Method for constructing a cycloalkene-quinolinone axis chiral compound by heck reaction

Abstract

The application discloses a method for constructing a cycloalkene-quinolinone axial chiral compound through a Heck reaction. The method uses a quinolinone compound containing central chirality as a substrate, uses palladium acetate (Pd(OAc)2) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (Xantphos) as a catalyst, uses silver phosphate (Ag3PO4) as an alkali, and uses toluene as a solvent to prepare a cycloalkene-quinolinone axial chiral compound. The compound can be reacted with diisobutylaluminum hydride to realize conversion of a functional group. The method has mild reaction conditions, raw materials are easy to obtain, the product has excellent enantioselectivity, and has excellent yield, and thus provides a new method for synthesizing a cycloalkene-quinolinone axial chiral compound.

Description

Technical Field

[0001] This invention relates to a method for constructing axially chiral compounds of cyclic olefins-quinolinones using the Heck reaction, belonging to the field of organic synthetic chemistry. Background Technology

[0002] For axially chiral skeletons with multiple substituents and skeletons containing ester, carboxyl, and halogen atoms, the former is affected by steric hindrance, which can hinder the construction of the chiral axis, while the latter requires higher reactivity and compatibility of functional groups. Therefore, selecting appropriate reaction strategies to synthesize structurally diverse axially chiral compounds and compatible functional groups is crucial. Transfer from central chirality to axial chirality is an efficient method for synthesizing axially chiral compounds. This strategy offers mild reaction conditions, a wide range of applicable substrates, and good functional group compatibility. (Baker RW, Hambley TW, Turner P, Chem. Commun., 1996, 22, 2571; Jia Feng, Bin Li, Yun He, Angew. Chem. Int. Ed. 2016, 128, 2226; Chao Sun, Xiao-Long Min, Xue-Dan Bai. Chem. Sci. 2020, 11, 10119; Jie Wang, Jun Gu, Jia-Yu Zou, Meng-Jie Zhang. Nat. Commun. 2024, 15, 3254.)

[0003] Cycloolefin-aromatic axially chiral compounds are an important class of axially chiral structures. Compared to biaryl axially chiral compounds, the olefin structural unit has certain reactivity and can undergo derivatization reactions to obtain a variety of derivatized products. Therefore, the synthesis of precursors containing olefin structural units can be used for the synthesis of drugs and natural products. At the same time, cycloolefin-aromatic axially chiral compounds can be used as chiral ligands. Compared with biaryl chiral ligands, different stereostructures of the cycloolefin moiety may have different effects on asymmetric catalytic reactions. For example, coordination with transition metals in the olefin moiety can regulate the enantioselectivity of the product. Summary of the Invention

[0004] The purpose of this invention is to provide a method for constructing cyclic olefin-quinolinone axially chiral compounds via the Heck reaction. This method uses a quinolinone centrally chiral compound as a substrate and achieves the transfer of central chirality to axial chirality through the Heck reaction to prepare the cyclic olefin-quinolinone axially chiral compound.

[0005] The technical solution for achieving the objective of this invention is as follows:

[0006] Cycloalkene-quinolinone axially chiral compounds, with the following structural formula:

[0007]

[0008] Among them, R 1 Selected from hydrogen, bromine, R 2 Selected from hydrogen, methyl, and methoxy.

[0009] The method for synthesizing cycloolefin-quinolinone axially chiral compounds of the present invention includes the following steps:

[0010] Using quinolone-centered chiral compound 1 as a starting material, palladium acetate (Pd(OAc)2) and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (Xantphos) as catalysts, silver phosphate (Ag3PO4) as a base, and toluene as a solvent, cyclic olefin-quinolone axial chiral compound 2 was prepared via the Heck reaction.

[0011] The specific synthesis route is as follows:

[0012]

[0013] Preferably, the amounts of palladium acetate and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene are 10% and 20% of 1 mole of the tert-butyl acrylate derivative of 2-((2-iodophenyl)(2-oxoquinoline-1(2H)-yl)meth)acrylate, respectively.

[0014] Preferably, the amount of silver phosphate used is 3 times the amount of 1 mole of 2-((2-iodophenyl)(2-oxoquinoline-1(2H)-yl)methyl)methacrylate tert-butyl ester derivative.

[0015] Preferably, the Heck reaction temperature is 40°C.

[0016] Compared with the prior art, the present invention has the following advantages:

[0017] This invention is based on a chirality transfer strategy, using the Heck reaction to achieve the transfer of central chirality to axial chirality, preparing a cyclic olefin-quinolinone axially chiral compound 2. The reaction conditions are mild, the product exhibits excellent enantioselectivity and high yield, providing a new method for the synthesis of cyclic olefin-quinolinone axially chiral compounds. The product molecule has convertible groups, such as ester groups that can be converted into hydroxyl groups, increasing the feasibility of subsequent derivatization experiments and showing broad application prospects in drug development and natural product synthesis. Attached Figure Description

[0018] Figure 1 The 1H NMR spectrum is of tert-butyl 3-(2-oxoquinoline-1(2H)-yl)-indole-2-carboxylic acid ester 2a prepared in Example 1.

[0019] Figure 2 The carbon spectrum of tert-butyl 3-(2-oxoquinoline-1(2H)-yl)-indole-2-carboxylic acid ester 2a prepared in Example 1.

[0020] Figure 3 The 1H NMR spectrum of tert-butyl 3-(2-6'-bromo-oxyquinoline-1(2H)-yl)-indole-2-carboxylic acid ester 2b prepared in Example 2.

[0021] Figure 4 The carbon spectrum of tert-butyl 3-(2-6'-bromo-oxyquinoline-1(2H)-yl)-indole-2-carboxylic acid ester 2b prepared in Example 2.

[0022] Figure 5 The 1H NMR spectrum of 2c of 7-methyl 3-(2-oxoquinoline-1(2H)-yl)-indole-2-carboxylic acid tert-butyl ester 2c prepared in Example 3.

[0023] Figure 6 The carbon spectrum of 2c of 7-methyl 3-(2-oxoquinoline-1(2H)-yl)-indole-2-carboxylic acid tert-butyl ester prepared in Example 3.

[0024] Figure 7 The 1H NMR spectrum of 2d tert-butyl 6-methoxy-3-(2-oxoquinoline-1(2H)-yl)-indene-2-carboxylic acid prepared in Example 4.

[0025] Figure 8 The carbon spectrum of 2d tert-butyl 6-methoxy-3-(2-oxoquinoline-1(2H)-yl)-indene-2-carboxylic acid prepared in Example 4.

[0026] Figure 9 The 1H NMR spectrum of 1-(2-(hydroxymethyl)-1H-indene-3-yl)quinoline-2(1H)-one 3 prepared by application example 1.

[0027] Figure 10 The carbon spectrum of 1-(2-(hydroxymethyl)-1H-indene-3-yl)quinoline-2(1H)-one 3 prepared by application example 1. Detailed Implementation

[0028] The present invention will be described in detail below through specific embodiments. However, the purpose and use of these embodiments are only for illustrating the present invention and do not constitute any limitation on the actual protection scope of the present invention, nor are they intended to limit the protection scope of the present invention to these embodiments.

[0029] Here, a chiral transfer strategy is disclosed to construct cyclic olefin-quinolinone axial chiral compounds by transferring central chirality to axial chirality through intramolecular Heck reaction.

[0030] Example 1: tert-butyl 3-(2-oxoquinoline-1(2H)-yl)-indene-2-carboxylate 2a

[0031]

[0032] The specific steps are as follows:

[0033] Compound 1a (48.7 mg, 0.1 mmol), palladium acetate (2.3 mg, 0.01 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (11.6 mg, 0.02 mmol), and silver phosphate (125.6 mg, 0.3 mmol) were added to a 4 mL reaction flask equipped with a stir bar. Toluene (1.0 mL) was used as the reaction solvent, and the reaction was carried out at 40 °C. The reaction was monitored by TLC. After the reaction was complete, column chromatography yielded compound 2a as a white solid with a yield of 91% and an ee value of 94%. The proton and carbon spectra of the target product are shown below. Figure 1 and Figure 2 As shown, the data is as follows:

[0034] 1 H NMR(500MHz,Chloroform-d)δ7.83(d,J=9.6Hz,1H),7.64–7.58(m,2H),7.43–7.31(m,2H),7.27(t,J=7.6Hz,1H),7. 25–7.18(m,1H),7.09(d,J=7.6Hz,1H),6.90(d,J=8.5Hz,1H),6.80(d,J=9.5Hz,1H),4.07–3.94(m,2H),1.10(s,9H). 13 C NMR(126MHz,Chloroform-d)δ162.53,161.02,143.91,142.68,140.19,140.17,139.60,134.80,130 .58,128.46,128.40,127.14,124.75,122.60,121.99,120.91,120.33,115.20,81.04,37.94,27.66.

[0035] Example 2: tert-butyl 3-(2-6'-bromo-oxyquinoline-1(2H)-yl)-indene-2-carboxylate 2b

[0036]

[0037] The specific steps are as follows:

[0038] Compound 1b (56.6 mg, 0.1 mmol), palladium acetate (2.3 mg, 0.01 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (11.6 mg, 0.02 mmol), and silver phosphate (125.6 mg, 0.3 mmol) were added to a 4 mL reaction flask equipped with a stir bar. Toluene (1.0 mL) was used as the solvent, and the reaction was carried out at 40 °C. The reaction was monitored by TLC. After the reaction was complete, column chromatography yielded compound 2b as a white solid, with a yield of 87% and an ee value of 93%. The proton and carbon spectra of the target product are shown below. Figure 3 and Figure 4 As shown, the data is as follows:

[0039] 1 H NMR(500MHz,Chloroform-d)δ7.82–7.78(m,2H),7.65(d,J=7.6Hz,1H),7.49–7.43(m,2H),7.34– 7.30(m,1H),7.10(d,J=7.6Hz,1H),6.85(dd,J=21.6,9.3Hz,2H),4.12–3.98(m,2H),1.21(s,9H). 13 C NMR(126MHz,Chloroform-d)δ162.27,160.48,143.34,142.64,139.83,138.87,138.51,135.04,133 .27,130.56,128.63,127.22,124.84,123.30,121.73,120.74,116.99,115.29,81.23,38.00,27.76.

[0040] Example 3: tert-butyl 7-methyl-3-(2-oxoquinoline-1(2H)-yl)-indene-2-carboxylate 2c

[0041]

[0042] The specific steps are as follows:

[0043] Compound 1c (50.2 mg, 0.1 mmol), palladium acetate (2.3 mg, 0.01 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (11.6 mg, 0.02 mmol), and silver phosphate (125.6 mg, 0.3 mmol) were added to a 4 mL reaction flask equipped with a stir bar. Toluene (1.0 mL) was used as the solvent, and the reaction was carried out at 40 °C. The reaction was monitored by TLC. After the reaction was complete, column chromatography yielded compound 2c as a white solid with a yield of 90% and an ee value of 92%. The proton and carbon spectra of the target product are shown below. Figure 3 and Figure 4 As shown, the data is as follows:

[0044] 1 H NMR(500MHz,Chloroform-d)δ7.82(d,J=9.6Hz,1H),7.61(d,J=7.8Hz,1H),7.37–7.32(m,1H),7.23– 7.17(m,3H),6.96–6.88(m,2H),6.80(d,J=9.6Hz,1H),3.98–3.82(m,2H),2.45(s,3H),1.11(s,9H). 13 C NMR(126MHz,Chloroform-d)δ162.65,161.03,144.21,141.40,140.14,139.80,139.65,134.46,134.11 ,130.53,129.61,128.35,127.55,122.55,122.01,120.30,118.62,115.24,80.98,36.93,27.66,18.20.

[0045] Example 4: 2d tert-butyl 6-methoxy-3-(2-oxoquinoline-1(2H)-yl)-indene-2-carboxylate

[0046]

[0047] The specific steps are as follows:

[0048] Compound 1d (51.7 mg, 0.1 mmol), palladium acetate (2.3 mg, 0.01 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (11.6 mg, 0.02 mmol), and silver phosphate (125.6 mg, 0.3 mmol) were added to a 4 mL reaction flask equipped with a stir bar. Toluene (1.0 mL) was used as the solvent, and the reaction was carried out at 40 °C. The reaction was monitored by TLC. After the reaction was complete, column chromatography yielded compound 2d as a white solid with a yield of 70% and an ee value of 95%. The proton and carbon spectra of the target product are shown below. Figure 7 and Figure 8 As shown, the data is as follows:

[0049] 1H NMR(500MHz,Chloroform-d)δ7.82(d,J=9.6Hz,1H),7.61(d,J=7.9Hz,1H),7.35(t,J=7.9Hz,1H),7.23–7.19(m,1H),7. 15(s,1H),6.99(d,J=8.4Hz,1H),6.92(d,J=8.4Hz,1H),6.84–6.77(m,2H),4.02–3.90(m,2H),3.84(s,3H),1.08(s,9H). 13 C NMR(126MHz,Chloroform-d)δ162.63,160.96,160.91,144.92,143.91,140.10,139.63,133.03,132.15 ,130.54,128.32,122.53,122.02,121.79,120.31,115.23,113.75,110.47,80.72,55.63,37.80,27.67.

[0050] Application Example 1: 1-(2-(hydroxymethyl)-1H-inden-3-yl)quinoline-2(1H)-one

[0051]

[0052] The specific steps are as follows:

[0053] Under an argon atmosphere, compound 2a (35.9 mg, 0.1 mmol) and anhydrous dichloromethane (1 mL) were added to a test tube equipped with a stir bar. Diisobutylaluminum hydride (0.3 mmol, 3.0 equiv) was then slowly added. The reaction was carried out at -78 °C, and the reaction was monitored by TLC. After the reaction was complete, column chromatography yielded compound 3 as a white solid with a yield of 65% and an ee value of 89%. The proton and carbon spectra of the target product are shown below. Figure 9 and Figure 10 As shown, the data is as follows:

[0054] 1H NMR(500MHz,Chloroform-d)δ7.87(d,J=9.6Hz,1H),7.65(d,J=6.3Hz,1H),7.55(d,J=7.4Hz,1H),7.37(t,J=7.1Hz,1H),7.28–7.23(m,2H),7.16(t,J=7.5Hz,1H),6.99(d,J=8.5Hz,1H),6.82(d,J=9.5Hz,1H),6.73(d,J=7.5Hz,1H),4.37(d,J=12.6Hz,1H),4.23(d,J=12.6Hz,1H),4.00(d,J=23.0Hz,1H),3.71(d,J=23.1Hz,1H),3.45(s,1H). 13 C NMR(126MHz,Chloroform-d)δ162.14,144.87,142.18,140.61,140.54,139.28,133.66,130.80,128.61,126.53,126.01,124.57,123.11,121.80,120.55,119.20,116.52,57.42,38.21.

Claims

1. A cycloolefin-quinolinone axially chiral compound, characterized in that, The structure is as follows: Among them, R 1 Selected from hydrogen, bromine, R 2 Selected from hydrogen, methyl, and methoxy.

2. A synthetic method for constructing axially chiral compounds of cyclic olefins-quinolinones via the Heck reaction, characterized in that, This method uses a centrally chiral quinolinone compound as a substrate, palladium acetate and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene as catalysts, silver phosphate as a base, and toluene as a solvent to synthesize cyclic olefin-quinolinone axially chiral compounds via the Heck reaction. Its synthetic route is as follows: Among them, R 1 Selected from hydrogen, bromine, R 2 Selected from hydrogen, methyl, and methoxy.

3. The method as described in claim 2, characterized in that, The molar amounts of palladium acetate and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene are 10% and 20% of the molar amount of 1 mole of 2-((2-iodophenyl)(2-oxoquinoline-1(2H)-yl)methyl)methacrylate derivative, respectively.

4. The method as described in claim 2, characterized in that, The amount of silver phosphate used is 3 times the amount of 1 mole of 2-((2-iodophenyl)(2-oxoquinoline-1(2H)-yl)methyl)tert-butyl acrylate derivative.

5. The method as described in claim 2, characterized in that, The Heck reaction is carried out at a temperature of 40°C.

6. An application of the cycloolefin-quinolinone axial chiral compound according to claim 1, characterized in that, The resulting cyclic olefin-quinolinone axially chiral compound was used for functional group transformation in a reaction with diisobutylaluminum hydride.

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