Process for the preparation of chiral 2-azaheteroarene amides by visible light catalyzed asymmetric reaction

Abstract

The application discloses a method for preparing chiral 2-azaheteroarene amide through visible light catalytic asymmetric reaction and belongs to the technical field of organic synthesis. Under a nitrogen atmosphere, a racemic 2-bromide amide I and an azaheteroarene II are used as raw materials, a photosensitizer 3DPAFIPN, a chiral phosphoric acid catalyst and an inorganic base are present, and visible light irradiation reaction is carried out in an organic solvent to obtain chiral 2-azaheteroarene amide III. The method has wide substrate universality, high atom economy and high enantioselectivity, is free of metal participation, provides a new idea for the preparation of the compounds, and the obtained chiral 2-azaheteroarene amide has good activity in resisting breast cancer MCF-7, cervical cancer Hela and malignant melanoma A-375.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing amide-substituted chiral azaheteroarenes through a Minisci reaction under visible light irradiation, in which 2-bromoamides generate amide radical. BACKGROUND

[0002] The radical pathway Minisci reaction is one of the most important pathways for constructing functionalized azaheteroarenes (Tetrahedron 1971, 27, 3575; Angew. Chem. Int. Ed. 2015, 54, 2199; J. Am. Chem. Soc. 1988, 110, 8736). The traditional Minisci reaction needs to use stoichiometric oxidants, radical initiators, strong acids and other harsh reaction conditions (RSC Adv. 2016, 6, 22777; Org. Biomol. Chem. 2016, 14, 6611). With the development of visible light catalysis, a large number of new Minisci reactions with milder reaction conditions have been reported by using photosensitizer redox pathways (Molecules 2014, 19, 16190; Nature 2015, 525, 87). Therefore, it is of great significance and application value to develop new radical types and create new Minisci products.

[0003] At present, the addition products of azaheteroarenes in the reported visible light catalytic Minisci reaction include alkyl radicals, α-amine alkyl radicals with strong electron-rich and α-oxygen atom-substituted radicals (Synthesis 2019, 51, A-J; Angew. Chem. Int. Ed. 2019, 58, 2). By using the mild system of photo-oxidation and reduction in cooperation with chiral Bronsted acid, i.e. “asymmetric Minisci reaction catalyzed by light”, a series of chiral azaheteroarene compounds with important functional skeletons are 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). However, the existing asymmetric Minisci reaction is still limited to alkyl radicals and α-N / O-substituted electron-rich radicals, and there is no report on the Minisci reaction of amides which are weak nucleophilic radicals.

[0004] Therefore, this invention utilizes a visible light asymmetric catalytic system to employ amide radical precursors in an asymmetric Minisci reaction to construct amide-substituted nitrogen-containing aromatic compounds with novel structures, exhibiting good yields and enantioselectivity. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art. This invention provides a method for the asymmetric amidation of nitrogen-containing aromatic hydrocarbons by visible light catalysis. This method uses simple and readily available substrates, has mild reaction conditions, high atom economy, high enantioselectivity, and does not require metal participation.

[0006] To achieve the above objectives, the present invention provides a method for preparing chiral 2-azaaromatic amides via a visible-light catalytic asymmetric reaction. The technical solution includes the following steps: using racemic 2-bromoamide I and azaaromatic amide II as raw materials, the mixture is reacted under visible light irradiation in an organic solvent in the presence of 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 Selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetoxybenzyl, or benzyl groups, with or without sulfur or oxygen atoms; R 2 It 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.

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

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

[0011] Furthermore, in the above technical solution, the inorganic base is selected from NaHCO3, NaH2PO4, KH2PO4, K2HPO4, Na2CO3 or Li2CO3, and the molar ratio with the azo 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-containing aromatic hydrocarbon II is 0.05 to 0.2:1.

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

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

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

[0016] Further, in the above technical solution, the visible light is selected from visible light with a wavelength of 360-450nm, and a 3-watt blue lamp can be used for irradiation.

[0017] The application further provides a chiral 2-azaheteroarene amide, a structure general formula of which is as follows:

[0018]

[0019] R is selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetoxybenzyl or benzyl containing or not containing sulfur and oxygen atoms; R 1 R is selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetoxybenzyl or benzyl containing or not containing sulfur and oxygen atoms; R 2 R is selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetoxybenzyl or benzyl containing or not containing sulfur and oxygen atoms; R R is selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetoxybenzyl or benzyl containing or not containing sulfur and oxygen atoms; R

[0020] The application further provides application of the chiral 2-azaheteroarene amide in preparation of an anticancer drug.

[0021] Further, 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 azaheteroarene compound constructed by the application has an amide functional group, no external oxidant is needed in the reaction, the reaction condition is mild, stable and efficient, the operation is simple, the environment is friendly, the atomic economy is high, and the selectivity is good.

[0023] Compared with the existing synthesis method, the biggest feature of the method of the application is that an amide radical is introduced into azaheteroarene, an organic small molecule catalyst is used, the reaction condition is mild, fast and efficient, the yield is high, the method is green and environmentally friendly, the synthesized product has certain anticancer activity, and the method has great popularization and application value.

[0024] The present application relates to a wide range of substrates, a variety of product types, and the constructed amide-substituted chiral nitrogen heteroaromatic compounds have not been reported. In addition, the present application does not require the use of oxidants, and the chiral phosphoric acid is used as an organic small molecule catalyst, which has the advantages of high catalytic efficiency, no metal residues in the reaction system, etc. DETAILED DESCRIPTION

[0025] The technical solutions of the present application are further described in detail below in combination with examples, but the protection scope of the present application is not limited thereto.

[0026]

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

[0028]

[0029]

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

[0031] Example 1

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

[0033]

[0034] Compound 1a (0.15 mmol, 40.0 mg), compound 2a (0.1 mmol, 12.9 mg), 3DPA FIPN (0.001 mmol, 0.65 mg), NaHC03(0.2 mmol, 16.4 mg) were accurately weighed into a 10 mL Schlenk tube, then 2.0 mL ethyl acetate was added, after stirring well, a sealing plug was covered, the air in the reaction bottle was removed by double-tube freeze-vacuum, and the degassing operation was repeated three times. Then the reaction bottle was placed in a -30 °C constant temperature box and stirred in the dark for 10 min, then the light was turned on for irradiation, after 24 h the reaction was stopped, quenched with water, and extracted with ethyl acetate. Concentrated by rotary evaporator, separated directly by basic silica gel column chromatography (n-hexane / ethyl acetate 30-5: 1) to obtain 22.9 mg of white solid 3a. Melting point 167.4-168.2 °C; 22.9 mg, 83% yield, 90% ee; [a] 2 D 2 -9.1 (c 1.0, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.53 (d, J = 5.8 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.77 (t, J = 7.4 Hz, 1H), 7.70 (dd, J = 9.6, 6.7 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.29 (t, J = 7.9 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 4.92 (q, J = 7.1 Hz, 1H), 1.85 (d, J = 7.2 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 171.4, 160.4, 141.0, 138.4, 136.9, 130.8, 129.0, 128.2, 127.8, 126.8, 124.7, 124.1, 120.6, 119.9, 45.6, 21.2; HRMS (ESI) m / z 299.1155 (M+Na + ), calc. for C 18 H 16 N2ONa +299.1155; Ee was determined by HPLC analysis: CHIRALPAK IC (4.6 mm i.d. x 250 mm); Hexane / 2-propanol = 70 / 30; flow rate 1.0 mL / min; 25 °C; 254 nm; retention time: 7.4 min (major) and 8.2 min (minor).

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

[0036]

[0037] In this example, la in Example 1 was replaced by 1b, and other steps were the same as in Example 1, to obtain 24.9 mg of chiral product 3b, 82% yield, 90% ee; [a] 2 D 2 -36.3 (c 1.0, CHCl3); 1 H NMR (600 MHz, CDC13) δ 10.09 (s, 1H), 8.55 (d, J = 5.7 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.1 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.57 (d, J = 7.6 Hz, 2H), 7.33 - 7.26 (m, 2H), 7.08 - 7.01 (m, 1H), 4.75 (t, J = 7.2 Hz, 1H), 2.35 - 2.17 (m, 2H), 1.48 - 1.23 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 170.4, 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 N2ONa +327.1468; Ee was determined by HPLC analysis: CHIRALPAK IC (4.6 mm i.d. x 250 mm); Hexane / 2-propanol = 95 / 5; flow rate 1.0 mL / min; 25 °C; 254 nm; retention time: 15.2 min (major) and 16.6 min (minor).

[0038] The specific preparation procedure of compound 3c in Example 3 is as follows:

[0039]

[0040] In this example, la in Example 1 was replaced by 1c, and other steps were the same as Example 1, to obtain 28.1 mg of chiral product 3c, 70% yield, 90% ee; [a] 2 D 2 -32.4 (c 1.0, CHCl3); 1 H NMR (600 MHz, CDC13) δ 10.50 (s, 1H), 8.60 (d, J = 5.6 Hz, 1H), 8.21 (t, J = 11.4 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.68 - 7.37 (m, 8H), 7.33 (t, J = 7.9 Hz, 2H), 7.25 - 7.18 (m, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.88 (d, J = 6.9 Hz, 1H), 5.15 (s, 1H), 4.25 (dd, J = 13.7, 5.0 Hz, 1H), 3.89 (dd, J = 13.5, 9.7 Hz, 1H). 13 C NMR (151 MHz, CDC13) δ 170.0, 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 N2ONa +425.1624; The ee was determined by HPLC analysis: CHIRALPAK ADH (4.6 mm i.d. x 250 mm); Hexane / 2-propanol = 90 / 10; flow rate 1.0 mL / min; 25 °C; 254 nm; retention time: 16.4 min (major) and 27.8 min (minor).

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

[0042]

[0043] In this example, la in Example 1 is replaced by 1d, and other steps are the same as those in Example 1, to obtain 24.2 mg of chiral product 3d, 80% yield, 93% ee; [a] 2 D 2 -10.7 (c 1.0, CHCl3); 1 H NMR (600 MHz, CDC13) δ 10.03 (s, 1H), 8.57 (d, J = 5.7 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.68 - 7.60 (m, 2H), 7.55 (d, J = 7.6 Hz, 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 (151 MHz, CDC13) δ 169.8, 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 / z 325.1311 (M + Na + ), calc. for C 20 H 18 N2ONa +325.1311; The ee was determined by HPLC analysis: CHIRALPAK IC (4.6 mm i.d. x 250 mm); Hexane / 2-propanol = 90 / 10; flow rate 1.0 mL / min; 25 °C; 254 nm; retention time: 11.5 min (major) and 13.1 min (minor).

[0044] The specific preparation procedure of compound 3e in this example is as follows:

[0045]

[0046] In this example, la in Example 1 was replaced by le, and other steps were the same as Example 1, to obtain 22.9 mg of chiral product 3e, 78% yield, 90% ee; (c 1.0, CHCl3); 1 H NMR (600 MHz, CDC13) δ 10.23 (s, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.73 (t, J = 7.3 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.57 - 7.49 (m, 2H), 7.05 - 6.94 (m, 2H), 4.79 (q, J = 7.3 Hz, 1H), 1.81 (d, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 171.4, 160.2 (d, J = 52.5 Hz), 158.5, 140.8, 136.9, 134.5 (d, J = 2.1 Hz), 130.8, 128.2, 127.8, 126.8, 124.6, 121.6 (d, J = 7.7 Hz), 120.7, 115.6 (d, J = 22.2 Hz), 45.3, 21.4. 19 F NMR (565 MHz, CDC13) δ -118.6; HRMS (ESI) m / z 317.1060 (M + Na + ), calc. for C 18 H 15 FN2ONa +317.1060; The ee was determined by HPLC analysis: CHIRALPAK IC (4.6 mm i.d. x 250 mm); Hexane / 2-propanol = 70 / 30; flowrate 1.0 mL / min; 25 °C; 254 nm; retention time: 6.2 min (major) and 6.7 min (minor).

[0047] The specific preparation procedure of compound 3f in this example is as follows:

[0048]

[0049] In this example, 2a in Example 1 is replaced by 2b, and other steps are the same as Example 1, to obtain 27.7 mg of chiral product 3f, 85% yield, 94% ee; (c 1.0, CHCl3); 1 H NMR (600 MHz, CDC13) δ 10.67 (s, 1H), 8.68 (d, J = 8.2 Hz, 1H), 8.59 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 7.3 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 7.80 (t, J = 7.4 Hz, 1H), 7.73 (dt, J = 22.8, 7.5 Hz, 2H), 7.63 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H), 4.86 (d, J = 5.6 Hz, 1H), 1.90 (d, J = 7.3 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 171.3, 160.8, 142.5, 138.5, 133.5, 131.3, 129.3, 129.2, 129.1, 128.1, 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 N2ONa +349.1311; Theee was determined by HPLC analysis: CHIRALPAK INB (4.6 mm i.d. x 250 mm); Hexane / 2-propanol = 80 / 20; flow rate 1.0 mL / min; 25 °C; 254 nm; retention time: 10.1 min (major) and 16.3 min (minor).

[0050] Substrate scope:

[0051]

[0052] Biological activity evaluation (cell level)

[0053] Breast cancer MCF-7, cervical cancer Hela, malignant melanoma A-375 three cell lines, take the logarithmic growth period cells, with 5000 cells per hole inoculated in 96 hole cell culture plate. 24h after cell point plate, add corresponding concentration of compound (example 1-5) respectively, after 48h, discard supernatant and add 1mg / mL MTT solution 50μL per hole, continue to cultivate 4h, add 100μL dimethyl sulfoxide per hole, after oscillation on the oscillator for 30min, use full wavelength enzyme label instrument to measure its OD value at 490nm wavelength, use formula: cell inhibition rate = (1-experimental group absorbance value / blank control group absorbance value) x 100%, calculate to obtain cell inhibition rate, statistics as follows:

[0054]

[0055]

[0056] From the above table, the chiral nitrogen heteroaromatic compound prepared by the application shows good cell proliferation inhibition activity on breast cancer MCF-7, cervical cancer Hela, malignant melanoma A-375 four types of tumor cells, and is expected to be applied to the preparation of anticancer drugs.

[0057] The above shows and describes the basic principles and main features of the application and the advantages of the application. Those skilled in the art should understand that the application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the application. Without departing from the spirit and scope of the application, various changes and improvements can be made to the application, and these changes and improvements all fall within the scope of the claimed application.

Claims

1. Process for the preparation of chiral 2-azaarene carboxamides by visible light catalyzed asymmetric reaction, characterized in that, The method comprises the following steps: The chiral 2-azaheteroarene amide III is obtained by irradiating the racemic 2-bromide amide I and the azaheteroarene II in an organic solvent under visible light in the presence of a photosensitizer 3DPAFIPN, a chiral phosphoric acid catalyst and an inorganic base; a reaction equation is shown as follows: wherein: R 1 selected from C1-C10 alkyl or cycloalkyl, allyl, propargyl, acetyl- oxybenzyl or benzyl, with or without sulfur, oxygen atoms; R 2 selected from phenyl, substituted phenyl, thiophene, naphthalene; in the substituted phenyl, the substitution is at least one of C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl; R is selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, dimethylamino, tert-butyl 1,4-diazepane-1-carboxylate.

2. The method of claim 1, wherein the chiral 2-azaarene amide is prepared by the asymmetric visible light catalyzed reaction, 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 azaheteroarene II is 0.5-3.0:

1.

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

1.

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

1.

5. The method for preparing chiral 2-azaaromatic amides by visible light photocatalytic 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 360-450 nm; and the reaction temperature is-30-0 DEG C.

6. The process for the preparation of chiral 2-azaheteroarene amides by visible light catalyzed asymmetric reaction according to any one of claims 1 to 5, characterized in that: The reaction is carried out under inert gas protection.

Images