Preparation of chiral calixarene and method for water-phase catalysis of enantioselective reaction of acetone and aromatic aldehyde by using chiral calixarene

Abstract

The invention relates to the technical field of asymmetric catalysis, and particularly discloses preparation of chiral calixarene and a method for catalyzing an enantioselective reaction of acetone and aromatic aldehyde in a water phase by using the chiral calixarene. The preparation method of the chiral calixarene comprises the following steps: generating a Schiff base intermediate from 5-aldehyde-25, 26, 27, 28-tetra-n-butyl calixarene [4] and N-((1S, 2S)-2-aminocyclohexyl) acetamide, and then reducing the Schiff base intermediate by sodium borohydride to obtain a calixarene imine intermediate; and substituting the imine intermediate with iodobutane, and then removing acetyl under the action of hydrochloric acid to prepare the chiral calixarene catalyst. The catalyst can efficiently catalyze an enantioselective reaction (up to 97% yield, 92% ee) of acetone and aromatic aldehyde in a water phase.

Description

Technical Field

[0001] The invention relates to the technical field of asymmetric catalysis, and specifically discloses a method for preparing chiral calixarene and carrying out an enantioselective reaction of acetone and aromatic aldehyde by using the method and the aqueous phase. Background Art

[0002] Asymmetric aldehyde-ketone condensation reaction is one of the important CC bond-building reactions in organic chemistry and is widely used in the synthesis of bioactive ingredients and drug molecules. The special structure of the reaction product β-hydroxyketone makes it play a very important role in the synthesis of natural products. Asymmetric catalytic reaction using chiral catalysts is one of the most effective methods to obtain optically pure compounds.

[0003] Through literature research, we found that most chiral calixarenes involved in organic asymmetric Aldol reactions are connected to proline derivatives. In 2017, Shi Lanxiang et al. designed and synthesized a pentaerythritol-supported proline catalyst, which catalyzed the asymmetric Aldol reaction of p-nitrobenzaldehyde and acetone with a yield of 68% and 76% ee. In the same year, Li Xinjuan et al. used the reversible addition-fragmentation chain transfer polymerization of vinyl pyridine monomers and reacted with halogenated alkanes to prepare polypyridine ionic liquids, and then used polypyridine ionic liquids to complex with L-proline chiral monomers and further prepared heterogeneous chiral catalysts based on polyionic liquids through chiral monomer free radical polymerization, catalyzing the asymmetric Aldol reaction of p-nitrobenzaldehyde and acetone with a yield of 80% and 85% ee. The synthesis conditions of the above two proline catalysts are harsh. The first catalyst needs to be synthesized using tetrakistriphenylphosphine palladium in an inert atmosphere, and the second catalyst needs to be frozen and thawed five times before the reaction to remove oxygen to ensure a strict oxygen-free environment. Moreover, the catalytic efficiency and selectivity of the two catalysts are low. Therefore, the development of efficient chiral catalysts for the organic asymmetric Aldol reaction of small molecule acetone compounds and aromatic aldehydes still faces great challenges. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing a chiral calixarene and a method for the enantioselective reaction of acetone and aromatic aldehyde catalyzed by the aqueous phase. The structure of the chiral calixarene is shown in the following formula:

[0005]

[0006] The present invention also provides a method for preparing chiral calixarene, which comprises the following steps:

[0007] (1) 5-formyl-25,26,27,28-tetra-n-butylcalix[4]arene reacts with N-((1S,2S)-2-aminocyclohexyl)acetamide to form a Schiff base intermediate, which is then reduced with sodium borohydride to obtain a calixarene imine intermediate;

[0008] (2) The imine intermediate is substituted with iodobutane, and then the acetyl group is removed under the action of an acid to obtain a calixarene derivative catalyst. The synthetic route is as follows:

[0009]

[0010] The preparation method of the chiral calixarene is as follows: in step (1), the molar ratio of 5-formyl-25,26,27,28-tetrapropoxycalix[4]arene to N-((1S,2S)-2-aminocyclohexyl)acetamide is 1:2, and the amount of sodium borohydride added is 8 molar equivalents of 5-formyl-25,26,27,28-tetrapropoxycalix[4]arene; in step (2), the molar ratio of iodobutane to imine intermediate is 1:8, 36% HCl is used to remove the acetyl group, and then NaOH is used for alkalization to obtain the calixarene derivative catalyst.

[0011] The chiral calixarene provided by the present invention catalyzes the enantioselective reaction of acetone and aromatic aldehyde in water phase under the action of acid at room temperature, that is, the Aldol catalytic reaction is carried out with acetone and aromatic aldehyde as raw materials, calixarene derivatives as catalysts, trifluoromethanesulfonic acid as co-catalyst, and water as solvent. The reaction formula is as follows:

[0012]

[0013] Among them, the aromatic aldehydes are: p-nitrobenzaldehyde, o-nitrobenzaldehyde, m-nitrobenzaldehyde, 2,4-dinitrobenzaldehyde, p-cyanobenzaldehyde, p-trifluorobenzaldehyde, 2-iodobenzaldehyde, 2-fluorobenzaldehyde, and 2-pyridinecarboxaldehyde.

[0014] The molar ratio of aromatic aldehyde to acetone is 1:13; the amount of catalyst used is 10 mol% of the aromatic aldehyde; the amount of trifluoromethanesulfonic acid used is 10 mol% of the aromatic aldehyde; and the amount of water used when 0.5 mmol of aromatic aldehyde participates in the reaction is 0.5 mL.

[0015] The beneficial effects of the present invention are as follows: the present invention introduces a chiral cyclohexanediamine group into a calixarene skeleton, thereby destroying the symmetry in the calixarene structure, making it an inherent chiral calixarene, and can give full play to the characteristics of the calixarene skeleton structure of being wide at the top and narrow at the bottom and the long fatty chain structure connected to the tertiary amine in the aqueous phase, so that the acetone small molecule substrate can easily enter the cavity of the calixarene and be effectively fixed inside, thereby overcoming the difficulties of the acetone small molecule being difficult to control, the reaction being inefficient, and the low selectivity in the aldehyde-ketone condensation reaction. The present invention has a catalytic yield of up to 97%, a selectivity of up to 92%ee, and also greatly enriches the application scope of the chiral compound in the field of organic synthesis. DETAILED DESCRIPTION

[0016] The present invention will be further described below in conjunction with specific examples. It should be understood that the examples are only used to illustrate the present invention but not to limit the scope of the present invention.

[0017] Example 1

[0018] Preparation of chiral calixarene:

[0019]

[0020] Weigh 5-formyl-25,26,27,28-tetrapropoxycalix[4]arene (620 mg, 1 mmol), cyclohexanediamine acetyl (314 mg, 2 mmol), and anhydrous sodium sulfate (100 mg) in a flask, add 20 mL of methanol, heat the mixture to reflux, monitor the reaction progress by TLC until all the raw materials have reacted, cool to room temperature, add sodium borohydride (189 mg, 5 mmol) in two batches under ice-water bath conditions, then raise the temperature to 60°C to react until the raw materials disappear, then lower the temperature to room temperature, concentrate the reaction solution, add 15 mL of water, and extract three times with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, remove the solvent, and recrystallize using dichloromethane / acetonitrile to obtain the calixarene imine intermediate compound (525 mg, yield 69%).

[0021] White solid; Mp: 1 H 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=12.8H z,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 ).13CNMR(75MHz,CDCl3)δ170.30,156.78,156.65,156.58,155.75,135.3 4,135.30,135.28,135.16,135.10,135.04,135.03,133.88,128.19,128. 15,128.13,128.07,127.97,127.90,121.98,121.90,121.65,76.77,59.8 2,53.42,49.98,32.63,31.82,31.07,24.93,24.77,23.80,23.31,10.42.

[0022] 5-Ethylamino-25,26,27,28-tetrapropoxycalix[4]arene (761 mg, 1 mmol) and potassium carbonate (1.1 g, 8 mmol) were weighed into a round-bottom flask, acetonitrile was used as solvent (40 mL), stirred at room temperature for 1 h, iodobutane (0.9 mL, 8 mmol) was added, and heated to reflux until the raw material reaction was complete. After quenching the reaction, the organic phase was removed by rotation, dichloromethane was added, and extracted with water three times. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed by rotation, and the acetyl-protected cyclohexanediaminecalixarene intermediate (653 mg, yield was 80%) was obtained by recrystallization using dichloromethane / acetonitrile. The intermediate was then added to a 50 mL round-bottom flask, CH3OH was used as a solvent (30 mL), 36% HCl (1.5 mL) was added dropwise in three batches, and the mixture was heated to reflux. The reaction progress was monitored by TLC. After 24 h of reaction, the reaction was stopped, the reaction solution was cooled to room temperature, water (10 mL) was added to dilute the reaction solution under ice-water bath conditions, the organic phase was removed by rotation, 20 mL of dichloromethane was added, and the mixture was extracted with water (15 mL x 3), the organic phases were combined and collected, dried over anhydrous sodium sulfate, filtered, and then spin-dried. The target catalyst (515 mg, yield 83%) was obtained by recrystallization using dichloromethane / acetonitrile.

[0023] Yellow solid; Mp: 62℃; 1 H NMR (300MHz, CDCl3) δ6.84–6.58(m,5H),6.46(s,6H),4.44(dd,J=13.3,5.5Hz,4H),3.98–3.71(m,8H),3.53(d,J=13.6Hz,1H),3.25–2.99(m,5 H),2.64–2.51(m,1H),2.46–2.36(m,1H),2.34–2.24(m,1H),2.18–2.09 (m,1H),2.00–1.61(m,13H),1.39–0.91(m,21H),0.86(t,J=7.1Hz,3H). 13C NMR (75MHz, CDCl3) δ157.12,156.30,156.28,155.76,135.83,135.78,135.22,134.83,1 34.77,134.72,134.70,134.01,128.88,128.41,128.37,128.02,127.98,127.94,127.9 2,121.98,121.71,76.87,76.83,65.90,53.67,51.44,49.51,35.28,31.42,31.14,31.09,26.13,25.34,23.45,23.41,23.32,23.28,22.86,20.70,14.29,10.58,10.37,10.31.

[0024] Example 2

[0025] This example uses p-nitrobenzaldehyde and acetone as substrates to explore the main influencing factors of chiral calixarene-catalyzed asymmetric Aldol reaction: the type of acid, the type of solvent, the amount of acetone, and the reaction temperature. The experimental method is: 75.56 mg (0.5 mmol) of p-nitrobenzaldehyde, acetone, 10 mol% of calixarene catalyst, 10 mol% of acid and solvent are added to a test tube, the reaction is stopped after stirring for 24 hours, 2 mL of dichloromethane is added, and the organic phase is extracted and separated. The Aldol addition product is obtained by column chromatography separation (ethyl acetate: petroleum ether = 1:2). The results are shown in Table 1.

[0026] Table 1 Effects of different experimental conditions on asymmetric aldol reactions catalyzed by calixarene derivatives

[0027] serial number Solvent type Types of Acid Amount of acetone / mmol Temperature / ℃ Yield / % ee / % 1 DCM <![CDATA[ClCH2COOH]]> 6.5 25 28 75 2 DCM <![CDATA[m-CH3PhCOOH]]> 6.5 25 9 67 3 DCM <![CDATA[CF3SO3H]]> 6.5 25 78 90 4 <![CDATA[H2O]]> <![CDATA[CF3SO3H]]> 6.5 25 92 90 5 DMSO <![CDATA[CF3SO3H]]> 6.5 25 53 91 6 <![CDATA[H2O]]> <![CDATA[CF3SO3H]]> 3 25 20 83 7 <![CDATA[H2O]]> <![CDATA[CF3SO3H]]> 10 25 82 78 8 <![CDATA[H2O]]> <![CDATA[CF3SO3H]]> 6.5 10 26 89 9 <![CDATA[H2O]]> <![CDATA[CF3SO3H]]> 6.5 40 80 87

[0028] Example 3-11

[0029] 0.5mmol benzaldehyde derivative, 0.5mL (6.5mmol) acetone, 10mol% calixarene catalyst, 10mol% trifluoromethanesulfonic acid, 0.5mL water were added to a test tube, stirred at room temperature, and the reaction was stopped after 24h, 2mL dichloromethane was added, and the organic phase was extracted and separated. The addition product was obtained by column chromatography separation (ethyl acetate: petroleum ether = 1:2).

[0030] Table 2 Investigation of the applicability of aldehyde substrates for asymmetric aldol reactions catalyzed by calixarene derivatives

[0031]

[0032]

[0033] Comparative Example 1

[0034] 0.5 mmol of p-nitrobenzaldehyde, 0.5 mL (6.5 mmol) of acetone, and 10 mol% of chiral calixarene substituted with benzyl bromide were added. 10 mol% trifluoromethanesulfonic acid and 0.5 mL water were added to a test tube, and the reaction was stopped at 25°C for 24 h, and 2 mL dichloromethane was added to extract and separate the organic phase. The addition product was obtained by column chromatography (ethyl acetate: petroleum ether = 1:2) with a yield of 61% and 91 ee%.

[0035] Based on the above ideal embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above description. The technical scope of the present invention is not limited to the contents of the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A chiral calixarene catalyst, characterized in that: The structure of the chiral calixarene catalyst is shown below:

2. A method for preparing a chiral calixarene catalyst as claimed in claim 1, characterized in that: The preparation method steps are as follows: (1) 5-formyl-25,26,27,28-tetra-n-butylcalix[4]arene reacts with N-((1S,2S)-2-aminocyclohexyl)acetamide to form a Schiff base intermediate, which is then reduced with sodium borohydride to obtain a calixarene imine intermediate; (2) The imine intermediate undergoes a substitution reaction with iodobutane, and then the acetyl group is removed under the action of an acid to obtain a chiral calixarene catalyst. The synthesis route is shown in the following formula:

3. The preparation method according to claim 2, characterized in that: In the step (1), the molar ratio of 5-formyl-25,26,27,28-tetrapropoxycalix[4]arene to N-((1S,2S)-2-aminocyclohexyl)acetamide is 1:2, and the amount of sodium borohydride added is 8 molar equivalents of 5-formyl-25,26,27,28-tetrapropoxycalix[4]arene.

4. The preparation method according to claim 2, characterized in that: In the step (2), the molar ratio of iodobutane to the imine intermediate is 1:8, 36% HCl is used to remove the acetyl group, and then NaOH is used for alkalization to obtain the calixarene derivative catalyst.

5. The use of the chiral calixarene catalyst according to claim 1, characterized in that: The chiral calixarene catalyst catalyzes the enantioselective reaction of acetone and aromatic aldehyde in an aqueous phase under the action of an acid, and the reaction formula is as follows:

6. The use of the chiral calixarene catalyst according to claim 5, characterized in that: The aromatic aldehydes are p-nitrobenzaldehyde, o-nitrobenzaldehyde, m-nitrobenzaldehyde, 2,4-dinitrobenzaldehyde, p-cyanobenzaldehyde, p-trifluorobenzaldehyde, 2-iodobenzaldehyde, 2-fluorobenzaldehyde and 2-pyridinecarboxaldehyde.

7. The use of the chiral calixarene catalyst according to claim 5, characterized in that: The acid is trifluoromethanesulfonic acid.

8. The use of the chiral calixarene catalyst according to claim 5, characterized in that: The molar ratio of aromatic aldehyde to acetone is 1:13; the amount of catalyst used is 10 mol% of the aromatic aldehyde; the amount of acid used is 10 mol% of the aromatic aldehyde; and the amount of water used when 0.5 mmol of aromatic aldehyde participates in the reaction is 0.5 mL.

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