CN114832862B - Catalytic composition for coupling reaction and application of catalytic composition in preparation of isoquinoline-1, 3-dione compounds - Google Patents
Catalytic composition for coupling reaction and application of catalytic composition in preparation of isoquinoline-1, 3-dione compounds Download PDFInfo
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- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
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Abstract
The invention provides a catalytic composition for coupling reaction and application thereof in preparation of isoquinoline-1, 3-diketone compounds, wherein the catalytic composition comprises a nickel catalyst, a ligand and a cocatalyst, the cocatalyst is halide, and the molar ratio of the nickel catalyst to the ligand to the cocatalyst is 1:1 to 3: 30-40, wherein the nickel catalyst exists in one or more of organic matters and inorganic matters, the valence state of nickel is 0 and +2, and the inorganic matters are bivalent and non-oxide. The catalyst composition has the advantages of low cost, easy obtainment, convenient operation, mild reaction condition, wide substrate range and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a catalytic composition for coupling reaction and application thereof in preparation of isoquinoline-1, 3-diketone compounds.
Background
Isoquinoline-1, 3-dione compounds are widely used as an important nitrogen-containing heterocyclic compound in natural products and medicines with biological activity, so that the introduction of new functional groups into the skeleton provides more opportunities for the discovery of new bioactive molecules. It is well known that the addition of fluorine-containing groups can alter the chemical and physical properties of biologically active compounds, and that fluorinated groups have higher solubility and lipophilicity, thereby increasing the permeability and bioavailability of the cell membrane. Therefore, how to introduce fluorine-containing groups into the structures of isoquinoline-1, 3-dione compounds has become a hot spot for organic chemists to study.
In 2017, wang group developed a method for preparing CF-containing products by direct difluoromethylation of methacryloyl benzamide under visible light catalysis 2 H/CF 3 Is a method for producing isoquinoline-1, 3-dione compounds (G.L.Zou, X.L.Wang, org.Biomol.Chem.,2017,15,8748-8754). In 2016, wang et al successfully developed a highly efficient Pd-catalyzed difluoroalkylation/cyclization reaction to prepare synthetic isoquinoline-1, 3-diones (X.F.Xia, S.L.Zhu, Y.Li, H.J.Wang, RSC adv.,2016,6,51703-51709.). Although many reports of introducing fluorine-containing groups into isoquinoline-1, 3-diketone structures exist, the reaction conditions are strict, the substrate range is narrow, an expensive metal catalyst is used, the reaction cost is high, and the economic applicability and the environment-friendly principle are not met.
Disclosure of Invention
To overcome these limitations, the direct introduction of fluorinated groups into aromatic hydrocarbon rings by transition metal catalyzed cross-coupling reactions is a direct route to valuable difluoroalkylated backbones. The nickel catalyst has unique catalytic activity and selectivity, is low in cost, easy to obtain, economical and applicable, and more importantly, has low electronegativity and higher oxidation addition activity, and can effectively avoid partial side reactions. The invention aims to provide a catalytic composition for coupling reaction with low cost and mild reaction conditions and an application of the catalytic composition in preparation of isoquinoline-1, 3-diketone compounds.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a catalytic composition for coupling reaction is prepared from nickel catalyst, ligand and promoter, wherein the promoter is halide, and the mole ratio of the nickel catalyst to the ligand to the promoter is 1:1 to 3: 30-40, wherein the nickel catalyst exists in one or more of organic matters and inorganic matters, the valence state of nickel is 0 and +2, and the inorganic matters are bivalent and non-oxide. The promoter is used for improving the activity of nickel catalyst, and common use is magnesium chloride, sodium iodide, potassium iodide, trimethyl chlorosilane and other halides. The nickel catalyst may be an organonickel catalyst, an inorganic nickel catalyst, preferably a nickel halide.
As a further improvement of the technical scheme, the nickel catalyst is nickel bromide in order to improve the catalytic effect.
As a further improvement of the technical scheme, the cocatalyst is anhydrous magnesium chloride.
As a further improvement of the technical scheme, the ligands are nitrogen-containing ligands and phosphine ligands.
As a further improvement of the technical scheme, the ligand is 2,2 '-bipyridine-4, 4' -dicarboxylic acid methyl ester (L1) and 1, 2-bis (diphenylphosphine) ethane (DPPE) for improving the yield.
The application of the catalytic composition in preparing isoquinoline-1, 3-diketone compounds comprises the following steps: under the action of the catalytic composition and the reducing agent, the o-iodoacryl-benzamide compound I and the difluoro compound II undergo a coupling reaction in a solvent to obtain an isoquinoline-1, 3-diketone compound, wherein the reaction route is shown as the formula (I):
in the formula (I), R 1 1 or more substituents for the benzene ring to which it is attached, each R 1 Independently selected from hydrogen, halogen or methyl; r is R 2 Is C1-C4 alkyl, phenyl or benzyl; r is R 3 Is C1-C4 alkyl; r is R 4 Is morpholine, -N (Et) 2 or-OCH 2 CH 3 . The reaction temperature of the application is 25-80 ℃, and the reaction condition is mild.
During catalysis, the nickel catalyst and the ligand form a complex, an intermediate is formed through oxidation addition and migration insertion, ni on the intermediate is subjected to valence state change under the action of a reducing agent, and after the reaction is finished, the stripped Ni ligand complex returns to the initial state under the action of the reducing agent.
After the o-iodoacryl-benzene amide compound and the difluoro compound are subjected to metal catalytic coupling reaction, the product can be separated and characterized by a conventional separation and purification method. Preferably, the post-treatment steps of the reaction liquid obtained after the metal catalytic coupling reaction of the o-iodoacryl-benzene amide compound and the difluoro compound are as follows: after the reaction is completed and the reaction liquid is cooled to room temperature, the saturated ammonium chloride solution is quenched, water and ethyl acetate are added for extraction for three times, the organic phases are combined, anhydrous sodium sulfate is dried, the solvent is removed by concentration under reduced pressure, the obtained crude product is separated and purified by column chromatography to obtain isoquinoline-1, 3-diketone products, and the eluent is a mixed solvent of ethyl acetate and petroleum ether, wherein the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent of ethyl acetate and petroleum ether is 0.05-0.1:1.
As a further improvement of the technical scheme, the application is carried out under the condition of air isolation, and inert atmosphere such as nitrogen and zero group element atmosphere is adopted for reducing side reactions.
As a further improvement of the technical scheme, R is used for reducing the reaction cost 1 Hydrogen, halogen or methyl; r is R 2 Is C1-C4 alkyl, phenyl or benzyl; r is R 3 Is C1-C4 alkyl.
As a further improvement of the technical scheme, in order to improve the yield, the molar ratio of the nickel catalyst, the reducing agent and the o-iodoacryl-benzamide compound is 0.05-0.15:2-5:1.
As a further improvement of the technical scheme, in order to improve the conversion rate, the molar ratio of the o-iodoacryloyl-benzamide compound to the difluoro compound is 1:1.5-3, preferably 1:3.
As a further improvement of the technical scheme, the solvent is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1, 4-dioxane and N-methylpyrrolidone.
Compared with the prior art, the catalyst composition provided by the invention has outstanding substantial characteristics and remarkable progress, and particularly, the catalyst composition provided by the invention adopts low-cost and easily-obtained transition metal nickel as a main catalyst, and cocatalysts and ligands are also conventional products, so that the catalyst composition is low in cost and easy to obtain. Furthermore, the catalyst composition provided by the invention is used for preparing isoquinoline-1, 3-diketone compounds, has high selectivity, and can effectively avoid side reactions. In a further step, the catalyst composition provided by the invention is used for preparing isoquinoline-1, 3-diketone compounds, and has the advantages of wide reaction condition and substrate range. The catalyst composition has the advantages of low cost, easy availability, mild reaction condition and wide substrate range.
Detailed Description
The technical scheme of the invention is further described in detail through the following specific embodiments.
Experimental methods for which specific conditions are not noted in the examples in this disclosure are generally in accordance with conventional conditions, or in accordance with conditions recommended by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
Example 1
A method for preparing isoquinoline-1, 3-diketone compound (IIIa) through nickel catalyzed metal coupling reaction comprises the following reaction route:
the preparation process comprises adding nickel catalyst (NiBr) into 10ml Schlenk bottle 2 0.05 mmol), ligand (L3, 0.05mmol; DPPE,0.05 mmol), reducing agent (Mn, 1.5 mmol), promoter (MgCl) 2 2 mmol), o-iodoacryloylbenzamide compound (i.e. raw material Ia, 0.5 mmol), difluoro compound (i.e. raw material IIa, 1.5 mmol) and dimethyl sulfoxide 2ml, then stirring and reacting under argon atmosphere at 60 ℃, and detecting the reaction progress by TLC until the raw material disappears (the reaction time is 24 h). After the reaction is completed and the reaction liquid is cooled to room temperature, the saturated ammonium chloride solution is quenched, water and ethyl acetate are added for extraction for three times, the organic phases are combined, dried over anhydrous sodium sulfate, the solvent is removed by vacuum concentration, and the obtained crude product is separated and purified by column chromatography (eluent is ethyl acetate: petroleum ether=1:20-1:10, v/v) to obtain the target product with the yield of 95mg and the yield of 52%.
Characterization data for isoquinoline-1, 3-dione compounds (IIIa) are as follows:
1 H NMR(300MHz,Chloroform-d):δ8.29(d,J＝6.7Hz,1H),7.66–7.61(t,J＝7.5Hz，1H),7.50–7.41(m,2H),4.04–3.88(m,4H),3.39-3.24(m,1H),2.99–2.83(m,1H),1.66–1.58(m,5H),1.47–1.37(m,2H),1.21(t,J＝7.2Hz,3H),0.97(t,J＝7.3Hz,3H).
13 C{ 1 H}NMR(150MHz,Chloroform-d):δ174.57,163.52,163.21(d,J＝32.0Hz),140.65,133.34,129.16,127.86,125.97,124.70,114.46(dd,J＝255.4,250.8Hz),63.02,44.62(dd,J＝23.6,21.7Hz),43.56(d,J＝5.0Hz),40.58,31.76,29.57,20.26,13.80,13.66.
19 F{ 1 H}NMR(282MHz,Chloroform-d):δ-101.06(d,J＝255.6Hz),-104.83(d,J＝255.6Hz).
HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 24 F 2 NO 4 368.1673；found 368.1687(+0.0014).
example 2
A method for preparing isoquinoline-1, 3-diketone compound (IIIb) through nickel catalyzed metal coupling reaction comprises the following reaction route:
the preparation process comprises adding nickel catalyst (NiBr) into 10ml Schlenk bottle 2 0.05 mmol), ligand (L3, 0.05mmol; DPPE,0.05 mmol), reducing agent (Mn, 1.5 mmol), promoter (MgCl) 2 2 mmol), o-iodoacryloylbenzamide compound (i.e. raw material Ib, 0.5 mmol), difluoro compound (i.e. raw material IIa, 1.5 mmol) and dimethyl sulfoxide 2ml, then stirring and reacting under argon atmosphere at 60 ℃, and detecting the reaction progress by TLC until the raw material disappears (the reaction time is 24 h). After the reaction is completed and the reaction liquid is cooled to room temperature, the saturated ammonium chloride solution is quenched, water and ethyl acetate are added for extraction for three times, the organic phases are combined, dried over anhydrous sodium sulfate, the solvent is removed by vacuum concentration, and the obtained crude product is separated and purified by column chromatography (eluent is ethyl acetate: petroleum ether=1:20-1:10, v/v) to obtain 102.8mg of target product with the yield of 51%.
Characterization data for isoquinoline-1, 3-dione compounds (IIIb) are as follows:
1 H NMR(300MHz,Chloroform-d):δ8.23(d,J＝8.5Hz,1H),7.45(dd,J＝8.5,1.9Hz,1H),7.39(d,J＝1.8Hz,1H),4.12–3.98(m,4H),3.41–3.26(m,1H),2.94–2.78(m,1H),1.66–1.57(m,5H),1.44–1.36(m,2H),1.27(t,J＝7.2Hz,3H),0.97(t,J＝7.3Hz,3H).
13 C{ 1 H}NMR(125MHz,Chloroform-d):δ173.98,163.09(t,J＝32.3Hz),162.68,142.45,140.02,130.84,128.49,126.10,123.22,114.28(t,J＝253.6Hz)63.20,44.53(t,J＝22.7Hz),43.62(d,J＝4.7Hz),40.69,31.61,29.52,20.22,13.75,13.74.
19 F{ 1 H}NMR(282MHz,Chloroform-d):δ-99.84(d,J＝267.4Hz),-103.95(d,J＝267.4Hz).
HRMS(ESI)m/z:[M+H] + Calcd for C 19 H 23 ClF 2 NO 4 402.1284；found 402.1292(+0.0008).
example 3
A method for preparing isoquinoline-1, 3-diketone compound (IIIc) through nickel catalyzed metal coupling reaction comprises the following reaction route:
the preparation process comprises adding nickel catalyst (NiBr) into 10ml Schlenk bottle 2 0.05 mmol), ligand (L3, 0.05mmol; DPPE,0.05 mmol), reducing agent (Mn, 1.5 mmol), promoter (MgCl) 2 2 mmol), o-iodoacryloylbenzamide compound (i.e. raw material ic, 0.5 mmol), difluoro compound (i.e. raw material IIa, 1.5 mmol) and dimethyl sulfoxide 2ml, then stirring and reacting under argon atmosphere at 60 ℃, and detecting the reaction progress by TLC until the raw material disappears (the reaction time is 24 h). After the reaction is completed and the reaction liquid is cooled to room temperature, the saturated ammonium chloride solution is quenched, water and ethyl acetate are added for extraction for three times, the organic phases are combined, dried over anhydrous sodium sulfate, the solvent is removed by vacuum concentration, and the obtained crude product is separated and purified by column chromatography (eluent is ethyl acetate: petroleum ether=1:20-1:10, v/v) to obtain the target product with the yield of 95mg and the yield of 47%.
Characterization data for isoquinoline-1, 3-dione compounds (IIIc) are as follows:
1 H NMR(300MHz,Chloroform-d):δ8.30(d,J＝7.9Hz,1H),7.64(t,J＝7.6Hz,1H),7.51–7.42(m,4H),7.35–7.29(m,2H),7.28–7.24(m,1H),5.29–5.17(m,2H),4.04–3.88(m,2H),3.42–3.27(m,1H),2.93(dt,J＝18.5,14.9Hz,1H),1.65(s,3H),1.21(t,J＝7.2Hz,3H).
13 C{ 1 H}NMR(125MHz,Chloroform-d):δ174.70,163.53,163.31(t,J＝31.8Hz),140.71,136.91,133.52,129.36,128.59,128.36,127.91,127.36,125.97,124.59,114.38(dd,J＝255.0,251.2Hz),63.01,44.34(t,J＝22.7Hz),43.94,43.89,31.89,13.66.
19 F{ 1 H}NMR(282MHz,Chloroform-d):δ-99.54(d,J＝266.3Hz),-103.88(d,J＝266.4Hz).
HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 22 F 2 NO 4 402.1517；found 402.1519(+0.0002).
example 4
A method for preparing isoquinoline-1, 3-diketone compound (IIId) through nickel catalyzed metal coupling reaction comprises the following reaction route:
the preparation process comprises adding nickel catalyst (NiBr) into 10ml Schlenk bottle 2 0.05 mmol), ligand (L3, 0.05mmol; DPPE,0.05 mmol), reducing agent (Mn, 1.5 mmol), promoter (MgCl) 2 2 mmol), o-iodoacryloylbenzamide compound (i.e. raw material Id, 0.5 mmol), difluoro compound (i.e. raw material IIa, 1.5 mmol) and dimethyl sulfoxide 2ml, then stirring and reacting under argon atmosphere at 60 ℃, and detecting the reaction progress by TLC until the raw material disappears (the reaction time is 24 h). After the reaction is completed and the reaction liquid is cooled to room temperature, the saturated ammonium chloride solution is quenched, water and ethyl acetate are added for extraction for three times, the organic phases are combined, dried over anhydrous sodium sulfate, the solvent is removed by vacuum concentration, and the obtained crude product is separated and purified by column chromatography (eluent is ethyl acetate: petroleum ether=1:20-1:10, v/v) to obtain the target product 62mg, and the yield is 33%.
Characterization data for isoquinoline-1, 3-dione compounds (IIId) are as follows:
1 H NMR(300MHz,Chloroform-d):δ8.30(d,J＝7.9Hz,1H),7.65(t,J＝7.0Hz,1H),7.48(t,J＝7.6Hz,1H),7.37(d,J＝7.9Hz,1H),4.06–3.86(m,4H),3.35–3.21(m,1H),2.98–2.82(m,1H),2.37–2.30(m,1H),1.94–1.87(m,1H),1.64–1.59(m,2H),1.46–1.39(m,2H),1.21(t,J＝7.2Hz,3H),0.98(t,J＝7.3Hz,3H),0.50(t,J＝7.4Hz,3H).
13 C{ 1 H}NMR(125MHz,Chloroform-d):δ174.06,163.65,163.42(t,J＝38.7Hz),138.95,133.40,128.96,127.82,126.49,125.68,114.53(dd,J＝250.5,252.8Hz),62.98,48.28(d,J＝4.9Hz),44.92(dd,J＝24.0,21.5Hz),40.58,38.07,29.62,20.33,13.77,13.65,7.99.
19 F{ 1 H}NMR(282MHz,Chloroform-d):δ-98.60(d,J＝266.1Hz),-104.09(d,J＝266.1Hz).
HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 26 F 2 NO 4 382.1830；found 382.1837(+0.0007).
example 5
A method for preparing isoquinoline-1, 3-diketone compound (IIIe) through nickel catalyzed metal coupling reaction comprises the following reaction route:
the preparation process comprises adding nickel catalyst (NiBr) into 10ml Schlenk bottle 2 0.05 mmol), ligand (L3, 0.05mmol; DPPE,0.05 mmol), reducing agent (Mn, 1.5 mmol), promoter (MgCl) 2 2 mmol), o-iodoacryloylbenzamide compound (i.e. raw material Ia, 0.5 mmol), difluoro compound (i.e. raw material IIe, 1.5 mmol) and dimethyl sulfoxide 2ml, then stirring and reacting under argon atmosphere at 60 ℃, and detecting the reaction progress by TLC until the raw material disappears (the reaction time is 24 h). After the reaction is completed and the reaction liquid is cooled to room temperature, the saturated ammonium chloride solution is quenched, water and ethyl acetate are added for extraction for three times, the organic phases are combined, dried over anhydrous sodium sulfate, the solvent is removed by vacuum concentration, and the obtained crude product is separated and purified by column chromatography (eluent is ethyl acetate: petroleum ether=1:20-1:10, v/v) to obtain 120.2mg of target product with the yield of 59%.
Characterization data for isoquinoline-1, 3-dione compounds (IIIe) are as follows:
1 H NMR(300MHz,Chloroform-d):δ8.27(dd,J＝8.3,1.3Hz,1H),7.63(t,J＝7.6Hz,1H),7.46(t,J＝7.8Hz,2H),4.01(dd,J＝8.3,6.8Hz,2H),3.68–3.47(m,9H),3.06–2.88(m,1H),1.67–1.55(m,5H),1.43–1.35(m,2H),0.95(t,J＝7.3Hz,3H).
13 C{ 1 H}NMR(125MHz,Chloroform-d):δ175.04,163.81,161.25(t,J＝28.5Hz),141.87,133.34,128.97,127.52,126.07,124.23,118.10(t,J＝257.1Hz),66.54,46.31(t,J＝6.2Hz),44.29(t,J＝20.5Hz),43.45,43.42,40.47,31.95,29.64,20.22,13.78.
19 F{ 1 H}NMR(282MHz,Chloroform-d):δ-95.43(d,J＝280.7Hz),-98.14(d,J＝280.6Hz).
HRMS(ESI)m/z:[M+H] + Calcd for C 21 H 27 F 2 N 2 O 4 409.1939；found 409.1944(+0.0005).
comparative example 1
This embodiment differs from embodiment 1 in that: no DPPE was added. The yield of the target product is 30%, which is far lower than that of example 1, indicating that the addition of phosphine ligand can accelerate the reaction progress and increase the reaction yield.
Comparative example 2
This embodiment differs from embodiment 1 in that: adding alkali. The yield of the target product was 0.
Comparative example 3
This embodiment differs from embodiment 1 in that: no manganese powder was added. The yield of the target product was 0.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same; while the invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that the present invention may be modified and equivalents substituted for elements thereof; without departing from the spirit of the invention, it is intended to cover the scope of the invention as claimed.
Claims (5)
1. A method for preparing isoquinoline-1, 3-dione compounds by nickel-catalyzed metal coupling reactions, comprising the steps of:
under the action of a catalytic composition and a metal reducing agent, the o-iodoacryl-benzamide compound and the difluoro compound are subjected to coupling reaction in a solvent, the reaction temperature is 25-80 ℃, and the isoquinoline-1, 3-dione compound is obtained, wherein the reaction route is as shown in the formula (I):
in the formula (I), R 1 1 or more substituents for the benzene ring to which it is attached, each R 1 Independently selected from hydrogen, halogen or methyl; r is R 2 Is C1-C4 alkyl, phenyl or benzyl; r is R 3 Is C1-C4 alkyl; r is R 4 Is morpholine, -N (Et) 2 or-OCH 2 CH 3 ；
The catalytic composition comprises a nickel catalyst, a ligand, and a promoter; the nickel catalyst is nickel bromide; the ligand is two of 4,4 '-dimethoxy-2, 2' -bipyridine and 1, 2-bis (diphenylphosphine) ethane; the cocatalyst is anhydrous magnesium chloride; the molar ratio of the nickel catalyst, the ligand and the cocatalyst is 1:1 to 3: 30-40.
2. The method for preparing isoquinoline-1, 3-dione compounds by nickel-catalyzed metal coupling reaction according to claim 1, wherein the molar ratio of the nickel catalyst, the metal reducing agent and the o-iodoacryl-benzamide compound is 0.05-0.15:2-5:1.
3. The method for preparing isoquinoline-1, 3-dione compounds by nickel-catalyzed metal coupling reaction according to claim 1, wherein the molar ratio of the o-iodoacryloylbenzamide compounds to the difluoro compounds is 1:1.5-3.
4. The method for preparing isoquinoline-1, 3-dione compounds by a nickel catalyzed metal coupling reaction according to claim 1, wherein the solvent is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1, 4-dioxane and N-methylpyrrolidone.
5. The method for preparing isoquinoline-1, 3-dione compounds by nickel-catalyzed metal coupling reactions according to claim 1, wherein the metal reducing agent is manganese powder or zinc powder.
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