A cerium catalytic system is applied to a preparation method of a medium ring cyclic ketone compound

Abstract

The application belongs to the technical field of photocatalytic synthesis, and particularly relates to a preparation method of a medium ring cyclic ketone compound by using a cerium catalytic system. The application directly and efficiently synthesizes a medium ring cyclic ketone compound with five to ten members by using a cerium catalyst, a cocatalyst and an additive in combination, starting from a fused tertiary alcohol substrate. The preparation method provided by the application has a wide application range of substrates, and can be used to synthesize a series of medium ring cyclic ketone compounds with different functional groups. The high selectivity of the cerium catalytic system is used to ensure high-purity output of the medium ring cyclic ketone compound, and a purification step is simplified.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of photocatalytic synthesis, and particularly relates to a preparation method of a medium ring cyclic ketone compound by using a cerium catalytic system. BACKGROUND

[0002] The carbon ring molecular skeleton is a key structural unit of various natural products, and is widely present in compounds with important biological activity and pharmacological value, and plays an important role in anti-inflammatory and cancer treatment. Compared with smaller or larger ring system structures, the medium ring cyclic ketone compound has significant advantages in biological activity due to its moderate rigidity characteristics and flexible spatial conformation. Such a molecular skeleton can not only effectively balance the receptor binding affinity and cell membrane permeability, but also due to its unique structure-activity relationship, has become one of the core structures that are concerned in the current pharmaceutical field.

[0003] With the increasing demand for medium ring cyclic ketone compounds, new synthesis methods of medium ring cyclic ketone compounds have been a core topic of organic synthesis. However, the construction of rings of different sizes has significant differences. Compared with five-membered and six-membered rings, the synthesis of seven-membered to ten-membered medium ring cyclic ketone compounds is more difficult. This is because the conformational stability of the medium ring cyclic ketone compound is poor, the ring strain is large, and factors such as transannular interaction, carbon-carbon bond torsional strain and entropy effect can significantly hinder the cyclization process.

[0004] Researchers have realized the synthesis of medium ring cyclic ketone compounds by adding a chain fragment in the molecule to an existing smaller ring system to generate a fused bicyclic system in situ, and then initiating a carbon-carbon bond cleavage ring expansion reaction to insert the molecular fragment into the original ring. However, in the carbon-carbon bond cleavage ring expansion reaction, transannular side reactions occur, which is not conducive to the synthesis of relatively unstable medium ring cyclic ketone compounds. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of a medium ring cyclic ketone compound by using a cerium catalytic system. The preparation method provided by the present application can synthesize medium ring cyclic ketone compounds with high selectivity.

[0006] In order to achieve the above purpose, the present application provides the following technical scheme:

[0007] The application provides a preparation method of a medium ring cyclic ketone compound by using a cerium catalytic system, and comprises the following steps: mixing a fused ring tertiary alcohol, a cerium catalytic system and a solvent, and performing a carbon-carbon bond breaking ring expansion reaction under light and oxygen-containing conditions to obtain the medium ring cyclic ketone compound; the cerium catalytic system comprises a cerium catalyst, a co-catalyst and an additive; the cerium catalyst comprises one or more of cerium bromide, cerium bromide hydrate and a cerium bromide complex; the co-catalyst comprises 2,4,5,6-tetrakis(9H-carbazole-9-yl)isophthalonitrile (4CzIPN); the additive comprises one or more of LiBr and KBr; the carbon-carbon bond breaking ring expansion reaction is performed at a temperature of-10-100 ℃, and the holding time is 0.3-12 hours.

[0008] Preferably, the molar ratio of the cerium catalyst and the co-catalyst is 1:0.1-5.

[0009] Preferably, the molar ratio of the cerium catalyst and the additive is 1:2-10.

[0010] Preferably, the fused ring tertiary alcohol comprises one or more of a five-membered and six-membered ring, a six-membered and six-membered ring and a [2,2,1] bridged fused ring.

[0011] Preferably, the molar ratio of the fused ring tertiary alcohol and the cerium catalyst is not less than 1:0.1.

[0012] Preferably, the solvent comprises one or more of a ketone solvent and a nitrile solvent.

[0013] Preferably, the molar ratio of the fused ring tertiary alcohol and the solvent is 1:100-500.

[0014] Preferably, the light is one or more of ultraviolet light and visible light; the oxygen-containing condition is air and / or oxygen; and the pressure of the air or oxygen is 0.01-10 bar.

[0015] Preferably, the carbon-carbon bond breaking ring expansion reaction is performed under stirring.

[0016] The application provides a preparation method of a medium ring cyclic ketone compound by using a cerium catalytic system. The application directly and efficiently synthesizes a five-membered to ten-membered medium ring cyclic ketone compound by using a cerium catalyst, a co-catalyst and an additive in combination with a fused ring tertiary alcohol substrate. Figure 1 The substrate of the preparation method provided by the application has a wide application range and can be used to synthesize a series of medium ring cyclic ketone compounds with different functional groups. The cerium catalytic system has high selectivity, the yield is more than 82%, the high-purity medium ring cyclic ketone compound is ensured, the purity is more than 95%, and the purification step is simplified.

[0017] The present application research found that cerium catalytic system in the synthesis of medium ring ketone compounds in the catalytic cycle, such as Figure 2 As shown in the figure. Metal cerium preferentially combines with alcohol in the cycloannular tertiary alcohol substrate to form cerium (IV) alcohol complex, and after absorbing light, the in-situ generated cerium (IV) alcohol complex is excited by single electron transfer from ligand to metal, generating high-energy alkoxy radical and cerium (III) species. Subsequently, the alkoxy radical is used to β - The carbon-carbon bond in the cycloannular structure is selectively cut off by the cleavage process, thereby expanding the cycloannular structure to generate a ketone and a more stable carbon-centered radical intermediate. The carbon-centered radical intermediate promotes the removal of the leaving group, generates an olefin through elimination reaction, and obtains a medium ring ketone compound. Subsequently, the cerium (III) species is oxidized by the excited state organic catalyst 2,4,5,6-tetra(9H-carbazole-9-yl) isophthalonitrile, and then undergoes a single electron transfer (SET) process, thereby regenerating the photoactive cerium (IV) complex, thereby completing the entire catalytic cycle. The present application can be compatible with a variety of leaving groups, including ortho-halogen, thioether, sulfoxide and sulfone, etc.

[0018] The present application directly synthesizes a series of five to ten-membered medium ring ketone compounds with internal double bonds using a cerium catalytic system, has high selectivity, high synthesis efficiency and simple operation. The substrate used in the present application is simple to synthesize, does not involve strong alkaline conditions, does not use noble metals, and has relatively low cost, so that the present application has good industrialization prospects. The preparation method provided by the present application can not only achieve ring expansion to generate ring ketones containing exocyclic double bonds, but also generate ring ketones containing endocyclic double bonds. More noteworthy is that the preparation method provided by the present application can not only achieve ring expansion of cycloannular substrates, but also achieve ring-opening reaction of non-strained ring alcohols. The preparation method provided by the present application has extremely high atom economy and only produces a small amount of by-products. The present application uses sunlight and cheap cerium resources to provide a green and mild new method for efficient synthesis of ring ketone skeleton, and provides a new idea for the development of alkoxy radical-mediated ring expansion reaction in the future. BRIEF DESCRIPTION OF DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed in the embodiments. Obviously, the drawings described below are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0020] Figure 1 The figure is a reaction schematic diagram of the carbon-carbon bond cleavage ring expansion reaction of the present application (taking a five-membered and six-membered heterocyclic compound as an example); wherein PC refers to a co-catalyst;

[0021] Figure 2 Mechanism diagram of the carbon-carbon bond cleavage and ring expansion reaction of the present application;

[0022] Figure 3 NMR hydrogen spectrum of the target product of Example 1;

[0023] Figure 4 NMR carbon spectrum of the target product of Example 1;

[0024] Figure 5 NMR hydrogen spectrum of the target product of Example 2;

[0025] Figure 6 NMR carbon spectrum of the target product of Example 2;

[0026] Figure 7 NMR hydrogen spectrum of the target product of Example 3;

[0027] Figure 8 NMR carbon spectrum of the target product of Example 3;

[0028] Figure 9 NMR hydrogen spectrum of the target product of Example 4;

[0029] Figure 10 NMR carbon spectrum of the target product of Example 4;

[0030] Figure 11 NMR hydrogen spectrum of the target product of Example 5;

[0031] Figure 12 NMR carbon spectrum of the target product of Example 5;

[0032] Figure 13 Continuous flow light reaction amplification device for Example 6;

[0033] Figure 14 Yield comparison chart of Example 1 and Comparative Example 4; wherein a refers to the yield determined by gas chromatography with internal standard method. DETAILED DESCRIPTION

[0034] The present application provides a preparation method of a medium ring cyclic ketone compound by using a cerium catalytic system, comprising the following steps: mixing a fused tertiary alcohol, a cerium catalytic system and a solvent, and performing a carbon-carbon bond cleavage and ring expansion reaction under light and oxygen-containing conditions to obtain the medium ring cyclic ketone compound; the cerium catalytic system comprises a cerium catalyst, a co-catalyst and an additive; the cerium catalyst comprises one or more of cerium bromide, cerium bromide hydrate and cerium bromide complex; the co-catalyst comprises 2,4,5,6-tetrakis(9H-carbazole-9-yl)isophthalonitrile; the additive comprises one or more of LiBr and KBr; the temperature of the carbon-carbon bond cleavage and ring expansion reaction is-10-100 ℃, and the holding time is 0.3-12 hours.

[0035] In the present application, the fused tertiary alcohol can include one or more of five-membered and six-membered, six-membered and six-membered, [2,2,1] bridged fused ring, adamantane skeleton and [3,3,1] bridged fused ring; the five-membered and six-membered can include 7a-(bromomethyl)octahydro-3aH-inden-3a-ol; the six-membered and six-membered can include 1-bromo octahydronaphthalene-4a(2H)-alcohol; the [2,2,1] bridged fused ring can include (1S,2R,4R,7S)-7-bromo-2-phenylbicyclo[2.2.1]heptane-2-ol; the adamantane skeleton can include (1r,3s,5R,7S)-3-bromoadamantane-1-alcohol; the [3,3,1] bridged fused ring can include (1R,2S,5R,9R)-2-bromo-9-phenylbicyclo[3.3.1]nonane-9-alcohol.

[0036] In the present application, the cerium bromide hydrate can be CeBr 3· H2O; the cerium bromide complex can be CeBr33MeCN.

[0037] In the present application, the molar ratio of the cerium catalyst and the co-catalyst can be 1:0.1~5, specifically 1:0.5, 1:1, 1:2, 1:3, 1:4 or 1:5. The co-catalyst of the present application, as a photo-induced electron transfer co-catalyst, accelerates the turnover of the cerium catalytic cycle.

[0038] In the present application, the molar ratio of the cerium catalyst and the additive can be 1:2~10, specifically 1:2.5, 1:3.5, 1:5, 1:7 or 1:9. The additive of the present application, as a ligand additive, promotes the coordination and dissociation process of cerium metal in the cerium catalyst and the substrate, activates the substrate to generate oxygen free radicals after coordination, and then dissociates to proceed the subsequent reaction under the promotion of the additive.

[0039] In the present application, the molar ratio of the fused tertiary alcohol and the cerium catalyst can be not less than 1:0.1, specifically 1:0.02, 1:0.04, 1:0.06, 1:0.08 or 1:0.1.

[0040] In the present application, the additive can be in the form of additive element or additive aqueous solution; the concentration of the additive aqueous solution can be 0.01~0.1wt%, specifically 0.05wt%.

[0041] In the present application, the solvent can include one or more of ketone solvent and nitrile solvent; the ketone solvent can be acetone; the nitrile solvent can be acetonitrile. The solvent of the present application, especially acetone, has good solubility for raw materials, thereby avoiding the blockage of the reaction pipeline.

[0042] In the present application, the molar ratio of the fused tertiary alcohol and the solvent can be 1:100-500, and specifically can be 1:150, 1:250, 1:350 or 1:450.

[0043] In the present application, the light can be one or several of ultraviolet light and visible light; the wavelength of the ultraviolet light can be 300-780 nm, and specifically can be 360-420 nm; the light source of the light can be sunlight or LED light.

[0044] In the present application, the oxygen-containing condition can be air and / or oxygen; the pressure of the air or oxygen can be 0.01-10 bar, and specifically can be 0.1 bar, 1 bar, 2 bar, 4 bar, 6 bar, 7 bar or 9 bar. The oxygen in the oxygen-containing condition is used as the oxidant.

[0045] In the present application, the oxygen-containing condition can be obtained by the following steps: connecting the reaction bottle to an oxygen cylinder or an air cylinder, using a long needle to blow air into the reaction bottle, and then immediately sealing the reaction bottle to ensure that the oxygen in the reaction bottle is sufficient and no leakage occurs; the blowing time can be 3-10 minutes.

[0046] In the present application, the temperature of the carbon-carbon bond cleavage ring expansion reaction can be -10-100 ℃, and specifically can be -5 ℃, 0 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, 60 ℃ or 80 ℃, and the holding time can be 0.3-12 hours, and specifically can be 1 hour, 3 hours, 5 hours, 6 hours, 7 hours or 10 hours; the carbon-carbon bond cleavage ring expansion reaction can be carried out under stirring conditions.

[0047] In the present application, the carbon-carbon bond cleavage ring expansion reaction can be monitored by GC-MS, GC-FID or 1 H-NMR to detect the reaction progress, and the reaction endpoint is that the cyclic ketone compound no longer increases.

[0048] In the present application, after the carbon-carbon bond cleavage ring expansion reaction, the obtained product system can be quenched, and then sequentially extracted, the organic phase is dried and filtered, concentrated and purified.

[0049] In the present application, the quencher used for quenching can be water; the extractant used for extraction can be ethyl acetate; the temperature of drying and filtering can be 15-35 ℃, specifically 25 ℃; the fold of concentration can be 5-10, specifically 7; the concentration can be reduced pressure concentration; the vacuum degree of reduced pressure concentration can be 10-300 mbar, specifically 50 mbar, 100 mbar, 150 mbar, 200 mbar or 250 mbar; the purification can be column chromatography purification; the chromatographic column used for purification can be a silica gel packed chromatographic column; the particle size of the silica gel can be 200-300 mesh, specifically 240 mesh.

[0050] In order to further illustrate the present application, the schemes of the present application are described in detail below in conjunction with the accompanying drawings and examples, but they should not be understood as limiting the scope of protection of the present application.

[0051] In the present application, the reagents and raw materials used are all commercially available products unless otherwise specified.

[0052] Example 1

[0053] This example prepares 5-methylene cyclononanone according to Formula I, and the specific steps are as follows:

[0054] Formula I;

[0055] Into a reaction vial equipped with a magnetic stir bar was added the substrate alcohol (0.1 mmol, 1 equiv.), CeBr3(1.5 mg, 0.004 mmol, 4 mol%), 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (1.5 mg, 0.002 mmol, 2 mol%), LiBr (1 mg, 0.01 mmol, 10 mol%), and acetone (1 mL) sequentially. The reaction vial was sealed with a polytetrafluoroethylene liner, bubbled with dry air for 10 minutes, and then stirred at room temperature under 400 nm LED irradiation for 6 hours. After the reaction was completed, water was added for quenching and extraction with ethyl acetate, and the organic phase was dried and filtered at 15 ℃, followed by concentration under reduced pressure (vacuum degree 250 mbar) by 7 times. The crude system was purified by flash column chromatography using a 200 mesh silica gel packed chromatographic column to obtain the target product 5-methylene cyclononanone, a colorless oily liquid (13.6 mg, 0.1 mmol, yield 90%, purity 98%), whose nuclear magnetic hydrogen spectrum and carbon spectrum are shown in Figures 3-4 .

[0056] 1 H NMR (400 MHz, Chloroform- d ) δ 4.93 (d, J= 12 Hz, 2H), 2.45–2.42 (m,2H), 2.39–2.36 (m, 2H), 2.12–2.06 (m, 4H), 2.01–1.95 (m, 2H), 1.87–1.80 (m,2H), 1.69–1.63 (m, 2H).

[0057] 13 C NMR (101 MHz, Chloroform- d ) δ 216.88, 146.69, 115.14, 44.15, 39.96, 36.28, 33.10, 24.99, 23.80, 23.26.

[0058] Example 2

[0059] In this embodiment, (E)-cyclodec-5-en-1-one was prepared according to Formula II, and the specific steps are as follows:

[0060] Formula II;

[0061] To a reaction flask equipped with a magnetic induction device, the following were added sequentially: substrate alcohol (0.1 mmol, 1.0 equiv.), CeBr3 (1.5 mg, 0.004 mmol, 4 mol%), 2,4,5,6-tetrakis(9H-carbazol-9-yl)isobenzonitrile (1.5 mg, 0.002 mmol, 2 mol%), LiBr (1 mg, 0.01 mmol, 10 mol%), and acetone (1 mL). The reaction flask was sealed with a polytetrafluoroethylene liner, and dry air was bubbled through it for 10 minutes. The reaction was then stirred at room temperature for 6 hours under 400 nm LED illumination. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried at 20 °C, filtered, and concentrated 5-fold under reduced pressure (200 mbar). The crude system was purified by rapid column chromatography using a 300-mesh silica gel-packed column to obtain the target product (E)-cyclodecyl-5-en-1-one, a colorless oily liquid (14.4 mg, 0.1 mmol, yield 95%, purity 97%). The 1H and 1C NMR spectra are shown below. Figures 5-6 As shown.

[0062] 1 H NMR (400 MHz, Chloroform- d) δ 5.38 - 530 (m 1H), 5.19 - 5.11 (m, 1H), 2.58 - 2.45 (m, 1H), 2.42 - 2.32 (m, 1H), 2.28 - 2.11 (m, 4H), 1.99 - 1.85 (m, 2H), 1.83 - 1.71 (m, 2H), 1.68 - 1.58 (m, 2H), 1.38 - 1.28 (m, 2H).

[0063] 13 C NMR (101 MHz, Chloroform- d ) δ 213.05, 134.61, 131.34, 45.69, 43.23, 34.29, 33.39, 28.89, 28.14, 22.24.

[0064] Example 3

[0065] This example prepared 2-(cyclopent-2-en-1-yl)-1-phenylethanone according to Formula III, in particular steps as follows:

[0066] Formula III;

[0067] To a reaction vial equipped with a magnetic stir bar was added the substrate alcohol (0.1 mmol, 1.0 equiv.), CeBr3(1.5 mg, 0.004 mmol, 4 mol%), 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (1.5 mg, 0.002 mmol, 2 mol%), LiBr (1 mg, 0.01 mmol, 10 mol%), and acetone (1 mL) sequentially. The reaction vial was sealed with a polytetrafluoroethylene liner, bubbled with dry air for 10 minutes, and then stirred at room temperature under irradiation with a 400 nm LED for 6 hours. After completion of the reaction, water was added to quench and extracted with ethyl acetate, the organic phase was dried over filter and concentrated 10 times under reduced pressure (vacuum degree of 180 mbar), the crude system was purified by flash column chromatography using a chromatography column packed with 240 mesh silica gel to obtain the target product 2-(cyclopent-2-en-1-yl)-1-phenylethanone as a colorless oily liquid (16.3 mg, 0.1 mmol, yield 88%, purity 96%), the nuclear magnetic hydrogen spectrum and carbon spectrum are shown in Figures 7-8 .

[0068] 1 H NMR (500 MHz, Chloroform- d ) δ 7.99 - 7.95 (m 2H), 7.55 (t, J= 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 5.79–5.76 (m, 1H), 5.74–5.70 (m, 1H), 3.31–3.23(m, 1H), 3.08 (dd, J = 16.5 Hz, J = 6.5 Hz, 1H), 2.97 (dd, J = 16 Hz, J = 7.5 Hz,1H), 2.43–2.28 (m, 2H), 2.25–2.15 (m, 1H), 1.51–1.42 (m, 1H).

[0069] 13 C NMR (101 MHz, Chloroform- d ) δ 199.95, 137.36, 134.36, 133.06,131.39, 128.70, 128.23, 44.92, 41.53, 31.98, 30.16.

[0070] Example 4

[0071] In this embodiment, 5-methylenecyclononane-1-one was prepared according to Formula IV, and the specific steps are as follows:

[0072] Formula IV;

[0073] To a reaction flask equipped with a magnetic induction device, the following were added sequentially: substrate alcohol (0.1 mmol, 1.0 equiv.), CeBr3 (1.5 mg, 0.004 mmol, 4 mol%), 2,4,5,6-tetrakis(9H-carbazol-9-yl)isobenzonitrile (1.5 mg, 0.002 mmol, 2 mol%), LiBr (1 mg, 0.01 mmol, 10 mol%), and acetone (1 mL). The reaction flask was sealed with a polytetrafluoroethylene liner, and dry air was bubbled through it for 10 minutes. The reaction was then stirred at room temperature for 6 hours under 400 nm LED illumination. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried at 30 °C, filtered, and concentrated 8-fold under reduced pressure (vacuum degree 120 mbar). The crude system was purified by rapid column chromatography using a 280-mesh silica gel-packed column to obtain the target product 5-methylenecyclononane-1-one, a colorless oily liquid (65 mg, yield 90%, purity 98%). The 1H and 1C NMR spectra are shown below. Figures 9-10 As shown.

[0074] 1H NMR (400 MHz, Chloroform- d ) δ 4.78 (s, 2H), 2.44–2.34 (m, 8H), 2.28–2.24 (m, 2H), 1.97–1.87 (m, 2H).

[0075] 13 C NMR (101 MHz, Chloroform- d ) δ 211.20, 141.86, 114.86, 47.52,41.56, 32.25, 30.97.

[0076] Example 5

[0077] In this embodiment, (Z)-cyclooct-4-en-1-yl(phenyl)methyl ketone is prepared according to formula V, and the specific steps are as follows:

[0078] Formula V;

[0079] To a reaction flask equipped with a magnetic induction device, the following were added sequentially: substrate alcohol (0.1 mmol, 1.0 equiv.), CeBr3 (1.5 mg, 0.004 mmol, 4 mol%), 2,4,5,6-tetrakis(9H-carbazol-9-yl)isobenzonitrile (1.5 mg, 0.002 mmol, 2 mol%), LiBr (1 mg, 0.01 mmol, 10 mol%), and acetone (1 mL). The reaction flask was sealed with a polytetrafluoroethylene liner, and dry air was bubbled through it for 10 minutes. The reaction was then stirred at room temperature for 6 hours under 400 nm LED illumination. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried at 35 °C, filtered, and concentrated 8-fold under reduced pressure (90 mbar). The crude system was purified by rapid column chromatography using a 260-mesh silica gel-packed column to obtain the target product (Z)-cyclooct-4-en-1-yl(phenyl) ketone, a colorless oily liquid (20 mg, 0.1 mmol, yield 93%, purity 96%). The 1H and 1C NMR spectra are shown below. Figures 11-12 As shown.

[0080] 1 H NMR (400 MHz, Chloroform- d) δ 7.92-7.90 (m, 2H), 7.56-7.53 (m, 1H), 7.47-7.44 (m, 2H), 5.83-5.70 (m, 2H), 3.46-3.41 (m, 1H), 2.51-2.42 (m, 1H), 2.31-2.15 (m, 3H), 2.02-1.98 (m, 1H), 1.85-1.58 (m, 4H), 1.54-1.43 (m, 1H).

[0081] 13 C NMR (101 MHz, Chloroform- d ) δ 204.69, 136.54, 132.83, 130.92, 130.05, 128.73, 128.46, 45.09, 31.60, 29.52, 27.96, 26.13, 24.43.

[0082] Example 6

[0083] The scale-up application of carbon-carbon bond cleavage and ring expansion reaction was carried out by using continuous flow photoreaction.

[0084] The substrate of this example was a five-membered and six-membered heterocyclic compound (10 mmol), a cerium catalyst, an organic photocatalyst was 2,4,5,6-tetrakis(9H-carbazol-9-yl)isophthalonitrile, an additive was lithium bromide, acetone was a solvent, and the raw material was prepared into a reaction solution according to the proportion of Example 1, and was used for scale-up reaction.

[0085] A polytetrafluoroethylene pipeline with an inner diameter of 1 / 8 inch and a length of 8 meters was uniformly wound around the outer surface of a glass container as a continuous flow photoreaction scale-up device, so that the retention volume of the photoreaction reached 10 mL. At the same time, the polytetrafluoroethylene pipeline was placed in a water bath to ensure that the reaction temperature was maintained at 20 °C (as shown in Figure 13 ).

[0086] The pre-prepared reaction solution was slowly injected into the polytetrafluoroethylene pipeline at a rate of 8 mL / min by using a syringe pump, and the reaction solution in the polytetrafluoroethylene pipeline was continuously irradiated by a 400 nm LED lamp after the reaction started, and the target product 5-methylene cyclononanone (1.3 g, yield 85%, purity 98%) was obtained.

[0087] The results show that the yield of 5-methylene cyclononanone in this example is 85%, which achieves basically the same effect as the standard reaction conditions of Examples 1-5. The longer the residence time of the reaction solution in the continuous flow photoreactor, the better the catalytic cycle of the cerium catalyst under light conditions can be promoted.

[0088] Example 7

[0089] The preparation method in this embodiment is the same as that in Example 1, except that the additive is replaced with KBr.

[0090] Example 8

[0091] The preparation method in this embodiment is the same as in Example 1, except that the cerium catalyst is replaced with CeBr. 3· H2O.

[0092] Example 9

[0093] The preparation method in this embodiment is the same as in Example 1, except that the cerium catalyst is replaced with CeBr33MeCN.

[0094] Example 10

[0095] The preparation method in this embodiment is the same as in Example 1, except that the solvent is replaced with acetonitrile.

[0096] Example 11

[0097] The preparation method of this embodiment is the same as that of Example 1, except that: the molar ratio of cerium catalyst to co-catalyst is 1:5; the molar ratio of cerium catalyst to additive is 1:10; the molar ratio of tertiary cyclic alcohol to cerium catalyst is 1:0.1; the temperature of carbon-carbon bond breaking and ring expansion reaction is 100 °C, and the holding time is 0.3 hours.

[0098] Example 12

[0099] The preparation method of this embodiment is the same as that of Example 1, except that: the molar ratio of cerium catalyst to co-catalyst is 1:1; the molar ratio of cerium catalyst to additive is 1:5; the molar ratio of tertiary cyclic alcohol to cerium catalyst is 1:0.02; the temperature of carbon-carbon bond breaking and ring expansion reaction is -10 °C, and the holding time is 12 hours.

[0100] Comparative Example 1

[0101] The preparation method of this comparative example is the same as that of Example 1, except that the cerium catalyst is replaced with CeCl3, ( n -Bu4N)2CeCl6, Ce(OTf)3, Ce(NO3)36H2O or (NH4)2Ce(NO3)6.

[0102] Comparative Example 2

[0103] The preparation method of this comparative example is the same as that of Example 1, except that the additives are replaced with ( n -Bu)4NCl、( nNaBr, KCl or LiCl.

[0104] Comparative Example 3

[0105] The preparation method of the present comparative example is the same as that of Example 1, except that the solvent is replaced by EA, THF, DMF, PhCF3 or CHCl3, respectively.

[0106] Comparative Example 4

[0107] The preparation method of the present comparative example is the same as that of Example 1, except that the co-catalyst is replaced by cat-1 compound, cat-2 compound, cat-3 compound, cat-4 compound, cat-5 compound, cat-6 compound, cat-7 compound, cat-8 compound, cat-9 compound, cat-10 compound, cat-11 compound or cat-12 compound, respectively.

[0108] Test Example 1

[0109] The yield of Example 1, Examples 8-9 and Comparative Example 1 is compared and tested, and the results are shown in Table 1.

[0110] Table 1 Product yield of Example 1 and Comparative Example 1

[0111]

[0112] As can be seen from Table 1, the cerium catalyst used in the present application has obvious high selectivity for the substrate, which finally makes the product yield more than 82%, which is much better than other catalysts.

[0113] Test Example 2

[0114] The yield of Example 1, Example 7 and Comparative Example 2 is compared and tested, and the results are shown in Table 2.

[0115] Table 2 Product yield of Example 1, Example 7 and Comparative Example 2

[0116]

[0117] As can be seen from Table 2, the additive used in the present application can make the yield of the target product higher.

[0118] Test Example 3

[0119] The yield of Example 1, Example 10 and Comparative Example 3 is compared and tested, and the results are shown in Table 3.

[0120] Table 3 Product yield of Example 1 and Comparative Example 3

[0121]

[0122] As can be seen from Table 3, the solvent used in the present application can make the yield of the target product higher.

[0123] Test Example 4

[0124] The yield of Example 1 and Comparative Example 4 was compared, and the results are shown in Table 4. Figure 14 As can be seen from Table 4, the co-catalyst used in the present application can make the yield of the target product higher. Figure 14

[0125] As can be seen from the above examples, the preparation method provided by the present application has a yield of more than 82%, ensuring high-purity output of the meso-cyclic ketone compound with a purity of more than 95%, and simplifying the purification step.

[0126] Although the above examples have made a detailed description of the present application, it is only a part of the embodiments of the present application, not all the embodiments, and other embodiments can be obtained according to the present embodiments without creativity, which all belong to the protection scope of the present application.​

Claims

1. A method for preparing a medium-cyclic ketone compound using a cerium catalytic system, characterized in that, Includes the following steps: The tertiary cyclic alcohol, cerium catalytic system and solvent were mixed and subjected to carbon-carbon bond breaking and ring expansion reaction under light and oxygen-containing conditions to obtain the medium-cyclic ketone compound; The cerium catalytic system includes a cerium catalyst, a cocatalyst, and additives; The cerium catalyst includes one or more of cerium bromide and cerium bromide hydrate; The cocatalyst comprises 4CzlPN; The additives include one or more of LiBr and KBr; The carbon-carbon bond breaking and ring expansion reaction is carried out at a temperature of -10 to 100 °C for 0.3 to 12 hours. The fused tertiary alcohol is selected from one or more of the following: pentagonal fused hexa-membered alcohol, hexa-fused hexa-membered alcohol, [2,2,1]-bridged fused ring, adamantane skeleton, and [3,3,1]-bridged fused ring; the pentagonal fused hexa-membered alcohol is 7a-(bromomethyl)octahydro-3aH-indene-3a-ol; the hexa-fused hexa-membered alcohol is 1-bromooctahydronaphthalene-4a(2H)-ol; the [2,2,1]-bridged fused ring is (1S,2R,4R,7S)-7-bromo-2-phenylbicyclo[2.2.1]heptane-2-ol; the adamantane skeleton is (1r,3s,5R,7S)-3-bromoadamantane-1-ol; The [3,3,1]-bridged fused ring is (1R,2S,5R,9R)-2-bromo-9-phenyl bicyclic [3.3.1]nonane-9-ol; the cerium bromide hydrate is CeBr3·H2O; The solvent includes one or more of ketone solvents and nitrile solvents; the ketone solvent is acetone; and the nitrile solvent is acetonitrile.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the cerium catalyst to the co-catalyst is 1:0.1~5.

3. The preparation method according to any one of claims 1 to 2, characterized in that, The molar ratio of the cerium catalyst to the additive is 1:2~10.

4. The preparation method according to claim 1, characterized in that, The molar ratio of the cycloalcohol to the cerium catalyst is not less than 1:0.

1.

5. The preparation method according to claim 1 or 4, characterized in that, The molar ratio of the cycloalcohol to the solvent is 1:100~500.

6. The preparation method according to claim 1, characterized in that, The light is one or more of ultraviolet light and visible light; The oxygen-containing conditions are air and / or oxygen; The pressure of the air or oxygen is 0.01 to 10 bar.

7. The preparation method according to claim 1, characterized in that, The carbon-carbon bond breaking and ring expansion reaction is carried out under stirring conditions.

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