Preparation method of acetophenone oxime Zhishan new reagent

Abstract

The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of an acetophenone oxime Zhishan reagent, which comprises the following steps: in the presence of alkali, reacting an acetophenone oxime compound as shown in a formula (II) with a Zhishan reagent as shown in a formula (III) to obtain the acetophenone oxime Zhishan reagent as shown in a formula (I), r1 and R2 are independently selected from any one of H, an ester group, a cyano group, a nitro group, a hydroxyl group, a phenyl group, a methylenedioxy group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, halogen, a halogenated C1-C6 alkyl group or a halogenated C1-C6 alkoxy group; the alkali comprises triethylamine and sodium hydroxide; according to the method, the new acetophenone oxime Zhishan reagent shown in the formula (I) is obtained by selecting a proper reaction substrate and selecting and synergistic effects of a proper catalyst and a ligand, reaction conditions are simple, meanwhile, a good yield is obtained, a new synthesis route is provided for preparation of chromone compounds, and the method has good application value and potential in industry and scientific research.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and in particular to a preparation method of a Mukaiyama's reagent from acetophenone oxime. Background Art

[0002] Mukaiyama's reagent, namely 2-chloro-1-methylpyridinium iodide (CMPI), is mainly used as an acid activator in organic synthesis to promote reactions such as the dehydration of carboxylic acids to form ketenes and the conversion of hydroxy acids to lactones; it performs excellently in the synthesis of macrocyclic lactones, lactamization reactions, and reactions with aldehydes, ketones and their derivatives, and can efficiently promote the esterification reaction of carboxylic acids, especially achieving ideal results on substrates that are difficult to obtain good results under other conditions; in addition, when synthesizing complex molecules, especially polyketide compounds, Mukaiyama's reagent provides a rapid way to construct larger carbon skeletons through the vinyl Mukaiyama aldol reaction (VMAR), while introducing a 1,5-relationship and generating two new stereocenters and a double bond at the same time;

[0003] However, Mukaiyama's reagent also has some limitations in practical applications; it has poor solubility in most standard organic solvents, and the by-products of the reaction are usually difficult to remove by chromatography, and these limitations affect its practicality; in addition, in the medium-sized lactonization reaction, Mukaiyama's reagent sometimes produces dimerization products. Summary of the Invention

[0004] The problem solved by the present invention is to provide a preparation method of a Mukaiyama's reagent from acetophenone oxime. This Mukaiyama's reagent from acetophenone oxime can be used as a donor of iminium ions, has good liposolubility, and does not undergo self-polymerization, which extends the application of Mukaiyama's reagent to a certain extent.

[0005] To achieve the above object, the present invention adopts the following technical scheme: A preparation method of a Mukaiyama's reagent from acetophenone oxime, comprising the following steps: in the presence of a base, reacting an acetophenone oxime compound shown in formula (II) with a Mukaiyama's reagent shown in formula (III) to obtain the Mukaiyama's reagent from acetophenone oxime shown in formula (I).

[0006]

[0007] The R1 and R2 are independently selected from any one of H, ester group, cyano group, nitro group, hydroxyl group, phenyl group, methylenedioxy group, C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, halogen, halogenated C1-C6 alkyl group or halogenated C1-C6 alkoxy group;

[0008] Among them, the meaning of C1-C6 alkyl refers to a straight-chain or branched-chain alkyl group having 1-6 carbon atoms, which includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl, and can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl, etc.;

[0009] Among them, C1-C6 alkoxy refers to the group formed by connecting C1-C6 alkyl to an O atom;

[0010] Among them, the meaning of halogen refers to halogen elements, and can be F, Cl, Br or I;

[0011] Among them, the meaning of halogenated C1-C6 alkyl refers to C1-C6 alkyl substituted by halogen, and can be trifluoromethyl, pentafluoroethyl, difluoromethyl, chloromethyl, etc.;

[0012] Among them, the meaning of halogenated C1-C6 alkoxy refers to C1-C6 alkoxy substituted by halogen, and can be trifluoromethoxy, pentafluoroethoxy, difluoromethoxy, chloromethoxy, etc.

[0013] Preferably, the base includes any one or more of triethylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, sodium ethoxide, tributylamine, pyridine, 2-fluoropyridine, 2-chloropyridine, potassium tert-butoxide.

[0014] Preferably, the reaction is carried out in an organic solvent; the organic solvent includes any one or more of acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dichloromethane, chlorobenzene, benzene, xylene, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and preferably dichloromethane.

[0015] Preferably, the molar ratio of the acetophenone oxime compound (II) to the base is 1:1-3, for example, it can be 1:1, 1:2 or 1:3.

[0016] Preferably, the molar ratio of the acetophenone oxime compound (II) to the Mukaiyama reagent (III) is 1:1-3, for example, it can be 1:1, 1:1.5 or 1:3.

[0017] Preferably, the ratio of the acetophenone oxime compound (II) to the solvent is 1 mmol:5-15 mL, for example, 1 mmol:5 mL, 1 mmol:8 mL, 1 mmol:10 mL, 1 mmol:12 mL or 1 mmol:15 mL.

[0018] Preferably, the temperature of the reaction is 25-80 °C, for example, it can be 25 °C, 40 °C, 60 °C or 80 °C, and the reaction time is 0.5-8 hours, for example, it can be 0.5 hour, 1 hour, 2 hours, 4 hours or 8 hours.

[0019] Preferably, after the reaction, a post-treatment step is further included; the post-treatment includes any one treatment means or a combination of multiple treatment means such as extraction, concentration, crystallization, recrystallization, and column chromatography purification;

[0020] As an exemplary post-treatment means, for example, it can be: after the reaction is complete, the reaction system is naturally cooled to room temperature, a mixed solution of ethyl acetate and saturated brine with an equal volume ratio is added, and extraction is carried out by shaking 2-4 times. The organic layer is collected, dried, and concentrated by rotary evaporation to obtain a crude product. The crude product is subjected to silica gel column chromatography with a 200-300 mesh, and a mixed solution of ethyl acetate and petroleum ether is used as the eluent, where the volume ratio of ethyl acetate to petroleum ether is 1:5-10, thereby obtaining the acetophenone oxime xiangshin reagent of formula (I).

[0021] The beneficial effects of the present invention are: by selecting appropriate reaction substrates and the selection and synergistic effect of appropriate catalysts and ligands, the acetophenone oxime xiangshin reagent of formula (I) is obtained. The reaction conditions are simple, and at the same time, a good yield is achieved, providing a new synthetic route for the preparation of chromone compounds, and having good application value and potential in industry and scientific research. Detailed implementation manners

[0022] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0023] Example 1

[0024] A preparation method of an acetophenone oxime xiangshin reagent includes the following steps: in the presence of a base, reacting an acetophenone oxime compound shown in formula (II) with a xiangshin reagent shown in formula (III) to obtain the acetophenone oxime xiangshin reagent of formula (I).

[0025]

[0026] R1 and R2 are independently selected from any one of H, ester group, cyano group, nitro group, hydroxyl group, phenyl group, methylenedioxy group, C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, halogen, halogenated C1-C6 alkyl group, or halogenated C1-C6 alkoxy group.

[0027] The specific preparation method is as follows:

[0028]

[0029] Add the compounds of formula (II) and (III) and triethylamine to dichloromethane, then heat to 60 °C and stir and seal the reaction at this temperature for 4 hours;

[0030] Among them, the molar ratio of the compound of formula (II) to triethylamine is 1:0.1, and the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:1; the ratio of the compound of formula (II) in millimoles (mmol) to dichloromethane in milliliters (ml) is 1:8;

[0031] After the reaction is complete, naturally cool the reaction system to room temperature, directly filter, and wash three times with a mixed solution of ethyl acetate: petroleum ether = 1:1, so as to obtain the target product, the compound of formula (I) (C14H15IN2O), a yellow liquid, with a yield of 88.7%;

[0032] Nuclear magnetic resonance: 1HNMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 6.4 Hz, 1H), 8.57 - 8.52 (m, 1H), 8.80 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.70 - 7.67 (m, 1H), 7.63 - 7.53 (m, 3H), 4.19 (s, 3H), 2.65 (s, 3H); 13CNMR (100 MHz, DMSO-d6) δ 165.9, 159.8, 147.9, 143.5, 132.8, 131.6, 128.9 (2C), 127.3 (2C), 119.7, 112.8, 41.8, 14.9.

[0033] Example 2

[0034] A preparation method of acetophenone oxime to Yamaguchi reagent, comprising the following steps: in the presence of a base, react the acetophenone oxime compound shown in formula (II) with the Yamaguchi reagent shown in formula (III) to obtain the acetophenone oxime to Yamaguchi reagent shown in formula (I),

[0035]

[0036] R1 and R2 are independently selected from any one of H, ester group, cyano group, nitro group, hydroxyl group, phenyl group, methylenedioxy group, C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, halogen, halogenated C1-C6 alkyl group or halogenated C1-C6 alkoxy group.

[0037] The specific preparation method is as follows:

[0038]

[0039] Add the compounds of formula (II) and (III) and triethylamine to dichloromethane, then stir and seal the reaction at room temperature for 8 hours;

[0040] Among them, the molar ratio of the compound of formula (II) to triethylamine is 1:0.2; the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:2; the ratio of the compound of formula (II) in millimoles (mmol) to dichloromethane in milliliters (ml) is 1:10;

[0041] After the reaction is complete, the reaction system is naturally cooled to room temperature, the organic layer is collected, dried, concentrated by rotary evaporation to obtain a crude product, and the crude product is chromatographed on a silica gel column of 200-300 mesh. A mixed solution of methanol and dichloromethane is used as the eluent, in which the volume ratio of methanol to dichloromethane is 1:1, thereby obtaining the target product, the compound of formula (I) (C14H15IN2O), and the yield is 86.3%;

[0042] Nuclear magnetic resonance: 1HNMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 6.4 Hz, 1H), 8.57 - 8.52 (m, 1H), 8.80 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.70 - 7.67 (m, 1H), 7.63 - 7.53 (m, 3H), 4.19 (s, 3H), 2.65 (s, 3H); 13CNMR (100 MHz, DMSO-d6) δ 165.9, 159.8, 147.9, 143.5, 132.8, 131.6, 128.9 (2C), 127.3 (2C), 119.7, 112.8, 41.8, 14.9.

[0043] Example 3

[0044] A preparation method of acetophenone oxime Mukaiyama reagent, comprising the following steps: in the presence of a base, reacting the acetophenone oxime compound shown in formula (II) with the Mukaiyama reagent shown in formula (III) to obtain the acetophenone oxime Mukaiyama reagent shown in formula (I),

[0045]

[0046] R1 and R2 are independently selected from any one of H, ester group, cyano group, nitro group, hydroxyl group, phenyl group, methylenedioxy group, C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, halogen, halogenated C1-C6 alkyl group or halogenated C1-C6 alkoxy group.

[0047] The specific preparation method is as follows:

[0048]

[0049] Add the above compounds of formula (II), (III) and triethylamine to DMF, and then stir and seal the reaction at room temperature for 2 hours;

[0050] Among them, the molar ratio of the compound of formula (II) to triethylamine is 1:0.3; the molar ratio of the compound of formula (II) to the compound of (III) is 1:1.2; the ratio of the compound of formula (II) in millimoles (mmol) to dichloromethane in milliliters (ml) is 1:8;

[0051] After the reaction is complete, the reaction system is naturally cooled to room temperature, concentrated by rotary evaporation to obtain a crude product, and the crude product is chromatographed on a silica gel column of 200-300 mesh. A mixed solution of methanol and dichloromethane is used as the eluent, where the volume ratio of methanol to dichloromethane is 1:1, thereby obtaining the target product, the compound of formula (I) (C14H15IN2O), with a yield of 87.5%;

[0052] Nuclear magnetic resonance: 1HNMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 6.4 Hz, 1H), 8.57 - 8.52 (m, 1H), 8.80 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.70 - 7.67 (m, 1H), 7.63 - 7.53 (m, 3H), 4.19 (s, 3H), 2.65 (s, 3H); 13CNMR (100 MHz, DMSO-d6) δ 165.9, 159.8, 147.9, 143.5, 132.8, 131.6, 128.9 (2C), 127.3 (2C), 119.7, 112.8, 41.8, 14.9.

[0053] Example 4

[0054] A preparation method of acetophenone oxime Mukaiyama reagent, comprising the following steps: in the presence of a base, reacting an acetophenone oxime compound shown in formula (II) with a Mukaiyama reagent shown in formula (III) to obtain the acetophenone oxime Mukaiyama reagent shown in formula (I),

[0055]

[0056] R1 and R2 are independently selected from any one of H, ester group, cyano group, nitro group, hydroxyl group, phenyl group, methylenedioxy group, C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, halogen, halogenated C1-C6 alkyl group or halogenated C1-C6 alkoxy group.

[0057] The specific preparation method is as follows:

[0058]

[0059] Into DMF, add the above compounds of formula (II), (III) and triethylamine, then raise the temperature to 70 °C, and stir and seal the reaction at this temperature for 12 hours;

[0060] The molar ratio of the compound of formula (II) to triethylamine is 1:0.5; the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:2.5; the ratio of the compound of formula (II) in millimole (mmol) to dichloromethane in milliliter (ml) is 1:12;

[0061] After the reaction was complete, the reaction system was naturally cooled to room temperature, directly vacuum filtered, the solid was collected, and washed three times with a mixture of ethyl acetate: petroleum ether = 1:1, thereby obtaining the target product compound of formula (I) (C18H14O4), with a yield of 89.2%;

[0062] Nuclear magnetic resonance: 1H NMR (400 MHz, DMSO-d6) 8.80 (d, J = 6.4 Hz, 1H), 8.57-8.52 (m, 1H), 8.80 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.70-7.67 (m, 1H), 7.63-7.53 (m, 3H), 4.19 (s, 3H), 2.65 (s, 3H); 13C NMR (100 MHz, DMSO-d6) 165.9, 159.8, 147.9, 143.5, 132.8, 131.6, 128.9 (2C), 127.3 (2C), 119.7, 112.8, 41.8, 14.9.

[0063] Embodiment 5-40

[0064] According to the corresponding relationship shown in Table 2, the ligand triethylamine in Example 1-4 was replaced with other ligands of the same molar amount, and other operations were different. The yields of the obtained products are shown in Table 2;

[0065] Table 2. Product yields under different ligands

[0066]

[0067] It can be seen that among all the bases, triethylamine, n-tributylamine and tri-tert-butylamine have suitable alkalinity, while the yields of other bases are significantly reduced or even no product can be obtained.

[0068] In summary, it can be clearly seen from all the above embodiments that when the method of the present invention is adopted, the compounds of formula (II) and (III) can react smoothly to obtain the target product with good yield and simple post-treatment. The achievement of these effects depends on the comprehensive synergistic effect of multiple factors such as base and solvent.

[0069] The above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, shall be covered by the protection scope of the present invention.

Claims

1. A method for preparing a new acetophenone oxime reagent, characterized in that: The method comprises the following steps: reacting an acetophenone oxime compound as shown in formula (II) and a Mukaiyama reagent as shown in formula (III) in the presence of a base to obtain a new acetophenone oxime Mukaiyama reagent as shown in formula (I); The R1 and R2 are independently selected from any one of H, ester group, cyano group, nitro group, hydroxyl group, phenyl group, methylenedioxy group, C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, halogen, halogenated C1-C6 alkyl group or halogenated C1-C6 alkoxy group.

2. The method for preparing a new acetophenone oxime reagent according to claim 1, characterized in that: The base includes any one or more of triethylamine, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, sodium ethoxide, tributylamine, pyridine, 2-fluoropyridine, 2-chloropyridine, and potassium tert-butoxide.

3. The method for preparing a new acetophenone oxime reagent according to claim 1, characterized in that: The reaction is carried out in an organic solvent, and the organic solvent includes any one or more of acetonitrile, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, chlorobenzene, benzene, xylene, dimethyl sulfoxide, and N-methylpyrrolidone.

4. The method for preparing a new acetophenone oxime reagent according to claim 1, characterized in that: The molar ratio of the acetophenone oxime compound to the base compound is 1:1-3.

5. The method for preparing a new acetophenone oxime reagent according to claim 1, characterized in that: The molar ratio of the acetophenone oxime compound to the Mukaiyama reagent is 1:1-3.

6. The method for preparing a new acetophenone oxime reagent according to claim 1, characterized in that: The ratio of the acetophenone oxime compound to the organic solvent is 1 mmol:5-15 mL.

7. The method for preparing a new acetophenone oxime reagent according to claim 1, characterized in that: The reaction temperature is 25-80°C.

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