阅读说明：本技术 一种3-烷基异吲哚啉酮类衍生物的合成方法 (Synthetic method of 3-alkyl isoindolinone derivatives ) 是由 李阳 何柳 李剑 于 2021-02-05 设计创作，主要内容包括：本发明为3-烷基异吲哚啉酮衍生物的合成工艺,涉及具有生物活性的天然产物、农用化学品及药物领域。所用原料是邻氰基苯甲醛衍生物、末端炔和二苯基碘鎓三氟甲磺酸盐,三氟甲磺酸铜为催化剂,三氟甲磺酸作为添加剂,邻二氯乙烷溶液中110℃下发生反应,得到3-烷基异吲哚啉酮类衍生物。使用本发明提出的方法,在110℃条件下,反应2小时,即可得到3-烷基异吲哚啉酮类衍生物,产率为52%-91%。本反应采用简单易得的原料,一锅法合成3-烷基异吲哚啉酮类衍生物,为合成该类衍生物提供了一条简便、高效、绿色的合成新方法。(The invention discloses a synthesis process of a 3-alkyl isoindolinone derivative, and relates to the fields of natural products with biological activity, agricultural chemicals and medicines. The raw materials are o-cyanobenzaldehyde derivatives, terminal alkyne and diphenyl iodonium trifluoromethanesulfonate, copper trifluoromethanesulfonate is used as a catalyst, trifluoromethanesulfonic acid is used as an additive, and the reaction is carried out in an o-dichloroethane solution at 110 ℃ to obtain the 3-alkyl isoindolinone derivatives. The 3-alkyl isoindolinone derivative can be obtained by reacting for 2 hours at 110 ℃ by using the method provided by the invention, and the yield is 52-91%. The reaction adopts simple and easily obtained raw materials, and the 3-alkyl isoindolinone derivatives are synthesized by a one-pot method, thereby providing a simple, convenient, efficient and green new synthesis method for synthesizing the derivatives.)

1. A preparation method of 3-alkyl isoindolinone is characterized in that under the catalysis of copper, o-cyanobenzaldehyde derivatives, terminal alkyne and diphenyl iodonium trifluoromethanesulfonate are used as raw materials, a proper amount of catalyst, additive and solvent are added, and the reaction is carried out for 2 hours under the condition of air and at the temperature of 110 ℃ under stirring to generate the 3-alkyl isoindolinone derivatives.

2. The process of claim 1, wherein the catalyst is copper triflate.

3. The process of claim 1, wherein the additive is trifluoromethanesulfonic acid.

4. The method for preparing 3-alkylisoindolinone according to claim 1, wherein the molar ratio of the raw materials is ortho-cyanobenzaldehyde derivative, terminal alkyne, diphenyl iodonium trifluoromethanesulfonate =1:2: 1.5.

5. A process for the preparation of a 3-alkylisoindolinone according to claim 1, characterized in that said solvent is 1, 2-dichloroethane; the amount of the solvent used was 2mL/mmol of o-cyanobenzaldehyde.

6. The method of claim 1, wherein the o-cyanobenzaldehyde derivative is selected from the group consisting of 2-cyanobenzaldehyde, 5-fluoro-2-formylbenzonitrile, 5-methoxy-2-formylbenzonitrile and 5-chloro-2-formylbenzonitrile.

7. The method of claim 1, wherein the starting terminal alkyne is phenylacetylene, 4-methylphenylacetylene, 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4-trifluoromethylphenylacetylene, 4-nitrophenylacetylene, 4-methylphenylacetylene, 2-methylphenylacetylene, naphthylacetylene, 2,3,4, 5-tetrafluorophenylacetylene, 2-ethynylthiophene, etc.

8. The process of claim 1, wherein the R group of the diphenyliodonium trifluoromethanesulfonate is R =4-H, 4-F, 4-CF₃，4-Br，4-Cl，4-CH₃4-OMe, etc.

Technical Field

The invention relates to a synthesis process for preparing 3-alkyl isoindolinone, belonging to the technical field of drug synthesis and active natural products.

Background

Nitrogen-containing heterocyclic backbones are widely found in biologically active natural products and pharmaceutical chemistry. Among the various nitrogen-containing compounds, 3-alkylisoindolinones are an important class of biologically active and therapeutically potential building blocks, such as paqinlong, paglong, JM1232, zopiclone, etc. At present, the synthetic methods reported in the literature have the defects that the reaction needs to synthesize the starting raw materials step by step, the yield is not high, the conditions are harsh, toxic or flammable reagents need to be used in the preparation process, and the like, so that the development of a simple, efficient and green synthetic method of the isoindolinone derivatives still has important significance.

We used o-cyanobenzaldehyde derivatives, terminal alkynes, diphenyliodonium trifluoromethanesulfonate and the additive trifluoromethanesulfonic acid to react at 110 ℃ under the catalysis of copper trifluoromethanesulfonate to give a series of 3-alkylisoindolinone derivatives.

Disclosure of Invention

The technical problem solved by the invention is to provide a method for synthesizing a 3-alkyl isoindolinone derivative by using an o-cyanobenzaldehyde derivative, terminal alkyne and diphenyl iodonium trifluoromethanesulfonate as raw materials through a one-pot tandem reaction under the catalysis of copper. The method has the advantages of simple and easily obtained raw materials, simple and convenient operation and high substrate universality.

The invention adopts the following technical scheme: a method for synthesizing isoindolinone by copper catalysis is developed, wherein o-cyanobenzaldehyde derivatives, terminal alkyne and diphenyl iodonium trifluoromethanesulfonate are used as raw materials, a proper amount of solvent is added under the catalysis of trifluoromethanesulfonic acid additive and copper trifluoromethanesulfonate, and then the raw materials are stirred and reacted for 2 hours at 110 ℃ under the air condition to generate 3-alkyl isoindolinone derivatives.

The molar ratio of the raw materials is O-cyanobenzaldehyde derivative, terminal alkyne and diphenyl iodonium trifluoromethanesulfonate =1:2: 1.5.

The additive is trifluoromethanesulfonic acid, and the amount of the trifluoromethanesulfonic acid is 1.5 equivalents based on the moles of the o-cyanobenzaldehyde derivative.

The catalyst is copper trifluoromethanesulfonate, and the dosage of the copper trifluoromethanesulfonate is 10% mmol of the mol number of the o-cyanobenzaldehyde derivative.

The above-mentioned o-cyanobenzaldehyde derivative may be 2-cyanobenzaldehyde, 5-fluoro-2-formylbenzonitrile, 5-methoxy-2-formylbenzonitrile, 5-chloro-2-formylbenzonitrile, etc.

The alkyne at the tail end of the raw material is phenylacetylene, 4-methylphenylacetylene, 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4-trifluoromethylphenylacetylene, 4-nitrophenylacetylene, 4-methylphenylacetylene, 2-methylphenylacetylene, naphthylacetylene, 2,3,4, 5-tetrafluorophenylacetylene, 2-ethynylthiophene and the like.

The above-mentioned starting diphenyliodonium trifluoromethanesulfonate R group may be R =4-H, 4-F, 4-CF₃，4-Br，4-Cl，4-CH₃4-OMe, etc.

The reaction process and the structural formula of the obtained product are as follows:

the post-reaction treatment is simple and convenient, and the pure 3-alkyl isoindolinone derivative can be obtained by using a mixed solvent of petroleum ether and ethyl acetate as an eluent only by recrystallization or a simple column chromatography separation method. The synthesized compound adopts¹H NMR and¹³c NMR characterization, and the spectrogram data is matched with the structure.

The invention has the beneficial effects that: 3-alkylisoindolinones are important molecules with pharmaceutical activity and have wide application in the fields of natural products, agrochemicals and medicines. The method is characterized in that o-cyanobenzaldehyde derivatives, terminal alkyne and diphenyl iodonium trifluoromethanesulfonate are used as raw materials for the first time, trifluoromethanesulfonic acid is used as an additive, and a series of 3-alkyl isoindolinone is prepared by a copper-catalyzed one-pot method, wherein the yield is 52-91%. Three reaction substrates, namely o-cyanobenzaldehyde, terminal alkyne and diphenyl iodonium trifluoromethanesulfonate, are easy to expand, and the reaction universality is good.

Detailed Description

Example 1

O-cyanobenzaldehyde (1 mmol), phenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to obtain 4a in 79% yield.¹H NMR (400 MHz, CDCl3) δ 7.95-7.92 (m, 1H), 7.87-7.85 (m, 2H), 7.60-7.51 (m, 8H), 7.46-7.41 (m, 2H), 5.96 (dd, J = 9.4, 3.0 Hz, 1H), 3.52 (dd, J = 17.8, 3.0 Hz, 1H), 3.27-3.19 (m, 1H). ¹³C NMR (125 MHz, CDCl3) δ 197.5, 166.9, 145.0, 136.2, 135.7, 133.9, 132.6, 132.4, 131.5, 128.8, 128.1, 124.3, 123.2, 118.6, 56.7, 41.8。

Example 2

O-cyanobenzaldehyde (1 mmol), 4-fluorophenylacetylene (2 mmol),bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were charged in a 15mL pressure-resistant tube, stirred at 110 ℃ and reacted for 2 hours, and the product was chromatographed on a silica gel column to give 4b in 75% yield.¹H NMR (400 MHz, CDCl₃) δ 7.95-7.88 (m, 3H), 7.55-7.52 (m, 7H), 7.12 (t, J = 8.2 Hz, 2H), 5.96-5.94 (m, 1H), 3.49 (dd, J = 10.0, 3.0 Hz, 1H), 3.23-3.17 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 195.8, 167.2, 165.5 (d, J = 218.9 Hz), 144.9, 135.7, 132.6, 132.4, 131.5, 130.8 (d, J = 9.6 Hz), 128.9, 124.4 (d, J = 17.2 Hz), 123.1, 118.7, 115.9 (d, J = 21.9 Hz), 56.7, 41.7. ¹⁹F NMR (282 MHz, CDCl₃) δ -103.4. HRMS (ESI) calcd for C₂₂H₁₆BrFNO₂ ([M+H]⁺): 424.0343 found 424.0338。

Example 3

O-cyanobenzaldehyde (1 mmol), 4-chlorophenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4c in 69% yield.¹H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.56-7.49 (m, 7H), 7.42 (d, J = 8.2 Hz, 2H), 5.96-5.94 (m, 1H), 3.52-3.47 (m, 1H), 3.23-3.17 (m, 1H). ¹³C NMR (125 MHz, CDCl3) δ 196.3, 166.8, 144.8, 140.5, 135.7, 134.5, 132.7, 132.4, 131.5, 129.1, 128.9, 123.1, 118.7, 56.6, 41.8. HRMS (ESI) calcd for C₂₂H₁₆BrClNO₂ ([M+H]+): 440.0047 found 440.0039。

Example 4

O-cyanobenzaldehyde (1 mmol), 4-bromophenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4d in 65% yield.

Example 5

O-cyanobenzaldehyde (1 mmol), 4-trifluoromethylphenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were charged in a 15mL pressure tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4e in 65% yield.

Example 6

O-cyanobenzaldehyde (1 mmol), 4-nitrophenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4f in a yield of 72%.

Example 7

O-cyanobenzaldehyde (1 mmol), 4-methylphenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were charged in a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4g of 81% yield.

Example 8

O-cyanobenzaldehyde (1 mmol), 2-methylphenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give a yield of 79% for 4 hours.

Example 9

O-cyanobenzaldehyde (1 mmol), naphthylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to obtain 4i in 85% yield.

Example 10

O-cyanobenzaldehyde (1 mmol), 2,3,4, 5-tetrafluorophenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ and reacted for 2 hours, and the product was separated by silica gel column chromatography to give 4j in 75% yield.

Example 11

O-cyanobenzaldehyde (1 mmol), 2-thiophenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4k in 52% yield.

Example 12

O-cyanobenzaldehyde (1 mmol), phenylacetylene (2 mmol), diphenyliodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4l of 91% yield.

Example 13

O-cyanobenzaldehyde (1 mmol), phenylacetylene (2 mmol), bis (4-fluorobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to obtain 4m of 78% yield.

Example 14

O-cyanobenzaldehyde (1 mmol), phenylacetylene (2 mmol), bis (4-chlorobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to obtain 4n in 79% yield.

Example 15

O-cyanobenzaldehyde (1 mmol), phenylacetylene (2 mmol), bis (4-toluene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were charged in a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to obtain 4 ℃ in 82% yield.

Example 16

O-cyanobenzaldehyde (1 mmol), phenylacetylene (2 mmol), bis (4-benzyl ether) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to obtain 4p in 83% yield.

Example 17

O-cyanobenzaldehyde (1 mmol), phenylacetylene (2 mmol), bis (4-trifluorotoluene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were charged in a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to obtain 4q of 70% yield.

Example 18

5-fluoro-2-acylbenzonitrile (1 mmol), phenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4r in 66% yield.

Example 19

5-chloro-2-acylbenzonitrile (1 mmol), phenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were charged in a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give a yield of 4s of 76%.

Example 20

5-methoxy-2-acylbenzonitrile (1 mmol), phenylacetylene (2 mmol), bis (4-bromobenzene) iodonium trifluoromethanesulfonate (1.5mmol), trifluoromethanesulfonic acid (1.5mmol), copper trifluoromethanesulfonate (10 mmol%) and 2mL of o-dichloroethane were added to a 15mL pressure-resistant tube, stirred at 110 ℃ for 2 hours, and subjected to silica gel column chromatography to give 4t of 79% yield.