,J=7.4Hz,3H). 13 C NMR (151MHz, CDCl3) δ170.4,159.7,138.5,136.9,130.9,129.0,128.2,127. 7,127.6,125.0,124.0,120.6,119.8,51.2,38.4,21.2,14.0; HRMS(ESI)m / z 327.1468(M+Na + ),calc.for C 20 H 20 N2O +327.1468; Ee was determined by HPLC analysis: CHIRALPAK IC (4.6mm idx 250mm); Hexane / 2-propanol=95 / 5; flow rate 1.0mL / min; 25℃; 254nm; retention time: 15.2min (major) and 16.6min (minor).

[0038] The specific preparation steps of Example 3 Compound 3c are as follows:

[0039]

[0040] In this example, 1a in Example 1 was replaced by 1c, and the other steps were the same as in Example 1 to obtain 28.1 mg of chiral product 3c, 70% yield, 90% ee; [α] 2 D 2 -32.4 (c 1.0, CHCl3); 1 H NMR (600MHz, CDCl3) δ10.50 (s, 1H), 8.60 (d, J = 5.6Hz, 1H), 8.21 (t, J = 11.4Hz, 1H) ,7.76(d,J=8.1Hz,1H),7.71(d,J=8.2Hz,1H),7.68–7.37(m,8H),7.33(t,J=7.9H z,2H),7.25–7.18(m,1H),7.09(t,J=7.4Hz,1H),7.05–6.97(m,1H),6.88(d,J=6. 9Hz,1H),5.15(s,1H),4.25(dd,J=13.7,5.0Hz,1H),3.89(dd,J=13.5,9.7Hz,1H). 13 C NMR (151MHz, CDCl3) δ170.0,159.0,138.4,136.4,134.4,133.9,131.8,129.0,128.9,128.0,127.6 ,127.4,127.3,127.2,126.4,125.6,125.1,124.1,123.6,120.7,120.0,51.7,39.8; HRMS(ESI)m / z 425.1624.(M+Na + ),calc.for C 28 H 22 N2O +425.1624; The ee was determined by HPLC analysis: CHIRALPAKADH (4.6mm idx 250mm); Hexane / 2-propanol=90 / 10; flow rate 1.0mL / min; 25℃; 254nm; retention time: 16.4min (major) and 27.8min (minor).

[0041] The specific preparation steps of compound 3d in Example 4 are as follows:

[0042]

[0043] In this example, 1a in Example 1 was replaced by 1d, and the other steps were the same as in Example 1 to obtain 24.2 mg of chiral product 3d, 80% yield, 93% ee; [α] 2 D 2 -10.7 (c 1.0, CHCl3); 1 H NMR (600MHz, CDCl3) δ10.03(s,1H),8.57(d,J=5.7Hz,1H),8.33(d,J=8.5H z,1H),7.86(d,J=8.1Hz,1H),7.77–7.70(m,1H),7.68–7.60(m,2H),7.55(d ,J=7.6Hz,2H),7.35–7.27(m,2H),7.11–7.03(m,1H),5.84–5.64(m,1H),5 .07–4.99(m,1H),4.97–4.88(m,1H),4.82–4.74(m,1H),3.13–2.88(m,2H). 13 C NMR(151MHz, CDCl3)δ169.8,158.9,140.98(s),138.3,136.8,134.8,130.8,129.0,128.2, 127.7,127.6,124.9,124.1,120.6,119.9,117.6,51.1,40.2; HRMS(ESI)m / z325.1311(M+Na + ),calc.for C 20 H 18 N2O +325.1311; The ee was determined by HPLC analysis: CHIRALPAK IC (4.6mm idx 250mm); Hexane / 2-propanol=90 / 10; flow rate1.0mL / min; 25℃; 254nm; retention time:11.5min(major)and 13.1min(minor).

[0044] The specific preparation steps of Example 5 Compound 3e are as follows:

[0045]

[0046] In this example, 1a in Example 1 was replaced with 1e, and the other steps were the same as in Example 1 to obtain 22.9 mg of chiral product 3e, 78% yield, 90% ee; (c 1.0, CHCl3); 1 H NMR (600MHz, CDCl3) δ10.23(s,1H),8.53(d,J=5.7Hz,1H),8.31(d,J=8.5Hz,1H),7.87(d,J=8.1Hz,1H),7.73(t,J= 7.3Hz,1H),7.68–7.60(m,2H),7.57–7.49(m,2H),7.05–6.94(m,2H),4.79(q,J=7.3Hz,1H),1.81(d,J=7.3Hz,3H). 13 C NMR (151MHz, CDCl3) δ171.4,160.2(d,J=52.5Hz),158.5,140.8,136.9,134.5(d,J=2.1Hz),13 0.8,128.2,127.8,126.8,124.6,121.6(d,J=7.7Hz),120.7,115.6(d,J=22.2Hz),45.3,21.4. 19 F NMR (565MHz, CDCl3) δ-118.6; HRMS (ESI) m / z317.1060 (M+Na + ),calc.for C 18 H 15 FWf +317.1060; The ee was determined by HPLC analysis: CHIRALPAK IC (4.6mm idx 250mm); Hexane / 2-propanol=70 / 30; flowrate 1.0mL / min; 25℃; 254nm; retention time: 6.2min (major) and 6.7min (minor).

[0047] The specific preparation steps of Example 6 Compound 3f are as follows:

[0048]

[0049] In this example, 2a in Example 1 was replaced by 2b, and the other steps were the same as in Example 1 to obtain 27.7 mg of chiral product 3f, 85% yield, 94% ee; (c 1.0, CHCl3); 1 H NMR (600MHz, CDCl3) δ10.67(s,1H),8.68(d,J=8.2Hz,1H),8.59(d,J=8.1Hz,1H ),8.40(d,J=7.3Hz,1H),8.21(d,J=7.9Hz,1H),7.89(t,J=7.5Hz,1H),7.80(t, J=7.4Hz,1H),7.73(dt,J=22.8,7.5Hz,2H),7.63(d,J=7.9Hz,2H),7.32(t,J=7 .8Hz,2H),7.08(t,J=7.4Hz,1H),4.86(d,J=5.6Hz,1H),1.90(d,J=7.3Hz,3H). 13 C NMR (151MHz, CDCl3) δ171.3,160.8,142.5,138.5,133.5,131.3,129.3,129.2,129.1,12 8.1,127.5,125.7,124.7,124.1,123.8,122.9,122.3,119.9,45.6,21.4; HRMS(ESI)m / z 349.1311(M+Na + ),calc.for C 22 H 18 N2O +349.1311; Theee was determined by HPLC analysis: CHIRALPAK INB (4.6mm idx 250mm); Hexane / 2-propanol=80 / 20; flow rate 1.0mL / min; 25℃; 254nm; retention time: 10.1min (major) and 16.3min (minor).

[0050] Substrate application range:

[0051]

[0052] Example 6 Evaluation of biological activity (cellular level)

[0053] Three cell lines of breast cancer MCF-7, cervical cancer Hela, and malignant melanoma A-375 were taken from the logarithmic growth phase cells and inoculated into 96-well cell culture plates at 5000 cells per well. The corresponding concentrations of compounds (Examples 1-5) were added 24 hours after the cells were spotted, and the supernatant was discarded after 48 hours of action and 50 μL of 1 mg / mL MTT solution was added to each well. After continuing to culture for 4 hours, 100 μL of dimethyl sulfoxide was added to each well, and the OD value was measured at a wavelength of 490 nm using a full-wavelength microplate reader after oscillating on an oscillator for 30 minutes. The cell inhibition rate was calculated using the formula: cell inhibition rate = (1-absorbance value of the experimental group / absorbance value of the blank control group) × 100%, and the statistics are as follows:

[0054]

[0055]

[0056] As can be seen from the above table, the chiral nitrogen aromatic compounds prepared by the present invention show good inhibitory activity on cell proliferation of four types of tumor cells: breast cancer MCF-7, cervical cancer Hela, and malignant melanoma A-375, and are expected to be used in the preparation of anticancer drugs.

[0057] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art 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 spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A method for preparing chiral 2-azaarene amides by visible light catalytic asymmetric reaction, characterized in that: The following steps are involved: Racemic 2-bromoamide I and azaarene II are used as raw materials, and in the presence of photosensitizer 3DPAFIPN, chiral phosphoric acid catalyst and inorganic base, visible light is irradiated in an organic solvent to obtain chiral 2-azaarene amide III; the reaction equation is as follows: Where: R 1 is selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetyloxybenzyl or benzyl, which may contain sulfur or oxygen atoms; R 2 Selected from phenyl, substituted phenyl, thiophene, naphthalene; the substituted phenyl is substituted with at least one of C1-C4 alkyl, C1-C4 alkoxy, halogen, and trifluoromethyl.

2. The method for preparing chiral 2-azaaromatic amides by visible light catalytic asymmetric reaction according to claim 1, characterized in that: The azaaromatic hydrocarbon II is selected from isoquinoline, substituted isoquinoline, and phenanthridine; the substituted isoquinoline is substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, dimethylamino, and tert-butyl 1,4-diazacycloheptane-1-carboxylate.

3. The method for preparing chiral 2-azaaromatic amides by visible light catalytic asymmetric reaction according to claim 1, characterized in that: The inorganic base is selected from NaHCO3, NaH2PO4, KH2PO4, K2HPO4, Na2CO3 or Li2CO3, and the molar ratio of the inorganic base to the nitrogen aromatic hydrocarbon II is 0.5 to 3.0:

1.

4. The method for preparing chiral 2-azaaromatic amides by visible light catalytic asymmetric reaction according to claim 1, characterized in that: The photosensitizer is 3DPAFIPN, and the molar ratio of the photosensitizer to the nitrogen heteroaromatic hydrocarbon II is 0.001-0.01:

1.

5. The method for preparing chiral 2-azaaromatic amides by visible light catalytic asymmetric reaction according to claim 1, characterized in that: The molar ratio of the chiral phosphoric acid catalyst to the nitrogen heteroaromatic hydrocarbon I is 0.05-0.2:

1.

6. The method for preparing chiral 2-azaaromatic amides by visible light catalytic asymmetric reaction according to claim 1, characterized in that: The organic solvent is selected from ethyl acetate, butyl acetate, dichloromethane or toluene; the visible light is selected from a wavelength of 360 to 450 nm; and the reaction temperature is -30°C to 0°C.

7. The method for preparing chiral 2-azaarene amides by visible light catalytic asymmetric reaction according to any one of claims 1 to 6, characterized in that: The reaction was carried out under inert gas protection.

8. A chiral 2-azaarene amide, characterized in that The general structural formula is: Where: R 1 is selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetyloxybenzyl or benzyl, which may contain sulfur or oxygen atoms; R 2 is selected from phenyl, substituted phenyl, thiophene, naphthalene; the substituted phenyl is substituted with at least one of C1-C4 alkyl, C1-C4 alkoxy, halogen, and trifluoromethyl; Selected from isoquinoline, substituted isoquinoline, phenanthridine; the substituted isoquinoline is substituted with C1-C4 alkyl, C1-C4 alkoxy, halogen, dimethylamino, tert-butyl 1,4-diazacycloheptane-1-carboxylate.

9. Use of the chiral 2-azaaromatic amide as claimed in claim 8 in the preparation of anticancer drugs.

10. The use of the chiral 2-azaarene amide in the preparation of anticancer drugs according to claim 9, characterized in that: The anticancer agent is selected from anti-breast cancer MCF-7, anti-cervical cancer Hela, and anti-malignant melanoma A-375.

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