Detailed Description
The invention will be further illustrated with reference to specific examples, which are to be understood as illustrative only and are not intended to limit the scope of the invention.
Example 1
1. Cup [4] cyclohexanediamine Synthesis of catalyst I
Sequentially weighing 5-aldehyde-25, 26,27, 28-tetrapropoxy calix [4] arene (620 mg,1 mmol), cyclohexanediamine acetyl (314 mg,2 mmol) and anhydrous sodium sulfate 100mg in a round bottom flask, taking methanol as a solvent (20 mL), carrying out reflux reaction, monitoring the reaction progress by TLC until the raw materials are completely reacted, adding sodium borohydride (189 mg,5 mmol) in two batches under the ice water bath condition, raising the reaction temperature to 60 ℃, quenching the reaction after the completion of the raw materials, concentrating the reaction liquid, and extracting with water and dichloromethane. The combined organic phases were collected and concentrated and recrystallized from dichloromethane/acetonitrile to give the pure calixarene imine intermediate compound (525 mg, 69% yield).
White solid ;Mp:1H NMR(300MHz,CDCl3)δ6.58–6.38(m,11H),5.43(d,J＝7.0Hz,1H),4.37(d,J＝13.3Hz,4H),3.76(t,J＝7.5Hz,8H),3.53–3.35(m,2H),3.26(d,J＝12.8Hz,1H),3.12–2.99(m,4H),2.19–2.05(m,1H),1.99(d,J＝9.4Hz,1H),1.92–1.77(m,12H),1.72–1.54(m,1H),1.30–1.02(m,4H),0.91(t,J＝7.4Hz,12H).13C NMR(75MHz,CDCl3)δ170.30,156.78,156.65,156.58,155.75,135.34,135.30,135.28,135.16,135.10,135.04,135.03,133.88,128.19,128.15,128.13,128.07,127.97,127.90,121.98,121.90,121.65,76.77,59.82,53.42,49.98,32.63,31.82,31.07,24.93,24.77,23.80,23.31,10.42.
Calixarene imine intermediate compound (761 mg,1 mmol) and potassium carbonate (1.1 g,8 mmol) are weighed in turn into a round bottom flask, dichloromethane is taken as solvent (40 mL), stirring is carried out for 1h at 0 ℃, benzyl bromide (1.92 mL,8 mmol) is added, stirring is carried out at room temperature, the reaction progress is monitored by TLC, after 6h, the raw materials are completely reacted, the reaction solution is concentrated, and the pure acetyl protected cyclohexanediamine calixarene intermediate is obtained by recrystallization by using dichloromethane/acetonitrile. The intermediate was then added to a round bottom flask with CH3 OH as solvent (30 mL), 36% HCl (1.5 mL) was added dropwise in three portions, the reaction was refluxed for 24h, the reaction stopped, extracted three times with water and dichloromethane, the concentrated organic phases were combined and recrystallized from dichloromethane/acetonitrile to give compound I (495 mg, 68% yield).
White solid ;Mp:81℃;1H NMR(300MHz,CDCl3)δ7.40–7.12(m,5H),6.71–6.40(m,10H),6.29(t,J＝7.5Hz,1H),4.43(d,J＝13.2Hz,4H),3.91–3.73(m,8H),3.55(dd,J＝30.1,13.5Hz,2H),3.29–2.93(m,6H),2.67–2.48(m,1H),2.17–2.02(m,1H),2.02–1.83(m,10H),1.79–1.55(m,4H),1.14–0.90(m,16H).13C NMR(75MHz,CDCl3)δ156.69,156.65,156.59,155.53,140.48,135.32,135.28,135.07,135.01,134.77,134.75,133.23,129.08,128.61,128.29,128.23,128.18,128.13,126.76,122.01,121.78,76.88,76.83,76.80,64.61,53.91,52.99,51.38,35.18,31.17,31.09,31.06,25.93,25.35,23.40,23.35,23.30,22.67,10.50,10.46,10.43,10.41.
2. Cup [4] cyclohexanediamine Synthesis of catalyst II
Calixarene imine intermediate compound (761 mg,1 mmol), potassium carbonate (1.1 g,8 mmol) were weighed in sequence in a 100mL round bottom flask, acetonitrile as solvent (40 mL), stirred at room temperature for 1h, iodoethane (0.64 mL,8 mmol) was added, reflux reaction was stopped for 12h, extraction was performed three times with dichloromethane and water, the organic phase was concentrated, and recrystallization was performed with dichloromethane/acetonitrile to obtain pure acetyl protected cyclohexanediamine calixarene intermediate. The intermediate was then added to a 50mL round bottom flask with CH3 OH as solvent (30 mL), 36% HCl (1.5 mL) was added dropwise in three portions, the reaction was refluxed for 24h, stopped, extracted three times with dichloromethane and water, the organic phase was concentrated and recrystallized from dichloromethane/acetonitrile to give compound II (526 mg, 88% yield).
Yellow solid ;Mp:57℃;1H NMR(300MHz,CDCl3)δ6.67–6.52(m,11H),4.50–4.38(m,4H),3.89–3.78(m,8H),3.51(d,J＝14.0Hz,1H),3.18–3.09(m,4H),3.03(d,J＝14.1Hz,1H),2.58–2.49(m,1H),2.38–2.21(m,2H),2.18–2.11(m,1H),1.99–1.87(m,9H),1.83–1.60(m,5H),1.22–0.96(m,16H),0.91(t,J＝7.0Hz,3H).13C NMR(75MHz,CDCl3)δ156.73,156.58,156.54,155.38,135.30,135.25,135.22,135.15,135.09,134.98,134.77,134.71,133.96,128.26,128.17,128.09,127.79,122.03,121.95,121.75,77.36,76.88,76.83,76.80,76.77,65.17,52.96,51.30,43.52,35.25,31.12,31.05,26.12,25.27,23.39,23.33,23.06,14.54,10.47,10.44,10.42.
3. Cup [4] cyclohexanediamine Synthesis of catalyst III
Calixarene imine intermediate compound (761 mg,1 mmol), potassium carbonate (1.1 g,8 mmol) were weighed into a 100mL round bottom flask, acetonitrile as solvent (40 mL), stirred at room temperature for 1h, iodohexane (1.1 mL,8 mmol) was added, reflux reaction was stopped for 12h, extraction was performed three times with dichloromethane and water, the organic phase was concentrated, and recrystallisation was performed with dichloromethane/acetonitrile to obtain pure acetyl protected cyclohexanediamine calixarene intermediate. The intermediate was then added to a 50mL round bottom flask with CH3 OH as solvent (30 mL) and 36% hcl (1.5 mL) was added dropwise in three portions, the reaction was refluxed for 24h, stopped, extracted three times with dichloromethane and water, the organic phase was concentrated and recrystallized from dichloromethane/acetonitrile to give compound III (337 mg, 60% yield).
Yellow solid ;Mp:49℃;1H NMR(300MHz,CDCl3)δ6.82–6.56(m,5H),6.47(s,6H),4.44(dd,J＝13.4,5.7Hz,4H),3.94–3.74(m,8H),3.52(d,J＝13.7Hz,1H),3.22–3.01(m,5H),2.62–2.48(m,1H),2.49–2.33(m,1H),2.35–2.21(m,1H),2.13(t,J＝9.4Hz,1H),2.04–1.67(m,13H),1.42–1.10(m,12H),1.07–0.83(m,16H).13C NMR(75MHz,CDCl3)δ157.06,156.32,156.30,155.72,135.76,135.72,135.20,135.16,134.89,134.83,134.79,134.77,133.89,128.82,128.41,128.33,127.99,127.94,121.99,121.75,77.36,76.86,76.83,76.78,65.52,53.60,51.34,49.81,34.90,32.00,31.11,31.06,29.13,27.30,26.04,25.26,23.43,23.40,23.33,23.28,22.89,22.85,14.29,10.57,10.38,10.32.
4. Cup [4] cyclohexanediamine Synthesis of catalyst IV
Calixarene imine intermediate compound (761 mg,1 mmol), potassium carbonate (1.1 g,8 mmol) were weighed into a 100mL round bottom flask, acetonitrile as solvent (40 mL), stirred at room temperature for 1h, 2-iodopropane (0.8 mL,8 mmol) was added, reflux reaction was stopped for 12h, extraction was performed three times with dichloromethane and water, the organic phase was concentrated, and recrystallisation was performed with dichloromethane/acetonitrile to obtain pure acetyl protected cyclohexanediamine calixarene intermediate. The intermediate was then added to a 50mL round bottom flask with CH3 OH as solvent (30 mL) and 36% hcl (1.5 mL) was added dropwise in three portions, the reaction was refluxed for 24h, stopped, extracted three times with dichloromethane and water, the organic phase was concentrated and recrystallized from dichloromethane/acetonitrile to give compound IV (416 mg, 78% yield).
Yellow solid ;Mp:71℃;1H NMR(300MHz,CDCl3)δ6.72–6.47(m,11H),4.44(dd,J＝13.3,5.8Hz,4H),3.83(t,J＝7.5Hz,8H),3.48(d,J＝14.2Hz,1H),3.31–3.02(m,5H),2.94–2.73(m,1H),2.52–2.34(m,1H),2.23–2.05(m,1H),2.00–1.55(m,14H),1.35–0.88(m,22H).13C NMR(75MHz,CDCl3)δ156.77,156.54,156.50,155.32,135.35,135.33,135.22,135.18,135.10,135.04,134.85,134.72,134.57,128.18,128.15,128.13,128.10,128.06,128.04,127.84,122.00,121.93,121.65,76.81,76.79,62.64,51.83,48.64,48.02,35.08,31.09,31.03,28.19,26.38,25.37,23.37,23.34,23.31,22.96,18.60,10.45,10.39.
Example 2
Screening the catalytic effect of the cyclohexane diamine derivatives I-IV of the calix [4 ]. The experimental method comprises the steps of sequentially adding p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (0.5 mmol), a calixarene catalyst (2 mol%), p-nitrobenzoic acid (2 mol%) and water (1.5 mL) into a test tube, stirring at 25 ℃ for reaction for 24 hours, ending the reaction, concentrating the reaction solution after the reaction, and separating by a chromatographic column (ethyl acetate: petroleum ether=1:5), thereby obtaining an Aldol addition product.
1. The calixarene catalyst I is used, the yield of the target product is 88%, the anti/syn is 59:41, and the ee of the anti product is 88%;
2. the calixarene catalyst II is used, the yield of the target product is 94%, the anti/syn is 87:13, and the ee of the anti product is 94%;
2. The calixarene catalyst III is used, the yield of the target product is 90%, the anti/syn is 80:20, and the ee of the anti product is 90%;
2. the calixarene catalyst IV is used, the yield of the target product is 91%, the anti/syn is 64:36, and the ee of the anti product is 91%.
Example 3
The solvent dosage of the reaction is screened. The experimental method comprises the steps of sequentially adding p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (0.5 mmol), calixarene catalyst II (2 mol%), p-nitrobenzoic acid (2 mol%) and water into a test tube, stirring at 25 ℃ for reaction for 24 hours, ending the reaction, concentrating the reaction solution after the reaction, and separating by a chromatographic column (ethyl acetate: petroleum ether=1:5), thereby obtaining an Aldol addition product.
1. The water consumption is 0.5mL, the yield of the target product is 68%, the anti/syn is 86:14, and the ee of the anti product is 93%;
2. the water consumption is 1mL, the yield of the target product is 92%, the anti/syn is 87:13, and the ee of the anti product is 93%;
3. The water consumption is 1.5mL, the yield of the target product is more than or equal to 99%, the anti/syn is 87:13, and the ee of the anti product is 94%;
4. the water consumption is 2mL, the yield of the target product is more than or equal to 99%, the anti/syn is 63:37, and the ee of the anti product is 94%.
Example 4
The range of application of aldehyde substrates to catalyze asymmetric reactions was examined using the best experimental conditions in example 3. The experimental method comprises the steps of sequentially adding p-nitrobenzaldehyde (0.5 mmol), cyclohexanone (0.5 mmol), calixarene catalyst II (2 mol%), p-nitrobenzoic acid (2 mol%) and water (1.5 mL) into a test tube, stirring at 25 ℃ for reaction for 24 hours, ending the reaction, concentrating the reaction solution after the reaction, separating by a chromatographic column (ethyl acetate: petroleum ether=1:5), and obtaining a pure Aldol addition product, wherein the yield is more than or equal to 99%, the anti/syn is 87:13, and the ee of the anti product is 94%.
Example 5
This example was identical to example 4, using o-nitrobenzaldehyde instead of p-nitrobenzaldehyde to give an Aldol addition product in 87% yield with an anti/syn of 71:29 and an ee of 93%.
Example 6
This example is similar to example 4, using m-nitrobenzaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product in 92% yield, 75:25 anti/syn and 87% ee of anti product.
Example 7
This example is similar to example 4, using m-2, 4-dinitrobenzaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product in a yield of 91%, 86:14 anti/syn and 91% ee of anti product.
Example 8
This example is similar to example 4, using p-cyanobenzaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product with a yield of 93%, an anti/syn of 74:26 and an ee of 93%.
Example 9
This example is similar to example 4, using para-trifluoromethylbenzaldehyde instead of para-nitrobenzaldehyde to give an Aldol addition product in 93% yield, 87:13 anti/syn and 93% ee of anti product.
Example 10
This example is similar to example 4, using 2-fluorobenzaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product in 77% yield, 99:1 anti/syn and 93% ee of anti product.
Example 11
This example was identical to example 4, and 4-fluorobenzaldehyde was used instead of p-nitrobenzaldehyde to give an Aldol addition product in a yield of 72%, anti/syn of 75:25 and ee of 93%.
Example 12
This example is similar to example 4, using 4-chlorobenzaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product in a yield of 70%, an anti/syn of 61:39 and an ee of 88%.
Example 13
This example is similar to example 4, using 3-chlorobenzaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product in 80% yield, 70:30 anti/syn and 89% ee of anti product.
Example 14
This example is similar to example 4, using 4-bromobenzaldehyde instead of p-nitrobenzaldehyde to give an Aldol addition product in 77% yield, 64:36 anti/syn and 88% ee of anti product.
Example 15
This example is similar to example 4, using 2-iodobenzaldehyde instead of p-nitrobenzaldehyde to give an Aldol addition product in 83% yield, 71:29 anti/syn and 95% ee of anti product.
Example 16
This example was identical to example 4, using benzaldehyde instead of p-nitrobenzaldehyde to give an Aldol addition product in a yield of 72%, anti/syn of 65:35 and ee of 84%.
Example 17
This example is similar to example 4, using 1-naphthacene instead of p-nitrobenzaldehyde gives an Aldol addition product in 63% yield, 57:43 anti/syn and 86% ee of anti product.
Example 18
This example is similar to example 4, using 2-naphtalene benzaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product with a yield of 85%, an anti/syn of 76:24 and an ee of 89%.
Example 19
This example is similar to example 4, using p-phenyl benzaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product in 75% yield, 67:33 anti/syn and 96% ee of anti product.
Example 20
This example is similar to example 4, using para-2-pyridylaldehyde instead of para-nitrobenzaldehyde gives an Aldol addition product with a yield of 84%, an anti/syn of 68:32 and an ee of 89%.
Example 21
This example is similar to example 4, using p-5-phenyl-2-thiophenecarboxaldehyde instead of p-nitrobenzaldehyde gives an Aldol addition product with a yield of 55%, an anti/syn of 64:36 and an ee of 83%.
Example 22
This example, with reference to example 4, using cyclobutanone instead of cyclohexanone gives a pure Aldol addition product with a yield of >50%, an anti/syn of 37:63 and an anti product ee of 34%.
Example 23
This example was identical to example 4, using cyclopentanone instead of cyclohexanone to give an Aldol addition product in 75% yield, 56:44 anti/syn and 92% ee of anti product.
Example 24
This example was identical to example 4, using cycloheptanone instead of cyclohexanone to give an Aldol addition product in 66% yield with an anti/syn of 46:54 and an anti product ee of 64%.
Example 25
This example is similar to example 4, using tetrahydrothiopyranone instead of cyclohexanone to give an Aldol addition product in 63% yield, 59:41 anti/syn and 80% ee of anti product.
Example 26
This example was identical to example 4, and replaced with cyclohexanone by tetrahydropyranone to give an Aldol addition product in 60% yield, 44:56 anti/syn and 81% ee of anti product.
Comparative example 1
This comparative example was identical to example 4, using acetic acid as an additive instead of p-nitrobenzoic acid to give an Aldol addition product in a yield of 26%, anti/syn of 80:20 and an ee of 92%.
Comparative example 2
This comparative example was identical to example 4, using trifluoroacetic acid as an additive instead of p-nitrobenzoic acid to give an Aldol addition product in 61% yield, 81:19 anti/syn and 91% ee of anti product.
Comparative example 3
This comparative example was identical to example 4, using cyclohexanone itself in excess as solvent to give an Aldol addition product in a yield of 50%, anti/syn of 41:59 and ee of 45%.
With the above-described preferred embodiments according to the present invention as an illustration, the above-described descriptions can be used by persons skilled in the relevant art to make various changes and modifications without departing from the scope of the technical idea of the present invention. The technical scope of the present invention is not limited to the description, but must be determined according to the scope of claims.