Electrophilic chlorination method taking trichloroacetonitrile as chlorine source

Abstract

The invention discloses an electrophilic chlorination method using trichloroacetonitrile as a chlorine source, which comprises the following steps: using trichloroacetonitrile as an electrophilic chlorination reagent to realize electrophilic alpha-monochlorination or alpha-dichlorination of carbonyl compounds under certain conditions, the compounds can be used for preparing 1, 3-diketone, oxindole, simple ketone compounds and carbonyl compounds containing halogen heteroatoms. The novel chlorination method developed by the invention can be used for pre-functionalization of molecules, so that diversified conversion of the molecules is realized, or chlorine atoms are introduced into drugs and drug-like molecules. The chlorination method has the advantages of low cost, high yield, simplicity in operation, mild reaction conditions, short reaction time and the like.

Description

Technical Field

[0001] The invention belongs to the field of chemistry, and in particular relates to an electrophilic chlorination method using trichloroacetonitrile as a chlorine source. Background Art

[0002] Organic chlorides play an important role in organic synthetic chemistry and are widely used in the synthesis of fine chemicals, medicines, pesticides, natural products, and organic functional materials. Direct electrophilic chlorination of organic matter has the advantages of simple operation, mild conditions, low cost, environmental friendliness, and industrialization. It is one of the most efficient methods for preparing organic chlorides. Cl2, SO2Cl2, and tBuOCl are electrophilic chlorination reagents that were used earlier, but they have been gradually abandoned due to their strong corrosiveness, poor reaction selectivity, difficulty in storage, and complex experimental operation. Later developed N-Cl electrophilic reagents, such as N-chlorosuccinimide (NCS), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), trichloroisocyanuric acid (TCCA), etc., can effectively overcome the above shortcomings. However, due to their poor reactivity, additional catalysts or additives are often required in the reaction to activate such reagents, such as Lewis acids, Lewis bases, Acid, etc. 2,3,4,5,6,6-hexachloro-2,4-cyclohexadien-1-one (C6Cl6O) as an electrophilic chlorination reagent shows excellent corresponding selectivity in the asymmetric α-chlorination of carbonyl compounds, but it is expensive and has poor atom economy. Baran et al. developed 2-chloro-1,3-(bis(methoxycarbonyl)guanidine) (Palau'chlor) reagent and N-chloro-N-acetoxy-p-nitrobenzamide electrophilic chlorination reagent in 2014 and 2024, respectively. These reagents have good activity and regioselectivity in aromatic chlorination reactions [J.Am.Chem.Soc.,2014,136,6908-6911; NatureChemistry.,2024,16,1539-1545.]. In 2015-2016, Yang Xianjin's research group developed N-chloro-N-fluorobenzenesulfonamide (CFBSA) and N-chloro-N-methoxybenzenesulfonamide (CMOBSA) electrophilic chlorination reagents, which have good activity in the electrophilic chlorination of aromatic hydrocarbons and carbonyl compounds [Chem. Commun., 2015, 51, 14852-14855; Eur. J. Org. Chem., 2016, 5937-5940.]. The above electrophilic chlorination reagents are either expensive or commercially unavailable, and all have poor atom economy. Therefore, it is of great significance to develop electrophilic chlorination methods using cheap, readily available and highly atom-economical reagents, such as trichloroacetonitrile, as chlorine sources.

[0003] Summary of the invention

[0004] The object of the present invention is to provide a method for achieving monochlorination or dichlorination of carbonyl compounds using trichloroacetonitrile as an electrophilic chlorination reagent:

[0005] Method 1:

[0006]

[0007] Wherein, R1 and R2 are one or more functional groups selected from alkyl, alkoxy, aryl, substituted aryl, alkylamino and aliphatic substituents with functional groups;

[0008] R3 is one or more functional groups selected from the group consisting of alkyl, alkoxy, aryl, substituted aryl, alkylamino, halogen, and functional aliphatic substituents.

[0009] The alkyl group is methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, etc.;

[0010] The aryl group is phenyl, naphthyl, anthracenyl, pyridyl, furyl, thienyl, etc.;

[0011] The substituent on the substituted aryl group is halogen, alkyl, fluoroalkyl, alkoxy, nitro, cyano, etc.;

[0012] The aliphatic substituent with a functional group is a carbon chain with a double bond, a triple bond, an ester group, an amide group, a carbonyl group, a thiol group, an amine group, a cyano group, an ether bond or a halogen atom.

[0013] A method for monochlorination of a carbonyl compound, using trichloroacetonitrile as an electrophilic chlorination reagent and a carbonyl compound as a starting material, specifically comprising the following steps:

[0014] S1. Add the carbonyl compound, base, trichloroacetonitrile and organic solvent in a molar ratio of 1:0.2:1:5 to 1:3:5:20 into a reaction kettle and stir at -20 to 80°C for 0.1 to 24h;

[0015] S2. After the reaction is completed, water and an extractant equal in volume to the organic solvent are added respectively for extraction, the organic phase is washed with dilute hydrochloric acid solution and saturated brine, and then dried over anhydrous sodium sulfate, filtered, the filtrate is collected, and the solvent is evaporated to remove, and the crude product is purified by column chromatography using a washing solution of ethyl acetate and petroleum ether in a volume ratio of 1:1 to 200 to obtain a monochlorinated product of the carbonyl compound.

[0016] In S1, the carbonyl compound includes malonate, β-ketoamide, 1,3-diketone, oxidized indole, simple ketone compound and carbonyl compound containing heterohalogen atom.

[0017] In S1, the base includes any one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (TEDA), tetramethylguanidine (TMG), triethylamine, 4-dimethylaminopyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and potassium tert-butoxide.

[0018] In S1 and S2, the organic solvent includes any one of toluene (Tol), N,N-dimethylformamide (DMF), ethyl acetate (EA), dichloromethane (DCM), tetrahydrofuran (THF), tert-butyl methyl ether (MTBE), and diethyl ether.

[0019] Method 2:

[0020]

[0021] R1 and R2 are one or more functional groups selected from the group consisting of alkyl, alkoxy, aryl, substituted aryl, alkylamino, and aliphatic substituents with functional groups;

[0022] The alkyl group is methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, etc.;

[0023] The aryl group is phenyl, naphthyl, anthracenyl, pyridyl, furyl, thienyl, etc.;

[0024] The substituent on the substituted aryl group is halogen, alkyl, fluoroalkyl, alkoxy, nitro, cyano, etc.;

[0025] The aliphatic substituent with a functional group is a carbon chain with a double bond, a triple bond, an ester group, an amide group, a carbonyl group, a thiol group, an amine group, a cyano group, an ether bond or a halogen atom.

[0026] A method for dichlorination of a carbonyl compound, using trichloroacetonitrile as an electrophilic chlorination reagent and a carbonyl compound as a starting material, specifically comprising the following steps:

[0027] S1. Add the carbonyl compound, base, trichloroacetonitrile and organic solvent into the reaction kettle in a molar ratio of 1:1:2:5 to 1:3:5:20, and stir at -20 to 80°C for 0.1 to 24h;

[0028] S2. After the reaction is completed, water and an extractant having an equal volume to the organic solvent are added respectively for extraction, the organic phase is washed with a dilute hydrochloric acid solution and a saturated saline solution, and then dried over anhydrous sodium sulfate, filtered, the filtrate is collected, and the solvent is evaporated to remove the solvent. The crude product is purified by column chromatography using a washing liquid having a volume ratio of ethyl acetate to petroleum ether of 1:1 to 200, or by column chromatography using a washing liquid having a volume ratio of methanol to dichloromethane of 1:90 to 200, to obtain a dichlorinated product of the carbonyl compound.

[0029] In S1, the carbonyl compound includes malonate, β-ketoester, β-ketoamide, 1,3-diketone, oxidized indole, and simple ketone compounds.

[0030] In S1, the base includes any one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (TEDA), tetramethylguanidine (TMG), triethylamine, 4-dimethylaminopyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and potassium tert-butoxide.

[0031] In S1 and S2, the organic solvent includes any one of toluene (Tol), N,N-dimethylformamide (DMF), ethyl acetate (EA), dichloromethane (DCM), tetrahydrofuran (THF), tert-butyl methyl ether (MTBE), and diethyl ether.

[0032] Compared with the prior art, the present invention has the following advantages:

[0033] The present invention uses trichloroacetonitrile as a chlorine source to realize α-monochlorination or α-dichlorination of carbonyl compounds. The new electrophilic chlorination method using trichloroacetonitrile as a chlorine source developed by the present invention can be used for pre-functionalization of molecules to realize molecular diversification conversion, or introduce chlorine atoms into drugs and drug-like molecules. The electrophilic chlorination method of the present invention has the characteristics of simple operation, mild reaction conditions, short reaction time, high yield and low cost, and has application prospects in industrial reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 . The H-NMR spectrum of 2a of the present invention;

[0035] Figure 2 . The H-NMR spectrum of 2b of the present invention;

[0036] Figure 3 . The NMR carbon spectrum of 2b of the present invention;

[0037] Figure 4 .H-NMR spectrum of 2c of the present invention;

[0038] Figure 5 . The H-NMR spectrum of 2d of the present invention;

[0039] Figure 6 . The nuclear magnetic carbon spectrum of 2d of the present invention;

[0040] Figure 7 .H NMR spectrum of 2e of the present invention;

[0041] Figure 8. The H-NMR spectrum of 2f of the present invention;

[0042] Fig. 9 . The H-NMR spectrum of 2g of the present invention;

[0043] Fig.10 . The H-NMR spectrum of 2h of the present invention;

[0044] Fig.11 . The H-NMR spectrum of 2i of the present invention;

[0045] Fig.12 . The H NMR spectrum of 2j of the present invention;

[0046] Fig.13 . The 2k H-NMR spectrum of the present invention;

[0047] Fig.14 . The 2k NMR carbon spectrum of the present invention;

[0048] Fig.15 . The nuclear magnetic hydrogen spectrum of 21 of the present invention;

[0049] Fig.16 .Nuclear magnetic resonance hydrogen spectrum of the anticancer drug molecule 3 of the present invention;

[0050] Fig.17 .Nuclear magnetic resonance hydrogen spectrum of the anti-diabetic drug molecule 5 of the present invention. DETAILED DESCRIPTION

[0051] The present invention is further described below in conjunction with embodiments, but the present invention is not limited to these embodiments. Any improvements made without departing from the spirit of the present invention shall fall within the protection scope of the present invention.

[0052] Example 1

[0053] A method for preparing a monochlorinated product (2a) of a β-ketoester carbonyl compound is as follows:

[0054]

[0055] Weigh 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid tert-butyl ester (1a) (41 mg, 0.2 mmol) and add it to a dry reaction tube, add tert-butyl methyl ether (1 mL) to dissolve it, then pipette DBU (6 μL, 0.04 mmol) and add it to the dissolved 1a, and stir the reaction mixture at room temperature. Finally, use a pipette to pipette trichloroacetonitrile (30 μL, 0.3 mmol) and add it to the reaction mixture and continue stirring at room temperature. After the reaction is complete, the reaction solution is quenched with 1 mL of distilled water and extracted with ethyl acetate (3×2 mL), the organic phase is washed with deionized water (3×6 mL), then with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent is removed by vacuum rotary evaporation. The crude product is purified by silica gel column chromatography, the eluent is ethyl acetate: petroleum ether = 1:120-1:110, and 2a is 48 mg, the reaction time is 15 minutes, the yield is 86%, and it is a colorless oily liquid. 1HNMR (500 MHz, CDCl3) δ8.09 (dd, J = 7.9, 1.5 Hz, 1H), 7.53 (td, J = 7.5, 1.5 Hz, 1H), 7.39-7.30 (m, 1H), 7.29-7.24 (m, 1H), 3.25 (m, J = 17.1, 8.7, 4.8 Hz, 1H), 3.06-2.90 (m, 2H), 2.51 (m, J = 14.0, 6.0, 4.7 Hz, 1H), 1.46 (s, 9H). 2a is a known substance. The NMR data are consistent with those reported in the literature [Tetrahedron., 2012, 53 (29), 3811-3814.].

[0056] Example 2

[0057] Weigh 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid tert-butyl ester (1a) (1.01 g, 4.10 mmol) into a dry reaction tube, add MTBE (10 mL) to dissolve it, then pipette DBU (113 μL, 0.82 mmol) into the dissolved 1a, and stir the reaction mixture at room temperature. Finally, pipette trichloroacetonitrile (617 μL, 6.15 mmol) into the reaction mixture and continue stirring at room temperature. After the reaction was complete, the reaction solution was quenched with 10 mL of distilled water and extracted with ethyl acetate (3×20 mL). The organic phase was washed with deionized water (3×60 mL) and then with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography with ethyl acetate: petroleum ether = 1:120-1:110 as the eluent to obtain 0.92 g of 2a. The reaction time was 15 minutes, the yield was 80%, and it was a colorless oily liquid.

[0058] Example 3

[0059] A method for preparing a monochlorinated product (2b) of a β-ketoamide carbonyl compound is as follows:

[0060]

[0061] The method for preparing 2b is as described in Example 1, and 46 mg of 2b is obtained. The raw material is 1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-amide (1b). The reaction time is 12 minutes, the yield is 98%, and the product is a colorless oily liquid. 1H NMR (500MHz, CDCl3) δ8.93(s,1H),8.11(dd,J=8.0,1.5Hz,1H),7.60(d,J=7.7Hz,2H),7.55(td,J=7.5,1.5Hz,1H),7.35(q,J=8.0Hz,3H), 7.29(d,J=7.7Hz,1H),7.15(td,J=7.4,1.2Hz,1H),3.29(m,J=17.8,10.8,4.6Hz,1H),3.15-3.02(m,2H),2.67(dt,J=14.5,4.7Hz,1H).13C NMR (126MHz, CDCl3) δ189.84,164.73,143.47,137.11,134.92,129.68,129.24, 129.10,128.89,127.37,125.12,120.27,69.23,34.21,25.48.HRMS(ESI)calcd forC17H15O2NCl+([M+H]+):303.0790,Found:303.0789.

[0062] Example 4

[0063] A method for preparing a monochlorinated product (2c) of a 1,3-diketone carbonyl compound is as follows:

[0064]

[0065] The method for preparing 2c is as described in Example 1, and 34 mg of 2c is obtained. The raw material is 2-methyl-1-phenyl-1,3-butanedione (1c), the reaction time is 1 hour, the yield is 81%, and the product is a colorless oily liquid. 1H NMR (500MHz, CDCl3) δ7.93-7.90 (m, 2H), 7.59-7.55 (m, 1H), 7.46-7.42 (m, 2H), 2.39 (s, 3H), 1.95 (s, 3H). 2c is a known substance, and the NMR data are consistent with those reported in the literature [Chem. Commun., 2009, 6991-6993.].

[0066] Example 5

[0067] A method for preparing a monochlorinated product (2d) of an oxidized indole carbonyl compound is as follows:

[0068]

[0069] The method for preparing 2d was the same as that described in Example 1, and 50 mg of 2d was obtained. The raw material used was 3-methyl-1-phenylindole-2-one (1d). The reaction time was 0.5 hours, the yield was 98%, and the product was a colorless oily liquid. 1H NMR(500MHz, CDCl3)δ7.50-7.39(m,3H),7.38-7.31(m,3H),7.19(td,J=7.7, 1.3Hz,1H),7.08(td,J=7.5,1.0Hz,1H),6.76(dt,J=8.0,0.8Hz,1H),1.94(s ,3H).13CNMR(126MHz,CDCl3)δ173.69,142.19,133.84,130.85,130.14,129 .76,128.46,126.45,124.19,123.92,110.06,62.09,26.22.HRMS(ESI)calcd for C15H13ONCl+([M+H]+):258.0680,Found:258.0681.

[0070] Example 6

[0071] A method for preparing a monochlorinated product (2e) of a simple ketone carbonyl compound is as follows:

[0072]

[0073] Use a pipette to transfer 2-methyl-1-indanone (1e) (41 μL, 0.3 mmol) to a dry reaction tube, and add tert-butyl methyl ether (1 mL) to dissolve it. Then weigh KOtBu (37 mg, 0.3 mmol) and add it to the above reaction tube. The reaction mixture is stirred at room temperature. Finally, use a pipette to transfer trichloroacetonitrile (30 μL, 0.3 mmol) to the reaction mixture and continue stirring at room temperature. After the reaction is complete, the reaction solution is quenched with 1M HCl (1 mL) and extracted with ethyl acetate (3×2 mL). The organic phase is washed with saturated brine (3×6 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent is removed by vacuum rotary evaporation. The crude product is purified by silica gel column chromatography, and the eluent is ethyl acetate: petroleum ether = 1:40-1:30. 2e is 39 mg, the reaction time is 1 hour, the yield is 72%, and it is a colorless oily liquid. 1H NMR (500 MHz, CDCl3) δ7.77 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.0 Hz, 2H), 3.58 (d, J = 17.8 Hz, 1H), 3.38 (d, J = 17.7 Hz, 1H), 1.73 (s, 3H). 2e is a known substance, and the NMR data are consistent with those reported in the literature [Chem. Sci., 2024, 15, 13058-13067.].

[0074] Example 7

[0075] A method for preparing a monochlorinated product (2f) of a halogen-containing heteroatom carbonyl compound is as follows:

[0076]

[0077] The method for preparing 2f was the same as that described in Example 6, and 40 mg of 2f was obtained. The raw material used was 2-fluoro-3,4-dihydronaphthalen-1(2H)-one (1f), the reaction time was 1 hour, the yield was 80%, and the product was a white solid. 1HNMR (500MHz, CDCl3) δ8.13 (d, J=7.9Hz, 1H), 7.58 (t, J=7.5Hz, 1H), 7.40 (t, J=7.6Hz, 1H), 7.30 (d, J=7.7Hz, 1H), 3.35 (m, J=16.9, 11.7, 4.9Hz, 1H), 3.11 (m, J=17.4, 5.2, 2.6Hz, 1H), 2.81 (m, J=13.9, 5.4, 2.9Hz, 1H), 2.76-2.65 (m, 1H). 2f is a known substance, and the NMR data are consistent with those reported in the literature [Angew. Chem. Int. Ed., 2022, 61, e202211199.].

[0078] Example 8

[0079] A method for preparing a dichlorinated product (2 g) of a malonic acid ester carbonyl compound is as follows:

[0080]

[0081] Use a pipette to transfer diethyl malonate (1g) (30μL, 0.2mmol) to a dry reaction tube, and add tert-butyl methyl ether (1mL) to dissolve it. Then weigh anhydrous K2CO3 (51mg, 0.4mmol) and add it to the above reaction tube, stir the reaction mixture at room temperature, and finally use a pipette to transfer trichloroacetonitrile (40μl, 0.4mmol) to the reaction mixture and continue stirring at room temperature. After the reaction is complete, the reaction solution is quenched with 1MHCl (1mL) and extracted with ethyl acetate (3×2mL). The organic phase is washed with saturated brine (3×6mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent is removed by vacuum rotary evaporation. The crude product is purified by silica gel column chromatography, and the eluent is ethyl acetate: petroleum ether = 1:40-1:30, and 2g is 35mg. The reaction time is 1.5 hours, and the yield is 76%, a colorless oily liquid. 1H NMR (500 MHz, CDCl3) δ4.23 (m, J = 14.2, 7.2 Hz, 4H), 1.33 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). 2g is a known substance, and the NMR data are consistent with those reported in the literature [Synthesis., 2022, 54 (10), 2457-2463.].

[0082] Example 9

[0083] A method for preparing a dichlorinated product (2h) of a β-ketoester carbonyl compound is as follows:

[0084]

[0085] The method for preparing 2h is as described in Example 8, and 2h is obtained in an amount of 24.5 mg. The raw material is ethyl benzoyl acetate (1h), the reaction time is 1.5 hours, the yield is 64%, and the product is a colorless oily liquid. 1HNMR (500MHz, CDCl3) δ7.74 (m, J=7.0, 1.5Hz, 2H), 7.59-7.48 (m, 3H), 4.22 (m, J=7.2, 1.4Hz, 2H), 1.10 (td, J=7.1, 1.4Hz, 3H). 2h is a known substance, and the NMR data are consistent with those reported in the literature [Synthesis., 2015, 47(06), 777-782.].

[0086] Example 10

[0087] A method for preparing a dichlorinated product (2i) of a 1,3-diketone carbonyl compound is as follows:

[0088]

[0089] The method for preparing 2i is as described in Example 8, and 44 mg of 2i is obtained. The raw material is 1-phenyl-1,3-butanedione (1i), the reaction time is 23 hours, the yield is 96%, and it is a colorless oily liquid. 1HNMR (500MHz, CDCl3) δ7.85-7.81 (m, 2H), 7.68 (m, J = 7.6, 1.3Hz, 1H), 7.54 (td, J = 7.8, 1.2Hz, 2H), 2.50 (d, J = 1.2Hz, 3H). 2i is a known substance, and the NMR data are consistent with those reported in the literature [Tetrahedron., 2021, 81, 153335.].

[0090] Embodiment 11

[0091] A method for preparing a simple ketone carbonyl compound dichlorinated product (2j), specifically as follows:

[0092]

[0093] Weigh diphenylacetone (1j) (39 mg, 0.2 mmol) and add it to a dry reaction tube, then add tert-butyl methyl ether (1 mL) to dissolve it. Then weigh KOtBu (49 mg, 0.4 mmol) and add it to the above reaction tube, stir the reaction mixture at room temperature, and finally use a pipette to transfer trichloroacetonitrile (40 μL, 0.4 mmol) to the reaction mixture and continue stirring at room temperature for 0.5 hours. The reaction solution is quenched with 1M HCl (1 mL) and extracted with ethyl acetate (3×2 mL). The organic phase is washed with saturated brine (3×6 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent is removed by vacuum rotary evaporation. The crude product is purified by silica gel column chromatography, and the eluent is ethyl acetate: petroleum ether = 1:100-1:90, and 2j is obtained as a white solid of 32 mg, with a yield of 60%. 1HNMR (500 MHz, CDCl3) δ7.79 (dd, J=8.5, 1.4 Hz, 2H), 7.70-7.61 (m, 2H), 7.49-7.39 (m, 4H), 7.34-7.28 (m, 2H). 2j is a known substance, and the NMR data are consistent with those reported in the literature [Org. Biomol. Chem., 2024, 22, 3080-3085.].

[0094] Example 12

[0095] A method for preparing a dichlorinated product (2k) of a β-ketoamide carbonyl compound is as follows:

[0096]

[0097] The method for preparing 2k was the same as that described in Example 11, and 51 mg of 2k was obtained. The raw material used was 1-morpholine-3-phenylpropane-1,3-dione (1k). The reaction time was 7 hours, the yield was 85%, and the product was a white solid. 1H NMR (500MHz, CDCl3) δ8.05-8.00(m,2H),7.66-7.60(m,1H),7.48(t,J=7.9Hz,2H),3.64(dd,J=16.1,5.2Hz,4H),3.45(s,4H).13C NMR(126MHz, CDCl3)δ184.26,162.00,134.46,131.20,130.43,128.75,85.17,66.46,65.70,47.50,44.43.HRMS(ESI)calcd for C13H14 O3NCl2+([M+H]+):302.0345,Found:302.0346.

[0098] Embodiment 13

[0099] A method for preparing a dichlorinated product of an oxidized indole carbonyl compound (2l) and an anticancer drug molecule 3 is as follows:

[0100]

[0101] Step 1: Weigh 5-chloro-2-indolone (1l) (1.006g, 6mmol) and add it to a dry reaction tube, add N,N-dimethylformamide (15mL) to dissolve it, then pipette DBU (826μL, 6mmol) and add it to the dissolved 1l, and stir the reaction mixture at room temperature. Finally, use a pipette to pipette trichloroacetonitrile (1203μL, 2mmol) and add it to the reaction mixture and continue stirring at room temperature. After the reaction is complete, the reaction solution is quenched with distilled water (15mL) and extracted with DCM (3×30mL). The organic phase is washed with distilled water (3×90mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent is removed by vacuum rotary evaporation. The crude product is purified by silica gel column chromatography, and the eluent is ethyl acetate: petroleum ether = 1:15-1:12. 2l is 0.752mg, the reaction time is 5 minutes, the yield is 53%, and it is a white solid. 1H NMR (500 MHz, CDCl3) δ9.29 (s, 1H), 7.61 (d, J = 2.1 Hz, 1H), 7.35 (dd, J = 8.4, 2.1 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H). 2l is a known substance, and the NMR data are consistent with those reported in the literature [J.Org.Chem., 2023, 88, 7, 4839-4847].

[0102] Step 2: Weigh compound 21 (67 mg, 0.28 mmol) and add it to a dry reaction tube, add 2.6 mL of tetrahydrofuran to dissolve it, cool it to 0 ° C, then slowly add NaH (12 mg, 0.308 mmol), stir the reaction mixture for 0.5 hours, and then drop benzyl bromoacetate (49 μL, 0.308 mmol). Finally, stir the reaction at room temperature and monitor the reaction by TLC until the reaction is complete. The reaction solution is quenched with 2.6 mL of distilled water and extracted with ethyl acetate (3×5 mL). The organic phase is washed with deionized water (15 mL), then with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent is removed by vacuum rotary evaporation. The crude product is purified by silica gel column chromatography, and the eluent is ethyl acetate: petroleum ether = 1:30-1:25. The anticancer drug molecule 3 is 89 mg, the reaction time is 0.5 hours, the yield is 82% (total yield: 68%), and the white solid is obtained. 1HNMR (500MHz,CDCl3)δ7.64(d,J=2.2Hz,1H),7.37-7.27(m,6H),6.63(d,J=8.5Hz,1H),5.19(s,2H),4.51(s,2H). Anticancer drug molecule 3 is a known substance, and the NMR data are consistent with those reported in the literature [Org.Biomol.Chem.,2023,21,179-186.].

[0103] Embodiment 14

[0104] A method for preparing an antidiabetic drug molecule 5 is as follows:

[0105]

[0106] 5-Chloro-2-indolone (4) (40 mg, 0.1 mmol) was weighed and added to a dry reaction tube, N,N-dimethylformamide (1 mL) was added to dissolve it, and then DBU (28 μL, 0.2 mmol) was pipetted and added to the dissolved 4, and the reaction mixture was stirred at room temperature. Finally, trichloroacetonitrile (20 μL, 0.2 mmol) was pipetted and added to the reaction mixture and continued to stir at room temperature. After the reaction was complete, the reaction solution was quenched with distilled water (1 mL) and extracted with DCM (3×2 mL). The organic phase was washed with distilled water (3×6 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by vacuum rotary evaporation. The crude product was purified by silica gel column chromatography, and the eluent was dichloromethane:methanol = 1:100-1:90. The antidiabetic drug molecule 5 was obtained in an amount of 35 mg, the reaction time was 10 minutes, and the yield was 74%, and the product was a white solid. 1H NMR (500 MHz, DMSO) δ 11.90 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 8.3, 1.9 Hz, 1H), 7.81-7.76 (m, 2H), 7.22 (d, J = 8.3 Hz, 1H), 6.99-6.92 (m, 2H), 3.47-3.43 (m, 4H), 3.05 (t, J = 5.0 Hz, 4H), 2.44 (s, 3H). The antidiabetic drug molecule 5 is a known substance, and the NMR data are consistent with those reported in the literature [J. Med. Chem., 2012, 55 (17), 7546-7559.].

Claims

1. An electrophilic chlorination method using trichloroacetonitrile as a chlorine source, characterized in that: Using trichloroacetonitrile as an electrophilic chlorination reagent and a carbonyl compound as a starting material, the monochlorination or dichlorination of the carbonyl compound is achieved.

2. The method according to claim 1, characterized in that: The monochlorination reaction formula using trichloroacetonitrile as the electrophilic chlorination reagent and carbonyl compounds as the starting materials is: Wherein, R1 and R2 are one or more functional groups selected from alkyl, alkoxy, aryl, substituted aryl, alkylamino and aliphatic substituents with functional groups; R3 is one or more functional groups selected from the group consisting of alkyl, alkoxy, aryl, substituted aryl, alkylamino, halogen, and functional aliphatic substituents; The alkyl group is methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl or tert-butyl; The aryl group is phenyl, naphthyl, anthracenyl, pyridyl, furanyl or thienyl; The substituent on the substituted aryl group is halogen, alkyl, fluoroalkyl, alkoxy, nitro or cyano; The aliphatic substituent with a functional group is a carbon chain with a double bond, a triple bond, an ester group, an amide group, a carbonyl group, a thiol group, an amine group, a cyano group, an ether bond or a halogen atom.

3. The method according to claim 2, characterized in that: The specific steps include: S1. Add the carbonyl compound, base, trichloroacetonitrile and organic solvent in a molar ratio of 1:0.2:1:5 to 1:3:5:20 into a reaction kettle and stir at -20 to 80°C for 0.1 to 24h; S2. After the reaction is completed, water and an extractant equal in volume to the organic solvent are added respectively for extraction, the organic phase is washed with dilute hydrochloric acid solution and saturated brine, and then dried over anhydrous sodium sulfate, filtered, the filtrate is collected, and the solvent is evaporated to remove, and the crude product is purified by column chromatography using a washing solution of ethyl acetate and petroleum ether in a volume ratio of 1:1 to 200 to obtain a monochlorinated product of the carbonyl compound.

4. The method according to claim 3, characterized in that: In S1, the carbonyl compound includes malonate, β-ketoamide, 1,3-diketone, oxidized indole, simple ketone compound and carbonyl compound containing heterohalogen atom.

5. The method according to claim 3 or 4, characterized in that: In S1, the base includes any one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (TEDA), tetramethylguanidine (TMG), triethylamine, 4-dimethylaminopyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and potassium tert-butoxide.

6. The method according to claim 1, characterized in that: The double chlorination reaction formula with trichloroacetonitrile as the electrophilic chlorination reagent and carbonyl compounds as the starting materials is: R1 and R2 are one or more functional groups selected from the group consisting of alkyl, alkoxy, aryl, substituted aryl, alkylamino, and aliphatic substituents with functional groups; The alkyl group is methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl or tert-butyl; The aryl group is phenyl, naphthyl, anthracenyl, pyridyl, furanyl or thienyl; The substituent on the substituted aryl group is halogen, alkyl, fluoroalkyl, alkoxy, nitro or cyano; The aliphatic substituent with a functional group is a carbon chain with a double bond, a triple bond, an ester group, an amide group, a carbonyl group, a thiol group, an amine group, a cyano group, an ether bond or a halogen atom.

7. The method according to claim 6, characterized in that: The specific steps include: S1. Add the carbonyl compound, base, trichloroacetonitrile and organic solvent into the reaction kettle in a molar ratio of 1:1:2:5 to 1:3:5:20, and stir at -20 to 80°C for 0.1 to 24h; S2. After the reaction is completed, water and an extractant having an equal volume to the organic solvent are added respectively for extraction, the organic phase is washed with a dilute hydrochloric acid solution and a saturated saline solution, and then dried over anhydrous sodium sulfate, filtered, the filtrate is collected, and the solvent is evaporated to remove the solvent. The crude product is purified by column chromatography using a washing liquid having a volume ratio of ethyl acetate to petroleum ether of 1:1 to 200, or by column chromatography using a washing liquid having a volume ratio of methanol to dichloromethane of 1:90 to 200, to obtain a dichlorinated product of the carbonyl compound.

8. The method according to claim 6, characterized in that: In S1, the carbonyl compound includes malonate, β-ketoester, β-ketoamide, 1,3-diketone, oxidized indole, and simple ketone compounds; the base includes any one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (TEDA), tetramethylguanidine (TMG), triethylamine, 4-dimethylaminopyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and potassium tert-butoxide.

9. The method according to claim 7 or 8, characterized in that: In S1 and S2, the organic solvent includes any one of toluene (Tol), N,N-dimethylformamide (DMF), ethyl acetate (EA), dichloromethane (DCM), tetrahydrofuran (THF), tert-butyl methyl ether (MTBE), and diethyl ether.

10. Use of the method according to claim 1, 3 or 7 in preparing anticancer drug molecules and antidiabetic drug molecules.

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