Method for stereodivergently synthesizing tetra-substituted axially chiral quinolinone

Abstract

The invention discloses a method for stereodivergently synthesizing tetra-substituted axially chiral quinolinone. According to the method, MBH carbonate and quinolin-2 (1H)-ketone are used as raw materials, cinchona alkaloid is used as a catalyst, DME is used as a solvent, a quinolinone central chiral compound is synthesized, DBU or sodium methoxide is used as alkali, toluene is used as a solvent, and enantiomer-enriched E-or Z-tetra-substituted axially chiral quinolinone is obtained. The method has the advantages of mild reaction conditions, easily available raw materials, high product enantioselectivity and excellent yield, and provides four stereoisomers (S, E), (R, E), (S, Z) and (R, Z) under specific conditions.

Description

Technical Field

[0001] The invention relates to a stereodivergent synthesis method of tetrasubstituted axial chiral quinolinone, belonging to the technical field of organic synthetic chemistry. Background Art

[0002] Since 2016, extensive research has been conducted on the catalytic synthesis of axially chiral styrenes. However, the synthesis of tetrasubstituted axially chiral styrenes is limited, primarily focusing on organocatalytic asymmetric addition of alkynes, transition-metal-catalyzed asymmetric C-H functionalization, and kinetic analysis. Despite the high efficiency of existing protocols, the stereoselective synthesis of axially chiral styrene analogs has, to date, been limited to the synthesis of only the E (or Z) stereoisomer in a single catalytic system. (Jin, L.; Zhang, P.; Li, Y.; Yu, 497-511.Song,H.Angew.Chem.,Int.Ed.2020,59,6576-6580.Yang,C.Chem.Sci.2021,12,3726-3732.Yan g,C.Org.Lett.2021,23,8132-8137.Zheng,S.-C.Nat.Commun.2017,8,15238.Jia,SJAm.Chem.Soc.2018, 140, 7056-7060. Wang, J.-Y. Chin. J. Chem. 2021, 39, 2163-2171. Zhang, C. Chem Catal. 2022, 2, 164-177.). Summary of the Invention

[0003] The present invention aims to provide a stereodivergent synthesis method for tetrasubstituted axially chiral quinolinones. This method successfully obtains four stereoisomers of tetrasubstituted axially chiral quinolinones through an asymmetric allylic substitution isomerization strategy, utilizing organic small molecule catalysis, and adjusting the catalyst and base.

[0004] The technical solution for achieving the purpose of the present invention is as follows: A method for stereodivergent synthesis of tetrasubstituted axially chiral quinolinones comprises the following steps:

[0005] MBH carbonate 1b' and quinolin-2(1H)-one 2a were used as the reaction materials, hydroquinine-2,5-diphenyl-4,6-pyrimidine dimethyl ether ((DHQD)2PYR) or hydroquinine-2,5-diphenyl-L-4,6-pyrimidine diyl diether ((DHQ)2PYR) was used as the catalyst, and ethylene glycol dimethyl ether (DME) was used as the solvent. After the asymmetric allylic substitution reaction was completed, 1,8-diazabicycloundec-7-ene (DBU) or sodium methoxide (MeONa) was used as the base, and toluene was used as the solvent to synthesize tetrasubstituted axial chiral quinolinone 4b' through isomerization reaction.

[0006] The specific synthetic route is as follows:

[0007]

[0008] Preferably, the molar ratio of MBH carbonate to quinolin-2(1H)-one is 3:1.

[0009] Preferably, the molar amount of the catalyst is 20% of the molar amount of quinolin-2(1H)-one.

[0010] Preferably, the temperature of the asymmetric allylic substitution reaction or the isomerization reaction is room temperature.

[0011] Preferably, the amount of DBU used is twice the molar amount of quinolin-2(1H)-one.

[0012] Preferably, the amount of sodium methoxide used is 1 times the molar amount of quinolin-2(1H)-one.

[0013] Compared with the prior art, the present invention has the following advantages:

[0014] This invention, based on the asymmetric allylic substitution isomerization (AASI) strategy, achieves the first stereodivergent synthesis of tetrasubstituted axially chiral quinolinones. Through complex reaction design, four stereoisomers of tetrasubstituted axially chiral quinolinones, (S,E), (R,E), (S,Z), and (R,Z), are available under specific circumstances. The reaction conditions are mild, and the products are obtained in high enantioselectivity and excellent yields. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the hydrogen spectrum of the (S,E)-tetrasubstituted axial chiral quinolinone prepared in Example 1.

[0016] Figure 2 This is the carbon spectrum of the (S,E)-tetrasubstituted axial chiral quinolinone prepared in Example 1.

[0017] Figure 3 This is the hydrogen spectrum of the (S,Z)-tetrasubstituted axial chiral quinolinone prepared in Example 3.

[0018] Figure 4This is the carbon spectrum of the (S,Z)-tetrasubstituted axial chiral quinolinone prepared in Example 3. DETAILED DESCRIPTION

[0019] The present invention is described in detail below through specific embodiments. However, the use and purpose of these examples are only used to illustrate the present invention and do not constitute any form of limitation on the actual protection scope of the present invention, nor do they limit the protection scope of the present invention to them.

[0020] Here, we disclose a stereodivergent synthesis of tetrasubstituted axially chiral quinolinones based on an asymmetric allylic substitution isomerization (AASI) strategy. Under mild reaction conditions, by adjusting the appropriate substrate and base, either the E or Z stereoisomer is generated in high yields and excellent enantioselectivity. In certain cases, the four stereoisomers ((S,E), (R,E), (S,Z), and (R,Z)) are afforded.

[0021] Example 1:

[0022] (S,E)-Tetrasubstituted Axially Chiral Quinolinones

[0023]

[0024] The specific steps are as follows:

[0025] MBH carbonate (263.8 mg, 0.9 mmol), quinolin-2(1H)-one (43.5 mg, 0.3 mmol), catalyst (DHQD)2PYR (52.9 mg, 0.06 mmol), and ethylene glycol dimethyl ether (1.5 mL) were added to a 4 mL reaction flask equipped with a stirrer. The reaction was allowed to proceed at room temperature and monitored by TLC. Upon completion, the solvent was removed by spin drying to yield the intermediate. DBU (91.2 mg, 0.6 mmol) and toluene (1 mL) were added and the reaction continued at room temperature. After completion, the crude product was purified by silica gel column chromatography to yield the (S,E)-tetrasubstituted axial chiral quinolinone.

[0026] In this example, (DHQD)2PYR is used as a catalyst to obtain an S-type compound, and DBU is used as a base to obtain an E-configuration compound. Therefore, this example ultimately obtains a (S,E)-tetrasubstituted axial chiral quinolinone.

[0027] The hydrogen and carbon spectra of the target product are as follows: Figure 1 and Figure 2 As shown, the data is as follows:

[0028] (S,E)-4b', white solid. 1HNMR(500MHz,Chloroform-d)δ8.56(d,J=4.6Hz,1H),7.79(d,J=9.6Hz,1H),7.59–7.53(m,2H),7.47–7.40(m,2H),7 .22(t,J=7.4Hz,1H),7.17(t,J=6.2Hz,1H),7.08(d,J=8.0Hz,1H),6.75(d,J=9.6Hz,1H),1.80(s,3H),1.46(s,9H). 13 CNMR(126MHz,Chloroform-d)δ168.42,161.10,153.28,148.77,140.36,139.30,136.53,136.02 ,134.53,131.15,128.55,122.99,122.87,122.11,121.54,120.46,115.66,81.90,27.93,16.77.

[0029] Example 2:

[0030] (R,E)-Tetrasubstituted Axially Chiral Quinolinones

[0031]

[0032] The specific steps are as follows:

[0033] MBH carbonate (263.8 mg, 0.9 mmol), quinolin-2(1H)-one (43.5 mg, 0.3 mmol), catalyst (DHQ)2PYR (52.9 mg, 0.06 mmol), and ethylene glycol dimethyl ether (1.5 mL) were added to a 4 mL reaction flask equipped with a stirrer. The reaction was allowed to proceed at room temperature and monitored by TLC. Upon completion, the solvent was removed by spin drying to yield the intermediate. DBU (91.2 mg, 0.6 mmol) and toluene (1 mL) were added and the reaction continued at room temperature. After completion, the crude product was purified by silica gel column chromatography to yield the (R,E)-tetrasubstituted axial chiral quinolinone.

[0034] In this example, (DHQ)2PYR is used as a catalyst to obtain an R-type compound, and DBU is used as a base to obtain an E-configuration compound. Therefore, this example ultimately obtains a (R,E)-tetrasubstituted axial chiral quinolinone.

[0035] Example 3:

[0036] (S,Z)-Tetrasubstituted Axially Chiral Quinolinones

[0037]

[0038] The specific steps are as follows:

[0039] MBH carbonate (263.8 mg, 0.9 mmol), quinolin-2(1H)-one (43.5 mg, 0.3 mmol), catalyst (DHQD)2PYR (52.9 mg, 0.06 mmol), and ethylene glycol dimethyl ether (1.5 mL) were added to a 4 mL reaction flask equipped with a stirrer. The reaction was allowed to proceed at room temperature and monitored by TLC. Upon completion, the solvent was removed by spin drying to yield the intermediate. Sodium methoxide (16.2 mg, 0.3 mmol) and toluene (1 mL) were added and the reaction continued at room temperature. After completion, the crude product was purified by silica gel column chromatography to yield the (S,Z)-tetrasubstituted axial chiral quinolinone.

[0040] In this example, (DHQD)2PYR is used as a catalyst to obtain an S-type compound, and sodium methoxide is used as a base to obtain a Z-configuration compound. Therefore, this example ultimately obtains a (S,Z)-tetrasubstituted axial chiral quinolinone.

[0041] The hydrogen and carbon spectra of the target product are as follows: Figure 3 and Figure 4 As shown, the data is as follows:

[0042] (S,Z)-4b', white solid. 1 HNMR(500MHz,Chloroform-d)δ8.61(d,J=4.9Hz,1H),7.73(d,J=9.6Hz,1H),7.64(t,J=7.9Hz,1H),7.53(d, J=7.7Hz,1H),7.45(d,J=7.6Hz,3H),7.18(q,J=7.6Hz,2H),6.71(d,J=9.5Hz,1H),2.37(s,3H),1.03(s,9H). 13 CNMR(126MHz,Chloroform-d)δ166.73,161.69,154.63,149.11,140.51,140.09,136.49,135.45 ,135.24,130.64,128.09,124.63,123.13,122.44,122.11,120.29,116.57,81.63,27.39,17.04.

[0043] Example 4:

[0044] (R,Z)-Tetrasubstituted Axially Chiral Quinolinones

[0045]

[0046] The specific steps are as follows:

[0047] MBH carbonate (263.8 mg, 0.9 mmol), quinolin-2(1H)-one (43.5 mg, 0.3 mmol), catalyst (DHQ)2PYR (52.9 mg, 0.06 mmol), and ethylene glycol dimethyl ether (1.5 mL) were added to a 4 mL reaction flask equipped with a stirrer. The reaction was allowed to proceed at room temperature and monitored by TLC. Upon completion, the solvent was removed by spin drying to yield the intermediate. Sodium methoxide (16.2 mg, 0.3 mmol) and toluene (1 mL) were added and the reaction continued at room temperature. After completion, the crude product was purified by silica gel column chromatography to yield the (R,Z)-tetrasubstituted axial chiral quinolinone.

[0048] In this example, (DHQ)2PYR is used as a catalyst to obtain an R-type compound, and sodium methoxide is used as a base to obtain a Z-configuration compound. Therefore, this example ultimately obtains a (R,Z)-tetrasubstituted axial chiral quinolinone.

Claims

1. A method for stereodivergent synthesis of tetrasubstituted axial chiral quinolinones, characterized in that: The steps include: MBH carbonate 1b' and quinolin-2(1H)-one 2a are used as the reaction materials, (DHQD)2PYR or (DHQ)2PYR is used as the catalyst, and DME is used as the solvent. After the asymmetric allylic substitution reaction is completed, DBU or MeONa is used as the base and toluene is used as the solvent to synthesize the tetrasubstituted axial chiral quinolinone 4b' through an isomerization reaction. The synthesis route is as follows:

2. The method according to claim 1, wherein The molar ratio of MBH carbonate to quinolin-2(1H)-one was 3:

1.

3. The method according to claim 1, wherein The molar amount of the catalyst was 20% of the molar amount of quinolin-2(1H)-one.

4. The method according to claim 1, wherein The temperature for the asymmetric allylic substitution reaction or the isomerization reaction is room temperature.

5. The method according to claim 1, wherein The amount of DBU used was twice the molar amount of quinolin-2(1H)-one.

6. The method according to claim 1, wherein The amount of MeONa used was 1 times the molar amount of quinolin-2(1H)-one.

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