CN111925356A - Synthesis and application of chiral quinoline-imidazoline ligands - Google Patents

Abstract

The present invention relates to a chiral quinoline-imidazoline ligand, its synthesis method and its application. The synthesis method mainly includes the following steps: quinoline-8-formic acid is condensed with β-amino alcohol to obtain an amide, and then reacts with a primary amine under the action of thionyl chloride or/and phosphorus pentachloride to obtain a quinoline-imidazoline compound. body. The chiral quinoline-imidazoline ligand can be used for the transition metal-catalyzed asymmetric bifunctionalization reaction of alkene-tethered amine acyl chlorides with halides to synthesize chiral lactam compounds with high yield and high enantioselectivity. The invention is green and environmentally friendly, starts from cheap and readily available raw materials, and synthesizes chiral ligands with potential for asymmetric catalysis regulation by a simple and efficient route, the synthesis reaction speed is fast, the yield is high, the product is stable to water and oxygen, and easy to store; Moreover, the ligands have important practical application value and potential in the field of asymmetric catalysis.

Description

Synthesis and application of chiral quinoline-imidazoline ligands

technical field

The invention relates to a method for synthesizing a quinoline-imidazoline ligand and application thereof, in particular to a chiral 8-(4,5-dihydro-1H-imidazoline) quinoline ligand and a preparation method thereof and The application of the invention in the asymmetric bifunctionalization reaction of alkene-tethered amine acyl chloride and halide belongs to the technical field of organic synthesis.

Background technique

Chem.Rev.,2011,111,PR284]。Asymmetric catalysis is a very important branch in the field of organic chemistry. Due to its central role in the development of chiral drugs, pesticides and other functional materials, asymmetric catalytic synthesis has developed rapidly in the past few decades and is still one of the hotspots of chemists' attention. Metal asymmetric catalytic reactions involve a wider range of asymmetric catalytic reactions that can be carried out, and the structures of chiral compounds that can be synthesized are also diverse and complex. Since organic ligands can affect the steric hindrance and electron cloud density of metal catalysts, the key to improving the reactivity, regioselectivity and enantioselectivity of metal asymmetric catalytic reactions is to develop new and efficient chiral ligands [Privileged Chiral Ligands and Catalysts] , ed. Q.-L. Zhou, Weinheim, Wiley-VCH, 2011; W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029; G. Desimoni, G. Faita and KA

Chem. Rev., 2011, 111, PR284].

In the early stage of the development of chiral ligands, chiral organophosphine ligands dominated due to their good synergistic catalytic activity in many metal-catalyzed reactions, but there are still many asymmetric reactions that cannot be achieved using chiral phosphine ligands. of. Chiral pyridine-oxazolines were subsequently developed [H.Brunner, U.Obermann and P.Wimmer, J.Organomet.Chem., 1986, 316, C1; H.Nishiyama, H.Sakaguchi, T.Nakamura, M. Horihata,M.Kondo and K.Itoh,Organometallics,1989,8,846;], bisoxazoline [J.Zhou and Y.Tang, J.Am.Chem.Soc., 2002,124,9030; R.E.Lowenthal, A .Abiko and S.Masamune, Tetrahedron Lett., 1990, 31, 6005; D.A.Evans, K.A.Woerpel, M.M.Hinman and M.M.Faul, J.Am.Chem.Soc., 1991,113,726], phenyl-phosphine-oxazoline [P. von Matt and A. Pfaltz, Angew. Chem., Int. Ed. Engl., 1993, 32, 566], and other types of chiral nitrogen ligands, overcome the Enantioselectivity inefficiency problem. Among them, chiral dinitrogen ligands are highly modifiable. In addition to the chelation angle between nitrogen atom and metal and the ring system of the coordination transition state, the electronic and steric effects of the ligand can also be adjusted to make the ligand in different It exhibits unique catalytic properties in asymmetric catalytic reactions.

Although chiral dinitrogen ligands have made great progress in the study of asymmetric metal catalysts, due to the limited applicability of each type of ligand to different reactions or different substrates for the same reaction, there are still many reaction pairs. Enantioselectivity and reaction efficiency are not both satisfactory. Therefore, designing chiral dinitrogen ligands with different catalytic activities and chirality-inducing environments, expanding such advantageous frameworks, and exploring the key inducing factors in asymmetric catalytic reactions are urgent problems to be solved.

Gamma-lactam compounds are the ubiquitous core skeletons of many biologically active molecules and drugs. In recent years, many chemists have made great efforts to develop more efficient methods to construct chiral gamma-lactams starting from organic synthesis and enzymatic catalysis. block. [M.Hayashi,S.Bachman,S.Hashimoto,C.C.Eichman and B.M.Stoltz,J.Am.Chem.Soc.2016,138,8997;C.Chen,S.Jin,Z.Zhang,B.Wei,H .Wang,K.Zhang,H.Lv,X.-Q.Dong and X.Zhang,J.Am.Chem.Soc.2016,138,9017; Y.Park and S.Chang,Nat.Catal.2019, 2, 219; K.F. Biegasiewicz, S.J. Copper, X. Gao, D.G. Oblinsky, J.H. Kim, S.E. Garfinkle, L.A. Joyce, B.A. Sandoval, G.D.Scholes and T.K.Hyster, Science 2019, 364, 1166.] However, due to potential overalkylation Side reactions and epimerization under basic conditions, the synthesis of asymmetric α-monosubstituted γ-lactams from simple and readily available lactams is still extremely challenging, even with stoichiometric chiral bases. Chiral lactams can only be obtained with lower enantioselectivities and yields [J.-i. Mastuo, S. Kobayashi and K. Koga, Tetrahedron Lett. 1998, 39, 9723].

Alkenes are one of the most commonly used synthons, and their diverse modifications are very important studies in organic synthesis. Transition metal-catalyzed asymmetric bifunctionalization of alkenes is a highly efficient synthetic strategy that enables the construction of complex molecules while introducing two distinct functional moieties. However, the cyclization of most intramolecular alkenes relies on 1,1-disubstituted alkenes to achieve the synthesis of benzoheterocyclic systems [K.Wang,Z.Ding,Z.Zhou and W.Kong,J.Am.Chem. Soc. 2018, 140, 12364; Y. Jin, C. Wang, Angew. Chem., Int. Ed. 2019, 58, 6722; T. Ma, Y. Chen, Y. Li, Y. Ping, W. Kong , ACS Catal. 2019, 9, 9127]. Probably because the migration and insertion are mostly through the free radical pathway, its stereoselectivity is difficult to control. Therefore, the synthesis of non-benzo-based chiral heterocyclic compounds by asymmetric bifunctionalization reactions involving monosubstituted alkenes is still one of the current difficulties. . [Y.Peng,X.-B.Xu,J.XiaoandY.-W.Wang,Chem.Commun.2014,50,472;Y.Kuang,X.Wang,D.Anthony,T.Diao,Chem.Commun.2018 , 54, 2558.]. Olefin-tethered amine acyl chlorides are very good precursors for the synthesis of nitrogen-containing heterocycles [A.Whyte, K.I.Burton, J.Zhang and Mark Lautens Angew.Chem., Int.Ed.2018,57,13927; P. Fan, Y. Lan, C. Zhang and Chuan Wang, J. Am. Chem. Soc. 2020, 142, 2180; Y. Lan, C. Wang, Commun. Chem. 2020, 3, 45.], its synthesis is simple , the raw materials are readily available, and the reactivity is different from the general alkene-tethered alkyl halides. Therefore, the asymmetric difunctionalization of monosubstituted alkene-tethered amine acyl chlorides has great research space and development prospects.

To sum up, there is an urgent need in the art for efficient catalytic ligands and efficient synthesis methods for chiral cyclic lactams that can mildly and efficiently realize the asymmetric bifunctionalization of alkenes with alkene-tethered amine acyl chlorides and halides.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a synthesis method of a chiral quinoline-imidazoline ligand and its application in the asymmetric bifunctionalization reaction of alkenes between alkene-tethered amine acid chlorides and halides. The quinoline-imidazoline ligand of the invention is insensitive to water and oxygen, has good stability, is simple and efficient to synthesize, and obtains high reaction yield and excellent enantiomer in catalyzing the asymmetric bifunctionalization reaction of olefins The selectivity provides a new type of ligand product for catalyzing the asymmetric difunctionalization of alkenes, and also provides an efficient, green and practical synthetic method for the synthesis of chiral lactams.

The present invention provides a chiral quinoline-imidazoline ligand as shown in formula 1:

wherein, R ¹ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl or optionally substituted heteroaryl;

R ² is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted heteroaryl, ester, amide, boron ester, Acyl, cyano, amine, amino;

^R3 - ^R8 are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted heteroaryl, nitro , ester group, amide group, boron ester group, acyl group, aldehyde group, cyano group, amine group, amino group, alkyl-oxy group, alkyl-S group, halogen;

The "optionally substituted" is unsubstituted or substituted by the following groups: alkyl, alkyl-oxy, alkyl-S, halogen, nitro, ester, acyl, cyano, aldehyde, boron ester group, amide group, amine group, amino group or optionally substituted phenyl group; the number of the "substitution" is not limited;

The carbons marked with * are S-configuration chiral carbons or R-configuration chiral carbons.

In a preferred embodiment of the present invention, when the R ¹ is an optionally substituted alkyl group, the alkyl group is a C ₁ -C ₁₀ alkyl group, preferably, the alkyl group is C ₁ -C ₆ Alkyl, more preferably, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl , neopentyl, or hexyl.

In a preferred embodiment of the present invention, when the R ¹ is an optionally substituted cycloalkyl group, the cycloalkyl group is a C ₃ -C ₃₀ cycloalkyl group, preferably, the cycloalkyl group is C ₃ ~C ₈ cycloalkyl, more preferably, the cycloalkyl is cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

In a preferred embodiment of the present invention, when the R ¹ is an optionally substituted aryl group, the optionally substituted aryl group is phenyl, methyl-substituted phenyl, trifluoromethyl-substituted phenyl , methoxy substituted phenyl, tert-butyl substituted phenyl, fluorine substituted phenyl, naphthyl.

In a preferred embodiment of the present invention, when the R ¹ is an optionally substituted heteroaryl, the heteroaryl is furyl, thienyl, indolyl or pyridyl.

In a preferred embodiment of the present invention, when the R ² is an optionally substituted alkyl group, the alkyl group is a C ₁ -C ₁₀ alkyl group, preferably, the alkyl group is C ₁ -C ₆ Alkyl, more preferably, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl , neopentyl, or hexyl.

In a preferred embodiment of the present invention, when the R ³ -R ⁸ are each independently an optionally substituted alkyl group, the alkyl group is a C ₁ -C ₁₀ alkyl group, preferably, the alkyl group is a C ₁ -C ₆ alkyl group, more preferably, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-butyl pentyl, isopentyl, neopentyl, or hexyl.

In a preferred embodiment of the present invention, when the R ³ -R ⁸ are each independently optionally substituted cycloalkyl, the cycloalkyl is a C ₃ -C ₃₀ cycloalkyl, preferably, the The cycloalkyl group is a C ₃ -C ₈ cycloalkyl group, more preferably, the cycloalkyl group is a cyclopropanyl group, a cyclobutanyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cycloalkyl group Octyl.

In a preferred embodiment of the present invention, when said R ³ -R ⁸ are each independently an optionally substituted aryl group, said aryl group is phenyl.

In a preferred embodiment of the present invention, when said R ³ -R ⁸ are each independently optionally substituted heteroaryl, said heteroaryl is furyl, thienyl, indolyl or pyridyl.

In a preferred embodiment of the present invention, the chiral quinoline-imidazoline ligand is any one of the following compounds:

The carbons marked with * are S-configuration chiral carbons or R-configuration chiral carbons.

The present invention also provides a method for preparing the above-mentioned ligand, comprising the steps of: in an organic solvent, under the action of a chlorinating agent and a base, the compound shown in formula b and the compound shown in formula d are subjected to The reaction shown below can obtain the compound shown in formula 1,

wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and * are as defined above.

In the present invention, the organic solvent can be a conventional organic solvent for this type of reaction in the field, such as the organic solvent including methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyl alcohol tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane , one or more of N,N-dimethylformamide, N,N-dimethylacetamide and thionyl chloride; preferably thionyl chloride.

In the present invention, the chlorinating agent can be a conventional chlorinating agent for this type of reaction in the art, such as the chlorinating agent being thionyl chloride and/or phosphorus pentachloride.

In the present invention, the alkali can be the conventional alkali of this type of reaction in the field, and the alkali as described is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, hydrogen carbonate Potassium, lithium hydride, potassium hydride, sodium hydride, pyridine, triethylamine, tributylamine, N,N-diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine, N-methylmorpholine, N,N-diethylisopropylamine, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, potassium methoxide, lithium methoxide; preferably triethylamine.

In the present invention, the reaction temperature can be the conventional reaction temperature of this type of reaction in the field, such as the reaction temperature of the first step is 0-120°C, more preferably 50-90°C, for example, 80°C °C; as described, the reaction temperature of the second step is 0-100 °C, more preferably, 10-60 °C, for example, room temperature.

In the present invention, the reaction time can be the conventional reaction time of this type of reaction in the field, such as the reaction time of the first step is 1-40h, more preferably, 5-20h, for example 12h; The reaction time is 1-40h, more preferably, 5-20h, such as 12h.

In a preferred embodiment of the present invention, the molar concentration of the compound represented by formula b in the organic solvent is 0.01-5 mol/L, more preferably, 0.1-2 mol/L, for example, 1 mol/L .

In a preferred embodiment of the present invention, the molar ratio of the compound shown in formula b to the chlorinating agent is 1:1-1:100, more preferably, 1:10-1:50, For example, 1:33.

In a preferred embodiment of the present invention, the molar ratio of the compound represented by formula b to the base is 1:1-1:30, more preferably, 1:5-1:20, for example, 1:10.

In a preferred embodiment of the present invention, the molar ratio of the compound shown in formula b to the compound shown in formula d is 1:0.5-1:3, more preferably, 1:1- 1:1.5, for example, 1:1.1.

In a preferred embodiment of the present invention, after the first step of the reaction is completed, it also includes desolvation under reduced pressure.

In a preferred embodiment of the present invention, quenching is also included after the second step reaction is completed. The solution used for the quenching can be a conventional quenching solution for this type of reaction in the art, such as sodium hydroxide solution or potassium hydroxide solution.

In a preferred embodiment of the present invention, after the second step of the reaction is completed, a post-processing step is further included, and the post-processing step can be a conventional post-processing step in the field, and the post-processing step includes washing, drying , one or more of the chromatography steps.

In a preferred embodiment of the present invention, the solution used for the washing can be a conventional washing solution in the field, such as a saturated sodium chloride solution; the drying can use a conventional drying agent in the field, such as anhydrous sodium sulfate, Magnesium sulfate water; the chromatography can be conventional column chromatography in the field, and the eluent used in the chromatography can be conventional eluent in the field, such as petroleum ether, dichloromethane, ethyl acetate and methanol. one or a mixture of several.

In a preferred embodiment of the present invention, it also includes the following steps: in an organic solvent, under the action of a carbonyl activator and a base, the compound represented by formula a and the compound represented by formula e are subjected to the following steps: reaction to obtain the compound shown in formula b,

wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and * are as defined above.

In the present invention, the alkali can be the conventional alkali of this type of reaction in the field, and the alkali as described is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, hydrogen carbonate Potassium, lithium hydride, potassium hydride, sodium hydride, pyridine, triethylamine, tributylamine, N,N-diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine, N-methylmorpholine, N,N-diethylisopropylamine, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, potassium methoxide, lithium methoxide; preferably triethylamine, N, N-diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine, N-methylmorpholine; more preferably N-methylmorpholine.

In the present invention, the organic solvent can be a conventional organic solvent for this type of reaction in the field, such as the organic solvent including methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyl alcohol tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane , one or more of N,N-dimethylformamide, N,N-dimethylacetamide and thionyl chloride; more preferably dichloromethane.

In the present invention, the carbonyl activator can be a conventional carbonyl activator for this type of reaction in the field, and the carbonyl activator is methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, chloroformic acid Isobutyl ester, tert-butyl chloroformate, carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and their The hydrochloride salt, more preferably, isobutyl chloroformate.

In the present invention, the reaction temperature can be the conventional reaction temperature of this type of reaction in the art, such as the reaction temperature is 0-100°C, more preferably 0-30°C, such as 0°C, 25°C.

In the present invention, the reaction time can be the conventional reaction time of this type of reaction in the art, such as 0.5-40h, for example, 24h.

In a preferred embodiment of the present invention, quenching is also included after the reaction is completed. The solution used for the quenching can be a conventional quenching solution for this type of reaction in the art, such as water.

In a preferred embodiment of the present invention, after the reaction is completed, a post-processing step is further included, and the post-processing step can be a conventional post-processing step in the field, and the post-processing step includes washing, drying, chromatography one or more of steps.

In a preferred embodiment of the present invention, the washing solution can be a conventional washing solution in the field, such as a saturated sodium chloride solution. For the drying, conventional desiccants in the art, such as anhydrous sodium sulfate, can be used. The chromatography can be conventional column chromatography in the art, and the eluent used in the chromatography can be a conventional eluent in the art, such as a mixture of petroleum ether and ethyl acetate.

The present invention also provides a complex comprising the above-mentioned quinoline-imidazoline ligand shown in formula 1 and a transition metal compound, wherein the transition metal compound includes cobalt chloride, cobalt bromide, nickel chloride, bromine Nickel chloride, nickel iodide, nickel perchlorate, nickel tetrafluoroborate, nickel hexafluorophosphate, nickel bromide (ethylene glycol dimethyl ether), nickel chloride (ethylene glycol dimethyl ether), bis( 1,5-Cyclooctadiene) nickel, bis(triphenylphosphine) nickel dichloride, nickel acetylacetonate and hydrates corresponding to the above nickel salts, cuprous chloride, cupric chloride, palladium chloride , palladium acetate, platinum chloride.

The present invention also provides a method for synthesizing a cyclic lactam compound, comprising the following steps, under protective gas, in an organic solvent, under the action of the above-mentioned complex compound and a reducing metal element, or in the above-mentioned quinoline-imidazoline Under the action of ligand 1, the transition metal compound and the reducing metal element, the compounds shown in formulas 2 and 3 are reacted as described below to obtain the compound shown in formula 4,

Wherein, R ⁹ and R ¹⁰ are each independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted heteroaryl, nitro , ester group, amide group, boron ester group, acyl group, aldehyde group, cyano group, amino group, amino group, alkyl-oxy group, alkyl-S group, halogen; halogen is fluorine, chlorine, bromine, iodine;

X is halogen; halogen is fluorine, chlorine, bromine, iodine;

The "optionally substituted" is unsubstituted or substituted by the following groups: alkyl, alkyl-oxy, alkyl-S, halogen, nitro, ester, acyl, cyano, aldehyde, boron ester group, amide group, amine group, amino group, or optionally substituted phenyl group; the number of the "substitution" is not limited;

The carbon marked with * is S-configuration chiral carbon or R-configuration chiral carbon;

When * in the quinoline-imidazoline ligand in the complex is an S-configuration chiral carbon, the formula 4 is the dominant configuration as shown by (S)-4.

In a preferred embodiment of the present invention, when the R ⁹ and R ¹⁰ are each independently an optionally substituted alkyl group, the alkyl group is a C ₁ -C ₁₀ alkyl group; preferably, the alkyl group is C ₁ -C ₆ alkyl; more preferably, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-butyl pentyl, isopentyl, neopentyl, or hexyl.

In a preferred embodiment of the present invention, when the R ⁹ and R ¹⁰ are each independently an optionally substituted cycloalkyl, the cycloalkyl is a C ₃ -C ₃₀ cycloalkyl; preferably, the The cycloalkyl group is a C ₃ -C ₈ cycloalkyl group; more preferably, the cycloalkyl group is a cyclopropanyl group, a cyclobutanyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cycloalkyl group Octyl.

In a preferred embodiment of the present invention, when the R ⁹ and R ¹⁰ are each independently an optionally substituted aryl group, the optionally substituted aryl group is phenyl, methyl-substituted phenyl, trifluoro Methyl substituted phenyl, methoxy substituted phenyl, tert-butyl substituted phenyl, fluorine substituted phenyl, naphthyl.

In a preferred embodiment of the present invention, when the R ⁹ and R ¹⁰ are each independently an optionally substituted heteroaryl, the heteroaryl is furyl, thienyl, indolyl or pyridyl.

In the present invention, the organic solvent can be a conventional solvent for this type of reaction in the art, such as the organic solvent is methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane Methane, chloroform, carbon tetrachloride, 1,2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane, N,N- One or more of dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, 1,3-dimethyl-2-imidazolidinone; N,N-dimethylformamide is preferred.

In the present invention, the reducing metal element can be a conventional reducing metal element for this type of reaction in the art, such as zinc and manganese.

In the present invention, in the method for synthesizing cyclic lactam compounds, the reactants also include metal salts, and the metal salts can be conventional metal salts for this type of reaction in the art. For example, the metal salts include lithium chloride , lithium bromide, lithium iodide, zinc chloride, sodium chloride, sodium bromide or sodium iodide; preferably lithium bromide.

In the present invention, the protective gas may be a conventional protective gas for this type of reaction in the art, for example, the protective gas includes nitrogen, argon, helium, neon, or krypton.

In the present invention, the molar concentration of the compound represented by formula 2 in the organic solvent is 0.01-2.0M; preferably 0.1-1M, such as 0.2M.

In the present invention, the molar ratio of the compound shown in formula 2 to the compound shown in formula 3 is 1:5-5:1; preferably 1:1-1:4, for example 1: 3.

In the present invention, the molar ratio of the compound shown in formula 2 to the ligand in the complex is 1:0.01-1:0.3; preferably 1:0.1-1:0.2, for example 1:0.18.

In the present invention, the molar ratio of the compound shown in formula 2 to the transition metal compound in the complex is 1:0.01-1:0.3; preferably 1:0.1-1:0.2, for example 1:0.15 .

In the present invention, the molar ratio of the compound shown in formula 2 to the metal salt is 1:3-3:1; more preferably, 2:1-1:2, such as 1:1.

In the present invention, the reaction temperature may be a conventional reaction temperature of this type of reaction in the art, such as the reaction temperature is -20-50°C; preferably -10-10°C, for example, 0°C.

In the present invention, the reaction time can be the conventional reaction time of this type of reaction in the art, such as the reaction time is 2-196h; preferably 20-108h, such as 72h.

In a preferred embodiment of the present invention, after the reaction is completed, a post-processing step is further included, and the post-processing step may be a conventional post-processing step in the field, and the post-processing step includes a chromatography step. The chromatography can be conventional column chromatography in the field.

The positive progressive effect of the present invention is:

The chiral quinoline-imidazoline ligand provided by the present invention is mainly characterized in that it has a quinoline skeleton and an imidazoline group. The synthesis method of the molecule uses quinolinecarboxylic acid as a starting material, and condenses with a chiral β-amino alcohol , followed by chlorination by thionyl chloride, and finally condensation with a primary amine to complete the synthesis of chiral quinoline-imidazoline ligands. The invention realizes concise, economical large-scale preparation of target molecules, mild reaction conditions and high efficiency; product molecules and synthesis methods have important application value and potential in catalyst framework design and natural medicine synthesis.

The chiral quinoline-imidazoline ligand provided by the present invention can be used as a chiral ligand for the asymmetric bifunctionalization reaction of alkene tethered with amine acyl chloride and halide, thereby synthesizing chiral cyclic lactams. It has high catalytic activity and high enantioselectivity, and has broad application prospects.

In a word, the synthesis method of the present invention is simple, and a large number of preparations can be realized. The practical use and application value of line-imidazoline ligands are of great significance.

Detailed ways

The present invention is further illustrated by the following examples, but the following examples are only helpful for further understanding of the present invention, but cannot limit the content of the present invention.

Example 1: Synthesis of (S)-N-(1-hydroxy-3,3-dimethyl-butan-2-yl)quinoline-8-carboxamide:

Quinoline-8-carboxylic acid (173.1 mg, 1 mmol) was added to a 100 mL dry reaction flask, replaced with nitrogen atmosphere, methylene chloride (20 mL), N-methylmorpholine (0.30 mL, 2.7 mmol) were added, and then The reaction flask was placed in an ice-water bath, isobutyl chloroformate (0.15 mL, 1.15 mmol) was added, the ice-water bath was stirred for 1 hour, and then (S)-2-amino-3,3-dimethyl-1-butane was added The alcohol (175.8 mg, 1.5 mmol) was returned to room temperature, stirred for 24 hours, and the reaction was completed by TLC monitoring. The reaction solution was quenched by adding water (20 mL), and the layers were separated. The aqueous phase was extracted with dichloromethane (20 mL×3), the organic phases were combined, washed with saturated sodium chloride solution, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate. , concentrated under reduced pressure, and column chromatography (petroleum ether/ethyl acetate=1:1) gave (S)-N-(1-hydroxy-3,3-dimethyl-butan-2-yl)quinoline-8 - Formamide: white solid, 360.7 mg, 98% yield.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.16 (d, J=6.1 Hz, 9H), 3.70-3.80 (m, 2H), 4.00-4.20 (m, 2H), 7.52 (dd, J=8.3, 4.3 Hz,1H),7.70(t,J=7.8Hz,1H),7.98(dd,J=8.1,1.6Hz,1H),8.32(dd,J=8.3,1.8Hz,1H),8.86(dd,J =7.4, 1.6Hz, 1H), 8.93 (dd, J=4.3, 1.8Hz, 1H), 11.70 (d, J=5.5Hz, 1H); Anal.calcd for C ₁₆ H ₂₀ N ₂ O ₂ :C, 70.55; H, 7.41; N, 10.29. Found: C, 70.63; H, 7.48; N, 10.27.

Example 2: Synthesis of (S)-8-(4-tert-butyl-1-p-tolyl-4,5-dihydro-1H-imidazol 2-yl)quinoline:

In a 50 mL reaction tube, add (S)-N-(1-hydroxy-3,3-dimethyl-but-2-yl)quinoline-8-carboxamide (S)-1a-b (1.5 mmol) Dissolved in thionyl chloride (1.5mL), refluxed at 90°C for 12 hours, until the TLC reaction was complete, desolvated under reduced pressure, the solid did not need further post-treatment, directly added to a 50mL reaction tube, added ether (10mL) to dissolve, add Triethylamine (15 mmol), p-methylaniline (1.65 mmol) was added, and the mixture was stirred at room temperature for 12 hours until the TLC reaction was complete. The reaction solution was quenched by adding 10% sodium hydroxide solution, extracted with dichloromethane (30 mL×3), and the organic phases were combined, washed with saturated sodium chloride solution, and separated. Concentrated under pressure, column chromatography (dichloromethane/methanol=10:1) gave (S)-8-(4-tert-butyl)-1-(p-tolyl)-4,5-dihydro-1H-imidazole 2-yl)quinoline: pale yellow solid, 320 mg, 62% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.80 (dd, J=4.0, 2.0 Hz, 1H), 8.06 (dd, J=8.0, 2.0 Hz, 1H), 7.86-7.81 (m, 2H), 7.52 (dd,J＝8.0,7.2Hz,1H),7.29(dd,J＝8.0,4.0Hz,1H),6.70(d,J＝8.4Hz,2H),6.56(d,J＝8.4Hz,2H) , 4.21–4.14 (m, 2H), 3.91–3.83 (m, 1H), 2.08 (s, 3H), 1.08 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 160.7, 150.7, 146.2, 139.3 , 135.9, 132.6, 131.9, 130.8, 129.7, 129.0, 128.2, 126.2, 121.3, 120.3, 73.6, 53.3, 34.6, 26.2, 20.6; HRMS(ESI): [M+H] ⁺ Calcd for C ₂₃ H ₂₆ N ₃ ⁺ : 344.2121; found: 344.2122.

Example 3: Synthesis of (S)-8-(4-tert-butyl-1-phenyl-4,5-dihydro-1H-imidazol 2-yl)quinoline:

The preparation method is the same as in Example 2, starting material (S)-1a-b 0.2 mmol, pale yellow solid, 43.8 mg, yield 66%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.74 (dd, J =4.0,1.6Hz,1H),8.07(dd,J=8.4,1.6Hz,1H),7.95(d,J=7.2Hz,1H),7.87(d,J=8.4,1H),7.56(t, J=7.6Hz, 1H), 7.29(dd, J=8.0, 4.0Hz, 1H), 6.92(t, J=8.0Hz, 2H), 6.77(d, J=7.2Hz, 1H), 6.67(d, J=8.0 Hz, 1H), 4.31-4.19 (m, 2H), 3.96 (dd, J=8.4, 7.6 Hz, 1H), 1.11 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 161. 2, 150.8, 145.9, 141.0, 136.0, 131.3, 130.4, 128.5, 128.2, 126.3, 123.1, 121.5, 120.5, 72.3, 53.2, 34.6, 26.1; HRMS(ESI): [M+H] ⁺ Calcd for C ₂₂ H ₂₄ N ₃₊ : ^330.1965 ; found:330.1967.

Example 4: Synthesis of (S)-8-(4-tert-butyl-1-(p-tert-butylphenyl)-4,5-dihydro-1H-imidazol 2-yl)quinoline:

In a 10 mL reaction tube, add (S)-N-(1-hydroxy-3,3-dimethyl-but-2-yl)quinoline-8-carboxamide (S)-1a-b (0.2 mmol) Dissolve with thionyl chloride (0.6mmol) in chloroform (2mL) and reflux for 2 hours, until the TLC reaction is complete, add phosphorus pentachloride (0.42mmol) to the system, reflux for 6 hours, until the TLC reaction is complete, the reaction system is Cool to 0°C, add a solution of triethylamine (1.46 mmol) and p-tert-butylaniline (0.44 mmol) in chloroform (14.6 mL), stir at room temperature for 2 hours, and then reflux for 12 hours until the TLC reaction is complete. The reaction solution was concentrated under reduced pressure, quenched by adding 20% sodium hydroxide (4 mL) solution, extracted with dichloromethane (30 mL×3), and the organic phases were combined, washed with saturated sodium chloride solution, separated, and the organic phase used Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography (dichloromethane/methanol=10:1) to obtain a pale yellow solid, 55.9 mg, yield 73%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.76 (dd, J=4.4, 2.0Hz, 1H), 8.08 (dd, J=8.0, 1.6Hz, 1H), 7.92 (dd, J=7.2, 1.2Hz, 1H), 7.87 (dd, J=8.4, 1.2 Hz, 1H), 7.55(t, J＝8.0Hz, 1H), 7.30(dd, J＝8.4, 4.4Hz, 1H), 6.93(d, J＝8.8Hz, 2H), 6.60(d, J＝8.8 Hz, 2H), 4.30-4.18 (m, 2H), 3.95 (dd, J=8.8, 7.2 Hz, 1H), 1.11 (s, 9H), 1.10 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ):δ161.4,150.8,146.2,146.0,138.1,136.0,131.3,130.5,128.3,126.2,125.4,121.5,120.1,71.8,53.3,34.6,34.2,31.3,26.0; HRMS(ESI):[M+H] ⁺ Calcd for _C26H32N3 ⁺ : _386.2591 ; found: _386.2584 .

Example 5: Synthesis of (S)-8-(4-tert-butyl-1-(p-fluorophenyl)-4,5-dihydro-1H-imidazol 2-yl)quinoline:

The preparation method is the same as in Example 2, starting material (S)-1a-b 0.2 mmol, pale yellow solid, 41.6 mg, yield 60%, ¹ H NMR (400 MHz, DMSO-d6): δ8.76 (d, J=2.4Hz, 1H), 8.37(dd, J=8.4, 1.6Hz, 1H), 8.09(dd, J=8.0, 0.8Hz, 1H), 7.85(d, J=6.8Hz, 1H), 7.66( dd,J=8.0,7.2Hz,1H),7.49(dd,J=8.4,4.4Hz,1H),4.09-3.92(m,3H),1.01(s,9H); HRMS(ESI):[M+ H] ⁺ Calcd for _C22H23N3F ⁺ : _348.1871 ; found: _348.1861 .

Example 6: Synthesis of (S)-8-(4-tert-butyl-1-(p-methoxyphenyl)-4,5-dihydro-1H-imidazol 2-yl)quinoline:

The preparation method is the same as in Example 4, starting material (S)-1a-b 0.2 mmol, white solid, 30.0 mg, yield 42%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.80 (dd, J= 4.0,1.6Hz,1H),8.05(dd,J＝8.4,1.6Hz,1H),7.88(dd,J＝7.2,1.6,Hz,1H),7.81(dd,J＝8.4,1.6Hz,1H) ,7.52(dd,J＝8.0,7.2Hz,1H),7.30(dd,J＝8.4,4.4Hz,1H),6.71(d,J＝8.8Hz,2H),6.46(d,J＝9.2Hz, 2H), 4.23-4.16 (m, 2H), 3.89-3.84 (m, 1H), 3.59 (s, 9H), 1.09 (s, 9H); ¹³ C NMR (100MHz, CDCl ₃ ): δ 161.9, 155.9, 150.7 ,146.0,136.0,134.9,131.3,131.1,130.0,128.2,126.1,123.4,121.4,113.7,73.0,55.4,54.3,34.6,26.1; HRMS(ESI):[M+H] ⁺ Calcd for C ₂₃ H _{26 N3O} ⁺ : 360.2070; found: 360.2066.

Example 7: Synthesis of (S)-8-(4-tert-butyl-1-(p-trifluoromethylphenyl)-4,5-dihydro-1H-imidazol 2-yl)quinoline:

The preparation method is the same as in Example 4, starting material (S)-1a-b 0.2 mmol, white solid, 54.6 mg, yield 69%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.72 (dd, J= 4.0,1.6Hz,1H),8.10(dd,J=8.4,1.6Hz,1H),7.90(d,J=7.6Hz,1H),7.59(t,J=7.6Hz,1H),7.31(dd, J=8.4, 4.4Hz, 1H), 7.11 (d, J=8.4, 1H), 6.58 (d, J=8.4Hz, 2H), 4.19-4.15 (m, 2H), 3.97-3.93 (m, 1H) , 1.08 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 159.3, 150.9, 146.0, 144.2, 136.0, 132.2, 130.7, 130.2, 128.4, 126.4, 125.6 (q, J _CF =3.7 Hz), 122.9 (q, J _CF = 33.3 Hz), 121.7, 117.7, 73.5, 52.2, 34.5, 26.1; ¹⁹ FNMR (376 MHz, CDCl ₃ ): -61.8; HRMS (ESI): [M+H] ⁺ Calcd for C ₂₃ H _{23 N3F3} ⁺ : _398.1839 ; found: 398.1835.

Example 8: (S)-8-(4-tert-butyl-1-(3,5-bis(trifluoromethyl)phenyl)-4,5-dihydro-1H-imidazol 2-yl)quinoline Synthesis of morpholino:

The preparation method is the same as in Example 4, starting material (S)-1a-b 0.2 mmol, white solid, 39.2 mg, yield 42%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.62 (dd, J= 4.0,1.6Hz,1H),8.10(dd,J＝8.4,1.6Hz,1H),7.97(dd,J＝7.2,1.6Hz,1H),7.93(dd,J＝8.4,1.6Hz,1H), 7.62(dd,J=8.0,7.2Hz,1H),7.28(dd,J=8.4,4.0Hz 1H),7.11(s,1H),6.85(s,2H),4.23-4.19(m,2H), 3.94-3.91 (m, 1H), 1.11 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 159.0, 150.7, 145.6, 142.4, 135.9, 131.4 (q, J _CF =32.8 Hz), 131.3, 130.9 , 130.5, 128.3, 126.4, 122.9 (q, J _CF = 271.2 Hz), 121.6, 117.3, 113.9 (q, J _CF = 3.6 Hz), 73.8, 51.7, 34.4, 26.1; ¹⁹ F NMR (376 MHz, CDCl ₃ ) : -63.5; HRMS (ESI): [M+H] ⁺ Calcd for C ₂₄ H ₂₂ N ₃ F ₆ ⁺ : 466.1712; found: 466.1722.

Example 9: (S)-8-(4-tert-butyl-1-(2,4,6-trimethylphenyl)-4,5-dihydro-1H-imidazol 2-yl)quinoline synthesis:

The preparation method is the same as that of Example 2, starting material (S)-1a-b 0.5 mmol, white solid, 160.2 mg, yield 86%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.82 (dd, J= 4.0,1.2Hz,1H),7.96(d,J=8.0Hz,1H),7.90(d,J=7.6Hz,1H),7.70(d,J=8.4Hz,1H),7.42(t,J= 8.0Hz, 1H), 7.28-7.25(m, 1H), 6.60(s, 1H), 6.55(s, 1H), 4.31(t, J＝10.8Hz, 1H), 3.89-3.84(m, 1H), 3.71 (t, J=9.6 Hz, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.03 (s, 3H), 1.12 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ163.9,149.9,146.0,137.5,136.7,136.5,135.8,135.3,131.1,130.0,129.1,129.1,127.9,125.6,121.2,73.8,53.0,34.6,26.4,20.8,18.7,18.6.[HRMS(ESI) M+H] ⁺ Calcd for C ₂₅ H ₃₀ N ₃ ⁺ : 372.2434; found: 372.2430.

Example 10: Synthesis of (S)-8-(4-tert-butyl-1-(adamantan-1-yl)-4,5-dihydro-1H-imidazol 2-yl)quinoline:

The preparation method is the same as in Example 2, starting material (S)-1a-b 0.2 mmol, white solid, 42.6 mg, yield 55%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.00 (dd, J=4.0 ,1.6Hz,1H),8.11(dd,J＝8.4,2.0Hz,1H),7.82(dd,J＝8.0,1.6Hz,1H),7.66(dd,J＝7.2,1.6Hz,1H),7.53 (d, J=8.0Hz, 1H), 7.38 (dd, J=8.4, 4.4Hz, 1H), 3.98–3.68 (m, 2H), 3.51 (t, J=9.6Hz, 1H), 1.91–1.22 ( m, 15H), 1.00 (s, 9H); HRMS (ESI): [M+H] ⁺ Calcd for C ₂₆ H ₃₄ N ₃ ⁺ : 388.2747; found: 388.2747.

Example 11: Synthesis of (S)-8-(4-tert-butyl-1-cyclohexyl-4,5-dihydro-1H-imidazol 2-yl)quinoline:

The preparation method is the same as in Example 4, starting material (S)-1a-b 0.2 mmol, white solid, 24.1 mg, yield 36%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.94 (dd, J= 4.4,1.6Hz,1H),8.16(dd,J＝8.0,1.6Hz,1H),7.88(dd,J＝8.4,1.2Hz,1H),7.81(dd,J＝7.2,1.2Hz,1H), 7.57(dd,J＝8.0,7.6Hz,1H),7.40(dd,J＝8.0,4.0Hz,1H),4.02(dd,J＝11.2,0.8Hz,1H),3.65(dd,J＝11.2, 9.6Hz, 1H), 3.42(t, J=9.2Hz, 1H), 2.80-2.72(m, 1H), 1.88-1.85(m, 1H), 1.65-1.39(m, 7H), 1.01(s, 9H) ), 0.98-0.76 (m, 2H); ¹³ C NMR (100MHz, CDCl ₃ ): δ164.0, 150.9, 146.3, 136.2, 131.0, 129.7, 128.2, 126.3, 121.5, 72.7, 55.0, 45.4, 34.8, 31.5, 30.4 , 26.1, 25.7, 25.5. HRMS(ESI): [M+H] ⁺ Calcd for C ₂₂ H ₃₀ N ₃ ⁺ : 336.2434; found: 336.2432.

Example 12: (S)-8-(4-tert-butyl-1-p-tolyl-4,5-dihydro-1H-imidazol 2-yl)-3-(pyridin-2-yl)quinoline synthesis:

The preparation method is the same as in Example 2, starting material (S)-1k-b 0.2 mmol, white solid, 53.0 mg, yield 63%, ¹ H NMR (400 MHz, CDCl ₃ ): δ9.40 (d, J= 2.0Hz, 1H), 8.75-8.73(m, 1H), 8.71(d, J=2.0Hz, 1H), 7.95(d, J=8.4, 1.2Hz, 1H), 7.90(d, J=6.8Hz, 1H),7.85-7.79(m,2H),7.57(dd,J=8.0,7.2Hz,1H),6.72(d,J=8.0Hz,2H),6.61(d,J=8.4Hz,2H), 4.26-4.17(m, 2H), 3.95-3.89(m, 1H), 2.07(s, 3H), 1.10(s, 9H).

Example 13: Synthesis of (S)-8-(4-tert-butyl-1-p-tolyl-4,5-dihydro-1H-imidazol 2-yl)-3-cyanoquinoline:

The preparation method is the same as in Example 2, starting material (S)-11-b 0.2 mmol, white solid, 45.0 mg, yield 61%, ¹ H NMR (400 MHz, DMSO-d6) δ 9.10-9.04 (m, 2H), 8.18(d, J＝8.0Hz, 1H), 8.02-8.00(m, 1H), 7.81(t, J＝7.6Hz, 1H), 6.72(d, J＝8.0Hz, 2H), 6.50( d, J=8.0Hz, 2H), 4.05–3.87 (m, 3H), 2.01 (s, 3H), 0.99 (s, 9H).

Example 14: Synthesis of (S)-8-(4-neopentyl-1-(p-tolyl)-4,5-dihydro-1H-imidazol-2-yl)quinoline:

The preparation method is the same as that of Example 2, starting material (S)-1m-b 1.0 mmol, white solid, 261.6 mg, yield 73%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.72 (d, J= 2.8Hz, 1H), 8.01 (dd, J=8.0, 1.2Hz, 1H), 7.78 (d, J=8.4Hz, 2H), 7.47 (d, J=7.6Hz, 1H), 7.24 (q, d= 4.0Hz, 1H), 6.65 (d, J=8.4Hz, 2H), 6.49 (d, J=8.4Hz, 2H), 4.44-4.36 (m, 1H), 4.24 (t, J=9.2Hz, 1H) ,3.78(t,J＝9.2Hz,1H),2.11(dd,J＝14.0,2.8Hz,1H),2.02(s,3H),1.61(dd,J＝13.6,8.8Hz,1H),0.968( s, 9H).

Example 15: Synthesis of (S)-8-(4-benzyl-1-(p-tolyl)-4,5-dihydro-1H-imidazol-2-yl)quinoline:

The preparation method is the same as in Example 2, starting material (S)-1n-b 1.0 mmol, white solid, 151 mg, yield 40%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.74 (dd, J=4.0 ,1.6Hz,1H),8.02(dd,J＝8.4,2.0Hz,1H),7.78(dd,J＝8.4,1.6Hz,1H),7.73(dd,J＝6.8,0.8Hz,1H),7.46 (dd,J=8.0,7.2Hz,1H),7.32-7.23(m,5H),7.18-7.16(m,1H),6.61(d,J=8.0Hz,2H),6.38(d,J=8.4 Hz,2H),4.73-4.67(m,1H),4.08(t,J＝10.0Hz,1H),3.84(dd,J＝9.2,7.6Hz,1H),3.31(dd,J＝14.0,4.4Hz , 1H), 2.96 (dd, J=13.6, 8.4 Hz, 1H), 2.0 (s, 3H).

Example 16: Synthesis of (S)-8-(4-(tert-butyl)-1-(naphthalen-2-yl)-4,5-dihydro-1H-imidazol-2-yl)quinoline:

The preparation method is the same as in Example 2, starting material (S)-1a-b 0.5 mmol, white solid, 80 mg, yield 42%, ¹ HNMR (400 MHz, CDCl ₃ ): δ8.63 (dd, J=4.0, 1.6Hz,1H),8.00-7.95(m,2H),7.82(dd,J=8.4,1.2Hz,1H),7.56-7.64(m,2H),7.4(d,J=8.4Hz,1H), 7.25(dd,J＝6.8,1.2Hz,2H),7.17(d,J＝4.4Hz,2H),7.11(d,J＝1.6Hz,1H),6.70(dd,J＝8.8,2.0Hz,1H ), 4.34 (t, J=10.0Hz, 1H), 4.21 (dd, J=10.8, 7.6Hz, 1H), 4.04 (dt, J=14.4, 7.2Hz, 1H), 1.08 (s, 9H); ¹³ CNMR (101MHz, CDCl ₃ ) δ 150.9, 145.9, 136.0, 133.6, 131.5, 130.8, 130.0, 128.3, 128.2, 127.5, 127.2, 126.5, 126.3, 124.8, 121.7, 120.6, 77.4, 53.6, 34.7, 26.1.

Example 17: (S)-8-(4-(tert-butyl)-1-(3,5-di-tert-butylphenyl)-4,5-dihydro-1H-imidazol-2-yl)quinoline morpholino

The preparation method is the same as in Example 2, starting material (S)-1a-b 0.2 mmol, white solid, 43 mg, yield 49%, ¹ HNMR (400 MHz, CDCl ₃ ): δ8.58 (d, J=2.8 Hz ,1H),8.06(s,1H),7.98(dd,J＝8.0,1.6Hz,1H),7.83(d,J＝8.4Hz,1H),7.55(t,J＝8.0Hz,1H),7.23 -7.19(m, 1H), 6.83(s, 1H), 6.53(s, 2H), 4.40(s, 1H), 43.1-4.32(m, 1H), 4.04(s, 1H), 1.12(s, 9H) ), 0.92(s, 18H).

Example 18: (S)-8-(1-([1,1':3',1"-terphenyl]-5'-yl)-4-(tert-butyl)-4,5-dihydro -1H-imidazol-2-yl)quinoline

The preparation method is the same as in Example 2, starting material (S)-1a-b 0.2 mmol, white solid, 77 mg, yield 80%, ¹ HNMR (400 MHz, CDCl ₃ ): δ8.72 (dd, J=4.4, 1.6Hz, 1H), 8.08(dd, J=8.0, 1.6Hz, 1H), 7.97-7.86(m, 2H), 7.57(t, J=7.2Hz, 1H), 7.23(m, 7H), 7.13( s,1H),7.06-7.01(m,4H),6.80(s,2H),4.30(t,J=9.6Hz,1H),4.23-4.15(m,1H),4.00(t,J=8.0Hz , 1H), 1.07(s, 9H).

Example 19: (S)-8-(4-isopropyl-1-(p-tolyl)-4,5-dihydro-1H-imidazol-2-yl)quinoline

The preparation method is the same as in Example 2, starting material (S)-1r-b 0.5 mmol, white solid, 150 mg, yield 91%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.74 (dd, J=4.4 ,2.0Hz,1H),8.01(dd,J=8.4,1.6Hz,1H),7.81-7.74(m,2H),7.46(dd,J=8.0,7.2Hz,1H),7.24(dd,J= 8.4,4.0Hz,1H),6.64(d,J=8.4Hz,2H),6.49(d,J=8.8Hz,2H),4.24-4.00(m.2H),3.80(t,J=8.8Hz, 1H), 2.08-1.95(m, 3H), 1.16(d, J=7.6Hz, 1H), 1.06(d, J=6.8Hz, 3H), 1.01(d, J=6.8Hz, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ): δ 160.8, 157.3, 150.7, 146.0, 139.0, 135.8, 132.0, 130.8, 129.9, 128.9, 126.1, 121.3, 120.2, 77.2, 46.0, 33.2, 20.6, 19.0, 18.0.

Example 20: (S)-8-(4-(tert-butyl)-1-(p-tolyl)-4,5-dihydro-1H-imidazol-2-yl)-6-methoxyquinoline

The preparation method is the same as in Example 2, starting material (S)-1s-b 0.2 mmol, white solid, 57.7 mg, yield 77%, ¹ H NMR (400 MHz, CDCl ₃ ): δ8.57 (dd, J= 4.4,1.6Hz,1H),7.88(dd,J=8.4,2.0Hz,1H),7.47(d,J=2.8Hz,1H),7.19-7.14(m,1H),7.02(d,J=2.8 Hz,1H),6.66(d,J=8.4Hz,2H),6.53(d,J=8.4Hz,2H),4.15-4.04(m,1H),3.85(s,3H),3.79(t,J = 6.0 Hz, 1H), 2.03 (s, 3H), 1.00 (s, 9H); ¹³ C NMR (101 MHz, CDCl ₃ ): δ 160.4, 157.1, 148.3, 142.4, 139.1, 134.7, 129.4, 129.1, 123.5, 121.6 , 120.5, 107.3, 77.4, 55.8, 53.5, 46.0, 34.6, 26.2, 20.7, 9.6.

Example 21: 8-((S)-4-(adamantan-1-yl)-1-p-tolyl-4,5-dihydro-1H-imidazol-2-yl)quinoline

The preparation method is the same as that of Example 2, starting material (S)-1t-b 0.26 mmol, white solid, 104 mg, yield 95%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (dd, J=4.4, 1.6Hz,1H),8.07(dd,J=8.4,1.6Hz,1H),7.96(dd,J=7.2,0.8Hz,1H),7.86(dd,J=7.2,0.8Hz,1H),7.55( t,J＝7.6Hz,1H),7.30(dd,J＝8.4,4.0Hz,1H),6.74(d,J＝8.4Hz,2H),6.62(d,J＝8.4Hz,2H),4.23- ¹³ C NMR(101MHz,CDCl ₃ )δ161.71,150.81,145.77,138.15,136.00,133.48,131.53,130.67,129.20,128.20,126.19,121.58,121.18,71.49,52.22,38.37,37.28,36.36,28.39,20.75。

Examples 22-59: Use of quinoline-imidazoline ligands for the asymmetric difunctionalization of alkenes with alkene-tethered amine acyl chlorides and halides.

Ligand (S)-1a (0.036 mmol), bis(1,5-cyclooctadiene)nickel (0.030 mmol), lithium bromide (0.2 mmol), and manganese (0.8 mmol) were weighed in a glove box In a dry and clean 10 mL reaction tube with a strong stirring bar, add 1 mL of N,N-dimethylformamide, alkene-tethered amine acyl chloride (0.2 mmol) and halogenated hydrocarbon (0.6 mmol), seal it and take it out. After stirring for 48 hours, the reaction solution was quenched with water, filtered through celite, the filter cake was washed with ethyl acetate, washed with water 3 times, back-extracted with ethyl acetate for 2 times, separated, and the organic phases were combined, and the solvent was removed by a rotary evaporator. The crude product was obtained, the conversion rate and yield of the reaction were analyzed by thin-layer chromatography or nuclear magnetic resonance, and the optical purity of the product was analyzed by high-performance liquid chromatography. The experimental results of the obtained chiral cyclic lactam are shown in Table 1.

Table 1. Asymmetric difunctionalization of alkene-tethered amine acyl chlorides with halides to form chiral cyclic lactams.

Example 60: Compatibility attempt of quinoline-imidazoline ligands for asymmetric difunctionalization of alkenes with alkene-tethered amine acyl chlorides and halides.

Ligand (S)-1a (0.036 mmol), nickel perchlorate hexahydrate (0.030 mmol), lithium bromide (0.2 mmol), and manganese (0.8 mmol) were weighed in a glove box in a dry, clean room equipped with a powerful stirring bar. In a 10 mL reaction tube, add 1 mL of N,N-dimethylformamide, alkene-tethered amine acyl chloride (0.2 mmol) and halogenated hydrocarbon (0.6 mmol), seal and take out, and stir at 0°C for 36 hours. Quenched with water, filtered through celite, washed the filter cake with ethyl acetate, washed with water 3 times, back-extracted with ethyl acetate 2 times, separated the layers, combined the organic phases, and removed the solvent with a rotary evaporator to obtain a crude product, which was washed with thin The conversion rate and yield of the reaction were analyzed by chromatography or nuclear magnetic resonance, and the optical purity of the product was analyzed by high-performance liquid chromatography. The chiral cyclic lactam product was obtained in 75% yield and 95% ee.

Example 61: Temperature compatibility attempts of quinoline-imidazoline ligands for the asymmetric difunctionalization of alkenes with alkene-tethered amine acyl chlorides and halides.

The reaction conditions and post-processing steps were the same as those in Example 60, except that the reaction was changed at 10°C. The chiral cyclic lactam product was obtained in 57% yield, 93% ee.

Example 62: Compatibility of quinoline-imidazoline ligands to metal salts in the asymmetric difunctionalization of alkene-tethered amine acyl chlorides with halides.

The reaction conditions and post-processing steps were the same as those in Example 60, except that the same amount of lithium iodide was used instead of lithium bromide. The chiral cyclic lactam product was obtained in 35% yield, 94% ee.

Example 63: Quinoline-imidazoline ligands used in alkene-tethered amine acyl chlorides and halides for alkene asymmetric bifunctionalization of alkenes for compatibility attempts with metal salts.

The reaction conditions and post-processing steps were the same as those in Example 60 except that the same amount of sodium iodide replaced lithium bromide. The chiral cyclic lactam product was obtained in 34% yield, 94% ee.

Example 64: Quinoline-imidazoline ligands used in alkene-tethered amine acyl chlorides and halides for alkene asymmetric bifunctionalization of alkene-based compatibility attempts on metal salts.

The reaction conditions and post-processing steps are the same as those in Example 60 except that the sodium bromide of the same material amount replaces the lithium bromide. The chiral cyclic lactam product was obtained in 43% yield, 93% ee.

Example 65: Solvent compatibility attempts of quinoline-imidazoline ligands for asymmetric difunctionalization of alkenes with alkene-tethered amine acyl chlorides and halides.

The reaction conditions and post-processing steps were the same as those in Example 60, except that the same volume of N-methylpyrrolidone was used instead of N,N-dimethylformamide. The chiral cyclic lactam product was obtained in 55% yield, 91% ee.

Example 66: Solvent compatibility attempts of quinoline-imidazoline ligands for asymmetric difunctionalization of alkene-tethered amine acyl chlorides with halides.

The reaction conditions and post-processing steps were the same as those in Example 60, except that the same volume of N,N-dimethylacetamide was used instead of N,N-dimethylformamide. The chiral cyclic lactam product was obtained in 38% yield, 94% ee.

Example 67: Solvent compatibility attempts of quinoline-imidazoline ligands for asymmetric difunctionalization of alkene-tethered amine acyl chlorides with halides.

The reaction conditions and post-processing steps were the same as those in Example 60, except that the same volume of 1,3-dimethyl-2-imidazolidinone was used instead of N,N-dimethylformamide. The chiral cyclic lactam product was obtained in 24% yield, 94% ee.

Example 68: Solvent compatibility attempts of quinoline-imidazoline ligands for asymmetric difunctionalization of alkenes with alkene-tethered amine acyl chlorides and halides.

The reaction conditions and post-processing steps were the same as those in Example 60, except that the same volume of acetonitrile was used instead of N,N-dimethylformamide. The chiral cyclic lactam product was obtained in 32% yield, 79% ee.

Example 69: Compatibility attempt of quinoline-imidazoline ligands for asymmetric difunctionalization of alkenes with alkene-tethered amine acyl chlorides and halides on reactant concentrations.

The reaction conditions and post-processing steps were the same as those in Example 60, except that 4 mL of N,N-dimethylformamide was used. The chiral cyclic lactam product was obtained in 66% yield, 94% ee.

Example 70: Compatibility attempts of quinoline-imidazoline ligands for nickel catalysts in asymmetric difunctionalization of alkene-tethered amine acyl chlorides with halides.

The reaction conditions and post-processing steps are the same as those in Example 60, except that the same amount of nickel bromide (ethylene glycol dimethyl ether) replaces the nickel perchlorate hexahydrate. The chiral cyclic lactam product was obtained in 43% yield, 77% ee.

Example 71: Compatibility attempts of quinoline-imidazoline ligands for nickel catalysts in asymmetric difunctionalization of alkene-tethered amine acyl chlorides with halides.

The reaction conditions and post-processing steps were the same as those of Example 60, except that the same amount of bis(1,5-cyclooctadiene) nickel was used instead of nickel perchlorate hexahydrate. The chiral cyclic lactam product was obtained in 86% yield, 94% ee.

Comparative Example 1: Quinoline-imidazoline-like ligands applied to alkene-tethered amine acyl chlorides and halides for asymmetric bifunctionalization of alkenes versus quinoline-imidazoline ligands.

The reaction conditions and post-treatment steps were the same as those in Example 65, except that (S)-L1 in the same amount of substances was used instead of (S)-1a. The chiral cyclic lactam product was obtained in 33% yield, 37% ee.

Comparative Example 2: Quinoline-imidazoline-like ligands applied to alkene-tethered amine acyl chlorides and halides for asymmetric bifunctionalization of alkenes versus quinoline-imidazoline ligands.

The reaction conditions and post-processing steps were the same as those in Example 65, except that (S,S)-L2 in the same amount of substances was used instead of (S)-1a. The chiral cyclic lactam product was obtained in 12% yield, 11% ee.

Comparative Example 3: Quinoline-imidazoline-like ligands applied to alkene-tethered amine acyl chlorides and halides for asymmetric bifunctionalization of alkenes versus quinoline-imidazoline ligands.

The reaction conditions and post-processing steps were the same as those in Example 65, except that (S)-L3 in the same amount of substances was used instead of (S)-1a. A chiral cyclic lactam product could not be obtained.

Comparative Example 4: Quinoline-imidazoline-like ligands applied to alkene-tethered amine acyl chlorides and halides for asymmetric bifunctionalization of alkenes versus quinoline-imidazoline ligands.

The reaction conditions and post-processing steps were the same as those in Examples 22-59 except that all reactants, the amount of solvent were halved, and (S)-L4 in the same amount of substances was used instead of (S)-1a. The chiral cyclic lactam product was obtained in 68% yield, 54% ee.

Claims (10)

1. A quinoline-imidazoline ligand represented by formula 1:

wherein R is¹Is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl or optionally substituted heteroaryl;

R²is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted heteroaryl, ester, amide, boroester, acyl, cyano, amine, amino;

R³-R⁸each independently is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, ester, amide, boroester, acyl, aldehyde, cyano, amine, amino, alkyl-oxy, alkyl-S group, halogen;

said "optionally substituted" is unsubstituted, or substituted with: alkyl, alkyl-oxy, alkyl-S group, halogen, nitro, ester group, acyl group, cyano, aldehyde group, boroester group, amide group, amine group, amino group, or optionally substituted phenyl group; the number of said "substitutions" may not be limited;

the carbon marked with x is an S configuration chiral carbon or an R configuration chiral carbon.

2. The ligand of claim 1, wherein when R is¹When it is an optionally substituted alkyl group, the alkyl group is C₁～C₁₀Preferably, the alkyl group is C₁～C₆More preferably, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl; when said R is¹When being optionally substituted cycloalkyl, said cycloalkyl is C₃～C₃₀Preferably, said cycloalkyl is C₃～C₈More preferably, the cycloalkyl group is a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane group; when said R is¹When optionally substituted aryl, the optionally substituted aryl is phenyl, methyl-substituted phenyl, trifluoromethyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl, fluoro-substituted phenyl, naphthyl; when said R is¹When optionally substituted, the heteroaryl is furyl, thienyl, indolyl or pyridyl;

and/or, when said R is²When it is an optionally substituted alkyl group, the alkyl group is C₁～C₁₀Preferably, the alkyl group is C₁～C₆More preferably, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl;

and/or, when said R is³-R⁸Each independently is an optionally substituted alkyl group, said alkyl group is C₁～C₁₀Preferably, the alkyl group is C₁～C₆Alkyl radicalMore preferably, the alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, or a hexyl group; when said R is³-R⁸When each is independently optionally substituted cycloalkyl, the cycloalkyl is C₃～C₃₀Preferably, said cycloalkyl is C₃～C₈More preferably, the cycloalkyl group is a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane group; when said R is³-R⁸When each is independently optionally substituted aryl, the aryl is phenyl; when said R is³-R⁸When each is independently optionally substituted heteroaryl, the heteroaryl is furyl, thienyl, indolyl or pyridyl.

3. Ligand according to claim 1 or 2, characterized in that it is any one of the compounds shown below:

wherein, the definition of the compound is as defined in claim 1.

4. A method for preparing a ligand according to any one of claims 1-3, comprising the steps of: in an organic solvent, under the action of a chlorinating agent and alkali, carrying out the following reaction on a compound shown as a formula b and a compound shown as a formula d to obtain the compound shown as the formula 1:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And is as defined in claim 1.

5. The production method according to claim 4,

the organic solvent comprises one or more of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide;

and/or the chlorinating agent is thionyl chloride and/or phosphorus pentachloride;

and/or the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydride, potassium hydride, sodium hydride, pyridine, triethylamine, tributylamine, N-diisopropylamine, N-diisopropylethylamine, 2, 6-dimethylpyridine, N-methylmorpholine, N-diethylisopropylamine, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium methoxide, potassium methoxide, lithium methoxide;

and/or the reaction temperature of the first step is 0-120 ℃;

and/or, the reaction temperature of the second step is 0-100 ℃;

and/or the molar concentration of the compound shown as the formula b in the organic solvent is 0.01-5 mol/L;

and/or the molar ratio of the compound shown as the formula b to the chlorinating agent is 1:1-1: 100;

and/or the molar ratio of the compound shown as the formula b to the alkali is 1:1-1: 30;

and/or the molar ratio of the compound shown as the formula b to the compound shown as the formula d is 1:0.5-1: 3.

6. The preparation method according to claim 4, further comprising the step of reacting the compound represented by the formula a with the compound represented by the formula e in an organic solvent under the action of a carbonyl activator and a base to obtain the compound represented by the formula b,

wherein R is²、R³、R⁴、R⁵、R⁶、R⁷、R⁸And is as defined in claim 1.

7. A complex comprising the quinoline-imidazoline ligand of formula 1 as claimed in any one of claims 1 to 3 and a transition metal compound comprising cobalt chloride, cobalt bromide, nickel chloride, nickel bromide, nickel iodide, nickel perchlorate, nickel tetrafluoroborate, nickel hexafluorophosphate, nickel (ethylene glycol dimethyl ether) bromide, nickel (ethylene glycol dimethyl ether) chloride, nickel bis (1, 4-cyclooctadiene) chloride, nickel bis (triphenylphosphine) dichloride, nickel acetylacetonate and hydrates corresponding to the above nickel salts, cuprous chloride, cupric chloride, palladium acetate, platinum chloride.

8. A method for synthesizing a cyclic lactam compound is characterized by comprising the following steps of carrying out the following reactions on compounds shown as formulas 2 and 3 in an organic solvent under the action of a complex compound and a simple reducing metal substance in claim 7 or under the action of a ligand in any one of claims 1 to 3, a transition metal compound and a simple reducing metal substance in a protective gas to obtain a compound shown as a formula 4,

wherein R is⁹、R¹⁰Each independently is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted benzyl, optionally substituted aryl, optionally substituted heteroaryl, nitro, ester, amide, boroester, acyl, aldehydeCyano, amino, alkyl-oxy, alkyl-S-yl, halogen;

x is halogen;

the halogen is fluorine, chlorine, bromine or iodine;

said "optionally substituted" is unsubstituted, or substituted with: alkyl, alkyl-oxy, alkyl-S group, halogen, nitro, ester group, acyl group, cyano, aldehyde group, boroester group, amide group, amine group, amino group, or optionally substituted phenyl group; the number of said "substitutions" may not be limited;

the carbon marked by the letter is S configuration chiral carbon or R configuration chiral carbon;

when the x in the quinoline-imidazoline ligand in the complex is S configuration chiral carbon, the formula 4 is the dominant configuration shown as 4a,

9. the method of claim 8, wherein when R is said⁹、R¹⁰Each independently is an optionally substituted alkyl group, said alkyl group is C₁～C₁₀Preferably, the alkyl group is C₁～C₆More preferably, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl; when said R is⁹、R¹⁰When each is independently optionally substituted cycloalkyl, the cycloalkyl is C₃～C₃₀Preferably, said cycloalkyl is C₃～C₈More preferably, the cycloalkyl group is a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane group; when said R is⁹、R¹⁰Each independently is optionally substituted aryl, said optionally substituted aryl is phenyl, methyl-substituted phenyl, trifluoromethyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl,Fluoro-substituted phenyl, naphthyl; when said R is⁹、R¹⁰When each is independently optionally substituted heteroaryl, the heteroaryl is furyl, thienyl, indolyl or pyridyl.

10. The method according to claim 8, wherein the organic solvent is one or more of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, benzene, toluene, xylene, diethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, 1, 3-dimethyl-2-imidazolidinone;

and/or, said method for synthesizing cyclic lactam compound, still include the metal salt in the reactant, said metal salt includes lithium chloride, lithium bromide, lithium iodide, zinc chloride, sodium bromide or sodium iodide;

and/or the reducing metal simple substance can be a reducing metal simple substance which is conventional in the reaction in the field, such as zinc and manganese;

and/or the protective gas comprises nitrogen, argon, helium, neon or krypton;

and/or the molar concentration of the compound shown as the formula 2 in the organic solvent is 0.01-2.0M;

and/or the molar ratio of the compound shown as the formula 2 to the compound shown as the formula 3 is 1: 5-5: 1;

and/or the molar ratio of the compound shown as the formula 2 to the ligand in the complex is 1: 0.05-1: 0.3;

and/or the molar ratio of the compound shown as the formula 2 to the transition metal compound in the complex is 1: 0.01-1: 0.3;

and/or the molar ratio of the compound shown as the formula b to the metal salt is 1: 0.01-1: 0.3;

and/or the reaction temperature is-20 to 50 ℃.