Method for preparing 1, 4-dicarbonyl compound containing heteroaromatic ring

Abstract

The invention relates to a method for preparing a 1, 4-dicarbonyl compound containing heteroaromatic ring. Specifically, under the condition of catalysis of a photosensitizer fac-Ir (ppy) 3, aromatic heterocycle substituted tertiary alcohol, carbon monoxide and a diazo compound are prepared through a one-pot method. According to the invention, starting from simple and easily available raw materials and catalyst, a series of heteroaromatic ring-containing 1, 4-dicarbonyl compounds are obtained through carbonylation reaction.

Description

Technical Field

[0001] The present invention relates to a method for preparing 1,4-dicarbonyl compounds containing heteroaromatic rings. Background Art

[0002] 1,4-Dicarbonyl compounds are versatile and valuable synthetic building blocks and are often used as precursors for the synthesis of various bioactive heterocycles such as pyrrole, furan, and thiophene. Based on the chemical and regioselective progress of radical reactions, radical-mediated olefin difunctionalization is a useful synthetic strategy for olefin utilization and has attracted extensive attention. In this context, the emergence of the intramolecular remote functional group migration (FGM) strategy has greatly expanded the reaction scope of olefin difunctionalization. In the past few decades, systematic studies have been carried out on the radical-promoted difunctionalization reactions of unactivated olefins, including the remote migration of functional groups. Various migration modes have been explored, such as 1,2-migration, 1,4-migration, and 1,5-migration. Unfortunately, to date, the 1,3-migration of distal functional groups is still unpopular. Carbon monoxide (CO) is a cost-effective and readily available C1 source, making it an important synthon in carbonylation reactions. Based on the above background, we have developed a strategy for radical-mediated olefin difunctionalization reactions involving CO and obtained 1,4-dicarbonyl compounds.

[0003] In summary, a method for preparing 1,4-dicarbonyl compounds containing heteroaromatic rings with high efficiency, atom economy, and good functional group compatibility is described herein. Summary of the Invention

[0004] The object of the present invention is to provide a method for preparing 1,4-dicarbonyl compounds containing heteroaromatic rings.

[0005]

[0006] Reaction Equation 1: Synthesis of 1,4-Dicarbonyl Compounds

[0007] The specific operation steps are as follows (Reaction Equation 1):

[0008] The reaction was carried out in a 300 mL high-pressure reactor. The catalyst and the heteroaromatic-substituted tertiary alcohol 2 were weighed, and in a nitrogen atmosphere, the solvent N,N-dimethylformamide, the diazo compound, and the additive water were injected to obtain a mixed material. The reaction was placed in a carbon monoxide gas atmosphere and irradiated with two 7 - 45 W blue light bulbs, preferably 10 - 20 W, and reacted at 20 - 50 °C, preferably 25 - 30 °C. The reaction time was 6 - 36 hours, preferably 12 - 24 hours; after the reaction was completed, the heteroaromatic-containing 1,4-dicarbonyl compound 4 was separated. The dosage ratio of the heteroaromatic-substituted tertiary alcohol 2 was 0.1 - 100 mmol, preferably 0.2 mmol. The dosage ratio of the diazo compound 1 was 0.2 - 100 mmol, preferably 0.6 mmol.

[0009] The catalyst is one or more of tris(2-phenylpyridine)iridium, [2,2'-bi(4-tert-butylpyridine)]bis[2-(2,4-difluorophenyl)pyridine]iridium(III) hexafluorophosphate, 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, ruthenium(III) chloride hexahydrate, preferably tris(2-phenylpyridine)iridium; the dosage of the catalyst is 0.5 mol% - 5 mol% of the dosage of the heteroaromatic-substituted tertiary alcohol 2, preferably 1 mol%.

[0010] The additive is one or more of water, methanol, acetic acid, hexafluoroisopropanol, preferably water; the dosage of water is 1:1 - 1:4 of the dosage of the heteroaromatic-substituted tertiary alcohol 2, preferably 1:3.

[0011] The solvent is one or more of N,N-dimethylformamide, toluene, acetonitrile, ethyl acetate, acetone, 1,2-dichloroethane; preferably N,N-dimethylformamide. The dosage of the solvent is 0.5 - 5.0 mL of the solvent per 0.2 mmol of the heteroaromatic-substituted tertiary alcohol 2, preferably 2.0 mL.

[0012] The air pressure of carbon monoxide is 1 - 50 atmospheres, preferably 40 atmospheres.

[0013] The present invention has the following advantages:

[0014] The present invention prepares heteroaromatic-containing 1,4-dicarbonyl compounds through radical-mediated under light irradiation. First, 1,4-dicarbonyl compounds are versatile and valuable synthetic building blocks and are often used as precursors for synthesizing various bioactive heterocycles, such as pyrrole, furan, and thiophene. Second, the reaction conditions are mild, greatly reducing the reaction energy consumption and danger; the raw materials of this system are simple and easy to obtain, broadening the applicability of the reaction; finally, using gaseous CO as the carbonyl source, it is cheap and easy to obtain, greatly reducing the cost. Specific Embodiments

[0015] Preparation of Raw Material 2

[0016]

[0017] R 1 is one or more of a hydrogen atom, a methyl group, a halogen atom (fluorine, chlorine, bromine);

[0018] R 2 is one or more of a hydrogen atom, a methoxy group, an ethoxy group, a benzyloxy group, a halogen atom (fluorine, chlorine, bromine);

[0019] Step I: At room temperature, benzoyl chloride (0.76 g, 4.0 mmol), thiazole (0.14 mL, 2.0 mmol) and triethylamine (0.84 mL, 6.0 mmol) were successively added to a solution of 4-dimethylaminopyridine (DMAP, 74 mg, 1.2 mmol) in acetonitrile (4.0 mL). The resulting mixture was heated at 80 °C for 24 h. After cooling to room temperature, the reaction was quenched by rapid cooling with 10 mL of saturated saline solution. The product was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na 2 SO 4 and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography with linear elution using different polarity eluents (dichloromethane / petroleum ether = 1 / 5 - 1 / 1, V / V) to obtain white or yellow solid 1.

[0020] Step II: Allylmagnesium bromide (1.1 mmol) was added dropwise to a solution of ketone 1 (1 mmol) in dry THF (5 mL) in an oven-dried 25 mL two-necked round-bottom flask. The resulting mixture was gradually heated to room temperature and stirred for 1 h. After the reaction was completed, the reaction was quenched by rapid cooling with saturated NH 4 Cl solution, extracted with ethyl acetate and dried, and then purified on a silica gel column using an eluent of 200 mL of ethyl acetate / petroleum ether (1 / 20, V / V) to obtain white or yellow solid 2. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0021] The detection data of 2a are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.7 Hz, 2H), 7.42 (t, J = 7.7 Hz, 1H), 5.79 - 5.68 (m, 2H), 5.28 - 5.18 (m, 2H), 3.72 (s, 1H), 3.44 (dd, J = 13.9 Hz, J = 6.6 Hz, 1H), 3.09 (dd, J = 13.8 Hz, J = 7.9 Hz, 1H).

[0022] 13 13C NMR (101 MHz, CDCl 3 ) δ 178.0, 153.2, 143.4, 135.7, 132.6, 128.5, 127.8, 126.0, 125.5, 125.0, 123.2, 121.8, 121.4, 77.8, 47.3.

[0023] HRMS (ESI-TOF) m / z: [M+H] + Calcd. for C 17 H 16 NOS 282.0947; found: 282.0949.

[0024] The operation process and conditions are the same as those in the preparation process of 2a. The difference is that m-fluorobenzoyl chloride is used to replace benzoyl chloride in an equimolar amount to obtain the substrate 2b. The structure of the compound is identified by nuclear magnetic resonance (1H NMR, 13C NMR) and high-resolution mass spectrometry.

[0025] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.54 - 7.41 (m, 3H), 7.40 - 7.26 (m, 2H), 7.03 - 6.86 (m, 1H), 5.81 - 5.63 (m, 1H), 5.39 - 5.17 (m, 2H), 3.67 (s, 1H), 3.43 (dd, J = 13.9, 6.6 Hz, 1H), 3.04 (dd, J = 13.9, 8.0 Hz, 1H).

[0026] 13 13C NMR (101 MHz, CDCl 3 ) δ 177.2, 162.8 (d, 1 J C-F = 245.7 Hz), 153.2, 146.0 (d, 3 J C-F = 7.0 Hz), 135.6, 132.2, 129.9 (d, 3 J C-F = 8.1 Hz), 126.1, 125.1, 123.3, 121.8, 121.7, 121.2 (d, 4 J C-F = 2.9 Hz), 114.6 (d, 2 J C-F = 21.2 Hz), 112.9 (d, 2 J C-F= 23.4 Hz), 77.4, 47.4.

[0027] 19 F NMR (376 MHz, CDCl 3 ) δ -122.3 (s, 1F).

[0028] HRMS (ESI-TOF) m / z: [M+H] + Calcd. for C 17 H 15 FNOS 300.0853; found: 300.0854.

[0029] The operation process and conditions are the same as those in the preparation process of 2a. The difference is that 5-bromobenzothiazole is used to replace benzothiazole in equimolar amounts to obtain the substrate 2c. The structure of the compound is identified by nuclear magnetic resonance (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0030] 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (d, J = 1.9 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.76 - 7.62 (m, 2H), 7.52 (dd, J = 8.7, 2.0 Hz, 1H), 7.42 - 7.30 (m, 2H), 7.29 - 7.19 (m, 1H), 5.83 - 5.55 (m, 1H), 5.39 - 5.10 (m, 2H), 3.58 (s, 1H), 3.41 (dd, J = 13.9, 6.7 Hz, 1H), 3.08 (dd, J = 13.9, 7.8 Hz, 1H).

[0031] 13 C NMR (101 MHz, CDCl 3 ) δ 178.6, 152.2, 143.1, 137.3, 132.3, 129.4, 128.5, 127.8, 125.4, 124.4, 124.3, 121.6, 118.6, 77.8, 47.2.

[0032] HRMS (ESI-TOF) m / z: [M+H] + Calcd. for C 17 H 15 BrNOS 360.0052; found: 360.0054.

[0033] The operation process and conditions are the same as those in the preparation process of 2a. The difference is that thiazole is used to replace benzothiazole in equimolar amounts to obtain the substrate 2d. The structure of the compound is identified by nuclear magnetic resonance (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0034] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J = 3.1 Hz, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.25 (d, J = 3.7 Hz, 2H), 5.81 - 5.52 (m, 1H), 5.32 - 5.13 (m, 2H), 3.50 (s, 1H), 3.32 (dd, J = 13.8, 6.7 Hz, 1H), 3.04 (dd, J = 13.8, 7.7 Hz, 1H).

[0035] 13 13C NMR (101 MHz, CDCl 3 ) δ 177.2, 144.0, 142.4, 132.6, 128.4, 127.5, 125.4, 121.1, 119.5, 77.5, 47.6.

[0036] HRMS (ESI-TOF) m / z: [M + H] + Calcd. for C 13 H 14 NOS232.0791; found: 232.0788.

[0037] The operation process and conditions were the same as those in the preparation process of 2a. The difference was that oxazole was used in equimolar amount to replace benzothiazole to obtain substrate 2e. The structure of the compound was identified by nuclear magnetic resonance (1H NMR, 13C NMR) and high-resolution mass spectrometry.

[0038] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 7.50 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.30 - 7.25 (m, 1H), 7.04 (s, 1H), 5.85 - 5.57 (m, 1H), 5.26 - 4.89 (m, 2H), 3.97 (s, 1H), 3.17 (dd, J = 14.1, 7.1 Hz, 1H), 2.95 (dd, J = 14.1, 7.1 Hz, 1H).

[0039] 13 13C NMR (101 MHz, CDCl 3 ) δ 166.6, 142.8, 139.3, 132.3, 128.4, 127.8, 126.7, 125.3, 120.1, 75.1, 46.0.

[0040] HRMS(ESI-TOF) m / z: [M+H] + Calcd. for C 13 H 14 NO 2 216.1019; found: 216.1023.

[0041] The operation process and conditions are the same as those in the preparation process of 2a. The difference is that 5-chlorobenzoxazole is used to replace benzothiazole in equimolar amount to obtain the substrate 2f. The structure of the compound is identified by nuclear magnetic resonance (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0042] 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (d, J = 2.0 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.43 - 7.32 (m, 3H), 7.32 - 7.25 (m, 2H), 5.88 - 5.66 (m, 1H), 5.27 - 5.08 (m, 2H), 3.86 (s, 1H), 3.30 (dd, J = 14.1, 7.2 Hz, 1H), 3.05 (dd, J = 14.1, 7.2 Hz, 1H).

[0043] 13 C NMR (101 MHz, CDCl 3 ) δ 169.7, 149.8, 141.8, 141.5, 131.9, 130.1, 128.6, 128.1, 125.6, 125.3, 120.8, 120.3, 111.7, 75.4, 45.7.

[0044] HRMS(ESI-TOF) m / z: [M+H] + Calcd. for C 17 H 15 ClNO 2 300.0786; found: 300.0785.

[0045] To better understand the present invention, it is illustrated by the following examples. The reaction raw materials and results of Examples 1 - 8 are shown in Table 1 and Table 2.

[0046] Table 1 Reaction results of tertiary alcohols 2 substituted with different heteroaromatic rings and ethyl diazoacetate

[0047]

[0048]

[0049] Example 1:

[0050] The reaction was carried out in a 300 mL high-pressure reactor. First, the heteroaromatic-substituted tertiary alcohol 2a (0.2 mmol) and tris(2-phenylpyridine)iridium (0.002 mmol) were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 2.0 mL of N,N-dimethylformamide was added as a solvent to the mixture. Methyl diazomalonate 1a (0.6 mmol) and water (0.6 mmol) were injected to obtain a mixed material. The vial was tightly capped with a rubber stopper. The tip of a syringe needle was inserted through the stopper into the vial to make the vial communicate with the outside through the needle. Then the reaction vial was placed in the high-pressure reactor, and the high-pressure reactor was purged with carbon monoxide and filled with 40 atmospheres of carbon monoxide. At this time, the carbon monoxide in the reactor was connected to the inside of the vial through the needle. Then, it was irradiated with two 15 W blue LEDs (wavelength 430 - 460 nm) at room temperature for 24.0 hours. After the reaction, the heteroaromatic-containing 1,4-dicarbonyl compound 4a was obtained by column chromatography separation with a yield of 72%. The compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0051] The detection data are as follows:

[0052] (4a): 63.2 mg, 72% yield, slight yellow oil. Eluent: pentane / ethyl acetate = 5:1 - 3:1

[0053] 1 H NMR (400 MHz, CDCl 3 ) δ 8.20–8.15 (m, 1H), 8.00–7.96 (m, 1H), 7.96–7.91 (m, 2H), 7.59–7.50 (m, 3H), 7.44 (t, J = 7.7 Hz, 2H), 4.55 (tt, J = 9.7, 5.0 Hz, 1H), 3.81 (dd, J = 18.0, 9.6 Hz, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 3.60 (dd, J = 8.5, 6.4 Hz, 1H), 3.43 (dd, J = 17.9, 4.6 Hz, 1H), 2.50–2.36 (m, 2H).

[0054] 13 C NMR (101 MHz, CDCl 3 ) δ 197.3, 196.7, 169.2, 169.2, 166.2, 153.6, 137.6, 136.0, 133.5, 128.7, 128.2, 127.7, 126.9, 125.7, 122.5, 52.8, 52.7, 49.7, 42.1, 40.0, 30.7.

[0055] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 23 H 22 NO 6 S 440.1162; Found: 440.1163.

[0056] Example 2:

[0057] The operation process and conditions were the same as those in Example 1, except that the starting material aromatic heterocyclic substituted tertiary alcohol 2b (equimolar substitution for 2a) in Table 1 was used. The yield of 4b was 62%, and the structure of the compound was identified by nuclear magnetic resonance (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0058] (4b): 56.7 mg, 62% yield, slight yellow oil. Eluent: pentane / ethyl acetate = 5:1 - 3:1

[0059] 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.60–7.51 (m, 2H), 7.47–7.41 (m, 1H), 7.27 (t, J = 9.5 Hz, 1H), 4.59–4.50 (m, 1H), 3.81–3.74 (m, 4H), 3.67 (s, 3H), 3.59 (dd, J = 8.6, 6.3 Hz, 1H), 3.38 (dd, J = 17.9, 4.6 Hz, 1H), 2.50–2.35 (m, 2H).

[0060] 13 C NMR (101 MHz, CDCl 3 ) δ 196.5, 196.2, 169.2, 169.1, 166.0, 162.8 (d, J C-F = 248.1 Hz), 153.6, 138.1 (d, J C-F = 6.2 Hz), 137.6, 130.4 (d, J C-F = 7.6 Hz), 127.8, 127.0, 125.7, 124.0 (d, J C-F = 3.0 Hz), 122.5, 120.5 (d, J C-F = 21.4 Hz), 115.0 (d, J C-F= 22.4 Hz), 52.8, 52.8, 49.6, 42.1, 40.0, 30.6.

[0061] 19 F NMR (56 MHz, CDCl 3 ) δ -111.6.

[0062] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 23 H 21 FNO 6 S 458.1068; Found: 458.1062.

[0063] Example 3:

[0064] The operation process and conditions are the same as those in Example 1. The difference is that the tertiary alcohol 2c substituted with an aromatic heterocycle in the raw material in Table 1 (substituting 2a in equimolar amount) is used. The yield of 4c is 68%. The structure of the compound is identified by nuclear magnetic resonance (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0065] (4c): 70.3 mg, 68% yield, slight yellow oil. Eluent: pentane / ethyl acetate = 5:1 - 3:1

[0066] 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 1.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.66 (dd, J = 8.8, 1.9 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 4.55–4.45 (m, 1H), 3.83–3.76 (m, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.57 (dd, J = 8.4, 6.5 Hz, 1H), 3.44 (dd, J = 18.0, 4.5 Hz, 1H), 2.49–2.34 (m, 2H).

[0067] 13 C NMR (101 MHz, CDCl 3 ) δ 197.3, 196.5, 169.1, 169.1, 166.6, 152.3, 139.1, 135.9, 133.6, 130.6, 128.7, 128.2, 126.7, 125.0, 121.9, 52.8, 52.8, 49.6, 42.1, 40.1, 30.7.

[0068] HRMS(ESI-TOF) m / z: [M+H] + Calcd for C 23 H 21 BrNO 6 S 518.0267; Found: 518.0270.

[0069] Example 4:

[0070] The operation process and conditions are the same as those in Example 1, the difference is that the starting material aromatic heterocyclic substituted tertiary alcohol 2d (equimolar substitution for 2a) in Table 1 is used, the yield of 4d is 69%, and the structure of the compound is identified by nuclear magnetic resonance (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0071] (4d): 53.7 mg, 69% yield, slight yellow oil. Eluent: pentane / ethyl acetate = 5:1 - 3:1

[0072] 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (d, J = 3.0 Hz, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.69 (d, J = 3.0 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 4.47–4.38 (m, 1H), 3.79–3.73 (m, 4H), 3.68 (s, 3H), 3.54 (dd, J = 8.4, 6.5 Hz, 1H), 3.35 (dd, J = 17.9, 4.6 Hz, 1H), 2.47–2.39 (m, 1H), 2.36–2.28 (m, 1H).

[0073] 13 C NMR (101 MHz, CDCl 3 ) δ 197.3, 195.1, 169.2, 169.2, 166.7, 144.9, 136.1, 133.4, 128.6, 128.2, 126.5, 52.7, 52.7, 49.6, 41.6, 40.1, 30.6.

[0074] HRMS(ESI-TOF) m / z: [M+H] + Calcd for C 19 H 20 NO 6 S 390.1006; Found: 390.1004.

[0075] Example 5:

[0076] The operation process and conditions are the same as those in Example 1, and the difference is that the starting material aromatic heterocycle-substituted tertiary alcohol 2e in Table 1 (equimolar substitution for 2a) is used. The yield of 4e is 55%. The structure of the compound was identified by NMR (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0077] (4e): 41.0 mg, 55% yield, slightly yellow oil. Eluent: pentane / ethyl acetate = 5:1 - 3:1

[0078] 1 H NMR (400 MHz, CDCl 3 ) δ 7.94–7.89 (m, 2H), 7.84 (s, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.36 (s, 1H), 4.29–4.19 (m, 1H), 3.76–3.68 (m, 7H), 3.54 (dd, J = 8.2, 6.7 Hz, 1H), 3.36 (dd, J = 18.0, 4.5 Hz, 1H), 2.46–2.36 (m, 1H), 2.35–2.26 (m, 1H).

[0079] 13 C NMR (101 MHz, CDCl 3 ) δ 197.2, 189.6, 169.1, 169.1, 158.0, 141.8, 135.9, 133.5, 129.3, 128.7, 128.2, 52.8, 52.8, 49.5, 41.6, 40.7, 30.5.

[0080] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C 19 H 20 NO 7 374.1234; Found: 374.1235. Example 6:

[0081] The operation process and conditions are the same as those in Example 1, and the difference is that the starting material aromatic heterocycle-substituted tertiary alcohol 2f in Table 1 (equimolar substitution for 2a) is used. The yield of 4f is 56%. The structure of the compound was identified by NMR (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0082] 1 H NMR (400 MHz, CDCl 3)δ 7.91 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 2.0 Hz, 1H), 7.61–7.55 (m, 2H), 7.50 (dd, J = 8.8, 2.0 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 4.40–4.30 (m, 1H), 3.79 (dd, J = 16.6, 8.3 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 3.57 (dd, J = 8.2, 6.6 Hz, 1H), 3.48 (dd, J = 18.1, 4.3 Hz, 1H), 2.48–2.34 (m, 2H).

[0083] 13 C NMR (101 MHz, CDCl 3 )δ 197.3, 191.4, 169.0, 169.0, 158.4, 149.5, 141.7, 135.7, 133.7, 131.3, 128.9, 128.7, 128.2, 122.1, 112.9, 52.8, 49.5, 42.4, 40.9, 30.6.

[0084] HRMS (ESI-TOF) m / z: [M+H]+ Calcd for C 23 H 21 ClNO 7 458.1001; Found: 458.0999.

[0085] Table 2 Reaction results of benzothiazole-substituted tertiary alcohols with diazo compounds

[0086]

[0087]

[0088] Example 7:

[0089] The reaction was carried out in a 300 mL high-pressure reactor. First, benzothiazole-substituted tertiary alcohol 2a (0.2 mmol) and tris(2-phenylpyridine)iridium(III) (0.002 mmol) were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 2.0 mL of N,N-dimethylformamide was added as a solvent to the mixture. Diazo compound 1 (0.6 mmol) and water (0.6 mmol) were injected to obtain a mixed material. The vial was tightly capped with a rubber stopper. One end of the tip of a syringe needle was inserted through the stopper into the vial to connect the vial to the outside through the needle. Then the reaction vial was placed in the high-pressure reactor, and the high-pressure reactor was purged with carbon monoxide and filled with carbon monoxide at 40 atmospheres. At this time, the carbon monoxide in the reactor was connected to the inside of the vial through the needle. Then it was irradiated with two 15 W blue LEDs (450 - 460 nm) at room temperature for 36.0 hours. After the reaction, the 1,4-dicarbonyl compound 4g containing heteroaromatic rings was obtained by column chromatography separation with a yield of 59%. The compound was identified by NMR (proton spectrum, carbon spectrum) and high-resolution mass spectrometry.

[0090] The detection data are as follows:

[0091] (4g): 46.6 mg, 59% yield, slightly yellow oil. Eluent: pentane / ethyl acetate = 5:1 - 3:1

[0092] 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J = 7.6 Hz, 1H), 8.01–7.93 (m, 3H), 7.59–7.50 (m, 3H), 7.45 (t, J = 7.7 Hz, 2H), 4.62–4.52 (m, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.80 (dd, J = 18.0, 10.0 Hz, 1H), 3.38 (dd, J = 18.0, 4.3 Hz, 1H), 2.52–2.39 (m, 2H), 2.26–2.17 (m, 1H), 2.16–2.07 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H).

[0093] 13 C NMR (101 MHz, CDCl 3 ) δ 197.7, 197.3, 172.7, 166.3, 153.7, 137.6, 136.1, 133.4, 128.6, 128.2, 127.6, 126.9, 125.7, 122.4, 60.6, 41.6, 41.1, 31.9, 27.1, 14.2.

[0094] HRMS(ESI-TOF) m / z: [M+H] + Calcd for C 22 H 22 NO 4 S 396.1264; Found: 396.1267.

[0095] Example 8:

[0096] The operation process and conditions are the same as those in Example 6. The difference is that the starting diazo compound is Compound 1 in Table 2. The yield after 4 h is 75%. The structure of the compound was identified by NMR (1H NMR, 13C NMR) and high-resolution mass spectrometry. (4 h): 63.5 mg, 75% yield, slight yellow oil. Eluent: pentane / ethyl acetate = 5:1 - 3:1

[0097] 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J = 7.5 Hz, 1H), 8.00–7.94 (m, 3H), 7.59–7.51 (m, 3H), 7.44 (t, J = 7.7 Hz, 2H), 4.61–4.49 (m, 1H), 3.79 (dd, J = 18.0, 10.1 Hz, 1H), 3.38 (dd, J = 18.0, 4.2 Hz, 1H), 2.48–2.29 (m, 2H), 2.22–2.01 (m, 2H), 1.41 (s, 9H).

[0098] 13 C NMR (101 MHz, CDCl 3 ) δ 197.8, 197.4, 172.0, 166.3, 153.7, 137.6, 136.2, 133.4, 128.6, 128.2, 127.6, 126.8, 125.7, 122.4, 80.6, 41.5, 41.1, 33.0, 28.1, 27.2.

[0099] HRMS(ESI-TOF) m / z: [M+H] + Calcd for C 24 H 26 NO 4 S 424.1577; Found: 424.1582.

[0100] Example 9:

[0101] The operation process and conditions were the same as those in Example 6. The difference was that the starting diazo compound was Compound 1 in Table 2, and the yield of 4i was 64%. The structure of the compound was identified by NMR (proton spectrum, carbon spectrum) and high-resolution mass spectrometry. (4i): 58.5 mg, 64% yield, slightly yellow oil. Eluent: pentane / ethyl acetate = 5:1 - 3:1

[0102] 1 H NMR(400MHz,CDCl 3 )δ8.19(d,J = 7.6Hz,1H),7.98(d,J = 7.4Hz,1H),7.94(d,J = 7.2Hz,2H),7.60–7.50(m,3H),7.44(t,J = 7.7Hz,2H),7.33–7.28(m,5H),5.09(s,2H),4.64–4.52(m,1H),3.80(dd,J = 18.0,10.0Hz,1H),3.37(dd,J = 18.0,4.3Hz,1H),2.61–2.45(m,2H),2.30–2.10(m,2H).

[0103] 13 C NMR(101MHz,CDCl 3 )δ197.7,197.2,172.6,166.3,153.7,137.6,136.1,135.8,133.4,128.6,128.6,128.3,128.2,127.6,126.9,125.8,122.4,66.5,41.6,41.1,31.9,27.0.

[0104] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 27 H 24 NO 4 S 458.1421;Found:458.1423.

[0105] Example 10

[0106] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions were the same as those in Example 1), the difference was that the solvent of the reaction was changed to acetonitrile, and the yield of the target product 1,4-dicarbonyl compound 4a decreased to 44%.

[0107] Example 11

[0108] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the blue light intensity of the reaction is changed to 45 W, and the yield of the target product 1,4-dicarbonyl compound 4a is reduced to 48%.

[0109] Example 12

[0110] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is changed to 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, and the yield of the target product 1,4-dicarbonyl compound 4a is reduced to 53%.

[0111] Comparative Example 1

[0112] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is changed to ruthenium(III) chloride hexahydrate, and the yield of the target product 1,4-dicarbonyl compound 4a is reduced to 0%.

[0113] Comparative Example 2

[0114] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the blue light of the reaction is removed, and the yield of the target product 1,4-dicarbonyl compound 4a is reduced to 2%.

[0115] Comparative Example 3

[0116] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is not added, and the yield of the target product 1,4-dicarbonyl compound 4a is reduced to 9%.

[0117] Comparative Example 4

[0118] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the CO of the reaction is removed, and the yield of the target product 1,4-dicarbonyl compound 4a is reduced to 0%.

[0119] Application Example 1: Conversion to pyrrole derivatives as apolipoprotein L-1 inhibitors. Reference: (Preparation of pyrrole derivatives as inhibitors of apolipoprotein L-1 for the treatment of diseases. World Intellectual Property Organization, WO2023194895A1 2023-10-12)

[0120]

[0121] Product 5 can be obtained by 4 condensation. This compound is a known compound and is used as an apolipoprotein L-1 inhibitor.

[0122] The reaction was carried out in a 300 mL high-pressure reactor. First, the trifluorotoluene-substituted tertiary alcohol 2 (0.2 mmol) and tris(2-phenylpyridine)iridium (0.002 mmol) were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 2.0 mL of N,N-dimethylformamide was added as a solvent to the mixture. Ethyl diazoacetate 1a (0.6 mmol) and water (0.6 mmol) were injected to obtain a mixed material. The vial was tightly capped with a rubber bottle cap. The tip of a syringe needle was inserted through the cap into the vial to make the vial communicate with the outside through the needle. Then the reaction vial was placed in the high-pressure reactor, and the high-pressure reactor was purged with carbon monoxide and filled with 40 atmospheres of carbon monoxide. At this time, the carbon monoxide in the reactor was connected to the inside of the vial through the needle. Then, it was irradiated with two 15 W blue LEDs (wavelength 430 - 460 nm) at room temperature for 24.0 hours; after the reaction was completed, product 4 was obtained by column chromatography separation. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0123] References: (Chem. Commun., 2014, 50, 6168 - 6170). The specific operation is as follows: 4 (0.2 mmol), ammonium acetate (154 mg, 20 mmol), and acetic acid (20 mmol) were added to 2 mL of methanol solution, and heated to 85 °C and reacted for 12 hours under nitrogen protection. After the reaction was completed, EA (20 mL) was added, and the reaction mixture was washed with water (20 ml) and saturated sodium bicarbonate solution (20 mL) and dried with sodium sulfate. The solvent of the organic layer was removed under reduced pressure, and the residue was purified by column chromatography (hexane∶EA = 5∶1) to obtain product 5. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

Claims

1. A method for preparing an aromatic heterocyclic-containing 1,4-dicarbonyl compound, characterized in that: using the diazo compound 1, aromatic heterocyclic-substituted tertiary alcohol 2, and carbon monoxide 3 shown in the following formula as raw materials to produce an aromatic heterocyclic-containing 1,4-dicarbonyl compound 4, and the reaction formula is as follows: R 1 is one or more of a hydrogen atom and a methyl formate group; R 2 is one or two or more of methoxy, ethoxy, tert-butoxy, phenoxy with substituents (the substituents on the phenyl group are one or two of methyl, ethyl, isopropyl, etc.), and benzyloxy; In addition, for the heteroaromatic ring-substituted tertiary alcohol 2, R in the general formula 3 is one or more of phenyl, phenyl with substituents (the substituents on the phenyl are one or two of methyl, F, Cl, methoxy, trifluoromethyl, etc.); R 4 It is one or two or more of phenyl with substituents (the substituents on the phenyl are one or two of methyl, F, methoxy, trifluoromethyl, etc.), benzothiazolyl with substituents (the substituents on the benzothiazolyl are one or two of methyl, F, Cl, Br, methoxy, etc.), benzofuranyl, thiazolyl, oxazolyl, benzofuranyl, benzothiophenyl.

2. The method for preparing an aromatic heterocyclic-containing 1,4-dicarbonyl compound according to claim 1, characterized in that: the specific operation steps are as follows: The reaction is carried out in a high-pressure reactor. Weigh the catalyst and the aromatic heterocyclic-substituted tertiary alcohol 2 and mix them to obtain a mixture. Under an inert gas atmosphere (such as nitrogen), inject the solvent N,N-dimethylformamide, the diazo compound 1, and the additive into the mixture to obtain a mixed material. Put the mixed material into the reactor or directly carry out the mixing or preparation of the above-mentioned mixed material in the reactor. Replace the gas atmosphere in the reactor with carbon monoxide gas, and react under irradiation with a wavelength of 400 nm - 480 nm, preferably 430 nm - 460 nm; at 20 - 50 °C, preferably 25 - 30 °C; the reaction time is 6 - 36 hours, preferably 12 - 24 hours; after the reaction is completed, one or more of the aromatic heterocyclic-containing 1,4-dicarbonyl compounds 4 are separated; The solvent is one or more of N,N-dimethylformamide, toluene, acetonitrile, ethyl acetate, acetone, 1,2-dichloroethane; preferably N,N-dimethylformamide; The catalyst is one or more of tris(2-phenylpyridine)iridium, [2,2'-bipyridine(4-tert-butylpyridine)]bis[2-(2,4-difluorophenyl)pyridine]iridium(III) hexafluorophosphate, 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, ruthenium(III) chloride hexahydrate, preferably tris(2-phenylpyridine)iridium; The additive is one or more of water, methanol, acetic acid, hexafluoroisopropanol, preferably water.

3. The method according to claim 2, characterized in that: The molar ratio of the aromatic heterocyclic-substituted tertiary alcohol 2 to the catalyst is 200:1 - 100:5, preferably 200:1 - 100:

1.

4. The method according to claim 2, characterized in that: The molar ratio of the aromatic heterocyclic-substituted tertiary alcohol 2 to the diazo compound 1 is 1:1 - 1:4, preferably 1:2 - 1:

3.

5. The method according to claim 2, characterized in that: The molar ratio of the aromatic heterocyclic-substituted tertiary alcohol 2 to the additive is 1:1 - 1:4, preferably 1:2 - 1:

3.

6. The method according to claim 2, characterized in that: The solvent is one or more of N,N-dimethylformamide, toluene, acetonitrile, ethyl acetate, acetone, 1,2-dichloroethane, preferably N,N-dimethylformamide; the amount of the solvent used is 0.5 - 5.0 ml of the solvent per 0.2 mmol of the aromatic heterocyclic-substituted tertiary alcohol 2, preferably 1.0 - 3.0 ml.

7. The method according to claim 2, characterized in that: The gas pressure of carbon monoxide is 1 - 50 atmospheres, preferably 20 - 40 atmospheres; The total volume of the catalyst, diazo compound 1, heteroaromatic ring-substituted tertiary alcohol 2, additive water and solvent does not exceed 50% of the volume of the high-pressure reactor.

8. According to the method described in claim 2, it is characterized in that: When the reaction solution is 2 mL, it is achieved by irradiating with two blue light sources with a power of 7-45 W, preferably a blue light source power of 10-20 W.

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