CN114832862A - Catalytic composition for coupling reaction and application thereof in preparation of isoquinoline-1, 3-diketone compounds - Google Patents

Abstract

The invention provides a catalytic composition for coupling reaction and its application in preparing isoquinoline-1,3-diketone compounds. The catalytic composition is composed of a nickel catalyst, a ligand and a cocatalyst, and the cocatalyst The catalyst is halide, the molar ratio of nickel catalyst, ligand and co-catalyst is 1:1~3:30~40, the existence form of nickel catalyst is one or more of organic matter and inorganic matter, and the valence state of nickel is 0, +2, where inorganics are divalent and non-oxides. The catalyst composition of the invention has the advantages of low cost and easy availability, convenient operation, mild reaction conditions, wide substrate range and the like.

Description

A kind of catalytic composition of coupling reaction and its application in the preparation of isoquinoline-1,3-dione compounds

technical field

The invention belongs to the field of organic synthesis, in particular to a catalytic composition for coupling reaction and its application for preparing isoquinoline-1,3-dione compounds.

Background technique

As an important nitrogen-containing heterocyclic compound, isoquinoline-1,3-diones are widely present in biologically active natural products and medicines. Therefore, the introduction of new functional groups into this skeleton will provide new insights into the discovery of New bioactive molecules offer more opportunities. It is well known that the addition of fluorine-containing groups can change the chemical and physical properties of biologically active compounds, and fluorinated groups improve the permeability and bioavailability of cell membranes due to their high solubility and lipophilicity. Therefore, how to introduce fluorine-containing groups into the structure of isoquinoline-1,3-diones has become a hot research topic for organic chemists.

In 2017, Wang's team developed a method for the preparation of CF ₂ H/CF ₃ -containing isoquinoline-1,3-diones by visible-light-catalyzed direct difluoromethylation of p-methacryloylbenzamide. (GLZou, XL Wang, Org. Biomol. Chem., 2017, 15, 8748-8754.). In 2016, Wang et al. successfully developed an efficient Pd-catalyzed difluoroalkylation/cyclization reaction to synthesize isoquinoline-1,3-diones (XFXia, SLZhu, Y.Li, HJWang, RSC Adv., 2016, 6, 51703–51709.). Although there have been many reports on the introduction of fluorine-containing groups into the structure of isoquinoline-1,3-dione, the reaction conditions are strict, the substrate scope is narrow, and expensive metal catalysts are used, resulting in high reaction costs, which are not suitable for economical application. with green principles.

SUMMARY OF THE INVENTION

To overcome these limitations, the direct introduction of fluorinated groups into arene rings via transition metal-catalyzed cross-coupling reactions is a straightforward route to obtain valuable difluoroalkylated backbones. Among them, nickel catalysts show unique catalytic activity and selectivity. Nickel catalysts are not only cheap and easy to obtain, but also economical and applicable. More importantly, they have low electronegativity and higher oxidative addition activity, which can effectively avoid some side reactions. The purpose of the present invention is to provide a kind of catalytic composition for coupling reaction with low cost and mild reaction conditions and its application for preparing isoquinoline-1,3-dione compounds.

In order to achieve the above object, the technical scheme adopted in the present invention is:

A catalytic composition for coupling reaction, which consists of a nickel catalyst, a ligand and a co-catalyst, the co-catalyst is a halide, and the molar ratio of the nickel catalyst, the ligand and the co-catalyst is 1:1-3:30-40 , the nickel catalyst exists in the form of one or more of organic matter and inorganic matter, the valence state of nickel is 0, +2, and the inorganic matter is divalent and non-oxide. Co-catalysts are used to improve the activity of nickel catalysts, and commonly used halides such as magnesium chloride, sodium iodide, potassium iodide, and trimethylchlorosilane. The nickel catalyst can be an organic nickel catalyst, an inorganic nickel catalyst, preferably a halogenated nickel.

As a further improvement of the technical solution, in order to improve the catalytic effect, the nickel catalyst is nickel bromide.

As a further improvement of the technical solution, the cocatalyst is anhydrous magnesium chloride.

As a further improvement of the technical solution, the ligands are nitrogen-containing ligands and phosphine ligands.

As a further improvement of the technical solution, in order to improve the yield, the ligands are 2,2'-bipyridine-4,4'-dicarboxylate (L1) and 1,2-bis(diphenylphosphine) Ethane (DPPE).

An application of the catalytic composition in the preparation of isoquinoline-1,3-dione compounds, the steps are as follows: under the action of the catalytic composition and a reducing agent, o-iodoacryloylbenzamide compounds I and The difluoro compound II undergoes a coupling reaction in a solvent to obtain isoquinoline-1,3-dione compounds. The reaction scheme is shown in formula (I):

In formula (I), R ₁ is one or more substituents of the connected benzene ring, each R ¹ is independently selected from hydrogen, halogen or methyl; R ² is C1-C4 alkyl, phenyl or benzyl R ³ is C1-C4 alkyl; R ⁴ is morpholine, -N(Et) ₂ or -OCH ₂ CH ₃ . The reaction temperature for this application is 25-80°C, and the reaction conditions are mild.

During catalysis, the nickel catalyst forms a complex with the ligand, and forms an intermediate through oxidative addition, migration and insertion, and the Ni on the intermediate undergoes a valence change under the action of a reducing agent. Under the action of the reducing agent, it returns to its original state.

After the metal-catalyzed coupling reaction between the o-iodoacryloylbenzamide compound and the difluoro compound, the product can be separated and characterized according to a conventional separation and purification method. Preferably, the post-processing steps of the reaction solution obtained after the metal-catalyzed coupling reaction between the o-iodoacryloylbenzamide compound and the difluoro compound is carried out are as follows: after the reaction is completed and the reaction solution is cooled to room temperature, the saturated ammonium chloride solution is quenched, Water and ethyl acetate were added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated and purified by column chromatography to obtain isoquinoline-1,3-dione products. It is a mixed solvent of ethyl acetate and petroleum ether, wherein the volume ratio of ethyl acetate and 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 solution, in order to reduce the side reaction, the application is carried out under the condition of isolated air, and an inert atmosphere, such as nitrogen and group zero element atmosphere, is used.

As a further improvement of the technical solution, in order to reduce the reaction cost, R ¹ is hydrogen, halogen or methyl; R ² is C1-C4 alkyl, phenyl or benzyl; R ³ is C1-C4 alkyl.

As a further improvement of the technical solution, in order to improve the yield, the molar ratio of the nickel catalyst, the reducing agent and the o-iodoacryloylbenzamide compound is 0.05-0.15:2-5:1.

As a further improvement of the technical solution, in order to improve the conversion rate, the molar ratio of the o-iodoacryloylbenzamide compound to the difluoro compound is 1:1.5-3, preferably 1:3.

As a further improvement of the technical solution, the solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4-dioxane and At least one of N-methylpyrrolidone.

Compared with the prior art, the present invention has outstanding substantive features and remarkable progress. Specifically, the catalyst composition of the present invention adopts cheap and easily available transition metal nickel as the main catalyst, and the cocatalyst and ligand are also conventional types. Cheap and easy to get. Furthermore, the catalyst composition of the present invention has high selectivity for preparing isoquinoline-1,3-dione compounds, and can effectively avoid side reactions. Furthermore, when the catalyst composition of the present invention is used for preparing isoquinoline-1,3-dione compounds, the reaction conditions are mild and the substrate range is wide. The catalyst composition of the present invention has the advantages of low cost and easy availability, mild reaction conditions and a wide range of substrates.

Detailed ways

The technical solutions of the present invention will be further described in detail below through specific embodiments.

The experimental methods without specific conditions in the examples of the present disclosure generally follow conventional conditions or conditions suggested by raw material or commodity manufacturers. Reagents with no specific source indicated are conventional reagents purchased in the market.

Example 1

A method for preparing isoquinoline-1,3-dione compounds (IIIa) by nickel-catalyzed metal coupling reaction, the reaction route is as follows:

The specific preparation steps are as follows: in 10ml Schlenk bottle, add nickel catalyst (NiBr ₂ , 0.05mmol), ligand (L , 0.05mmol; DPPE, 0.05mmol), reducing agent (Mn, 1.5mmol), cocatalyst (MgCl _{2 )} , 2mmol), o-iodoacryloylbenzamide compounds (that is, starting material Ia, 0.5 mmol), difluoro compound (that is, starting material IIa, 1.5 mmol) and 2ml of dimethyl sulfoxide, and then in an argon atmosphere, 60 ℃ conditions The reaction was stirred, and the progress of the reaction was detected by TLC until the raw material disappeared (the reaction time was 24 h). After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was quenched, water and ethyl acetate were added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained crude product was subjected to column chromatography ( The eluent is ethyl acetate:petroleum ether=1:20～1:10, v/v) separation and purification to obtain 95 mg of the target product with a yield of 52%.

Characterization data of isoquinoline-1,3-diones (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=7.2 Hz,3H),0.97(t,J=7.3Hz,3H).

¹³ C{ ¹ H} NMR (150MHz, Chloroform-d): δ 174.57, 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, 250.8 Hz), 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 (282 MHz, Chloroform-d): δ-101.06 (d, J=255.6 Hz), -104.83 (d, J=255.6 Hz).

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-dione compounds (IIIb) by nickel-catalyzed metal coupling reaction, the reaction route is as follows:

The specific preparation steps are as follows: in 10ml Schlenk bottle, add nickel catalyst (NiBr ₂ , 0.05mmol), ligand (L , 0.05mmol; DPPE, 0.05mmol), reducing agent (Mn, 1.5mmol), cocatalyst (MgCl _{2 )} , 2 mmol), o-iodoacryloylbenzamide compounds (that is, starting material Ib, 0.5 mmol), difluoro compound (that is, starting material IIa, 1.5 mmol) and 2 ml of dimethyl sulfoxide, and then under argon atmosphere, 60 ℃ conditions The reaction was stirred, and the progress of the reaction was detected by TLC until the raw material disappeared (the reaction time was 24 h). After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was quenched, water and ethyl acetate were added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained crude product was subjected to column chromatography ( The eluent is ethyl acetate:petroleum ether=1:20～1:10, v/v) separation and purification to obtain 102.8 mg of the target product with a yield of 51%.

The characterization data of isoquinoline-1,3-diones (IIIb) are as follows:

¹ H NMR (300MHz, Chloroform-d): δ 8.23 (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): δ 173.98, 163.09 (t, J=32.3 Hz), 162.68, 142.45, 140.02, 130.84, 128.49, 126.10, 123.22, 114.28 (t, J=253.6 Hz) 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 (282 MHz, Chloroform-d): δ-99.84 (d, J=267.4 Hz), -103.95 (d, J=267.4 Hz).

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-dione compounds (IIIc) by nickel-catalyzed metal coupling reaction, the reaction route is as follows:

The specific preparation steps are as follows: in 10ml Schlenk bottle, add nickel catalyst (NiBr ₂ , 0.05mmol), ligand (L , 0.05mmol; DPPE, 0.05mmol), reducing agent (Mn, 1.5mmol), cocatalyst (MgCl _{2 )} , 2mmol), o-iodoacryloylbenzamide compounds (that is, starting material Ic, 0.5 mmol), difluoro compound (that is, starting material IIa, 1.5 mmol) and 2 ml of dimethyl sulfoxide, and then in an argon atmosphere, under the conditions of 60 ℃ The reaction was stirred, and the progress of the reaction was detected by TLC until the raw material disappeared (the reaction time was 24 h). After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was quenched, water and ethyl acetate were added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained crude product was subjected to column chromatography ( The eluent is ethyl acetate:petroleum ether=1:20～1:10, v/v) separation and purification to obtain 95 mg of the target product with a yield of 47%.

The characterization data of isoquinoline-1,3-diones (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, 14.9 Hz, 1H), 1.65(s, 3H), 1.21(t, J=7.2Hz, 3H).

¹³ C{ ¹ H} NMR (125MHz, Chloroform-d): δ 174.70, 163.53, 163.31 (t, J=31.8Hz), 140.71, 136.91, 133.52, 129.36, 128.59, 128.36, 127.91, 127.36, 114.36, 114.389 (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=266.3 Hz), -103.88 (d, J=266.4 Hz).

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-dione compounds (IIId) by nickel-catalyzed metal coupling reaction, the reaction route is as follows:

The specific preparation steps are as follows: in 10ml Schlenk bottle, add nickel catalyst (NiBr ₂ , 0.05mmol), ligand (L , 0.05mmol; DPPE, 0.05mmol), reducing agent (Mn, 1.5mmol), cocatalyst (MgCl _{2 )} , 2mmol), o-iodoacryloylbenzamide compounds (that is, starting material Id, 0.5 mmol), difluoro compound (that is, starting material IIa, 1.5 mmol) and dimethyl sulfoxide 2ml, and then in an argon atmosphere, 60 ℃ conditions The reaction was stirred, and the progress of the reaction was detected by TLC until the raw material disappeared (the reaction time was 24 h). After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was quenched, water and ethyl acetate were added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained crude product was subjected to column chromatography ( The eluent is ethyl acetate:petroleum ether=1:20～1:10, v/v) separation and purification to obtain 62 mg of the target product with a yield of 33%.

The characterization data of isoquinoline-1,3-diones (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): δ 174.06, 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, 252.8 Hz),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=266.1 Hz), -104.09 (d, J=266.1 Hz).

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-dione compounds (IIIe) by nickel-catalyzed metal coupling reaction, the reaction route is as follows:

The specific preparation steps are as follows: in 10ml Schlenk bottle, add nickel catalyst (NiBr ₂ , 0.05mmol), ligand (L , 0.05mmol; DPPE, 0.05mmol), reducing agent (Mn, 1.5mmol), cocatalyst (MgCl _{2 )} , 2mmol), o-iodoacryloylbenzamide compounds (that is, starting material Ia, 0.5 mmol), difluoro compound (that is, starting material IIe, 1.5 mmol) and dimethyl sulfoxide 2ml, and then in an argon atmosphere, under the conditions of 60 ℃ The reaction was stirred, and the progress of the reaction was detected by TLC until the raw material disappeared (the reaction time was 24 h). After the reaction solution was cooled to room temperature, saturated ammonium chloride solution was quenched, water and ethyl acetate were added for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained crude product was subjected to column chromatography ( The eluent is ethyl acetate:petroleum ether=1:20～1:10, v/v) separation and purification to obtain 120.2 mg of the target product with a yield of 59%.

The characterization data of isoquinoline-1,3-diones (IIIe) are as follows:

¹ H NMR (300 MHz, Chloroform-d): δ 8.27 (dd, J=8.3, 1.3 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.46 (t, J=7.8 Hz, 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): δ 175.04, 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 (282 MHz, Chloroform-d): δ-95.43 (d, J=280.7 Hz), -98.14 (d, J=280.6 Hz).

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

The difference between this embodiment and Embodiment 1 is that DPPE is not added. The yield of the target product was 30%, and the yield was far lower than that of Example 1, indicating that the addition of a phosphine ligand could accelerate the reaction process and improve the reaction yield.

Comparative Example 2

The difference between this example and Example 1 is that alkali is added. The target product was obtained with a yield of 0.

Comparative Example 3

The difference between this example and Example 1 is that no manganese powder is added. The target product was obtained with a yield of 0.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should The specific embodiments of the invention are modified or some technical features are equivalently replaced; without departing from the spirit of the technical solutions of the present invention, all of them should be included in the scope of the technical solutions claimed in the present invention.

Claims (10)

1. A catalytic composition for coupling reaction is characterized by comprising a nickel catalyst, a ligand and a cocatalyst, wherein the cocatalyst is halide, and the molar ratio of the nickel catalyst, the ligand and the cocatalyst is 1: 1-3: 30-40, the nickel catalyst exists in one or more of organic matters and inorganic matters, the valence of the nickel is 0 and +2, and the inorganic matters are divalent and non-oxide.

2. The catalytic composition of claim 1, wherein the nickel catalyst is nickel bromide.

3. The catalytic composition of claim 1, wherein the cocatalyst is anhydrous magnesium chloride.

4. The catalytic composition of claim 1 wherein the ligands are nitrogen-containing ligands and phosphine ligands.

5. The catalytic composition of claim 4, wherein the ligand is 4,4 '-dimethoxy-2, 2' -bipyridine with 1, 2-bis (diphenylphosphino) ethane.

6. Use of a catalytic composition according to any one of claims 1 to 5 for the preparation of isoquinoline-1, 3-diones by the steps of: under the action of the catalytic composition and a metal reducing agent, the o-iodoacryloyl benzamide compound and the difluoro compound are subjected to coupling reaction in a solvent to obtain the isoquinoline-1, 3-diketone compound, wherein the reaction route is as shown in formula (I):

（Ⅰ）；

in the formula (I), R ¹ Is 1 or more substituents of the phenyl ring to which it is attached, each R ¹ Independently selected from hydrogen, halogen or methyl; r ² Is C1-C4 alkyl, phenyl or benzyl; r ³ Is C1-C4 alkyl; r ⁴ Is morpholine, -N (Et) ₂ or-OCH ₂ CH ₃ 。

7. The use of claim 6, wherein the molar ratio of the nickel catalyst, the metal reducing agent and the o-iodoacryloyl benzamide compound is 0.05-0.15: 2-5: 1.

8. The use of claim 6, wherein the molar ratio of the o-iodoacryloyl benzamide compound to the difluoro compound is 1: 1.5-3.

9. Use according to any one of claims 6 to 8, wherein the solvent is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, acetonitrile, 1, 4-dioxane and N-methylpyrrolidone.

10. Use according to any one of claims 6 to 8, wherein the metallic reducing agent is manganese powder or zinc powder and the use employs an inert atmosphere.