METHOD FOR CARRYING OUT REACTION OF ISATIN COMPOUND AND CYCLOPROPENONE COMPOUND AT LOW CATALYTIC AMOUNT

Abstract

A method for the reaction of an isatin and cyclopropenone compound at low catalytic amount. In the presence of an amine compound and phosphite, the isatin and cyclopropenone are reacted in an organic solvent using a silicon amino rare earth compound as a catalyst to synthesize pyrano[2,3-b]indol-2-one compounds. In the reaction above, the amount of catalyst is few, and noble metal is not needed for catalysis. The present method can achieve preparation of the pyrano[2,3]indol-2-one compound efficiently and simply.

Claims

1. A method for reacting an isatin with a cyclopropenone compound at low catalytic amount, comprising the following steps: using a silicon amino rare earth compound as a catalyst for reacting the isatin with the cyclopropenone compound in an organic solvent in the presence of an amine compound and a phosphite ester; the chemical structural formula of the silicon amino rare earth compound is as follows: ##STR00033## wherein: Ln is a trivalent rare earth metal ion; the chemical structural formula of the amine compound is as follows: ##STR00034## the general structure of the isatin is as follows: ##STR00035## wherein: R.sup.1 is selected from the group consisting of allyl, benzyl, ethyl, methyl, and acetyl; R.sup.2 is selected from the group consisting of chlorine, fluorine, bromine, methyl, methoxy, nitro, trifluoromethyl, and trifluoromethoxy; the general structure of the cyclopropenone is as follows: ##STR00036## wherein: Ar is selected from the group consisting of phenyl, 4-methylphenyl, 4-fluorophenyl, and 4-chlorophenyl.

2. The method according to claim 1, wherein a molar ratio of the catalyst to the amine compound is range from 1:1 to 1:3.

3. The method according to claim 1, wherein the organic solvent is selected from the group consisting of 1,4-dioxane, ethylene glycol dimethyl ether, tetrahydrofuran, 1,2-dichloroethane, chlorobenzene, toluene, and n-hexane; the isatin reacts with the cyclopropenone compound under anhydrous and anaerobic conditions; the phosphite ester is diethyl phosphite.

4. The method according to claim 1, wherein by moles, an amount of the isatin is 1.2 times that of the cyclopropenone compound; an amount of the silicon amino rare earth compound is 10% of the cyclopropenone compounds.

5. The method according to claim 1, wherein: a product of the reaction between the isatin and the cyclopropenone compound is a pyrano[2,3-b]indol-2-one compound.

6. The method according to claim 1, wherein a reaction temperature is from 100? C. to 120? C.; a reaction time is from 2 hours to 3 hours.

7. The method according to claim 1, wherein mixing the silicon amino rare earth compound and the amine compound in the organic solvent; then mixing the phosphite ester, the isatin and the organic solvent for reaction, and then the cyclopropenone compound and the organic solvent are added for reaction.

8. An application of an amine compound and a silicon amino rare earth compound in the reaction of an isatin and a cyclopropenone compound.

9. The application according to claim 8, wherein the chemical structural formula of the amine compound is as follows: ##STR00037## the chemical structural formula of the silicon amino rare earth compound is as follows: ##STR00038## wherein: Ln is a trivalent rare earth metal ion.

10. The application according to claim 8, wherein by moles, an amount of the silicon amino rare earth compound is 10% of that of the cyclopropenone compound; a molar ratio of the silicon amino rare earth to the amine compound is from 1:1 to 1:3.

Description

EXAMPLES OF THE PRESENT INVENTION

[0030] The present invention uses isatin compound, phosphite ester, and cyclopropenone as reactants, and silicon amino rare earth compound as catalyst to prepare pyrano[2,3-b]indol-2-one compounds in the presence of amine compound in an organic solvent under anhydrous and anaerobic conditions. It doesn't need other reagents and other reaction steps, and the reaction materials are mixed for reaction to obtain the product of the present invention. After conventional purification, the purified product is obtained with simple steps.

[0031] The raw materials of the present invention are all existing products, and the specific operating and testing methods are conventional methods in the field. Unless otherwise specified, they are all carried out under conventional conditions. The following is a further description of the present invention in conjunction with an Example: Synthesis Example 1: Synthesis of catalyst [(Me.sub.3Si).sub.2N].sub.3La(?-Cl)Li(THF).sub.3: n-buLi hexane solution (60 mmol, 2.52M) was drop wise added to a 100 mL Schlenk reaction flask containing (Me.sub.3Si).sub.2NH (60 mmol) at ?10? C., and the reaction was carried out at room temperature for 30 minutes. The above reaction solution was added to the anhydrous LaCl.sub.3 (20 mmol) THF (30 mL) suspension and stirred overnight at room temperature. The solvent was removed under reduced pressure to Cl) Li obtain the solid powder, which was extracted with hot toluene to remove LiCl, concentrated and placed at 0? C. to precipitate a large number of crystals, which were the desired aminosilylation lanthanum compound with a yield of 85%.

[0032] For the other catalysts, the preparation method of Example 1 can be used as reference.

[0033] Synthesis example 2: Synthesis of amine compound L.sub.1 and amine compound L.sub.2

##STR00009##

[0034] The aniline (1.82 mL, 20 mmol) and 1,3-diphenyl-1,3-dione (5.38 g, 24 mmol) were mixed in 80 mL of toluene, and then p-toluenesulfonic acid (0.35 g, 2 mmol) was added. The mixture was refluxed with an oil-water separator to remove water for 24 hours and cooled. The solvent was removed under reduced pressure, and the residue was separated using a silica gel column (eluent: ethyl acetate: petroleum ether=1:60) to obtain a yellow solid. The yellow solid was mixed with 2,6-dimethylaniline hydrochloride (1.77 g, 11.2 mmol) in 50 mL of ethanol and reflux for 48 hours. Then it was cooled and filtered. After the filtrate was concentrated, ethanol and water were added, neutralized with a sodium hydroxide aqueous solution, and extracted with ether. The obtained organic phase was dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and a yellow solid was obtained using a silica gel column, which was the desired L.sub.1 with a yield of 10%. The main nuclear magnetic testing data are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 12.90 (s, 1H), 7.45-7.43 (m, 2H), 7.31-7.16 (m, 8H), 7.07 (t, J=7.7 Hz, 2H), 6.92-6.80 (m, 4H), 6.70 (d, J=7.8 Hz, 2H), 5.42 (s, 1H), 2.10 (s, 6H).

[0035] 2,6-dimethylaniline (20 g, 0.17 mol), 2,4-pentanedione (8.25 g, 0.08 mol), and p-toluenesulfonic acid (14.2 g, 0.08 mol) were mixed in 250 mL of toluene and reflux for 24 hours. Toluene was poured out and 200 mL of ether, 150 mL of water, and 36 g of sodium carbonate decahydrate were added to the solid residue, and stirred for 25 min. The separated ether layer was dried with magnesium sulfate and the solvent was removed under reduced pressure. The residue was vacuum dried at 100? C. for 6 hours to obtain the required solid L.sub.2 with a yield of 70%. The main nuclear magnetic testing data are as follows: .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 12.25 (s, 1H), 7.09-6.97 (m, 6H), 4.93 (s, 1H), 2.21 (s, 12H), 1.74 (s, 6H).

[0036] Example: the preparation of pyrano[2,3-b]indol-2-one compound with [(Me.sub.3Si).sub.2N].sub.3La(?-Cl)Li(THF).sub.3 catalyzed N-ethyl isatin, diethyl phosphite and diphenylcyclopropenone: at room temperature, [(Me.sub.3Si).sub.2N].sub.3La(?-Cl)Li(THF).sub.3 (21.1 mg, 0.024 mmol, 10 mol %), L.sub.1 (9.7 mg, 0.024 mmol) and toluene (0.1 mL) were weighed into a reaction flask after dehydration and deoxygenation treatment under argon protection for conventional mixing for 10 minutes, then diethyl phosphite (Compound 2, 37 ?L, 0.29 mmol), isatin (N-ethyl isatin, 0.29 mmol) and toluene (0.3 mL) were added for conventional stirring and mixing for 30 min, and then toluene (0.6 mL) and 2,3-diphenylcyclohexanone (Compound 3, 50 mg, 0.24 mmol) were added and stirred at 110? C. for 2.5 h, and water was added to terminate the reaction. After that, it was extracted with ethyl acetate for three times, and the extract was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, a yellow solid product was obtained through rapid column chromatography with a silica gel column (eluent: ethyl acetate: petroleum ether=1:10), with a yield of 88%; the theoretical molecular formula and main nuclear magnetic testing data of the prepared product were as follows. Through analysis, it could be seen that the actual synthesized product is consistent with the theoretical analysis.

[0037] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.36-7.31 (m, 4H), 7.25-7.21 (m, 3H), 7.19-7.10 (m, 5H), 7.00-6.96 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H).

[0038] The isatin (Compound 1: 0.29 mmol) was changed with the remaining conditions keeping unchanged. The prepared product, pyrano[2,3-b]indol-2-one compound (Compound 4), and the separation yield are as follows.

##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##

[0039] The 2,3-diphenylcyclohexanone (Compound 3, 0.24 mmol) was changed with the remaining conditions keeping unchanged. The prepared product, pyrano[2,3-b]indol-2-one compound (Compound 4), and the separation yield are as follows.

##STR00016##

[0040] The above reaction process is as follows.

##STR00017##

[0041] The theoretical molecular formulas and main nuclear magnetic testing data of some of the products obtained are as follows:

##STR00018##

[0042] .sup.1H NMR (400 MHz, CDCl.sub.2) ?: 7.33-7.30 (m, 4H), 7.24-7.20 (m, 3H), 7.19-7.12 (m, 5H), 7.02-6.98 (m, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 3.82 (s, 3H).

##STR00019##

[0043] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.34-7.32 (m, 4H), 7.25-7.13 (m, 8H), 7.01-6.97 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.05-5.96 (m, 1H), 5.30-5.20 (m, 2H), 4.91 (d, J=5.2 Hz, 2H).

##STR00020##

[0044] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.35-7.24 (m, 11H), 7.21-7.12 (m, 6H), 7.00-6.96 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 5.50 (s, 2H).

##STR00021##

[0045] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.35 (d, J=8.4 Hz, 1H), 7.25-7.21 (m, 1H), 7.16-7.11 (m, 4H), 7.05-6.98 (m, 5H), 6.84 (d, J=8.0 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 2.37 (s, 3H), 2.26 (s, 3H), 1.50 (t, J=7.2 Hz, 3H).

##STR00022##

[0046] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.38 (d, J=8.0 Hz, 1H), 7.28-7.19 (m, 3H), 7.12-7.01 (m, 5H), 6.92-6.87 (m, 2H), 6.82 (d, J=8.0 Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 1.52 (t, J=7.2 Hz, 3H).

##STR00023##

[0047] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.33-7.31 (m, 3H), 7.28-7.24 (m, 1H), 7.22-7.11(m, 7H), 6.97-6.92 (m, 1H), 6.45-6.42 (m, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H).

##STR00024##

[0048] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.35-7.33 (m, 3H), 7.25-7.24 (m, 1H), 7.22-7.12 (m, 8H), 6.72 (d, J=2.0 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.49 (t, J=7.2 Hz, 3H).

##STR00025##

[0049] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.37-7.31 (m, 4H), 7.24-7.13 (m, 8H), 6.87 (d, J=2.0 Hz, 1H), 4.34 (q, J=7.2 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H).

##STR00026##

[0050] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.35-7.31 (m, 3H), 7.25-7.21 (m, 3H), 7.19-7.11 (m , 5H), 7.07-7.04 (m, 1H), 6.56-6.55 (m, 1H), 4.33 (q, J=7.2 Hz, 2H), 2.23 (s, 3H), 1.49 (t, J =7.2 Hz, 3H).

##STR00027##

[0051] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.35-7.32 (m, 3H), 7.25-7.22 (m, 3H), 7.18-7.11 (m, 5H), 6.86-6.83 (m, 1H), 6.22 (d, J=2.4 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 3.53 (s, 3H), 1.49 (t, J=7.2 Hz, 3H).

##STR00028##

[0052] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.29-7.27 (m, 1H), 7.18-7.15 (m, 5H), 7.14-7.09 (m, 4H), 7.07-7.04 (m, 3H), 4.39 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H).

##STR00029##

[0053] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.39-7.34 (m, 4H), 7.26-7.17 (m, 7H), 7.00-6.97 (m, 1H), 6.71 (d, J=8.4 Hz, 1H), 4.36 (q, J=7.2 Hz, 2H), 1.55 (t, J=7.2 Hz, 3H).

##STR00030##

[0054] .sup.1H NMR (400 MHz, CDCl.sub.3) ?: 7.34-7.32 (m, 3H), 7.21-7.14 (m, 8H), 6.87-6.84 (m, 1H), 6.61 (d, J=7.6 Hz, 1H), 4.76 (q, J=7.2 Hz, 2H), 1.55 (t, J=7.2 Hz, 3H).

[0055] Extended Example 1: at room temperature, [(Me.sub.3Si).sub.2N].sub.3La (?-Cl)Li(THF).sub.3 (211 mg, 0.24 mmol, 10 mol %) , L.sub.1 (97 mg, 0.24 mmol) and toluene (0.1 mL) were weighed into a reaction flask after dehydration and deoxygenation treatment under argon protection for conventional mixing for 10 minutes, then diethyl phosphite (2.9 mmol), N-ethyl isatin (2.9 mmol) and toluene (3 mL) were added for conventional stirring and mixing for 30 min, and then toluene (6 mL) and 2,3-diphenylcyclohexanone (2.4 mmol) were added and stirred at 110? C. for 2.5 h, and water was added to terminate the reaction. After that, it was extracted with ethyl acetate for three times, and the extract was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, a yellow solid product was obtained through rapid column chromatography with a silica gel column (eluent: ethyl acetate: petroleum ether=1:10), with a yield of 68%; the theoretical molecular formula and main nuclear magnetic testing data of the prepared product were as follows. Through analysis, it could be seen that the actual synthesized product is consistent with the theoretical analysis.

[0056] Reaction time 2.5 hours was adjusted to 5 hours, and the rest remained unchanged to obtain product 0.665 g, yield 76%; as follows:

##STR00031##

Extended Example 2: at room temperature, [(Me.sub.3Si).sub.2N].sub.3La(?-Cl)Li(THF).sub.3(21.1 mg, 0.024 mmol, 10 mol %) ,L.sub.1(28.9 mg, 0.072 mmol) and toluene (0.1 mL) were weighed into a reaction flask after dehydration and deoxygenation treatment under argon protection for conventional mixing for 10 minutes, then diethyl phosphite (Compound 2, 37 ?L, 0.29 mmol), isatin (N-ethyl isatin, 0.29 mmol) and toluene (0.3 mL) were added for conventional stirring and mixing for 30 min, and then toluene (0.6 mL) and 2,3-diphenylcyclohexanone (Compound 3, 50 mg, 0.24 mmol) were added and stirred at 110? C. for 2.5 h, and water was added to terminate the reaction. After that, it was extracted with ethyl acetate for three times, and the extract was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, a yellow solid product was obtained through rapid column chromatography with a silica gel column (eluent: ethyl acetate: petroleum ether=1:10), with a yield of 85%; the theoretical molecular formula and main nuclear magnetic testing data of the prepared product were as follows. Through analysis, it could be seen that the actual synthesized product is consistent with the theoretical analysis.

Control

[0057] ##STR00032##

[0058] At room temperature, [(Me.sub.3Si).sub.2N].sub.3La(?-Cl)Li(THF).sub.3(21.1 mg, 0.024 mmol, 10 mol %) ,L.sub.2(7.3 mg, 0.024 mmol) and toluene (0.1 mL) were weighed into a reaction flask after dehydration and deoxygenation treatment under argon protection for conventional mixing for 10 minutes, then diethyl phosphite (Compound 2, 37 ?L, 0.29 mmol), isatin (N-ethyl isatin, 0.29 mmol) and toluene (0.3 mL) were added for conventional stirring and mixing for 30 min, and then toluene (0.6 mL) and 2,3-diphenylcyclohexanone (Compound 3, 50 mg, 0.24 mmol) were added and stirred at 110? C. for 2.5 h, and water was added to terminate the reaction. After that, it was extracted with ethyl acetate for three times, and the extract was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, a yellow solid product was obtained through rapid column chromatography with a silica gel column (eluent: ethyl acetate: petroleum ether=1:10), with a yield of 55%; the theoretical molecular formula and main nuclear magnetic testing data of the prepared product were as follows. Through analysis, it could be seen that the actual synthesized product is consistent with the theoretical analysis.

[0059] At room temperature, [(Me.sub.3Si).sub.2N].sub.3La(?-Cl)Li(THF).sub.3(21.1 mg, 0.024 mmol, 10 mol %) ,L.sub.2(22.0 mg, 0.072 mmol) and toluene (0.1 mL) were weighed into a reaction flask after dehydration and deoxygenation treatment under argon protection for conventional mixing for 10 minutes, then diethyl phosphite (Compound 2, 37 ?L, 0.29 mmol), isatin (N-ethyl isatin, 0.29 mmol) and toluene (0.3 mL) were added for conventional stirring and mixing for 30 min, and then toluene (0.6 mL) and 2,3-diphenylcyclohexanone (Compound 3, 50 mg, 0.24 mmol) were added and stirred at 110? C. for 2.5 h, and water was added to terminate the reaction. After that, it was extracted with ethyl acetate for three times, and the extract was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, a yellow solid product was obtained through rapid column chromatography with a silica gel column (eluent: ethyl acetate: petroleum ether=1:10), with a yield of 55%; the theoretical molecular formula and main nuclear magnetic testing data of the prepared product were as follows. Through analysis, it could be seen that the actual synthesized product is consistent with the theoretical analysis.

[0060] At room temperature, [(Me.sub.3Si).sub.2N].sub.3La(?-Cl)Li(THF).sub.3(21.1 mg, 0.024 mmol, 10 mol %) and toluene (0.1 mL) were weighed into a reaction flask after dehydration and deoxygenation treatment under argon protection for conventional mixing for 10 minutes, then diethyl phosphite (Compound 2, 37 ?L, 0.29 mmol), isatin (N-ethyl isatin, 0.29 mmol) and toluene (0.3 mL) were added for conventional stirring and mixing for 30 min, and then toluene (0.6 mL) and 2,3-diphenylcyclohexanone (Compound 3, 50 mg, 0.24 mmol) were added and stirred at 110? C. for 2.5 h, and water was added to terminate the reaction. After that, it was extracted with ethyl acetate for three times, and the extract was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, a yellow solid product was obtained through rapid column chromatography with a silica gel column (eluent: ethyl acetate: petroleum ether=1:10), with a yield of 48%; the theoretical molecular formula and main nuclear magnetic testing data of the prepared product were as follows. Through analysis, it could be seen that the actual synthesized product is consistent with the theoretical analysis.

[0061] At room temperature, LaCl.sub.3(0.024 mmol, 10 mol %) ,L.sub.1(0.024 mmol) and toluene (0.1 mL) were weighed into a reaction flask after dehydration and deoxygenation treatment under argon protection for conventional mixing for 10 minutes, then diethyl phosphite (Compound 2, 37 ?L, 0.29 mmol), isatin (N-ethyl isatin, 0.29 mmol) and toluene (0.3 mL) were added for conventional stirring and mixing for 30 min, and then toluene (0.6 mL) and 2,3-diphenylcyclohexanone (Compound 3, 50 mg, 0.24 mmol) were added and stirred at 110? C. for 2.5 h, and water was added to terminate the reaction. After that, it was extracted with ethyl acetate for three times, and the extract was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, there was no product obtained through rapid column chromatography with a silica gel column (eluent: ethyl acetate: petroleum ether=1:10), with a yield of 0.

[0062] Extended Example 3: at room temperature, [(Me.sub.3Si).sub.2N].sub.3Yb(?-Cl)Li(THF).sub.3 (0.024 mmol, 10 mol %) ,L.sub.1 (9.7 mg, 0.024 mmol) and toluene (0.1 mL) were weighed into a reaction flask after dehydration and deoxygenation treatment under argon protection for conventional mixing for 10 minutes, then diethyl phosphite (Compound 2, 37 ?L, 0.29 mmol), isatin (N-ethyl isatin, 0.29 mmol) and toluene (0.3 mL) were added for conventional stirring and mixing for 30 min, and then toluene (0.6 mL) and 2,3-diphenylcyclohexanone (Compound 3, 50 mg, 0.24 mmol) were added and stirred at 110? C. for 2.5 h, and water was added to terminate the reaction. After that, it was extracted with ethyl acetate for three times, and the extract was dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Finally, a yellow solid product was obtained through rapid column chromatography with a silica gel column (eluent: ethyl acetate: petroleum ether=1:10), with a yield of 62%; the theoretical molecular formula and main nuclear magnetic testing data of the prepared product were as follows. Through analysis, it could be seen that the actual synthesized product is consistent with the theoretical analysis.

[0063] The pyrano[2,3-b]indol-2-one skeleton is a very important structural unit that widely exists in natural products and pharmaceutical molecules, and has certain biological activity. Therefore, studying the efficient synthesis techniques of pyrano[2,3-b]indol-2-one skeleton has important theoretical and practical significance.