Preparation of chiral calixarene and method for the enantioselective reaction of acetone with aromatic aldehydes catalyzed by aqueous phase

Abstract

The present invention relates to the field of asymmetric catalysis technology, and specifically discloses a method for preparing a chiral calixarene and its aqueous phase catalytic enantioselective reaction of acetone and aromatic aldehydes. The preparation method of the chiral calixarene comprises: 5-aldehyde-25,26,27,28-tetra-n-butylcalix[4]arene and N-((1S,2S)-2-aminocyclohexyl)acetamide generate a Schiff base intermediate, which is then reduced with sodium borohydride to obtain a calixarene imine intermediate; the imine intermediate is substituted with iodine butane, and then the acetyl group is removed under the action of hydrochloric acid to obtain a chiral calixarene catalyst. The catalyst can efficiently catalyze the enantioselective reaction of acetone and aromatic aldehydes in aqueous phase (up to 97% yield, 92% ee).

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 using the method through aqueous phase catalysis. Background Art

[0002] Asymmetric aldehyde-ketone condensation is a key reaction in organic chemistry for forming C-C bonds and is widely used in the synthesis of bioactive compounds and pharmaceuticals. The unique structure of the β-hydroxyketone product makes it a crucial component in the synthesis of natural products. Asymmetric catalysis using chiral catalysts is one of the most effective methods for obtaining optically pure compounds.

[0003] A literature review revealed that most chiral calixarenes involved in organic asymmetric aldol reactions are linked 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. synthesized a polypyridine ionic liquid (PIL) by reversible addition-fragmentation chain transfer polymerization of vinylpyridine monomers and reaction with alkyl halides. They then complexed the PIL with L-proline chiral monomers and further synthesized a PIL-based heterogeneous chiral catalyst by free radical polymerization of the chiral monomers. This catalyst catalyzed the asymmetric aldol reaction of p-nitrobenzaldehyde and acetone with an 80% yield and 85% ee. The synthesis conditions for these two PIL catalysts are demanding. The first catalyst requires tetrakistriphenylphosphine palladium catalysis under an inert atmosphere, while the second catalyst requires five freeze-thaw cycles to remove oxygen before the reaction to ensure a strictly 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 acetone small molecule compounds and aromatic aldehydes still faces great challenges. Summary of the Invention

[0004] The present invention aims to provide a method for preparing a chiral calixarene and for the enantioselective reaction of acetone with aromatic aldehydes using aqueous catalysts. 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 iodine butane, and then the acetyl group is removed under the action of 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, under the action of acid, catalyzes the enantioselective reaction of acetone and aromatic aldehyde in an aqueous phase at room temperature. Specifically, the aldol-catalyzed reaction is carried out using acetone and aromatic aldehyde as raw materials, a calixarene derivative as a catalyst, trifluoromethanesulfonic acid as a co-catalyst, and water as a solvent. The reaction formula is shown below:

[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 and making it an inherent chiral calixarene. The characteristics of the calixarene skeleton structure, which is wide at the top and narrow at the bottom, and the long fatty chain structure connected to the tertiary amine can be fully utilized in an 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 difficult control of the acetone small molecule, low reaction efficiency, and low selectivity in the aldehyde-ketone condensation reaction. The catalytic yield of the present invention is as high as 97%, and the selectivity is as high as 92% ee, which also greatly enriches the application range of chiral compounds in the field of organic synthesis. DETAILED DESCRIPTION

[0016] The present invention will be further described below with reference to 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] 5-Formyl-25,26,27,28-tetrapropoxycalix[4]arene (620 mg, 1 mmol), cyclohexanediaminoacetyl (314 mg, 2 mmol), and anhydrous sodium sulfate (100 mg) were weighed into a flask. 20 mL of methanol was added and the mixture was heated to reflux. The reaction progress was monitored by TLC until all the raw materials were reacted. The mixture was cooled to room temperature and sodium borohydride (189 mg, 5 mmol) was added in two batches in an ice-water bath. The temperature was then raised to 60°C and allowed to react until the raw materials disappeared. The temperature was then lowered to room temperature. The reaction solution was concentrated, 15 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by swirl, and the mixture was recrystallized from dichloromethane / acetonitrile to obtain the calixarene imine intermediate compound (525 mg, 69% yield).

[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 with acetonitrile as solvent (40 mL). The mixture was stirred at room temperature for 1 h, iodobutane (0.9 mL, 8 mmol) was added, and the mixture was heated under reflux until the reaction of the raw materials was complete. After quenching the reaction, the organic phase was removed by rotation, dichloromethane was added, and the mixture was extracted three times with water. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed by rotation, and the mixture was recrystallized from dichloromethane / acetonitrile to obtain the acetyl-protected cyclohexanediaminecalixarene intermediate (653 mg, yield 80%). The intermediate was then added to a 50 mL round-bottom flask, and CH3OH (30 mL) was used as the solvent. 36% HCl (1.5 mL) was added dropwise in three batches and heated to reflux. The reaction progress was monitored by TLC. After 24 h of reaction, the reaction was stopped and the reaction solution was cooled to room temperature. Water (10 mL) was added to dilute the reaction solution in an ice-water bath. 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, dried over anhydrous sodium sulfate, filtered, and then spin-dried to dryness. The target catalyst (515 mg, yield 83%) was obtained by recrystallization from dichloromethane / acetonitrile.

[0023] Yellow solid; Mp: 62°C; 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 investigate the key factors influencing the asymmetric aldol reaction catalyzed by chiral calixarene: acid type, solvent type, acetone dosage, and reaction temperature. The experimental method involves adding 75.56 mg (0.5 mmol) of p-nitrobenzaldehyde, acetone, 10 mol% of the calixarene catalyst, 10 mol% of the acid, and the solvent to a test tube. The reaction is stirred for 24 hours, then stopped. 2 mL of dichloromethane is added and the organic phase is extracted and separated. Column chromatography (ethyl acetate:petroleum ether = 1:2) yields the aldol addition product. 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] 0.5 mmol of a benzaldehyde derivative, 0.5 mL (6.5 mmol) of acetone, 10 mol% of a calixarene catalyst, 10 mol% of trifluoromethanesulfonic acid, and 0.5 mL of water were added to a test tube and stirred at room temperature for 24 hours. The reaction was terminated and 2 mL of dichloromethane was added for extraction and separation to obtain the organic phase. The addition product was obtained by column chromatography (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, 10 mol% of chiral calixarene with benzyl bromide substituents were added. 10 mol% trifluoromethanesulfonic acid and 0.5 mL of water were added to a test tube and allowed to react at 25°C for 24 h. The reaction was then stopped and 2 mL of dichloromethane was added for extraction and separation. The organic phase was separated by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain the addition product in a 61% yield (91 ee%).

[0035] With the above-described preferred embodiments of the present invention as a guide, and with reference to the above description, relevant personnel are fully capable of making various changes and modifications without departing from the technical scope of this invention. The technical scope of this invention is not limited to the contents of the specification and 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 according to claim 1, characterized in that: The preparation method comprises the following steps: (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 iodine butane, and then the acetyl group is removed under the action of acid to obtain a chiral calixarene catalyst. The synthesis route is shown in the following formula:

3. The preparation method according to claim 2, wherein 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, wherein In the step (2), the molar ratio of iodine 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.

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 shown below:

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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