CN114573438A - Mono-fluorine chlorine/bromoacetone compound and preparation method thereof - Google Patents
Mono-fluorine chlorine/bromoacetone compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a monofluoro-chlorine/bromoacetone compound and a preparation method thereof, wherein the compound has a structural formula shown as a formula 1-a or a formula 1-b:
in the formula, X is Cl or Br, and R is one of alkyl, phenyl, substituted phenyl, condensed ring aryl or heterocyclic substituent; and m is 0-2. The preparation method comprises the following steps:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a monofluoro-chlorine/bromoacetone compound and a preparation method thereof.
Background
The selective incorporation of fluorine-containing or fluorine-containing groups into organic molecules has become a popular and effective strategy for drug design and screening, and fluorine-containing compounds can often significantly improve the metabolic stability, lipophilicity and bioavailability of their parent molecules. Among all fluoroalkylated groups, a monofluoromethyl group (CH)2F) And their functionalized derivatives are widely present in many biologically active molecules, and exchange of hydrogen for fluorine prevents metabolic oxidation due to the electron withdrawing effect of fluorine and the strength of the C-F bond. Monofluoro compounds have found wide application in medicine and agrochemicals, and thus the addition of monofluoroalkyl groups to organic molecules is an active area of research in organic synthesis. The research on monofluoroalkylation reaction is relatively small compared to perfluoroalkylation and difluoroalkylation reactions, so that a simple and efficient monofluoroalkylation reagent needs to be developed. Only a few monofluorinating reagents are currently available, such as ClCFHCOOEt, (EtO)2P(O)CFHBr、C3H4ClFO、C2H4ClF、CH2FBr and C9H8BrFO2Etc. they canIntroduced into the molecule as monofluoroalkylated groups.
Disclosure of Invention
The invention aims to provide a monoflurochlorine/bromoacetone compound and a preparation method and application thereof.
The purpose of the invention can be realized by the following technical scheme:
a monofluoro-chloro/bromoacetone compound has a structural formula shown as formula 1-a or formula 1-b:
in the formula, X is Cl or Br, and R is one of alkyl, phenyl, substituted phenyl, condensed ring aryl or heterocyclic substituent; and m is 0-2.
The preparation method of the monofluoro-chloro/bromoacetone compound comprises the following steps:
mixing the compound shown in the formula 2-a, a halogen source and a halogenating agent in a solution, stirring for reaction, adding triethylamine for secondary reaction, and separating and purifying to obtain the monofluorochloro/bromoacetone compound shown in the formula 1-a;
mixing the compound shown in the formula 2-b, a halogen source and a halogenating reagent in a solution, stirring for reaction, adding triethylamine for secondary reaction, and separating and purifying to obtain the monofluorochloro/bromoacetone compound shown in the formula 1-b;
when X is Cl, the halogen source is a chloride salt; when X is Br, the halogen source is a bromide salt.
Preferably, the chloride salt is lithium chloride, and the bromide salt is lithium bromide.
Further, the halogenating agent comprises at least one of Selectfluor, N-bromosuccinimide (NBS), NIS, or N-chlorosuccinimide (NCS).
Furthermore, the molar ratio of the compound shown in the formula 2-a or the formula 2-b, the halogen source, the halogenating reagent and the triethylamine is 1 (2-8) to (2-10).
Further, the stirring reaction is carried out in an ice bath, and the stirring time is 10-40 min.
Furthermore, in the secondary reaction, the reaction temperature is-20 ℃ to 40 ℃, and the reaction time is 0.5-3.0 h.
Further, the reaction solvent comprises one of tetrahydrofuran, 1, 4-dioxane, diethyl ether, methyl tetrahydrofuran, cyclopentyl methyl ether or acetonitrile.
The application of the monofluro-chloro/bromoacetone compound comprises the application of the monofluro-chloro/bromoacetone compound monofluroination alkylation reagent in monofluroination reaction.
In the present invention, lithium chloride/lithium bromide is used as halogenating agent to remove trifluoroacetate, and chlorine/bromine negative ions in lithium chloride/lithium bromide and F in NCS, NBS or NIS+、I+、Br+The exchange is carried out to form halogen positive ions which are attacked by enol negative ions to finally obtain a final product, and because chlorine/bromine simple substances are generated in the reaction process, the triethylamine plays a role in polarizing the chlorine/bromine simple substances, so that one part of Cl-Cl/Br-Br bonds in the chlorine/bromine simple substances is provided with positive charges, and the other part of Cl-Cl/Br-Br bonds in the chlorine/bromine simple substances are provided with negative charges, and the reaction is accelerated.
In the invention, if the addition amount of the reactants is reduced, the raw materials are not reacted completely, and if the reaction time is prolonged, the yield of the monofluoro chloro/bromoacetone compound is reduced, and more byproducts of the monofluoro halogen acetone compound are generated.
Compared with the prior art, the method has the advantages of high reaction efficiency, short reaction time, high yield, mild reaction conditions and the like, can be used as a monofluoroalkyl reagent, and can also be used as a universal building block for various organic synthesis reactions, thereby having good application prospect in the field of organic synthesis.
Detailed Description
The present invention will be described in detail with reference to specific examples.
A monofluoro-chloro/bromoacetone compound has a structural formula shown as formula 1-a or formula 1-b:
in the formula, X is Cl or Br, and R is one of alkyl, phenyl, substituted phenyl, condensed ring aryl or heterocyclic substituent; and m is 0-2.
A preparation method of monofluoro-chloro/bromoacetone compounds comprises the following steps:
mixing the compound shown in the formula 2-a, a halogen source and a halogenating agent in a solution, stirring for reaction, adding triethylamine for secondary reaction, and separating and purifying the obtained product to obtain the monoflurochloro/bromoacetone compound shown in the formula 1-a; wherein, the raw material 2-a in the formula is prepared by taking ketone as a raw material and utilizing a strategy of removing trifluoroacetic acid, and the specific preparation process is shown in the literature: liang, J.Han, J.Wu, P.Wu, J.Hu, F.Hu and F.Wu, Nickel-catalyzed coupling interaction of α -Bromo- α -fluoroketones with arylboronic acids facing the synthesis of α -fluoroketones, org.Lett.,2019,21, 6844-.
Mixing the compound shown in the formula 2-b, a halogen source and a halogenating reagent in a solution, stirring for reaction, adding triethylamine for secondary reaction, and separating and purifying to obtain the monofluorochloro/bromoacetone compound shown in the formula 1-b; wherein, the raw material 2-b in the formula is prepared by taking ketone as a raw material and utilizing a strategy of removing trifluoroacetic acid, and the specific preparation process is shown in the literature: liang, J.Han, J.Wu, P.Wu, J.Hu, F.Hu and F.Wu, Nickel-catalyzed coupling interaction of α -Bromo- α -fluoroketones with arylboronic acids facing the synthesis of α -fluoroketones, org.Lett.,2019,21, 6844-.
Wherein, when X is Cl, the halogen source is a chloride salt; when X is Br, the halogen source is a bromide salt. And preferably, the chloride salt is lithium chloride and the bromide salt is lithium bromide. The halogenating agent comprises at least one of Selectfluor, NBS, NIS or NCS.
The molar ratio of the compound shown in the formula 2-a or the formula 2-b, the halogen source, the halogenating reagent and the triethylamine is 1 (2-8) to (2-10).
The reaction solvent comprises one of tetrahydrofuran, 1, 4-dioxane, diethyl ether, methyl tetrahydrofuran, cyclopentyl methyl ether or acetonitrile.
The application of monofluro-chloro/bromoacetone compound includes monofluro-chloro/bromoacetone compound monofluroination reagent for monofluroination reaction.
The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
Example 1:
this example was used to synthesize 2-fluoro-2-chloro-1-acetophenone, which has the following structural formula:
the preparation method comprises the following steps:
s1: adding 2,4,4, 4-tetrafluoro-3, 3-dihydroxy-1-phenylbutan-1-one (0.6304g, 2.5mmol) into a 250mL brown reaction bottle, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: respectively weighing lithium chloride (0.636g, 15mmol) and NCS (0.668g, 5mmol) in reaction bottles; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath was removed and stirred at 25 ℃ for 0.5 hour, and the reaction was monitored by TLC to be complete;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (about 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was separated by column chromatography to give 0.315g of a white bulk solid with 73% yield.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(400MHz,CDCl3):δ8.07(d,J＝8.0Hz,2H),7.65(tt,J＝10.0,2.0Hz, 1H),7.51(t,J＝8.0Hz,2H),6.92(d,J＝52.0Hz,1H).
13C NMR(100MHz,CDCl3):δ187.51(d,2JC-F＝22.0Hz),134.84,131.23,129.69 (d,3JC-F＝2.0Hz),129.00,96.37(d,1JC-F＝256.0Hz).
19F NMR(376MHz,CDCl3):δ-146.63(d,J＝48.9Hz).
example 2:
this example was used to synthesize 2-fluoro-2-chloro-3, 4-dihydronaphthalenone, which has the following structural formula:
the preparation method comprises the following steps:
s1: adding 2-fluoro-2- (2,2, 2-trifluoro-1, 1-dihydroxyethyl) -3, 4-dihydrodecalin-1 (2H) -ketone (0.7655g, 2.5mmol) into a 250mL brown reaction bottle, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: weighing lithium chloride (0.636g, 15mmol) and NCS (0.668g, 5mmol) in reaction bottles respectively; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath is removed, the mixture is stirred for 0.5 hour at 25 ℃, and the TLC monitors the complete reaction;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (about 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was isolated by column chromatography to give 0.3079g of a pale yellow solid in 62% yield.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(400MHz,CDCl3):δ8.17(d,J＝8.0Hz,1H),7.61(t,J＝6.0Hz,1H), 7.45(t,J＝8.0Hz 1H),7.34(d,J＝8.0Hz 1H),3.30-3.39(m,1H),3.10-3.17(m,1H), 2.85-2.91(m,1H),2.62-2.70(m,1H).
13C NMR(100MHz,CDCl3):δ185.82(d,2JC-F＝19.0Hz),141.90,135.03,129.39, 129.11,128.74,127.80,103.02,38.81(d,2’JC-F＝19.0Hz),28.22(d,3’JC-F＝8.0Hz).
19F NMR(376MHz,CDCl3):δ-114.32(s,1F).
example 3:
this example was used to synthesize 2-chloro-2-fluoro-2, 3-indanone, which has the following structural formula:
s1: adding 2-fluoro-2-2, 2, 2-trifluoro-1, 1-dihydroxyethyl-2, 3-dihydro-1H-indanone (0.6601g, 2.5mmol) into a 250mL brown reaction bottle, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: weighing lithium chloride (0.636g, 15mmol) and NCS (0.668g, 5mmol) in reaction bottles respectively; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath was removed and stirred at 25 ℃ for 0.5 hour, and the reaction was monitored by TLC to be complete;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (about 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was separated by column chromatography to give 0.337g of white bulk solid in 73% yield.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(400MHz,CDCl3):δ8.02(d,J＝8.0Hz,1H),7.49(t,J＝6.0Hz,1H), 7.43(t,J＝8.0Hz 1H),7.29(d,J＝8.0Hz 1H),3.39-3.42(m,1H),3.26-3.29(m,1H).
13C NMR(100MHz,CDCl3):δ186.92(d,2JC-F＝20.0Hz),145.62,134.03,130.25, 128.76,127.94,126.80,107.02,39.28(d,2’JC-F＝22.0Hz).
19F NMR(376MHz,CDCl3):δ-118.56(s,1F).
example 4:
this example was used to synthesize 2-fluoro-2-chloro-1- (1, 3-dioxole-5-phenyl) ethanone, which has the following structural formula:
the preparation method comprises the following steps:
s1: adding 1- (1, 3-dioxole-5-phenyl) -2,4,4, 4-tetrafluoro-3, 3-dihydroxybutane-1-one (0.7405 g, 2.5mmol) into a 250mL brown reaction flask, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: weighing lithium chloride (0.636g, 15mmol) and NCS (0.668g, 5mmol) in reaction bottles respectively; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath was removed and stirred at 25 ℃ for 0.5 hour, and the reaction was monitored by TLC to be complete;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (ca. 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was isolated by column chromatography to give 0.5514g of a pale yellow liquid with a yield of 75%.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(400MHz,CDCl3):δ7.68(d,J＝8.0Hz,1H),7.05-7.43(m,2H),5.38(d, J＝48.0Hz,1H),5.07(s,2H).
13C NMR(100MHz,CDCl3):δ193.58(d,2JC-F＝15.0Hz),134.23,133.75,129.01, 127.93,127.90,84.51(d,1JC-F＝19.0Hz),77.11(d,5JC-F＝32.0Hz),53.52.
19F NMR(376MHz,CDCl3):δ-24.66(t,J＝47.0Hz,1F).
HRMS(ESI)calculated[M+Na]+for C9H6FClO3:238.9887,found:238.9869.
example 5:
this example was used to synthesize 2-fluoro-2-chloro (2-naphthyl) ethanone, which has the following structural formula:
the preparation method comprises the following steps:
s1: adding 2,4,4, 4-tetrafluoro-3, 3-dihydroxy-1- (naphthyl) butanone (0.8417g, 2.5mmol) into a 250mL brown reaction bottle, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: respectively weighing lithium chloride (0.636g, 15mmol) and NCS (0.668g, 5mmol) in reaction bottles; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath was removed and stirred at 25 ℃ for 0.5 hour, and the reaction was monitored by TLC to be complete;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (about 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was isolated by column chromatography to give 0.3785g of a white block solid with a yield of 68%.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(400MHz,CDCl3):δ8.65(s,1H),8.10(d,J＝8.0Hz,1H),δ8.02(d,J＝8.0Hz,1H),7.90-7.96(m,2H),7.60-7.71(m,2H),7.08(d,J＝52.0Hz,1H).
13C NMR(100MHz,CDCl3):δ187.50(d,2JC-F＝88.0Hz),136.25,132.29,132.22 (d,3JC-F＝3.0Hz),130.03,129.65,128.98,128.49,127.94,127.32,124.34(d,4JC-F＝2.0Hz), 96.61(d,1JC-F＝255.0Hz).
19F NMR(376MHz,CDCl3):δ-145.82(d,J＝52.64Hz,1F).
HRMS(ESI)calculated[M+Na]+for C12H8FClO:246.0145,found:246.0145.
example 6:
this example was used to synthesize 2-fluoro-2-bromo-1-acetophenone, which has the following structural formula:
the preparation method comprises the following steps:
s1: adding 2,4,4, 4-tetrafluoro-3, 3-dihydroxy-1-phenylbutan-1-one (0.6304g, 2.5mmol) into a 250mL brown reaction bottle, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: weighing lithium bromide (1.303g, 15mmol) and NBS (0.890g, 5mmol) in reaction bottles respectively; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath was removed and stirred at 25 ℃ for 0.5 hour, and the reaction was monitored by TLC to be complete;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (ca. 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was isolated by column chromatography to yield 0.4612g of a white block solid with a yield of 85%.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(500MHz,CDCl3):δ8.08(d,J＝7.9Hz,2H),7.68(t,J＝7.5Hz,1H), 7.54(t,J＝7.8Hz,2H),7.24(d,J＝51.0Hz,1H).
13C NMR(125MHz,CDCl3):δ187.6(d,2JC-F＝20.0Hz),134.7,131.1,129.5(d, 3JC-F＝2.5Hz),128.9,85.9(d,1JC-F＝266.03Hz).
19F NMR(376MHz,CDCl3):δ-152.3(d,J＝52.6Hz,1F).
HRMS(EI-TOF)calculated[M]+for C8H6BrFO:215.9586,found:215.9583.
example 7:
this example was used to synthesize 2-fluoro-2-bromo-1-acetophenone, which has the following structural formula:
the preparation method comprises the following steps:
s1: adding 2-fluoro-2- (2,2, 2-trifluoro-1, 1-dihydroxyethyl) -3, 4-dihydrodecalin-1 (2H) -ketone (0.7655g, 2.5mmol) into a 250mL brown reaction bottle, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: weighing lithium bromide (1.303g, 15mmol) and NBS (0.890g, 5mmol) in reaction bottles respectively; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath was removed and stirred at 25 ℃ for 0.5 hour, and the reaction was monitored by TLC to be complete;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (about 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was isolated by column chromatography to give 0.4861g of a pale yellow solid with 80% yield.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(500MHz,CDCl3):δ8.12(d,J＝7.8Hz,1H),7.56(t,J＝7.4Hz,1H), 7.39(t,J＝7.5Hz,1H),7.29(d,J＝7.7Hz,1H),3.36-3.24(m,1H),3.09(d,J＝13.84 Hz,1H),2.84(d,J＝14.0Hz,1H),2.61(ddd,J＝19.1,12.1,6.7Hz,1H).
13C NMR(125MHz,CDCl3):δ185.5(d,2JC-F＝18.8Hz),141.7,134.8,129.2(d, 3JC-F＝1.3Hz),128.9,128.5,127.6,101.5(d,1JC-F＝265.0Hz),38.5(d,2’JC-F＝18.8 Hz),28.0(d,3’JC-F＝7.5Hz).
19F NMR(376MHz,CDCl3):δ-114.4(s,1F).
HRMS(EI-TOF)calculated[M]+for C10H8BrFO:241.9743,found:241.9742.
example 8:
this example is used to synthesize 2-bromo-2-fluoro-2, 3-dihydro-1H-inden-1-one, which has the following formula:
the preparation method comprises the following steps:
s1: adding 2-fluoro-2- (2,2, 2-trifluoro-1, 1-dihydroxyethyl) -2, 3-dihydro-1H-indene-1-one (0.6605g, 2.5mmol) into a 250mL brown reaction bottle, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: weighing lithium bromide (1.303g, 15mmol) and NBS (0.890g, 5mmol) in reaction bottles respectively; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath was removed and stirred at 25 ℃ for 0.5 hour, and the reaction was monitored by TLC to be complete;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (about 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was isolated by column chromatography to give 0.4639g of a pale yellow solid with a yield of 81%.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(500MHz,CDCl3):δ7.90(d,J＝7.7Hz,1H),7.74(t,J＝7.4Hz,1H), 7.50(t,J＝7.5Hz,1H),7.44(d,J＝7.7Hz,1H),4.01(dd,J＝17.9,4.0Hz,1H),3.88(t, J＝17.7Hz,1H).
13C NMR(125MHz,CDCl3):δ191.9(d,2JC-F＝20.0Hz),146.1(d,3JC-F＝6.3Hz), 137.1,130.4(d,4JC-F＝2.5Hz),129.1,126.5(d,5JC-F＝1.3Hz),126.3,99.9(d,1JC-F＝ 273.8Hz),45.1(d,2’JC-F＝22.5Hz).
19F NMR(376MHz,CDCl3):δ-112.1(d,J＝22.5Hz,1F).
HRMS(ESI-FT)calculated[M+Na]+for C9H6BrFO:250.9478,found:250.9477.
example 9:
this example was used to synthesize 3-bromo-3-fluoro-6- (trifluoromethyl) indol-2-one, which has the following structural formula:
the preparation method comprises the following steps:
s1: adding 3-fluoro-3- (2,2, 2-trifluoro-1, 1-dihydroxyethyl) -6- (trifluoromethyl) indol-2-one (0.8329g, 2.5mmol) into a 250mL brown reaction bottle, adding 60mL tetrahydrofuran, and stirring to dissolve completely; then placing the reaction bottle in an ice-water bath;
s2: weighing lithium bromide (1.303g, 15mmol) and NBS (0.890g, 5mmol) in reaction bottles respectively; after the feeding is finished, stirring and reacting for 10 minutes in an ice-water bath;
s3: the mixed solution of triethylamine (1.518g, 15mmol) and tetrahydrofuran (20mL) is slowly dripped into the brown reaction bottle; after the dropwise addition, the ice water bath was removed and stirred at 25 ℃ for 0.5 hour, and the reaction was monitored by TLC to be complete;
s4: after the reaction, water (150mL) and ethyl acetate (60mL) were added to the reaction system to conduct extraction; after extraction, the aqueous layer was extracted twice with ethyl acetate (60 mL); the aqueous layer was discarded, the organic layers were combined, and dried by adding anhydrous sodium sulfate (40g) (about 0.5 h); after drying, filtering, and removing the organic solvent in the filtrate by a rotary evaporator; the remaining product was isolated by column chromatography to give 0.5961g of a brown solid with 80% yield.
Wherein the stationary phase of the column chromatography is 200-300 mesh silica gel, and the mobile phase is petroleum ether.
The product characterization results are as follows:
1H NMR(500MHz,DMSO):δ11.55(s,1H),7.90(d,J＝7.8Hz,1H),7.51(d,J＝ 7.8Hz,1H),7.18(s,1H).
13C NMR(125MHz,DMSO):δ168.4(d,2JC-F＝23.8Hz),141.2(d,3’JC-F＝5.0 Hz),133.4(q,2”JC-F＝32.5Hz),129.5(d,2’JC-F＝17.5Hz),126.7,123.3(q,1JC-F＝271.3Hz),120.8(d,3’JC-F＝2.5Hz),108.5(dd,3”JC-F＝7.6,3.7Hz),91.7(d,1JC-F＝ 266.3Hz).
19F NMR(376MHz,DMSO):δ-57.1(s,3F),-120.5(s,1F).
HRMS(ESI-FT)calculated[M+Na]+for C9H4BrF4O:319.9305,found:319.9310.
the application example is as follows:
allyl fluoride is widely present in natural products and medicinal compounds, and allyl with diverse reactivity provides an effective means for obtaining various functional groups. Studies of mono-fluorination of alkynes are reported in very little literature compared to the rapidly evolving methods of trifluoromethylation and difluoroalkylation of alkynes, and thus the development of a straightforward method for allylic fluorides remains a challenging task. Heretofore, anycleaner et al reported the free radical addition of α -bromo- α -fluoroketone and alkyne catalyzed by bis (triphenylphosphine) cobalt chloride, building a chain-like structure of monofluorinated alkenes as follows:
in this embodiment, a cheaper cobalt bromide catalyst is used to complete the free radical addition of cyclic α -bromo- α -fluoroketone and alkyne, and a new method is provided for the synthesis of cyclic allyl fluoride, which specifically comprises:
the monofluoro bromoacetone compound prepared in example 7 is used as monofluoro alkylation reagent, phenylacetylene is used as reaction raw material, and the Ligand 1, 2-bis (diphenylphosphinyl) benzene (Ligand) and cobalt-based catalyst (CoBr) are added2) Under the action of the catalyst, a monofluoroalkylation reaction of a multi-component free radical series process is realized to prepare 2-bromo-2-phenyl vinyl-2-fluoro-3, 4-dihydronaphthalene-1-one:
firstly, taking a dried reaction tube, and adding CoBr2(PPh3)2(0.05mmol,5 mol%), 1, 2-bis (diphenylphosphinyl) benzene (Ligand) (0.05mmol,5 mol%), Zn (1mmol,1.0 equiv). The vessel was then evacuated and charged with N2Backfill (repeat 3 times). Dissolving in acetone: h2Phenylacetylene (1.2mmol, 1.2equiv) and 2-bromo-2-fluoro-3, 4-dihydronaphthalen-1-one (1mmol,1.0equiv) in O (total 3mL, 30:1 by volume) were injected into the tube. The reaction mixture was stirred at room temperature for 1 h. Then filtered through a plug of silica gel and washed with EtOAc (3X 10 mL). The filtrate was concentrated in vacuo and purified by flash column chromatography on silica gel to give the lightYellow oil, yield 81%.
Wherein the column chromatography stationary phase is 200-300 mesh silica gel, and the mobile phase is petroleum ether: ethyl acetate 200: 1
The product characterization results are as follows:
1H NMR(500MHz,CDCl3,ppm):δ7.83(d,J＝6Hz,2H),7.45-7.61(m,1H), 7.49-7.54(m,2H),7.25-7.47(m,3H),7.31-7.35(m,2H),6.48-6.52(m,1H),5.78(dd,J ＝12,45Hz,1H)；5.53-5.68(m,2H).
13C NMR(125MHz,CDCl3,ppm):δ190.31(d,J＝20Hz),143.94(d,J＝5Hz), 137.37(d,J＝10Hz),136.24,135.57(d,J＝15Hz),133.61,130.52(d,J＝3Hz), 129.65(d,J＝6Hz),129.46,128.92,128.72(d,J＝4Hz),128.61(d,J＝5Hz),127.85(d, J＝3Hz),127.56(d,J＝3Hz),126.83(d,J＝22Hz),90.38(d,J＝180Hz),32.39(d,J＝ 15Hz),25.73(d,J＝12Hz).
19F NMR(376MHz,CDCl3,ppm):δ-173.46(dd,J＝48.1,6.1Hz).
HRMS(ESI-FT)calculated[M+Na]+for C18H14BrFO:368.2024,found:368.2018.
the embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A monofluoro-chloro/bromoacetone compound is characterized in that the compound has a structural formula shown as a formula 1-a or a formula 1-b:
in the formula, X is Cl or Br, and R is one of alkyl, phenyl, substituted phenyl, condensed ring aryl or heterocyclic substituent; and m is 0-2.
2. The monofluro/bromoacetone compound of claim 1, wherein R is one of phenyl, substituted phenyl or naphthalene ring, wherein the substituent of the substituted phenyl comprises trifluoromethyl.
3. A process for the preparation of a monofluoro chloro/bromoacetone based compound as claimed in claim 1 or 2, comprising:
mixing the compound shown in the formula 2-a, a halogen source and a halogenating agent in a solution, stirring for reaction, adding triethylamine for secondary reaction, and separating and purifying to obtain the monofluorochloro/bromoacetone compound shown in the formula 1-a;
mixing the compound shown in the formula 2-b, a halogen source and a halogenating reagent in a solution, stirring for reaction, adding triethylamine for secondary reaction, and separating and purifying to obtain the monofluorochloro/bromoacetone compound shown in the formula 1-b;
when X is Cl, the halogen source is a chloride salt; when X is Br, the halogen source is a bromide salt.
4. The method according to claim 3, wherein the chloride salt is lithium chloride and the bromide salt is lithium bromide.
5. The method according to claim 3, wherein the halogenating agent comprises at least one of Selectfluor, N-bromosuccinimide, NIS or N-chlorosuccinimide.
6. The method for preparing monofluoro-chloro/bromoacetone compounds as claimed in claim 3, wherein the molar ratio of the compound represented by formula 2-a or formula 2-b, halogen source, halogenating agent and triethylamine is 1 (2-8) to (2-10).
7. The method for preparing the monofluoro-chloro/bromoacetone compound according to claim 3, wherein the stirring reaction is carried out in an ice bath for 10-40 min.
8. The method for preparing monofluoro-chloro/bromoacetone compounds according to claim 3, wherein the reaction temperature in the second reaction is-20 ℃ to 40 ℃ and the reaction time is 0.5 to 3.0 h.
9. The method according to claim 3, wherein the reaction solvent comprises one of tetrahydrofuran, 1, 4-dioxane, diethyl ether, methyl tetrahydrofuran, cyclopentyl methyl ether or acetonitrile.
10. The use of a monofluorochloro/bromoacetone-based compound according to claim 1 or 2, wherein the monofluorochloro/bromoacetone-based compound monofluoroalkylation reagent is used in a monofluoroalkylation reaction.
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