CN111575731A - Method for electrochemically synthesizing C5 and C7 dihalogenated quinoline amide derivatives - Google Patents
Method for electrochemically synthesizing C5 and C7 dihalogenated quinoline amide derivatives Download PDFInfo
- Publication number
- CN111575731A CN111575731A CN202010553275.3A CN202010553275A CN111575731A CN 111575731 A CN111575731 A CN 111575731A CN 202010553275 A CN202010553275 A CN 202010553275A CN 111575731 A CN111575731 A CN 111575731A
- Authority
- CN
- China
- Prior art keywords
- formula
- quinoline amide
- quinoline
- reaction
- amide derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
A method for electrochemically synthesizing a C5, C7 dihalogenated quinoline amide derivative shown as a formula (I) comprises the following steps: dissolving quinoline amide shown in a formula (II), a halogenating reagent and electrolyte in a solvent, inserting an electrode, stirring and reacting at a constant current of 5-15mA for 5-60min at 25-80 ℃, and then carrying out post-treatment on reaction liquid to obtain a product shown in a formula (I); the method adopts an electrochemical method to synthesize the C5 and C7 dihalogenated quinoline amide compound, does not use a large amount of oxidant and metal catalyst, has high product yield, milder reaction conditions and wide substrate applicability, and meets the requirement of green chemistry;
Description
Technical Field
The invention relates to a novel method for electrochemically synthesizing C5 and C7 halogenated quinoline amide, belonging to the field of organic synthesis.
Background
The halogenated quinoline compound has wide biological activity, has the structure in a plurality of medicaments, has wide biological activity, is a key component for constructing a plurality of medicaments and active intermediates, such as chloroquine, is used for treating malaria initially, has gradually expanded application later, and has certain effect for treating chloroquine rheumatoid arthritis. Meanwhile, halogenated quinoline derivatives are also key intermediates for constructing medicaments or active substances. Therefore, how to rapidly and effectively synthesize the halogenated quinoline amide compound is a focus of attention of researchers.
In modern organic synthesis, C-H functionalization is widely concerned by organic chemists because of the characteristics of no need of pre-functionalization of substrates, high atomic effect and the like. Therefore, the method for directly carrying out C-halogen functionalization is an effective synthetic method. Zhang et al used iodobenzene diacetic acid as an oxidant and copper acetate as a metal catalyst to carry out C5 and C7 dibromination reactions on quinoline amide; the dichlorination reaction of quinoline amide C5 and C7 is realized by adopting hydrochloric acid and potassium peroxymonosulfonate (Oxone). However, these methods either use toxic and harmful reagents, large amounts of oxidizing agents and metal catalysts, and do not meet the requirements of green chemistry.
Therefore, it is necessary to develop a method for synthesizing selective C5, C7 dihaloquinoline amide compound which does not use metal catalyst and oxidant and is green and environment-friendly. Compared with the previously reported methods, the method does not use a large amount of oxidant and metal catalyst, has high yield and milder reaction conditions.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing C5 and C7 dihalogenated quinoline amide derivatives, which is green, friendly, simple, convenient and efficient.
The technical scheme of the invention is as follows:
a method for electrochemically synthesizing a C5, C7 dihalogenated quinoline amide derivative shown as a formula (I) comprises the following steps:
dissolving quinoline amide shown in a formula (II), a halogenating reagent and electrolyte in a solvent, inserting an electrode, stirring and reacting at a constant current of 5-15mA (preferably 15mA) for 5-60min (preferably 15min) at 25-80 ℃ (preferably 50 ℃), and then carrying out aftertreatment on a reaction solution to obtain a product shown in a formula (I);
the mass ratio of the quinoline amide represented by the formula (II) to the halogenating agent is 1: 4; the halogenating agent is sodium halide, dihalo dimethyl hydantoin or N-halogen succinimide, preferably N-halogen succinimide;
the mass ratio of the quinoline amide represented by the formula (II) to the electrolyte is 3: 1; the electrolyte is tetrabutylammonium bromide or tetrabutylammonium fluoroborate, preferably tetrabutylammonium fluoroborate;
the volume usage amount of the solvent is 2-10 mL/mmol, preferably 5mL/mmol, based on the amount of the substance of the quinoline amide shown in the formula (II); the solvent is one or a mixed solvent of more than two of 1, 2-dichloroethane, dichloromethane, acetonitrile, acetone, ethyl acetate, dioxane and tetrahydrofuran in any proportion, preferably acetonitrile;
the electrode is C (+) -Pt (-), C (+) -C (-), or Pt (+) -Pt (-), preferably C (+) -Pt (-);
the post-treatment method comprises the following steps: after the reaction, the reaction solution was concentrated under reduced pressure, and the reaction solution was concentrated under reduced pressure using petroleum ether: the volume ratio of ethyl acetate is 20: 1 as developing agent, and obtaining the product shown in the formula (I) through column chromatography separation;
in the formula (I) or (II),
R1is phenyl, naphthyl, substituted phenyl, which is phenyl monosubstituted with 1 substituent, which is C1-C4 alkyl, C1-C4 alkoxy or halogen, or a heterocycle, which is, for example, thiophene;
R2is H, C1-C4 alkyl or C1-C4 alkoxy on the quinoline skeleton;
and X is Cl or Br.
The structure of the compound (I) obtained by the invention1H NMR、13C NMR, MS, HRMS and the like. In the past research, the brominated quinoline amide compound realizes the C5 site cyanation of quinoline amide, and further utilizes Suzuki to functionalize a quinoline ring, so that the brominated quinoline amide compound is applied to the chemical industry. The dibrominated products obtained according to the invention can be used for the synthesis of herbicides by further reaction (example 18).
The invention has the beneficial effects that: in the prior art, toxic and harmful reagents, a large amount of oxidants and metal catalysts are adopted, so that the requirements of green chemistry are not met. The method adopts an electrochemical method to synthesize the C5 and C7 dihalogenated quinoline amide compound, does not use a large amount of oxidant and metal catalyst, has high product yield, milder reaction conditions and wide substrate applicability, and meets the requirement of green chemistry.
Detailed Description
The technical solution of the present invention is further described below by specific examples, but the scope of the present invention is not limited thereto.
Example 1
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) benzamide (0.3mmol,74.4mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain the desired product Ia in 112.1mg as a white solid with a yield of 92%.
M.p.156-157℃.1H NMR(400MHz,CDCl3)9.13(s,1H),8.84(d,J＝3.4Hz,1H),8.50(d,J＝8.5 Hz,1H),8.11(s,1H),8.08(d,J＝7.5Hz,2H),7.55(dq,J＝18.5,7.4Hz,4H).13CNMR(101MHz, CDCl3)165.48,150.74,143.94,136.16,134.56,134.27,134.16,132.44,128.89,128.17,127.02, 122.96,120.10,118.96.
HRMS(ESI+):Calculated for C16H10Br2N2OH:[M+H]+404.9238,Founded,404.9240.
Example 2
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) -4-methylbenzamide (0.3mmol,78.7mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography to obtain the objective product Ib as a white solid (110.8 mg, 88% yield).
M.p.165-166℃.1H NMR(400MHz,CDCl3)9.20(s,1H),8.81(dd,J＝4.1,1.2Hz,1H),8.46(dd, J＝8.5,1.3Hz,1H),8.08(s,1H),7.97(d,J＝8.1Hz,2H),7.52(dd,J＝8.5,4.2Hz,1H),7.29(d,J＝8.0 Hz,2H),2.44(s,3H).13C NMR(101MHz,CDCl3)165.40,150.62,143.90,142.94,136.09,134.51, 134.40,131.26,129.47,128.16,126.95,122.88,120.11,118.76,21.71.
HRMS(ESI+):Calculated forC17H12Br2N2OH:[M+H]+418.9395,Found 417.9399.
Example 3
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) 4-methoxybenzamide (0.3mmol,83.5mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography to obtain the objective product Ic as a white solid (107.3 mg, yield 82%).
M.p.83-84℃.1H NMR(400MHz,CDCl3)9.17(s,1H),8.82(s,1H),8.48(d,J＝8.3Hz,1H),8.09 (s,1H),8.04(d,J＝8.6Hz,2H),7.57–7.50(m,1H),6.98(d,J＝8.6Hz,2H),3.88(s,3H).13C NMR (101MHz,CDCl3)165.03,162.99,150.61,143.88,136.17,134.56,134.51,130.12,126.98,126.38, 122.91,120.01,118.64,114.04,55.64.
HRMS(ESI+):Calculated for C17H12Br2N2O2H:[M+H]+434.9344,Founded,434.9347
Example 4
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) 4-tert-butylbenzamide (0.3mmol,91.3mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain the objective product Id as a white solid (119.2 mg, yield 86%).
1H NMR(400MHz,CDCl3)9.32(s,1H),8.81(d,J＝3.1Hz,1H),8.55–8.45(m,1H),8.10(s,1H), 8.02(d,J＝8.3Hz,2H),7.53(t,J＝6.7Hz,3H),1.37(s,9H).13C NMR(101MHz,CDCl3)165.28, 155.96,150.58,143.97,136.16,134.56,134.42,131.16,128.03,127.01,125.80,122.91,120.24,118.80, 35.18,31.30.
HRMS(ESI+):Calculated for C20H18Br2N2OH:[M+H]+460.9864,Found 460.9860.
Example 5
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) 4-fluorobenzamide (0.3mmol,80.0mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography to obtain the objective product Ie as a white solid (104.0 mg, yield 82%).
1H NMR(400MHz,CDCl3)9.24(s,1H),8.83(dd,J＝4.2,1.4Hz,2H),8.50(dd,J＝8.5,1.4Hz, 1H),8.12–8.05(m,4H),7.56(dd,J＝8.5,4.2Hz,1H),7.17(t,J＝8.6Hz,2H).19F NMR(376MHz, Chloroform-d)-106.79.13C NMR(101MHz,CDCl3)165.37(d,1JC-F＝252.0Hz),164.50,150.65, 143.87,136.37,134.55,134.05,130.58(d,3JC-F＝9.0Hz),130.18(d,4JC-F＝3.0Hz),127.06,122.98, 120.61,119.22,115.89(d,2JC-F＝22.0Hz).
HRMS(ESI+):Calculated for C16H9Br2FN2OH:[M+H]+422.9144,Found 422.9147
Example 6
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) 4-chlorobenzamide (0.3mmol,84.8mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain the objective product If as a white solid (109.7 mg, 83% yield).
1H NMR(400MHz,CDCl3)9.23(s,1H),8.83(d,J＝3.1Hz,1H),8.50(d,J＝8.3Hz,1H),8.10(s, 1H),8.00(d,J＝8.5Hz,2H),7.56(dd,J＝8.5,3.9Hz,1H),7.47(d,J＝8.4Hz,2H).13C NMR(101MHz, CDCl3)164.52,150.76,143.89,138.76,136.30,134.54,133.97,132.43,129.58,129.12,127.06,123.03, 120.42,119.27.
HRMS(ESI+):Calculated for C16H9Br2ClN2OH:[M+H]+438.8848,Found 438.8845
Example 7
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) 4-chlorobenzamide (0.3mmol,98.1mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain the desired product Ig, 115.0 mg as a white solid in 79% yield.
1H NMR(400MHz,DMSO-d6)10.61(s,1H),9.01(dd,J＝4.1,1.4Hz,2H),8.56(dd,J＝8.5,1.5 Hz,1H),8.37(s,1H),8.03(d,J＝8.5Hz,2H),7.79(dd,J＝8.5,5.1Hz,4H).13CNMR(101MHz, DMSO-d6)164.51,152.23,145.37,135.52,135.04,133.13,132.93,131.56,130.00,126.67,125.71, 123.86,123.64,120.31.
HRMS(ESI+):Calculated for C16H9Br3N2OH:[M+H]+482.8343,Found 482.8345.
Example 8
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) -3-methylbenzamide (0.3mmol,78.7mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography to obtain the objective product Ih as a white solid (110.8 mg) in 88% yield.
1H NMR(400MHz,CDCl3)9.16(s,1H),8.83(dd,J＝4.1,1.2Hz,1H),8.49(dd,J＝8.5,1.2Hz, 1H),8.09(s,1H),7.88(d,J＝5.2Hz,2H),7.54(dd,J＝8.5,4.2Hz,1H),7.40(d,J＝5.0Hz,2H),2.44(s, 3H).13C NMR(101MHz,CDCl3)165.61,150.67,143.91,138.73,136.15,134.53,134.28,134.00, 133.16,128.83,128.72,126.98,125.15,122.92,120.20,118.91,21.53.
HRMS(ESI+):Calculated for C17H12Br2N2OH:[M+H]+418.9395,Found 418.9399.
Example 9
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) -3-methoxybenzamide (0.3mmol,83.5mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification by silica gel column chromatography gave 113.8mg of the objective product Ii as a white solid in 87% yield.
1H NMR(400MHz,CDCl3)9.16(s,1H),8.83(dd,1H),8.50(dd,J＝8.5,1.1Hz,1H),8.10(s,1H), 7.65(d,J＝7.8Hz,1H),7.60(d,J＝2.2Hz,1H),7.55(dd,J＝8.5,4.2Hz,1H),7.42(t,J＝7.9Hz,1H), 7.13(dd,J＝8.3,2.6Hz,1H),3.88(s,3H).13C NMR(101MHz,CDCl3)165.30,160.03,150.73,143.94, 136.16,135.49,134.53,134.19,129.86,127.00,122.96,120.18,120.05,119.01,118.88,113.10,55.62.
HRMS(ESI+):Calculated for C17H12Br2N2O2H:[M+H]+434.9344,Found434.9349.
Example 10
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) -3-bromobenzamide (0.3mmol,98.1mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain the objective product Ij as a white solid (120.8 mg, 83% yield).
1H NMR(400MHz,CDCl3)9.26(s,1H),8.84(dd,J＝4.1,1.3Hz,1H),8.49(dd,J＝8.5,1.4Hz, 1H),8.19(t,J＝1.7Hz,1H),8.09(s,1H),7.99(d,J＝7.8Hz,1H),7.72–7.68(m,1H),7.56(dd,J＝8.5, 4.2Hz,1H),7.36(t,J＝7.9Hz,1H).13C NMR(101MHz,CDCl3)164.08,150.77,143.91,136.29, 135.95,135.32,134.50,133.81,131.33,130.39,127.05,126.60,123.06,123.03,120.61,119.45.
HRMS(ESI+):Calculated for C17H12Br2N2O2H:[M+H]+482.8343,Founded,482.8349.
Example 11
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) -2-methoxybenzamide (0.3mmol,83.5mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography to obtain the objective product Ik as a white solid (115.1 mg, 88% yield).
1H NMR(400MHz,CDCl3)10.49(s,1H),8.93(d,J＝3.1Hz,1H),8.50(d,J＝8.4Hz,1H),8.34 (dd,J＝7.8,1.7Hz,1H),8.11(s,1H),7.54(td,J＝8.4,7.4,2.8Hz,2H),7.19–7.05(m,2H),4.12(s, 3H).13C NMR(101MHz,CDCl3)163.28,158.10,151.14,144.79,136.00,134.85,134.20,133.63, 133.07,127.21,122.75,121.60,121.55,121.39,119.48,111.90,56.50.
HRMS(ESI+):Calculated for C17H12Br2N2O2H:[M+H]+434.9344,Found 434.9340.
Example 12
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) -2-chlorobenzamide (0.3mmol,84.8mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography to obtain the objective product Il as a white solid (103.1 mg, yield 78%).
1H NMR(400MHz,CDCl3)9.24(s,1H),8.84(d,J＝3.0Hz,1H),8.50(dd,J＝8.5,1.3Hz,1H), 8.09(s,1H),8.03(t,J＝1.7Hz,1H),7.95(d,J＝7.7Hz,1H),7.58–7.53(m,2H),7.43(t,J＝7.9Hz,1H). 13C NMR(101MHz,CDCl3)164.20,150.79,143.91,136.28,135.78,135.06,134.50,133.83,132.41, 130.16,128.45,127.06,126.14,123.04,120.55,119.43.
HRMS(ESI+):Calculated for C16H9Br2ClN2OH:[M+H]+438.8848,Founded,438.884
Example 13
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cmx 1cm) cathode, N- (quinolin-8-yl) -thiophene-2-carboxamide (0.3mmol,76.3mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain the objective product Im as a white solid (106.3 mg, 86% yield).
1H NMR(400MHz,CDCl3)9.64(s,1H),8.83(dd,J＝4.2,1.5Hz,1H),8.47(dd,J＝8.5,1.5Hz, 1H),8.07(s,1H),7.87(dd,J＝3.7,1.0Hz,1H),7.53(dd,J＝8.6,4.2Hz,2H),7.11(dd,J＝4.9,3.8Hz, 1H).13C NMR(101MHz,CDCl3)159.96,150.63,144.00,138.64,136.32,134.54,133.76,131.49, 130.14,128.04,127.07,122.98,120.90,119.28.
HRMS(ESI+):Calculated for C14H9Br2N2OSH:[M+H]+434.9344,Founded,434.9347.
Example 14
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cmx 1cm) cathode, N- (quinolin-8-yl) -2-naphthamide (0.3mmol,89.5mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography to obtain the desired product In as a white solid (104.0 mg, 76% yield).
1H NMR(400MHz,DMSO-d6)10.70(s,1H),9.03(d,J＝2.8Hz,1H),8.76(s,1H),8.60–8.55(m, 1H),8.39(s,1H),8.18–7.98(m,4H),7.80(dd,J＝8.5,4.2Hz,1H),7.66(p,J＝6.8,6.3Hz,2H).13C NMR(101MHz,DMSO-d6)165.47,152.17,145.37,135.69,135.31,134.48,133.26,132.16,131.15, 129.05,128.56,128.13,127.99,127.76,126.96,126.72,124.55,124.00,123.67,120.23.HRMS(ESI+): Calculated for C20H12Br2N2OH:[M+H]+454.9395,Founded,454.9399.
Example 15
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (2-methylquinolin-8-yl) benzamide (0.3mmol,78.7mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain the desired product Io as a white solid (100.8 mg, yield 80%).
1H NMR(400MHz,CDCl3)9.12(s,1H),8.34(d,J＝8.6Hz,1H),8.12–8.08(m,2H),8.01(s,1H), 7.61(t,J＝7.3Hz,1H),7.54(t,J＝7.4Hz,2H),7.40(d,J＝8.6Hz,1H),2.70(s,3H).13C NMR(101MHz, CDCl3)165.48,160.16,143.23,136.03,134.38,133.55,133.52,132.37,128.89,128.17,125.19,123.83, 119.53,118.64,25.36.
HRMS(ESI+):Calculated for C17H12Br2N2OH:[M+H]+418.9395,Founded,418.9395.
Example 16
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (6-methoxyquinolin-8-yl) benzamide (0.3mmol,83.4mg), N-bromosuccinimide (1.2mmol,213.0mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain the desired product, In, as a white solid (108.6 mg, 83% yield).
1H NMR(400MHz,CDCl3)9.27(s,1H),8.77(dd,J＝4.1,1.2Hz,1H),8.54(dd,J＝8.5,1.3Hz, 1H),8.11–8.05(m,2H),7.60(t,J＝7.4Hz,1H),7.56–7.49(m,3H),4.06(s,3H).13C NMR(101MHz, CDCl3)165.43,153.16,149.62,141.12,135.97,135.61,133.99,132.49,128.89,128.17,127.54,123.25, 119.10,112.44,61.34.
HRMS(ESI+):Calculated for C17H12Br2N2O2H:[M+H]+434.9344,Founded,434.9340.
Example 17
In a 10mL three-necked flask equipped with a carbon anode (d ═ 6mm), a platinum plate (1cm × 1cm) cathode, N- (quinolin-8-yl) benzamide (0.3mmol,74.4mg), N-chlorosuccinimide (1.2mmol,160.2mg), tetrabutylammonium fluoroborate (0.1mmol, 33.0mg) were added. Acetonitrile (3.0mL) was added. The reaction mixture was stirred at 50 ℃ for 15min at a constant current of 15 mA. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was carried out by silica gel column chromatography to obtain the desired product, In, as a white solid (108.6 mg, 85% yield).
1H NMR(400MHz,CDCl3)9.29(s,1H),8.84(dd,J＝4.2,1.5Hz,1H),8.50(dd,J＝8.5,1.4Hz, 1H),8.07–8.02(m,2H),7.72(s,1H),7.51(dq,J＝19.5,7.3Hz,4H).13C NMR(101MHz,CDCl3) 165.66,150.71,143.69,133.94,133.51,132.30,131.55,130.26,128.86,128.76,128.56,128.12,125.28, 122.44.
HRMS(ESI+):Calculated for C16H10Cl2N2OH:[M+H]+317.0248,Found317.0246.
Example 18
In a Schlenk tube, N- (5, 7-dibromoquinolin-8-yl) benzamide (0.2mmol,81.2mg), nano-copper oxide (5% mmol, 1.0mg), cesium carbonate (0.3mmol, 97.7mg) were added. DMSO (3.0mL) was added. The reaction mixture was stirred at 110 ℃ for 3 h. After the reaction was complete, TLC detection was performed and the reaction mixture was concentrated under reduced pressure. Purification was performed by silica gel column chromatography to obtain 52.1mg of the target product Ir as a white solid in a yield of 80%.
1H NMR(400MHz,DMSO-d6)9.17(dd,J＝4.2,1.5Hz,1H),8.74(dd,J＝8.6,1.5Hz,1H),8.68 (s,1H),8.35-8.32(m,2H),7.86(dd,J＝8.6,4.2Hz,1H),7.75-7.72(m,3H).13CNMR(101MHz, DMSO-d6)162.84,152.09,150.50,141.04,137.83,136.40,132.45,129.82,127.60,126.57,125.01, 122.88,118.38,116.80.
HRMS(ESI+):Calculated for C16H9BrN2OH:[M+H]+324.9971,Found 324.9977。
Claims (8)
1. A method for electrochemically synthesizing a C5, C7 dihalogenated quinoline amide derivative shown as a formula (I), which is characterized by comprising the following steps:
dissolving quinoline amide shown in a formula (II), a halogenating reagent and electrolyte in a solvent, inserting an electrode, stirring and reacting at a constant current of 5-15mA for 5-60min at 25-80 ℃, and then carrying out post-treatment on reaction liquid to obtain a product shown in a formula (I);
the mass ratio of the quinoline amide represented by the formula (II) to the halogenating agent is 1: 4; the halogenating reagent is sodium halide, dihalo dimethyl hydantoin or N-halogenated succinimide;
the mass ratio of the quinoline amide represented by the formula (II) to the electrolyte is 3: 1; the electrolyte is tetrabutylammonium bromide or tetrabutylammonium fluoroborate;
in the formula (I) or (II),
R1is phenyl, naphthyl, substituted phenyl or heterocycle, the substituted phenyl is phenyl which is mono-substituted by 1 substituent, and the substituent is C1-C4 alkyl, C1-C4 alkoxy or halogen;
R2is H, C1-C4 alkyl or C1-C4 alkoxy on the quinoline skeleton;
and X is Cl or Br.
2. The method for electrochemically synthesizing the quinoline amide derivative represented by the formula (I) represented by C5 or C7 as defined in claim 1, wherein the reaction conditions are as follows: the reaction was stirred at 50 ℃ for 15min at a constant current of 15 mA.
3. The method for electrochemically synthesizing the quinoline amide derivative represented by formula (I) C5, C7 as defined in claim 1, wherein the halogenating agent is N-halosuccinimide.
4. The method for the electrochemical synthesis of the quinoline amide derivative represented by formula (I) C5, C7 as defined in claim 1, wherein the electrolyte is tetrabutylammonium fluoroborate.
5. The method for electrochemically synthesizing the quinoline amide derivative represented by the formula (I) and having 5 and 7 dihalides in terms of volume as set forth in claim 1, wherein the solvent is used in an amount of 2 to 10mL/mmol, based on the amount of the substance of the quinoline amide represented by the formula (II).
6. The method for electrochemically synthesizing the quinoline amide derivative represented by formula (I) C5 or C7 according to claim 1, wherein the solvent is one or a mixture of two or more of 1, 2-dichloroethane, dichloromethane, acetonitrile, acetone, ethyl acetate, dioxane and tetrahydrofuran in any ratio.
7. The method for electrochemically synthesizing the quinoline amide derivative of formula (I) C5 or C7 as defined in claim 1, wherein the electrode is C (+) -Pt (-), C (+) -C (-), or Pt (+) -Pt (-).
8. The method for electrochemically synthesizing the quinoline amide derivative represented by the formula (I) C5, C7 as defined in claim 1, wherein the post-treatment method comprises: after the reaction, the reaction solution was concentrated under reduced pressure, and the reaction solution was concentrated under reduced pressure using petroleum ether: the volume ratio of ethyl acetate is 20: the mixed solution of 1 is used as developing agent, and the product shown in the formula (I) is obtained by column chromatography separation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010553275.3A CN111575731B (en) | 2020-06-17 | 2020-06-17 | Method for electrochemically synthesizing C5 and C7 dihalogenated quinoline amide derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010553275.3A CN111575731B (en) | 2020-06-17 | 2020-06-17 | Method for electrochemically synthesizing C5 and C7 dihalogenated quinoline amide derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111575731A true CN111575731A (en) | 2020-08-25 |
| CN111575731B CN111575731B (en) | 2021-08-24 |
Family
ID=72127432
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010553275.3A Active CN111575731B (en) | 2020-06-17 | 2020-06-17 | Method for electrochemically synthesizing C5 and C7 dihalogenated quinoline amide derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111575731B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112239871A (en) * | 2020-10-21 | 2021-01-19 | 南京先进生物材料与过程装备研究院有限公司 | Method for continuously preparing C-2 chloro-substituted quinoline by using electrochemical microchannel reaction device |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3557283A (en) * | 1965-02-19 | 1971-01-19 | Ici Ltd | Veterinary compositions containing a quinoline-3-carboxylic ester |
| US4466866A (en) * | 1983-06-16 | 1984-08-21 | Rhone-Poulenc Sante | Electrochemical process for the preparation of sulphoxides of thioformamide derivatives, which are useful as medicaments |
| US20110308963A1 (en) * | 2009-03-10 | 2011-12-22 | Fumitoshi Kakiuchi | Process for producing aromatic halogen compound utilizing electrolysis |
| CN103524411A (en) * | 2013-10-21 | 2014-01-22 | 哈尔滨理工大学 | Synthetic method of 5-cholro-8-quinoline oxyacetic acid |
-
2020
- 2020-06-17 CN CN202010553275.3A patent/CN111575731B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3557283A (en) * | 1965-02-19 | 1971-01-19 | Ici Ltd | Veterinary compositions containing a quinoline-3-carboxylic ester |
| US4466866A (en) * | 1983-06-16 | 1984-08-21 | Rhone-Poulenc Sante | Electrochemical process for the preparation of sulphoxides of thioformamide derivatives, which are useful as medicaments |
| US20110308963A1 (en) * | 2009-03-10 | 2011-12-22 | Fumitoshi Kakiuchi | Process for producing aromatic halogen compound utilizing electrolysis |
| CN103524411A (en) * | 2013-10-21 | 2014-01-22 | 哈尔滨理工大学 | Synthetic method of 5-cholro-8-quinoline oxyacetic acid |
Non-Patent Citations (3)
| Title |
|---|
| JIAHAO HOU ET AL.: "Metal-Free Electrochemical Oxidative Dihalogenation of Quinolines on the C5 and C7 Positions Using N-Halosuccinimides", 《EUR. J. ORG. CHEM》 * |
| JUN XU ET AL.: "Copper(II)-catalyzed C5 and C7 halogenation of quinolines using sodium halides under mild conditions", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
| YONG YUAN ET AL.: "Electrochemical Oxidative Clean Halogenation Using HX/NaX with Hydrogen Evolution", 《ISCIENCE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112239871A (en) * | 2020-10-21 | 2021-01-19 | 南京先进生物材料与过程装备研究院有限公司 | Method for continuously preparing C-2 chloro-substituted quinoline by using electrochemical microchannel reaction device |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111575731B (en) | 2021-08-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Liu et al. | One-pot, multistep reactions for the modular synthesis of N, N′-Diarylindazol-3-ones | |
| CN111690947B (en) | Electrochemical synthesis method of trifluoromethylated aryl amide derivative | |
| CN111705329B (en) | Electrochemical synthesis method of 5-arylthio uracil compound | |
| CN114000167A (en) | Method for electrochemically synthesizing pyrazole compound | |
| CN111575731B (en) | Method for electrochemically synthesizing C5 and C7 dihalogenated quinoline amide derivatives | |
| CN111303028B (en) | 4-cyano-2-difluoromethyl substituted quinoline compound and synthetic method thereof | |
| Qin et al. | Electrochemical difunctionalization of alkenes | |
| CN110483420A (en) | A kind of preparation method of tetrahydroquinoxaline class compound | |
| WO2023109254A1 (en) | Method for one-step direct preparation of 3-acyl imidazo[1,5-a]pyridine by means of [4+1] dual amination reactions of ketomethyl | |
| CN113024470B (en) | 4-perfluoroalkyl substituted pyrimidine compound and preparation method and application thereof | |
| CN114438523B (en) | Green and efficient electrochemical synthesis method of benzothiophene compound | |
| CN114075257B (en) | Method for preparing arylamine compound from On-DNA aryl halide | |
| CN111592489B (en) | Method for selective C5 halogenation of quinoline skeleton of quinoline amide | |
| CN110627823B (en) | Method for catalyzing arylamine to generate deamination boric acid esterification or halogenation | |
| CN111170924B (en) | Method for electrochemically synthesizing hexafluoroisopropoxyindole compound | |
| CN109952294A (en) | 4- ((6- (2- (2,4 difluorobenzene base) -1,1- two fluoro- 2- hydroxyl -3- (5- sulfydryl -1H-1,2,4- triazol-1-yl) propyl) pyridin-3-yl) oxygroup) benzonitrile and preparation method | |
| CN104710376B (en) | Method for synthesis of oxazoline derivative based on electrophilic iodocyclization reaction of propargylamide | |
| CN114214646B (en) | Synthesis method of electrochemical oxidation 2-trifluoromethyl-alpha-carbonyl dithio ketene compound | |
| CN111560022A (en) | Tetrahydrobenzofuran [3,2-d ] pyrimidine derivative and preparation method and application thereof | |
| CN114621137B (en) | Difluorobutoxy method of N-aryl-N-hydroxylamine compound participated in tetrahydrofuran | |
| CN111394747B (en) | Green electrochemical synthesis method of 2-acyloxy aniline derivatives | |
| CN113930791B (en) | Electric synthesis method of pyrido-bipyrimidine tetraketone compound | |
| CN111270260B (en) | Method for alkenylating ortho-position of aromatic amide compound | |
| CN109694335A (en) | The non-solvent preparation of disubstituted para orientation nitration derivative | |
| CN116356353A (en) | Method for electrocatalytic synthesis of nitrile compound by using thianthdinium salt as substrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |