Alpha, alpha-dihalogenated ketone compound and preparation method thereof

Abstract

The invention discloses an alpha, alpha-dihalogenated ketone compound and a preparation method thereof, and belongs to the technical field of organic synthesis. The structural general formula of the alpha, alpha-dihaloketone compound is # imgabs0, in the formula, R is aryl or heteroaryl, R1 is hydrogen, aryl or alkyl, and X is a halogen atom. The preparation method comprises the following steps: (1) carrying out heating reaction on an ethynyl compound, a halogenating reagent, water and an organic solvent; (2) pouring into water, extracting, collecting an organic phase, drying, and carrying out reduced pressure distillation; and (3) separating and purifying. The synthesis route provided by the invention has the advantages of cheap and easily available substrate and halogenating reagent, wide range, strong applicability, green oxygen source, no transition metal catalysis, mild condition, efficient reaction, energy saving, safe reaction route, simple operation and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more particularly to an α,α-dihalogenated ketone compound and a preparation method thereof. Background Art

[0002] α,α-dihalogenated ketone compounds are active building blocks. Due to their unique chemical properties and reactivity, their derivatives have a wide range of applications in bioorganic chemistry, medicine, materials science, and synthetic organic chemistry. In particular, in the pharmaceutical field, they can serve as key intermediates in the synthesis of various drugs and bioactive molecules. Therefore, their synthesis methods have attracted widespread attention, and some representative methods include:

[0003] (1) Metal-free halogen radical synthesis: Alkynes are synthesized by using NXS (N-bromo- or N-chlorosuccinimide) and TBHP (tert-butyl hydroperoxide) system. TBHP acts as an oxidant, donating electrons to NXS via a single electron transfer (SET) mechanism to generate halogen radicals. These halogen radicals attack the alkyne, ultimately generating α,α-dihaloketones. (Yadav, N.; Sahoo, AK.; Sarkar, D. Metal-free generation of halogen radicals using NXS / TBHP: Application in site-selective halogenation of quinoxalin-2(1H)-ones and synthesis of gem-dihaloketones. ChemRxiv.10.26434 / chemrxiv-2024-jqq3t.)

[0004] (2) Electrosynthesis: Using alkynes as substrates, an electrochemical reaction is carried out in aqueous solution using a constant current to convert terminal alkynes into α,α-dihaloketones. (Li, Z.; Qi, S.; Qian, P. Electrochemical synthesis of α,α-dihaloacetophenones from terminal alkyne derivatives. Chin. Chem. Lett. 2020, 31, 1855-1858.)

[0005] (3) Photocatalytic synthesis: Using CuCl2 as a photocatalyst and oxygen in the air as an oxidant at room temperature, the reaction is carried out by excitation of a halogen source (such as HCl) and visible light to oxidize terminal and internal aryl alkynes to α,α-dihaloketones. (Vaibhav, P.; Mahima, G.; Prof. K. Visible-Light-Induced Oxidative α-keto-Dichlorination of Arylalkynes by CuCl2 at Room Temperature. ChemSusChem. 2022, 15, 17.)

[0006] (4) Microwave synthesis: Alkynes are synthesized by ultrasound-assisted tandem reaction of trihaloisocyanuric acids (TXCA) and p-methylthiourea in water to form α,α-dihaloketones. (Zhang, X.; Wu, Y.; Zhang, Y.; Liu, H.; Xie, Z.; Fu, S.; Liu, F. Ultrasound-assisted tandem reaction of alkynes and trihaloisocyanuric acids by thiourea as catalyst in water. Tetrahedron. 2017, 73, 4513-4518.)

[0007] (5) Alkynes were synthesized by using tert-butyl hypochlorite (t-BuOCl) as a chlorination agent and water as an oxygen source for 9 hours at room temperature to form α,α-dihaloketones; or by using a variety of reactions of alkynes promoted by iodine and dimethyl sulfoxide (DMSO) with sodium chloride as a chlorination agent for 16 hours, which involved the synthesis of α,α-dihaloketones. (Shen, D.; Sun, C.; Han, Y. Additive-free oxychlorination of unsaturated CC bonds with tert-butyl hypochlorite and water. Org. Biomol. Chem. 2024, 22, 3080.; Suhail, A.; Atul, K.; and Qazi, N. Iodine-DMSO-promoted divergent reactivities of arylacetylenes. ChemComm. 2019, 55, 4511-4514.)

[0008] Summarizing the existing synthesis methods of α,α-dihalogenated ketone compounds, it is not difficult to see that the existing oxidative halogenation methods of alkynes have areas that need improvement: ① They require oxidants, without which the reaction cannot proceed; ② They require electrochemical equipment or visible light irradiation, which increases the experimental cost; ③ Although TCCA as a chlorination reagent has the advantages of high efficiency and stability, it also has the impact of environmental hazards; ④ The reaction time is long, requiring 9-16 hours; ⑤ They can only achieve the preparation of dichloroketones.

[0009] Therefore, how to provide a method for synthesizing α,α-dihalogenated ketone compounds that is greener, more efficient, has a faster reaction rate, is under mild conditions (catalyst-free, metal-free), and has strong compatibility (chlorinated or brominated) is a problem that those skilled in the art urgently need to solve. Summary of the Invention

[0010] In view of this, the object of the present invention is to provide an α,α-dihalogenated ketone compound and a preparation method thereof to address the deficiencies in the prior art.

[0011] In order to achieve the above object, the present invention adopts the following technical solutions:

[0012] An α,α-dihalogenated ketone compound having the general structural formula: In the formula, R is an aryl or heteroaryl group, R 1 is hydrogen, aryl or alkyl, and X is a halogen atom.

[0013] Furthermore, when R is an aryl group, the substitution mode and position are ortho-monosubstitution, meta-monosubstitution, para-monosubstitution or disubstitution (1,3,5-triethynylbenzene), ortho-monosubstitution is Me, meta-monosubstitution is Me, para-monosubstitution is Me, MeO, t-Bu, F, Cl, Br, NO2, CF3 or COOMe, and when R is an aryl group, it can also be naphthalene and biphenyl (2-ethynyl-naphthalene, 4-ethynylbiphenyl); when R is a heteroaryl group, it is thiophene;

[0014] R 1 When it is an aromatic group, it is a para-monosubstituted Br; R 1 When it is an alkyl group, it is Me, Cl or CH2OH;

[0015] The halogen atom is Cl or Br.

[0016] A method for preparing an α,α-dihalogenated ketone compound comprises the following steps:

[0017] (1) heating an acetylene compound, a halogenating agent, water, and an organic solvent to react to obtain a mixture;

[0018] (2) Pour the mixture into water, extract, collect the organic phase, dry, and distill under reduced pressure (to remove the organic solvent) to obtain a crude product;

[0019] (3) The crude product is separated and purified by silica gel column chromatography to obtain α,α-dihalogenated ketone compounds.

[0020] The synthetic route of the α,α-dihalogenated ketone compounds of the present invention is:

[0021]

[0022] Furthermore, in the above step (1), the general structural formula of the acetylene compound is: In the formula, R is an aryl or heteroaryl group, R 1 is hydrogen, aryl or alkyl.

[0023] Furthermore, when R is an aryl group, the substitution mode and position are ortho-monosubstitution, meta-monosubstitution, para-monosubstitution or disubstitution (1,3,5-triethynylbenzene), ortho-monosubstitution is Me, meta-monosubstitution is Me, para-monosubstitution is Me, MeO, t-Bu, F, Cl, Br, NO2, CF3 or COOMe, and when R is an aryl group, it can also be naphthalene and biphenyl (2-ethynyl-naphthalene, 4-ethynylbiphenyl); when R is a heteroaryl group, it is thiophene;

[0024] R 1 When it is an aromatic group, it is a para-monosubstituted Br; R 1 As an alkyl group, it is Me, Cl or CH2OH.

[0025] Furthermore, the acetylene compound is phenylacetylene, 4-tolylacetylene (1-ethynyl-4-methylbenzene), 4-ethynylanisole, 4-tert-butylphenylacetylene, 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4-nitrophenylacetylene, 4-ethynyl-α,α,α-trifluorotoluene, 4-ethynylbenzoic acid methyl ester, 2-methylphenylacetylene, 3-methylphenylacetylene, 1,3,5-triethynylbenzene, 2-ethynyl-naphthalene, 4-ethynylbiphenyl, 2-ethynylthiophene, 1,2-diphenylacetylene, 1,2-bis(4-bromophenyl)acetylene, prop-1-yn-1-benzene, (chloroethynyl)benzene or 3-phenylprop-2-yn-1-ol.

[0026] Furthermore, in the above step (1), the halogenating agent is at least one of NCS (N-chlorosuccinimide), NCP (N-chlorophthalimide), NBS (N-bromosuccinimide), NIS (N-iodosuccinimide), NIP (N-iodophthalimide) and Selectfluor (1-chloro-1,2,3,4-tetrahydro-2,6-naphthalenedione tetrafluoroborate), preferably at least one of NCS and NBS.

[0027] A further beneficial effect of adopting the above-mentioned method is that the NCS and NBS selected by the present invention are a kind of mild halogenating reagents, which have the significant advantage that they can react rapidly at room temperature and pressure under the conditions of the present invention, avoiding the complexity and safety hazards brought about by the extreme conditions of traditional halogenation methods. In addition, the market availability and relatively low price of NCS and NBS make them more attractive in laboratory and industrial applications. In the present invention, it is not only suitable for the conversion of terminal alkynes, but can also be effectively extended to the reaction of internal alkynes, showing excellent substrate adaptability. In addition, the unique activation effect between NCS and NBS and DMF greatly improves the reaction rate, thereby achieving efficient synthesis of the target product.

[0028] Furthermore, in the above step (1), the organic solvent is at least one of acetonitrile, N,N-dimethylformamide (DMF), tetrahydrofuran, dimethyl sulfoxide and 1,4-dioxane, preferably N,N-dimethylformamide.

[0029] Adopting the above-mentioned further beneficial effect is that the selected DMF of the present invention not only serves as solvent in the reaction, but also participates in the activation process of reaction. By acting with NCS or NBS, DMF significantly improves reaction efficiency, thereby accelerating the synthesis of product. In addition, DMF as solvent also has relatively stable characteristics, is easy to handle, and its use can not introduce additional environmental risks. This makes DMF not only efficient and reliable in chemical reaction, and conforms to the sustainable development concept of green chemistry, for promoting the application of environmentally friendly synthesis method provides strong support.

[0030] Furthermore, in the above step (1), the molar ratio of the acetylene compound, the halogenating agent, water and the organic solvent is 1:(1-3):(1-4):25, preferably 1:2:1:25.

[0031] Furthermore, in the above step (1), the temperature of the heating reaction is 30-100° C., preferably 60° C.; the time of the heating reaction is 5-420 min, preferably 5 min.

[0032] Furthermore, in the above step (2), the extraction reagent is dichloromethane, and the number of times is 3 times.

[0033] Furthermore, in the above step (3), the eluent for silica gel column chromatography is petroleum ether: dichloromethane = 20:1 (v:v).

[0034] It can be seen from the above technical solution that compared with the prior art, the beneficial effects of the present invention are as follows:

[0035] 1. Green and safe, no additional additives or catalysts are required, water is used as the oxygen source, avoiding the environmental and safety problems caused by the use of strong oxidants in traditional methods.

[0036] 2. Simple operation, efficient reaction, high yield and fast reaction rate.

[0037] 3. The substrates are highly universal and suitable for the conversion of terminal alkynes, internal alkynes and alkyne chlorides.

[0038] 4. The synthesis of chlorinated or brominated α,α-dihaloketone compounds can be achieved simultaneously.

[0039] 5. In summary, the synthetic route of the present invention has the advantages of cheap and easy availability of substrates and halogenation reagents, wide range, strong applicability, green oxygen source, no transition metal catalysis, mild conditions, efficient reaction and energy saving, safe reaction route, and simple operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 A diagram showing the application of α,α-dihaloketone compounds as core skeletons in natural products, bioactive molecules, and as drug intermediates. DETAILED DESCRIPTION

[0041] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0042] Example 1

[0043] The preparation method of 2,2-dichloroacetophenone specifically comprises the following steps:

[0044] (1) Phenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0045] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0046] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, which was the product 2,2-dichloroacetophenone, with a yield of 90%. The structural formula is as follows:

[0047]

[0048] 1H NMR (600MHz, CDCl3): δ = 8.02 (d, J = 8.4Hz, 2H), 7.58 (t, J = 8.1Hz, 1H), 7.45 (t, J = 7.9Hz, 2H), 6.61 (s, 1H).

[0049] 13 C NMR (150MHz, CDCl3): δ = 185.9, 134.5, 131.4, 129.7, 128.9, 67.8.

[0050] Example 2

[0051] The preparation method of 2,2-dichloro-4'-methylacetophenone specifically comprises the following steps:

[0052] (1) 4-Tolylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0053] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0054] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, which was the product 2,2-dichloro-4'-methylacetophenone, with a yield of 80%.

[0055] The structural formula is as follows:

[0056]

[0057] 1 H NMR (600MHz, CDCl3): δ = 7.98 (d, J = 8.3Hz, 2H), 7.31 (d, J = 8.5Hz, 2H), 6.65 (s, 1H), 2.44 (s, 3H).

[0058] 13 C NMR (150MHz, CDCl3): δ = 185.5, 145.8, 129.8, 129.6, 128.7, 67.8, 21.8.

[0059] Example 3

[0060] The preparation method of 2,2-dichloro-1-(4-methoxyphenyl)ethanone specifically comprises the following steps:

[0061] (1) 4-Ethynylanisole (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0062] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0063] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:3 (v:v)) to obtain a yellow liquid, which was the product 2,2-dichloro-1-(4-methoxyphenyl)ethanone, with a yield of 30%. The structural formula is as follows:

[0064]

[0065] 1 H NMR (600MHz, CDCl3): δ = 8.08 (d, J = 9.1Hz, 2H), 6.99 (d, J = 9.1Hz, 2H), 6.64 (s, 1H), 3.90 (s, 3H).

[0066] 13 C NMR (150MHz, CDCl3): δ = 184.6, 164.6, 132.3, 123.9, 114.2, 67.8, 55.6.

[0067] Example 4

[0068] The preparation method of 2,2-dichloro-1-[4-(tert-butyl)phenyl]ethanone specifically comprises the following steps:

[0069] (1) 4-tert-Butylphenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0070] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0071] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a pale yellow liquid, which was the product 2,2-dichloro-1-[4-(tert-butyl)phenyl]ethanone, with a yield of 63%. The structural formula is as follows:

[0072]

[0073] 1 H NMR (600MHz, CDCl3): δ = 8.03 (d, J = 8.8Hz, 2H), 7.53 (d, J = 8.9Hz, 2H), 6.67 (s, 1H), 1.36 (s, 9H).

[0074] 13 C NMR (150MHz, CDCl3): δ=185.5,158.7,129.7,128.6,125.9,67.8,35.3,30.9.

[0075] Example 5

[0076] The preparation method of 2,2-dichloro-1-(4-fluorophenyl)ethanone specifically comprises the following steps:

[0077] (1) 4-Fluorophenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0078] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0079] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a pale yellow liquid, which was the product 2,2-dichloro-1-(4-fluorophenyl)ethanone, with a yield of 75%. The structural formula is as follows:

[0080]

[0081] 1 H NMR (600MHz, CDCl3): δ=8.18-8.14(m,2H),7.22-7.18(m,2H),6.60(s,1H).

[0082] 13 C NMR (150MHz, CDCl3): δ=184.5,167.3,165.6,132.7,132.7,127.5,127.5,116.3,116.1,67.8.

[0083] Example 6

[0084] The preparation method of 2,2-dichloro-1-(4-chlorophenyl)ethanone specifically comprises the following steps:

[0085] (1) 4-Chlorophenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0086] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0087] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a white solid, 2,2-dichloro-1-(4-chlorophenyl)ethanone, in a yield of 44%. The structural formula is as follows:

[0088]

[0089] 1 H NMR (600MHz, CDCl3): δ=8.07-8.04(m,2H),7.51-7.49(m,2H),6.59(s,1H).

[0090] 13 C NMR (150MHz, CDCl3): δ=184.9,141.2,131.2,129.4,129.3,67.7.

[0091] Example 7

[0092] The preparation method of 2,2-dichloro-1-(4-bromophenyl)ethanone specifically comprises the following steps:

[0093] (1) 4-Bromophenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0094] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0095] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a white solid, 2,2-dichloro-1-(4-bromophenyl)ethanone, in a yield of 47%. The structural formula is as follows:

[0096]

[0097] 1 HNMR (600MHz, CDCl3): δ=7.99-7.96(m,2H),7.68-7.66(m,2H),6.58(s,1H).

[0098] 13 C NMR (150MHz, CDCl3): δ=185.1,132.3,131.2,130.0,129.9,67.7.

[0099] Example 8

[0100] The preparation method of 2,2-dichloro-1-(3-nitrophenyl)ethanone specifically comprises the following steps:

[0101] (1) 4-Nitrophenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0102] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0103] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 4:1 (v:v)) to obtain a yellow liquid, which was the product 2,2-dichloro-1-(3-nitrophenyl)ethanone, with a yield of 85%. The structural formula is as follows:

[0104]

[0105] 1 H NMR (600MHz, CDCl3): δ=8.38-8.36(m,2H),8.32-8.29(m,2H),6.59(s,1H).

[0106] 13 C NMR (150MHz, CDCl3): δ=179.9,146.1,131.0,126.3,119.2,72.5,72.2,72.0,63.0.

[0107] Example 9

[0108] The preparation method of 2,2-dichloro-1-(4-trifluoromethylphenyl)ethanone specifically comprises the following steps:

[0109] (1) 4-Ethynyl-α,α,α-trifluorotoluene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0110] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0111] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, namely the product 2,2-dichloro-1-(4-trifluoromethylphenyl)ethanone, with a yield of 65%. The structural formula is as follows:

[0112]

[0113] 1 H NMR (600MHz, CDCl3): δ=8.23 (d, J=8.2Hz, 2H), 7.79 (d, J=8.3Hz, 2H), 6.60 (s, 1H).

[0114] 13 C NMR (150MHz, CDCl3): δ=185.1,135.7,135.5,135.3,134.0,130.2,126.0,125.9,125.9,125.8,125.8,124.1,122.3,120.5,67.7.

[0115] Example 10

[0116] The preparation method of methyl 4-(2,2-dichloroacetyl)benzoate specifically comprises the following steps:

[0117] (1) Methyl 4-ethynylbenzoate (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0118] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0119] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a white solid, methyl 4-(2,2-dichloroacetyl)benzoate, in a yield of 40%. The structural formula is as follows:

[0120]

[0121] 1 H NMR (600MHz, CDCl3): δ = 8.16 (d, J = 3.2Hz, 4H), 6.65 (s, 1H), 3.97 (s, 3H).

[0122] 13 C NMR (150MHz, CDCl3): δ=185.5,165.8,135.1,134.6,131.6,129.9,129.7,129.5,67.8,52.6.

[0123] Example 11

[0124] The preparation method of 2,2-dichloro-1-(2-methylphenyl)ethanone specifically comprises the following steps:

[0125] (1) 2-Methylphenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0126] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0127] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, namely the product 2,2-dichloro-1-(2-methylphenyl)ethanone, with a yield of 86%. The structural formula is as follows:

[0128]

[0129] 1 H NMR (600MHz, CDCl3): δ=7.73 (dd, J=7.9, 1.5Hz, 1H), 7.47 (td, J=7.5, 1.5Hz, 1H), 7.34-7.29 (m, 2H), 6.66 (s, 1H), 2.53 (s, 3H).

[0130] 13C NMR (150MHz, CDCl3): δ=188.4,140.6,132.8,132.4,132.3,128.5,125.7,68.9,21.2.

[0131] Example 12

[0132] The preparation method of 2,2-dichloro-1-(3-methylphenyl)ethanone specifically comprises the following steps:

[0133] (1) 3-Methylphenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0134] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0135] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, namely the product 2,2-dichloro-1-(3-methylphenyl)ethanone, with a yield of 83%. The structural formula is as follows:

[0136]

[0137] 1 H NMR (600MHz, CDCl3): δ=7.87 (d, J=6.5Hz, 2H), 7.46 (d, J=8.0Hz, 1H), 7.42-7.39 (m, 1H), 6.70 (s, 1H), 2.44 (s, 3H).

[0138] 13 C NMR (150MHz, CDCl3): δ=186.0,138.9,135.4,131.4,130.1,128.7,126.8,67.7,21.3.

[0139] Example 13

[0140] The preparation method of 2,2-dichloro-1-(3,5-diethynylphenyl)ethanone specifically comprises the following steps:

[0141] (1) 1,3,5-Triethynylbenzene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0142] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0143] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a white solid, 2,2-dichloro-1-(3,5-diethynylphenyl)ethanone, in a yield of 50%. The structural formula is as follows:

[0144]

[0145] 1 H NMR (600MHz, CDCl3): δ = 8.15 (d, J = 1.5Hz, 2H), 7.83 (t, J = 1.5Hz, 1H), 6.59 (s, 1H), 3.20 (s, 2H).

[0146] 13 C NMR (150MHz, CDCl3): δ=184.5,140.5,133.1,131.7,123.7,81.0,79.8,67.5.

[0147] Example 14

[0148] The preparation method of 2,2-dichloro-1-(2-naphthyl)ethanone specifically comprises the following steps:

[0149] (1) 2-Ethynyl-naphthalene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0150] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0151] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 5:1 (v:v)) to obtain a white solid, 2,2-dichloro-1-(2-naphthyl)ethanone, in a yield of 50%. The structural formula is as follows:

[0152]

[0153] 1 HNMR (600MHz, CDCl3): δ=8.65(s,1H),8.09(dd,J=8.6,1.9Hz,1H),8.00(d,J=8.3Hz,1H),7.95( d,J=8.6Hz,1H),7.91(d,J=8.2Hz,1H),7.66(t,J=7.5Hz,1H),7.60(t,J=7.6Hz,1H),6.83(s,1H)

[0154] 13 C NMR (150MHz, CDCl3): δ=185.9,136.1,132.2,131.9,129.8,129.5,128.9,128.6,127.9,127.2,124.6,67.8.

[0155] Example 15

[0156] The preparation method of 2,2-dichloro-1-(4'-biphenyl)ethanone specifically comprises the following steps:

[0157] (1) 4-Ethynylbiphenyl (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0158] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0159] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 10:3 (v:v)) to obtain a white solid, 2,2-dichloro-1-(4'-biphenyl)ethanone, in a yield of 31%. The structural formula is as follows:

[0160]

[0161] 1 H NMR (600MHz, CDCl3): δ = 8.17 (d, J = 8.8Hz, 2H), 7.74 (d, J = 8.7Hz, 2H), 7.64 (d, J = 7.1Hz, 2H), 7.49 (t, J = 7.5Hz, 2H), 7.43 (t, J = 7.4Hz, 1H), 6.70 (s, 1H).

[0162] 13C NMR (150MHz, CDCl3): δ=185.5,147.3,139.3,130.4,129.9,129.0,128.7,127.5,127.3,67.9.

[0163] Example 16

[0164] The preparation method of 2,2-dichloro-1-(2-thienyl)ethanone specifically comprises the following steps:

[0165] (1) 2-Ethynylthiophene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0166] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0167] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a yellow liquid, which was the product 2,2-dichloro-1-(2-thienyl)ethanone, with a yield of 40%. The structural formula is as follows:

[0168]

[0169] 1 H NMR (600MHz, CDCl3): δ=8.01 (dd, J=3.9, 1.1Hz, 1H), 7.80 (dd, J=4.9, 1.1Hz, 1H), 7.21 (dd, J=4.9, 3.9Hz, 1H), 6.48 (s, 1H).

[0170] 13 C NMR (150MHz, CDCl3): δ=179.8,137.1,136.3,134.9,128.5,68.0.

[0171] Example 17

[0172] The preparation method of 2,2-dichloro-1,2-diphenylethanone specifically comprises the following steps:

[0173] (1) 1,2-Diphenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0174] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0175] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 10:1 (v:v)) to obtain a white solid, 2,2-dichloro-1,2-diphenylethanone, in a yield of 50%. The structural formula is as follows:

[0176]

[0177] 1 H NMR (600MHz, CDCl3): δ = 7.80 (d, J = 8.4Hz, 2H), 7.66 (d, J = 6.6Hz, 2H), 7.48-7.40 (m, 4H), 7.31 (t, J = 7.9Hz, 2H).

[0178] 13 C NMR (151MHz, CDCl3): δ=186.7,133.2,131.7,131.6,131.1,129.8,128.9,128.1,126.0,89.9.

[0179] Example 18

[0180] The preparation method of 2,2-dichloro-1,2-bis(4-bromophenyl)ethanone specifically comprises the following steps:

[0181] (1) 1,2-Bis(4-bromophenyl)acetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0182] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0183] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a white solid, 2,2-dichloro-1,2-bis(4-bromophenyl)ethanone, in a yield of 55%. The structural formula is as follows:

[0184]

[0185] 1H NMR (600MHz, CDCl3): δ=7.71 (d, J=8.9Hz, 2H), 7.57 (d, J=8.9Hz, 2H), 7.50 (d, J=8.8Hz, 4H).

[0186] 13 C NMR (150MHz, CDCl3): δ=185.4,138.3,132.5,132.2,131.6,130.1,129.0,127.8,124.5,88.5.

[0187] Example 19

[0188] The preparation method of α,α-dichloropropiophenone specifically comprises the following steps:

[0189] (1) Prop-1-yn-1-benzene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0190] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0191] (3) The crude product was chromatographed on a silica gel column using petroleum ether as an eluent to obtain a colorless liquid, which was the product α,α-dichloropropiophenone, with a yield of 85%. The structural formula is as follows:

[0192]

[0193] 1 H NMR (600MHz, CDCl3): δ = 8.32 (d, J = 8.4Hz, 2H), 7.61-7.57 (m, 1H), 7.47 (t, J = 7.9Hz, 2H), 2.35 (s, 3H).

[0194] 13 C NMR (150MHz, CDCl3): δ=188.1,133.5,131.3,131.1,128.1,82.7,34.2.

[0195] Example 20

[0196] The preparation method of 2,2,2-trichloroacetophenone specifically comprises the following steps:

[0197] (1) (Chloroethynyl)benzene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0198] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0199] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, which was the product 2,2,2-trichloroacetophenone, with a yield of 70%. The structural formula is as follows:

[0200]

[0201] 1 H NMR (600MHz, CDCl3): δ=8.26 (dd, J=8.6, 1.2Hz, 2H), 7.66-7.63 (m, 1H), 7.53-7.49 (m, 2H).

[0202] 13 C NMR (150MHz, CDCl3): δ = 181.2, 134.2, 131.5, 129.1, 128.4.

[0203] Example 21

[0204] The preparation method of 2,2-dichloro-3-hydroxy-1-phenylacetone specifically comprises the following steps:

[0205] (1) 3-Phenylprop-2-yn-1-ol (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NCS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0206] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0207] (3) The crude product was chromatographed on a silica gel column using petroleum ether as an eluent to obtain a yellow liquid, which was the product 2,2-dichloro-3-hydroxy-1-phenylacetone, with a yield of 35%. The structural formula is as follows:

[0208]

[0209] 1 H NMR (600MHz, CDCl3): δ = 8.32 (d, J = 7.7Hz, 2H), 7.63 (t, J = 6.9Hz, 1H), 7.49 (t, J = 7.9Hz, 2H), 4.27 (d, J = 7.0Hz, 2H), 2.89 (s, 1H).

[0210] 13 C NMR (150MHz, CDCl3): δ=189.2,134.2,131.1,131.1,128.3,83.5,70.6.

[0211] Example 22

[0212] The preparation method of 2,2-dibromoacetophenone specifically comprises the following steps:

[0213] (1) Phenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0214] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0215] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, 2,2-dibromoacetophenone, with a yield of 70%. The structural formula is as follows:

[0216]

[0217] 1 H NMR (600MHz, CDCl3): δ = 8.10-8.08 (m, 2H), 7.64 (t, J = 7.4Hz, 1H), 7.52 (t, J = 7.9Hz, 2H), 6.71 (s, 1H).

[0218] 13 C NMR (150MHz, CDCl3): δ = 185.9, 134.4, 130.8, 129.7, 128.9, 39.7.

[0219] Example 23

[0220] The preparation method of 2,2-dibromo-4'-methylacetophenone specifically comprises the following steps:

[0221] (1) 1-Ethynyl-4-methylbenzene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0222] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0223] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a white solid, which was the product 2,2-dibromo-4'-methylacetophenone, with a yield of 75%.

[0224] The structural formula is as follows:

[0225]

[0226] 1 H NMR (600MHz, CDCl3): δ = 7.98 (d, J = 8.4Hz, 2H), 7.31 (d, J = 7.9Hz, 2H), 6.69 (s, 1H), 2.45 (s, 3H).

[0227] 13 C NMR (150MHz, CDCl3): δ = 185.6, 145.7, 129.8, 129.6, 128.2, 39.8, 21.8.

[0228] Example 24

[0229] The preparation method of 2,2-dibromo-1-(4-methoxyphenyl)ethanone specifically comprises the following steps:

[0230] (1) 4-Ethynylanisole (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0231] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0232] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 5:1 (v:v)) to obtain a white solid, 2,2-dibromo-1-(4-methoxyphenyl)ethanone, in a yield of 45%. The structural formula is as follows:

[0233]

[0234] 1 H NMR (600MHz, CDCl3): δ = 8.09-8.07 (m, 2H), 6.98-6.96 (m, 2H), 6.66 (s, 1H), 3.90 (s, 3H).

[0235] 13 C NMR (150MHz, CDCl3): δ = 184.6, 164.5, 132.2, 123.3, 114.2, 55.6, 39.8.

[0236] Example 25

[0237] The preparation method of 2,2-dibromo-1-[4-(tert-butyl)phenyl]ethanone specifically comprises the following steps:

[0238] (1) 4-tert-Butylphenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0239] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0240] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a light colorless liquid, namely the product 2,2-dibromo-1-[4-(tert-butyl)phenyl]ethanone, with a yield of 50%. The structural formula is as follows:

[0241]

[0242] 1 H NMR (600MHz, CDCl3): δ=8.04-8.02(m,2H),7.53-7.51(m,2H),6.70(s,1H),1.35(s,9H).

[0243] 13 C NMR (150MHz, CDCl3): δ=185.6,158.6,129.7,128.1,125.9,39.8,35.3,31.0.

[0244] Example 26

[0245] The preparation method of 2,2-dibromo-1-(4-fluorophenyl)ethanone specifically comprises the following steps:

[0246] (1) 4-Fluorophenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0247] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0248] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a light colorless liquid, the product 2,2-dibromo-1-(4-fluorophenyl)ethanone, in a yield of 78%. The structural formula is as follows:

[0249]

[0250] 1 H NMR (600MHz, CDCl3): δ=8.15 (dd, J=7.9, 5.6Hz, 2H), 7.19 (t, J=8.6Hz, 2H), 6.61 (s, 1H).

[0251] 13 C NMR (150MHz, CDCl3): δ=184.5,167.2,165.5,132.7,132.6,127.1,127.1,116.3,116.1,39.3.

[0252] Example 27

[0253] The preparation method of 2,2-dibromo-1-(4-chlorophenyl)ethanone specifically comprises the following steps:

[0254] (1) 4-Chlorophenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0255] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0256] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:3 (v:v)) to obtain a white solid, 2,2-dibromo-1-(4-chlorophenyl)ethanone, in a yield of 30%. The structural formula is as follows:

[0257]

[0258] 1 H NMR (600MHz, CDCl3): δ=8.07-8.04(m,2H),7.50-7.48(m,2H),6.60(s,1H).

[0259] 13 C NMR (150MHz, CDCl3): δ=184.9,141.0,131.2,129.3,129.1,39.2.

[0260] Example 28

[0261] The preparation method of 2,2-dibromo-1-(4-bromophenyl)ethanone specifically comprises the following steps:

[0262] (1) 4-Bromophenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0263] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0264] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:3 (v:v)) to obtain a white solid, 2,2-dibromo-1-(4-bromophenyl)ethanone, in a yield of 45%. The structural formula is as follows:

[0265]

[0266] 1 HNMR (600MHz, CDCl3): δ=7.97 (d, J=8.7Hz, 2H), 7.66 (d, J=8.8Hz, 2H), 6.59 (s, 1H).

[0267] 13 C NMR (150MHz, CDCl3): δ=185.1,132.3,131.2,129.9,129.5,39.1.

[0268] Example 29

[0269] The preparation method of 2,2-dibromo-1-(2-methylphenyl)ethanone specifically comprises the following steps:

[0270] (1) 2-Methylphenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0271] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0272] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, namely the product 2,2-dibromo-1-(2-methylphenyl)ethanone, with a yield of 84%. The structural formula is as follows:

[0273]

[0274] 1 H NMR (600MHz, CDCl3): δ = 7.68 (d, J = 6.4Hz, 1H), 7.46 (td, J = 7.5, 1.4Hz, 1H), 7.34-7.26 (m, 2H), 6.68 (s, 1H), 2.52 (s, 3H).

[0275] 13 C NMR (150MHz, CDCl3): δ=188.5,140.2,132.6,132.2,128.0,125.7,42.1,21.0.

[0276] Example 30

[0277] The preparation method of 2,2-dibromo-1-(3-methylphenyl)ethanone specifically comprises the following steps:

[0278] (1) 3-Methylphenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0279] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0280] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, the product 2,2-dibromo-1-(3-methylphenyl)ethanone, in a yield of 79%. The structural formula is as follows:

[0281]

[0282] 1 HNMR (600MHz, CDCl3): δ = 7.87 (d, J = 6.3Hz, 2H), 7.45 (d, J = 7.3Hz, 1H), 7.41-7.38 (m, 1H), 6.72 (s, 1H), 2.44 (s, 3H).

[0283] 13 C NMR (150MHz, CDCl3): δ=188.5,140.2,132.6,132.2,128.0,125.7,42.1,21.0.

[0284] Example 31

[0285] The preparation method of 2,2-dibromo-1-(3,5-diethynylphenyl)ethanone specifically comprises the following steps:

[0286] (1) 1,3,5-Triethynylbenzene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0287] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0288] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 10:1 (v:v)) to obtain a white solid, 2,2-dibromo-1-(3,5-diethynylphenyl)ethanone, in a yield of 40%. The structural formula is as follows:

[0289]

[0290] 1 H NMR (600MHz, CDCl3): δ = 8.14 (s, 2H), 7.84 (d, J = 22.3Hz, 1H), 6.60 (s, 1H), 3.20 (s, 2H).

[0291] 13C NMR (150MHz, CDCl3): δ=184.4,140.4,138.3,137.8,133.7,133.0,131.4,130.5,123.7,81.1,79.7,38.8.

[0292] Example 32

[0293] The preparation method of 2,2-dibromo-1-(2-naphthyl)ethanone specifically comprises the following steps:

[0294] (1) 2-Ethynyl-naphthalene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0295] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0296] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 4:1 (v:v)) to obtain a white solid, which was the product 2,2-dichloro-1-(2-naphthyl)ethanone, with a yield of 80%. The structural formula is as follows:

[0297]

[0298] 1 HNMR (600MHz, CDCl3): δ=8.64(s,1H),8.09(d,J=8.7Hz,1H),7.99(d,J=8.2Hz,1H),7.94(d,J =8.7Hz,1H),7.90(d,J=8.2Hz,1H),7.66(t,J=7.5Hz,1H),7.60(t,J=7.5Hz,1H),6.86(s,1H).

[0299] 13 C NMR (150MHz, CDCl3): δ=186.0,136.0,132.3,131.7,129.8,129.4,128.9,128.1,127.8,127.2,124.7,39.7.

[0300] Example 33

[0301] The preparation method of 2,2-dibromo-1-(4'-biphenyl)ethanone specifically comprises the following steps:

[0302] (1) 4-Ethynylbiphenyl (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0303] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0304] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 5:1 (v:v)) to obtain a white solid, 2,2-dichloro-1-(4'-biphenyl)ethanone, in a yield of 79%. The structural formula is as follows:

[0305]

[0306] 1 H NMR (600MHz, CDCl3): δ = 8.17 (d, J = 8.2Hz, 2H), 7.73 (d, J = 8.3Hz, 2H), 7.64 (d, J = 7.6Hz, 2H), 7.49 (t, J = 7.6Hz, 2H), 7.43 (t, J = 7.4Hz, 1H), 6.72 (s, 1H).

[0307] 13 C NMR (150MHz, CDCl3): δ=185.5,147.2,139.4,130.3,129.4,129.0,128.6,127.5,127.3,39.7.

[0308] Example 34

[0309] The preparation method of 2,2-dibromo-1-(2-thienyl)ethanone specifically comprises the following steps:

[0310] (1) 2-Ethynylthiophene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0311] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0312] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 5:1 (v:v)) to obtain a yellow liquid, which was the product 2,2-dibromo-1-(2-thienyl)ethanone, with a yield of 60%. The structural formula is as follows:

[0313]

[0314] 1 H NMR (600MHz, CDCl3): δ=7.99 (d, J=3.9Hz, 1H), 7.78 (d, J=4.9Hz, 1H), 7.19 (t, J=4.5Hz, 1H), 6.49 (s, 1H).

[0315] 13 C NMR (150MHz, CDCl3): δ=179.7,136.5,136.3,134.6,128.5,38.9.

[0316] Example 35

[0317] The preparation method of 2,2-dibromo-1,2-diphenylethanone specifically comprises the following steps:

[0318] (1) 1,2-Diphenylacetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0319] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0320] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 10:1 (v:v)) to obtain a white solid, 2,2-dibromo-1,2-diphenylethanone, in a yield of 50%. The structural formula is as follows:

[0321]

[0322] 1 H NMR (600MHz, CDCl3): δ = 7.74 (d, J = 7.4Hz, 2H), 7.65 (d, J = 7.0Hz, 2H), 7.44 (t, J = 7.4Hz, 1H) ,7.38(t,J=7.4Hz,2H),7.34(t,J=7.3Hz,1H),7.28(d,J=8.5Hz,1H),7.26(d,J=2.4Hz,1H).

[0323] 13 C NMR (150MHz, CDCl3): δ=186.2,141.0,133.1,131.4,130.8,129.6,128.9,128.0,126.7,69.5.

[0324] Example 36

[0325] The preparation method of 2,2-dibromo-1,2-bis(4-bromophenyl)ethanone specifically comprises the following steps:

[0326] (1) 1,2-Bis(4-bromophenyl)acetylene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0327] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0328] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a white solid, 2,2-dibromo-1,2-bis(4-bromophenyl)ethanone, in a yield of 45%. The structural formula is as follows:

[0329]

[0330] 1 H NMR (600MHz, CDCl3): δ=7.64 (d, J=8.8Hz, 2H), 7.52 (d, J=9.0Hz, 2H), 7.49 (d, J=9.0Hz, 2H), 7.46 (d, J=8.8Hz, 2H).

[0331] 13 C NMR (150MHz, CDCl3): δ=184.9,139.8,132.8,132.2,131.6,129.2,128.8,128.3,124.2,67.3.

[0332] Example 37

[0333] The preparation method of α,α-dibromopropiophenone specifically comprises the following steps:

[0334] (1) Prop-1-yn-1-benzene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by the addition of NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL). The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture;

[0335] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0336] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, α,α-dibromopropiophenone, with a yield of 80%. The structural formula is as follows:

[0337]

[0338] 1 H NMR (600MHz, CDCl3): δ=8.40 (dd, J=8.6, 1.3Hz, 2H), 7.58 (t, J=7.4Hz, 1H), 7.49-7.46 (m, 2H), 2.76 (s, 3H).

[0339] 13 C NMR (150MHz, CDCl3): δ=188.3,133.4,131.7,131.3,127.9,57.9,37.7.

[0340] Example 38

[0341] The preparation method of 2,2-dibromo-2-chloro-1-phenylethanone specifically comprises the following steps:

[0342] (1) (Chloroethynyl)benzene (1 mmol) was added to a 10 mL dry round-bottom flask equipped with a magnetic rotor, followed by NBS (2 mmol) and H2O (0.018 mL), and then DMF (2 mL) was injected. The mixture was stirred at 60°C for 5 min, and the reaction endpoint was monitored by TLC to obtain a mixture.

[0343] (2) The mixture was poured into water and extracted with dichloromethane three times. The organic phases were combined, dried, and distilled under reduced pressure to remove DMF to obtain a crude product;

[0344] (3) The crude product was chromatographed on a silica gel column using an eluent (petroleum ether: dichloromethane = 20:1 (v:v)) to obtain a colorless liquid, namely the product 2,2-dibromo-2-chloro-1-phenylethanone, with a yield of 60%. The structural formula is as follows:

[0345]

[0346] 1 H NMR (600MHz, CDCl3): δ=8.31 ​​(dd, J=8.6, 1.2Hz, 2H), 7.64-7.61 (m, 1H), 7.51-7.48 (m, 2H).

[0347] 13 C NMR (150MHz, CDCl3): δ=181.7,134.06,131.7,128.7,128.3,61.3.

[0348] Example 39

[0349] α,α-Dihalogenated ketone compounds are a class of organic compounds with great research value, and their skeletons are widely present in various drugs and natural products. Figure 1 As shown, chloramphenicol and synthetic antibacterial or antitumor agent precursors all contain a core structural skeleton of α,α-dihaloketone. In addition, mitotane, used to treat adrenocortical carcinoma and Cushing's syndrome, can be directly synthesized in two steps using 2,2-dichloro-1-(4-fluorophenyl)ethanone as a substrate (Yadav, N.; Sahoo, AK.; Sarkar, D. Metal-free generation of halogen radicals using NXS / TBHP: Application in site-selective halogenation of quinoxalin-2(1H)-ones and synthesis of gem-dihaloketones. ChemRxiv.2024.10.26434 / chemrxiv-2024-jqq3t.).

[0350] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. An α,α-dihalogenated ketone compound, characterized in that: The general structural formula is: In the formula, R is an aryl or heteroaryl group, R 1 is hydrogen, aryl or alkyl, and X is a halogen atom.

2. An α,α-dihalogenated ketone compound according to claim 1, characterized in that When R is an aryl group, the substitution mode and position are ortho-monosubstitution, meta-monosubstitution, para-monosubstitution or disubstitution, ortho-monosubstitution is Me, meta-monosubstitution is Me, para-monosubstitution is Me, MeO, t-Bu, F, Cl, Br, NO2, CF3 or COOMe; when R is a heteroaryl group, it is thiophene; R 1 When it is an aromatic group, it is a para-monosubstituted Br; R 1 When it is an alkyl group, it is Me, Cl or CH2OH; The halogen atom is Cl or Br.

3. A method for preparing an α,α-dihalogenated ketone compound, characterized in that: The specific steps include: (1) heating an acetylene compound, a halogenating agent, water, and an organic solvent to react to obtain a mixture; (2) pouring the mixture into water, extracting, collecting the organic phase, drying, and distilling under reduced pressure to obtain a crude product; (3) The crude product is separated and purified by silica gel column chromatography to obtain the α,α-dihalogenated ketone compound.

4. The method for preparing an α,α-dihalogenated ketone compound according to claim 3, characterized in that: In step (1), the general structural formula of the acetylene compound is: In the formula, R is an aryl or heteroaryl group, R 1 is hydrogen, aryl or alkyl.

5. The method for preparing an α,α-dihalogenated ketone compound according to claim 4, characterized in that: When R is an aryl group, the substitution mode and position are ortho-monosubstitution, meta-monosubstitution, para-monosubstitution or disubstitution, ortho-monosubstitution is Me, meta-monosubstitution is Me, para-monosubstitution is Me, MeO, t-Bu, F, Cl, Br, NO2, CF3 or COOMe; when R is a heteroaryl group, it is thiophene; R 1 When it is an aromatic group, it is a para-monosubstituted Br; R 1 As an alkyl group, it is Me, Cl or CH2OH.

6. The method for preparing an α,α-dihalogenated ketone compound according to claim 3, characterized in that: In step (1), the halogenating agent is at least one of NCS, NCP, NBS, NIS, NIP and Selectflour.

7. The method for preparing an α,α-dihalogenated ketone compound according to claim 3, characterized in that: In step (1), the organic solvent is at least one of acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and 1,4-dioxane.

8. The method for preparing an α,α-dihalogenated ketone compound according to claim 3, characterized in that: In step (1), the molar ratio of the acetylene compound, the halogenating agent, water and the organic solvent is 1:(1-3):(1-4):

25.

9. The method for preparing an α,α-dihalogenated ketone compound according to claim 3, characterized in that: In step (1), the heating reaction temperature is 30-100° C. and the time is 5-420 min.

10. The method for preparing an α,α-dihalogenated ketone compound according to claim 3, characterized in that: In step (2), the extraction reagent is dichloromethane, and the number of times is 3 times.

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