A tridentate nitrogen ligand and its synthesis method

Abstract

This invention belongs to the field of organic chemistry ligands and discloses a tridentate nitrogen ligand having the structure of general formula I: wherein, R 1 Selected from alkyl, phenyl, benzyl and R 2 It is hydrogen, or R 1 R 2 =-(CH2)4-; R 3 It is quinolinyl, isoquinolinyl or R 5 Selected from hydrogen, alkyl, alkoxy, benzyl, Ph₂CH⁻, halogen, trifluoromethyl, polycyclic aromatic hydrocarbon group, substituted phenyl; R 4 The ligand is methyl or ethyl. This invention also discloses the synthesis method and applications of tridentate nitrogen ligands. This invention assembles an amide group, a pyridyl group (or a quinolinyl or isoquinolinyl group), and a tertiary alkylamine into the same ligand, developing a novel class of tridentate NNN ligands. This ligand can not only be widely used in the asymmetric cross-coupling reactions of tertiary alkyl chlorides and terminal alkynes, but also has significant implications for developing novel catalytic systems to solve other types of free radical asymmetric reactions.

Description

[0001] This application is a divisional application of application number 2022102207951, filed on March 8, 2022, entitled "A Tridentate Nitrogen Ligand and Its Synthesis Method and Use". Technical Field

[0002] This invention belongs to the field of organic chemical ligands, specifically a tridentate nitrogen ligand, its synthesis method, and its uses. Background Technology

[0003] Tridentate ligands hold a very important position in coordination chemistry. Currently, they have been widely applied in synthetic chemistry, catalysis chemistry, materials chemistry, and chemical biology. Due to the good stability of nitrogen-containing ligands, their wide availability of raw materials, and their ability to form coordination interactions with numerous metals, NNN tridentate ligands have become one of the most important branches of tridentate ligands. In recent years, with the rapid development of chiral chemistry, many nitrogen-containing chiral ligands have been developed, and nitrogen-containing chiral ligands complexed with transition metals are playing an increasingly important role in asymmetric catalytic reactions.

[0004] In the development of asymmetric catalysis, the design and synthesis of novel chiral ligands has always been a hot topic. In recent years, with the advancement of free radical asymmetric chemistry, there is an urgent need to develop chiral ligands with different skeleton types to effectively regulate the stereoselectivity of free radical intermediates. Among numerous ligand structural units, the amide group is widely found in nature and is an important structural unit in coordination chemistry. The pyridyl group can form complexes with various transition metals, which has long attracted the attention of chemists. Assembling amide, pyridyl, and tertiary alkylamines in the same ligand can serve as a novel class of tridentate NNN ligands for catalytic reactions. Furthermore, introducing the chiral skeleton of cyclohexanediamine and different types of amino acid derivative skeletons into ligands provides a specific chiral environment for the catalytic reaction, thereby inducing high enantioselectivity. Summary of the Invention

[0005] The purpose of this invention is to provide a novel chiral tridentate nitrogen ligand with a skeleton based on amide group, pyridyl group (or quinolinyl group, isoquinolinyl group), and tertiary alkylamine group.

[0006] Another object of the present invention is to provide a method for synthesizing the tridentate nitrogen ligand.

[0007] Another object of the present invention is to provide the use of the tridentate nitrogen ligand.

[0008] To achieve one of the above objectives, the present invention adopts the following technical solution:

[0009] A tridentate nitrogen ligand having the structure of general formula I:

[0010]

[0011] Among them, R 1 Selected from alkyl, phenyl, benzyl and R 2 It is hydrogen, or R 1 R 2 =-(CH2)4-;

[0012] R 3 It is quinolinyl, isoquinolinyl or

[0013] R 5 Selected from hydrogen, alkyl, alkoxy, benzyl, Ph2CH-, halogen, trifluoromethyl, polycyclic aromatic hydrocarbon group, substituted phenyl;

[0014] R 4 It can be methyl or ethyl.

[0015] Furthermore, the R 1 Selected from (C1-C4) alkyl, phenyl, benzyl and R 2 It is hydrogen, or R 1 R 2 =-(CH2)4-.

[0016] Furthermore, the R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, phenyl, benzyl and R 2 It is hydrogen, or R 1 R 2 =-(CH2)4-.

[0017] Furthermore, the R 3 It is quinolinyl, isoquinolinyl or

[0018] R 5 Selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, benzyl, Ph2CH-, halogen, trifluoromethyl, polycyclic aromatic hydrocarbon group, and substituted phenyl.

[0019] Furthermore, the R 3 It is quinolinyl, isoquinolinyl or

[0020] R 5 Selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, Ph2CH-, halogen, trifluoromethyl, polycyclic aromatic hydrocarbon group, substituted phenyl.

[0021] Furthermore, the R 3 It is quinolinyl, isoquinolinyl or

[0022] R 5Selected from hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, benzyl, Ph2CH-, halogen, trifluoromethyl, naphthyl, anthraceneyl, phenanthrene, pyrene, and substituted phenyl.

[0023] Furthermore, the R 3 It is quinolinyl, isoquinolinyl or

[0024] R 5 Selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, benzyl, Ph2CH-, fluorine, chlorine, bromine, trifluoromethyl, naphthyl, anthracene, phenanthrene, pyrene, and substituted phenyl.

[0025] Furthermore, the substituted phenyl group is...

[0026] R 6 It is selected from hydrogen, alkyl, phenyl, alkyl or phenyl-substituted phenyl, polycyclic aromatic hydrocarbon group, 9-phenylanthrayl, where m is 1 to 6.

[0027] Furthermore, the substituted phenyl group is...

[0028] R 6 It is selected from hydrogen, (C1-C4)alkyl, phenyl, (C1-C4)alkyl or phenyl-substituted phenyl, polycyclic aromatic hydrocarbon group, and 9-phenylanthrayl.

[0029] Furthermore, the substituted phenyl group is...

[0030] R 6 It is selected from hydrogen, (C1-C4)alkyl, phenyl, 4-tert-butylphenyl, 3,5-di-tert-butylphenyl, 3,5-diphenylphenyl, polycyclic aromatic hydrocarbon group, and 9-phenylanthrayl.

[0031] Furthermore, the substituted phenyl group is...

[0032] R 6 It is selected from hydrogen, (C1-C4)alkyl, phenyl, 4-tert-butylphenyl, 3,5-di-tert-butylphenyl, 3,5-diphenylphenyl, naphthyl, anthracene, phenanthryl, and 9-phenylanthryl.

[0033] Furthermore, the substituted phenyl group is...

[0034] R 6 Selected from hydrogen, tert-butyl, phenyl, 4-tert-butylphenyl, 3,5-di-tert-butylphenyl, 3,5-diphenylphenyl, naphthyl, anthracene, phenanthryl, and 9-phenylanthryl.

[0035] Furthermore, m is 1 or 2.

[0036] Furthermore, the R 5 When the phenyl group is substituted, the substitution position is:

[0037] Furthermore, the R 4 It is a methyl group.

[0038] Furthermore, the tridentate nitrogen ligand is selected from the following compounds:

[0039]

[0040]

[0041] A method for preparing the above-mentioned tridentate nitrogen ligand includes the following steps: Compound S1 and compound S2 react in the presence of EDCI and DMAP as follows:

[0042]

[0043] Among them, R 1 Selected from alkyl, phenyl, benzyl and R 2 It is hydrogen, or R 1 R 2 =-(CH2)4-;

[0044] R 3 It is quinolinyl, isoquinolinyl or

[0045] R 5 Selected from hydrogen, alkyl, alkoxy, benzyl, Ph2CH-, halogen, and trifluoromethyl;

[0046] R 4 It can be methyl or ethyl.

[0047] Further, the molar ratio of compound S1, compound S2, EDCI and DMAP is (1-2):1:(2-6):(1.5-3); the reaction is carried out in dichloromethane as solvent; the reaction temperature is above 20°C; and the reaction time is at least 24 hours.

[0048] A method for preparing the above-mentioned tridentate nitrogen ligand includes the following steps:

[0049] In the presence of EDCI and DMAP, compound S3 and compound S2 react to give S4;

[0050] Compound S4 and compound S5 react to give the product;

[0051]

[0052] Among them, R1 R 2 =-(CH2)4-;

[0053] R 5 Selected from polycyclic aromatic hydrocarbon groups and substituted phenyl groups;

[0054] R 4 It can be methyl or ethyl.

[0055] Furthermore, the molar ratio of compound S3, compound S2, EDCI and DMAP is (1-2):1:(2-6):(1.5-3); the reaction is carried out in dichloromethane as a solvent; the reaction temperature is above 20°C; and the reaction time is at least 24 hours.

[0056] Furthermore, the reaction is carried out with tetratetraphenylphosphine palladium as a catalyst and potassium carbonate as a base; the molar ratio of compound S4, compound S5 and potassium carbonate is 1:(1-2):(2-4); the amount of tetratetraphenylphosphine palladium is 4-12 mol%; the reaction is carried out with tetrahydrofuran as a solvent; the reaction temperature is 80-120℃ and the reaction time is 24-72 h.

[0057] Application of tridentate nitrogen ligands in radical asymmetric Sonogashira cross-coupling reactions of tertiary alkyl chloroalkanes and terminal alkynes.

[0058] As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0059] As used herein, "alkoxy group" refers to -O- (alkyl) and -O- (cycloalkyl), where alkyl and cycloalkyl are defined as described herein. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups typically have 1 to 7 carbon atoms connected by oxygen bridges. Alkoxy groups also include substituted alkoxy groups. Alkoxy groups may optionally be substituted with halogens once or multiple times.

[0060] The term "halogen" as used in this article refers to fluorine, chlorine, bromine, and iodine.

[0061] The term "trifluoromethyl" used in this article refers to -CF3.

[0062] The term "benzyl" as used in this article refers to PhCH2-.

[0063] The "substitution" in "substituted phenyl" or "substituted phenyl" as used herein can be monosubstituted, polysubstituted, or unsubstituted (i.e., entirely composed of hydrogen atoms); "substituted phenyl" or "substituted phenyl" includes: (1) a benzene ring with one non-hydrogen substituent; (2) a benzene ring with two or more identical or different non-hydrogen substituents; (3) a benzene ring consisting entirely of hydrogen atoms with no substituents. The substitution position can be any position of the 2nd, 3rd, 4th, 5th, or 6th position of the benzene ring.

[0064] The term "polycyclic aromatic hydrocarbon group" as used in this article refers to a substituent formed by reducing one hydrogen atom in an aromatic hydrocarbon compound consisting of an aromatic ring that does not contain heterocycles or substituents. Substituents include naphthyl, anthraceneyl, phenanthryl, pyrene, and tetraphenyl. Benzyl, triphenylene, pentanephenyl, etc.

[0065] "Naphthyl" refers to It includes 1-naphthyl and 2-naphthyl.

[0066] "Anthracene" refers to It includes 1-anthrayl, 2-anthrayl and 9-anthrayl.

[0067] "Fiki" refers to Including 1-Feghi, 2-Feghi, 3-Feghi, 4-Feghi, and 9-Feghi.

[0068] "Pyrgy" refers to It includes 1-pyrene, 2-pyrene, 4-pyrene and 5-pyrene.

[0069] "9-Phenylanthrene" refers to

[0070] "Isoquinolinyl" refers to It includes 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl.

[0071] "Kinolinyl" refers to It includes 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, and 8-quinolinyl.

[0072] EDCI refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and DMAP refers to 4-dimethylaminopyridine.

[0073] The present invention has the following beneficial effects:

[0074] This invention assembles an amide group, a pyridinyl group (or a quinolinyl or isoquinolinyl group), and a tertiary alkylamine into a single ligand, developing a novel class of tridentate NNN ligands, which have been successfully applied to asymmetric catalytic reactions. These novel chiral ligands possess a rich variety of structures; the introduction of substituents with different electronic and steric effects on the pyridinium ring of the ligand can modulate the reaction activity and enantioselectivity. Another significant advantage lies in the introduction of the cyclohexanediamine chiral skeleton and different types of amino acid derivatives into the ligand. Different types of chiral skeletons provide unique chiral environments for different types of catalytic reactions, thereby inducing excellent enantioselectivity. The ligands of this invention can not only be widely applied to asymmetric cross-coupling reactions of tertiary alkyl chlorides and terminal alkynes, but also have important significance for developing novel catalytic systems to solve other types of free radical asymmetric reactions. Detailed Implementation

[0075] Unless otherwise stated, all chemicals were purchased commercially available and were not further purified. All solvents used in the experiments, such as dichloromethane, were anhydrous. Thin-layer chromatography (TLC) was performed using 60F254 silica gel plates. Silica gel column chromatography was performed using Qingdao marine silica gel (particle size 0.040-0.063 mm). TLC development was performed using UV light (254 nm) or iodine. NMR spectra were characterized using a Bruker DPX400 nuclear magnetic resonance instrument. 1 ¹H NMR was performed at 400 MHz using deuterated chloroform as the solvent and tetramethylsilane (TMS) as an internal standard. Chemical shifts are expressed in ppm, and coupling constants are expressed in Hz. 1 In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, p represents quintet, m represents multiplet, and br represents broad peak.

[0076] Example 1

[0077]

[0078] To a 50 mL solution of compound S1 (10–15 mmol, preferably 12 mmol) and compound S2 (10 mol) in dichloromethane, add EDCI (20–60 mmol, preferably 30 mmol) and DMAP (15–30 mmol, preferably 20 mmol). Stir the reaction at room temperature for 24 hours, then quench with water. Separate the organic layer, dry, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography to give the product (60–80% yield).

[0079] Compounds 1 to 19 were synthesized using the method described above.

[0080]

[0081] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=2.2Hz,1H),8.16(s,1H),8.06(d,J=8.3Hz,1H),7.94(dd,J=8.4,2.3Hz,1H), 3.81–3.68(m,1H),2.54–2.37(m,2H),2.24(s,6H),1.94–1.77(m,2H),1.75–1.63(m,1H),1.45–1.11(m,4H).

[0082] Example 2

[0083]

[0084] 1 H NMR (400MHz, CDCl3) δ8.93–8.80(m,1H),8.42–8.23(m,2H),8.21–8.03(m,1H),3.89–3.70(m, 1H),2.55–2.45(m,2H),2.27(s,6H),1.96–1.82(m,2H),1.78–1.68(m,1H),1.40–1.15(m,4H).

[0085] 19 F NMR (376MHz, CDCl3) δ-62.50.

[0086] Example 3

[0087]

[0088] 1 H NMR (400MHz, CDCl3) δ8.83(d,J=2.0Hz,1H),8.41(d,J=2.0Hz,1H),8.36(d,J=6.8Hz,1H),7.75–7.51(m,4H),3.70(td d,J=10.8,6.6,4.0Hz,1H),2.50–2.32(m,2H),2.28(s,6H),1.91–1.73(m,2H),1.71–1.60(m,1H),1.41–1.14(m,4H).

[0089] Example 4

[0090]

[0091] 11H NMR (400 MHz, CDCl3) δ 8.71 (dd, J = 5.5, 3.4 Hz, 1H), 8.56 (d, J = 7.5 Hz, 1H), 8.30 (d, J = 6.4 Hz, 1H), 8.05 (dd, J = 7.5, 1.5 Hz, 1H), 7.89 (ddd, J = 5.2, 3.4, 1.5 Hz, 1H), 7.71 (dd, J = 5.5, 3.5 Hz, 2H), 3.60–3.43 (m, 1H), 2.35 (dt, J = 9.8, 7.5 Hz, 1H), 2.30 (s, 6H), 1.99–1.80 (m, 2H), 1.76–1.60 (m, 1H), 1.50–1.22 (m, 4H).

[0092] Example 5

[0093]

[0094] 1 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 7.5 Hz, 1H), 8.26 (ddd, J = 15.0, 7.4, 1.5 Hz, 2H), 8.20 (s, 1H), 7.94–7.83 (m, 2H), 7.57 (td, J = 7.5, 1.7 Hz, 1H), 3.42 (dt, J = 9.8, 7.6 Hz, 1H), 2.36 (dt, J = 9.8, 7.5 Hz, 1H), 2.29 (s, 6H), 2.10 (dt, J = 7.6, 5.6 Hz, 1H), 1.76–1.59 (m, 3H), 1.55–

[0095] 1.21 (m, 4H).

[0096] Example 6

[0097]

[0098] 1 1H NMR (400 MHz, CDCl3) δ 8.79 (dd, J = 8.1, 1.3 Hz, 1H), 8.38 (d, J = 6.8 Hz, 1H), 8.01 (dd, J = 7.9, 5.0 Hz, 1H), 7.57 (td, J = 8.1, 1.3 Hz, 1H), 3.39 (dt, J = 9.8, 7.6 Hz, 1H), 2.37–2.30 (m, 1H), 2.27 (s, 6H), 2.06 (dt, J = 7.8, 5.6 Hz, 1H), 1.75–1.56 (m, 4H), 1.50–1.28 (m, 3H).

[0099] Example 7

[0100]

[0101] 1 H NMR (400MHz, CDCl3) δ8.96(d,J=1.2Hz,1H),8.33(br,1H),8.09(d,J=8.0Hz,1H),7.56(dd,J=8.1,1.3Hz,1H) ,3.44–3.33(m,1H),2.37–2.29(m,1H),2.27(s,6H),2.11–2.01(m,1H),1.71–1.45(m,4H),1.50–1.25(m,3H).

[0102] Example 8

[0103]

[0104] 1 H NMR (400MHz, CDCl3) δ8.60(d,J=5.0Hz,1H),8.18(br,1H),7.51(dd,J=5.0,1.0Hz,1 H),7.36(d,J=1.1Hz,1H),3.79(s,3H),3.36–3.11(m,1H),2.74–2.48(m,1H),2.37–

[0105] 2.32(m,1H),2.29(s,6H),1.73–1.63(m,3H),1.64–1.47(m,3H),1.40–1.33(m,1H).

[0106] Example 9

[0107]

[0108] 1 H NMR (400MHz, CDCl3) δ8.78(d,J=5.0Hz,1H),8.35(d,J=6.8Hz,1H),8.19(d,J=1.1Hz,1H),7.85(dd,J=5.1,1.0Hz, 1H),3.34–3.21(m,1H),2.68–2.52(m,1H),2.41–2.32(m,1H),2.29(s,6H),1.75–1.58(m,4H),1.50–1.22(m,3H).

[0109] Example 10

[0110]

[0111] 1H NMR (400MHz, CDCl3) δ8.37(br,1H),7.84(dd,J=7.9,1.1Hz,1H),7.69(t,J=8.0Hz,1H),7.34(dd,J=7.9,1.0Hz,1H),3.4 8(dt,J=10.0,7.6Hz,1H),2.55(s,6H),2.54–2.49(m,1H),2.27(s,6H),2.01(dt,J=7.6,5.6Hz,1H),1.74–1.38(m,7H).

[0112] Example 11

[0113]

[0114]

[0115] 1 H NMR(400MHz, CDCl3)δ8.32(br,1H),7.87(dd,J=8.0,1.1Hz,1H),7.63(t,J=8.0Hz,1H),7.43(dd,J=8.0,1.1Hz,1H),3.48–3.20(m,1H), 2.76(q,J=6.7Hz,2H),2.38–2.29(m,1H),2.27(s,6H),2.13–2.01(m,1H),1.77–1.57(m,4H),1.55–1.36(m,3H),1.17(t,J=6.7Hz,3H).

[0116] Example 12

[0117]

[0118] 1 H NMR (400MHz, CDCl3) δ8.40(br,1H),7.82(dd,J=7.9,1.1Hz,1H),7.69(t,J=8.0Hz,1H),7.45(dd,J=8.0,1.1Hz,1H),3.52–3 .42(m,1H),3.00–2.89(m,1H),2.60–2.48(m,1H),2.27(s,6H),2.08–1.98(m,1H),1.75–1.39(m,7H),1.27(d,J=6.4Hz,6H).

[0119] Example 13

[0120]

[0121] 1 H NMR (400MHz, CDCl3) δ8.29(br,1H),7.93(dd,J=7.9,1.1Hz,1H),7.73(t,J=8.0Hz,1H),7.49(dd,J=8.0,1.1H z,1H),3.31–3.12(m,1H),2.64–2.51(m,1H),2.39–2.34(m,1H),2.30(s,6H),1.74–1.40(m,7H),1.38(s,9H).

[0122] Example 14

[0123]

[0124] 1 H NMR (400MHz, CDCl3) δ8.43(br,1H),8.02(dd,J=8.1,1.2Hz,1H),7.96(td,J=7.9,4.8Hz,1H),7 .25–7.14(m,1H),3.35–3.21(m,1H),2.65–2.52(m,1H),2.35–2.23(m,7H),1.75–1.32(m,7H).

[0125] Example 15

[0126]

[0127] 1 H NMR (400MHz, CDCl3) δ8.40(br,1H),8.11(dd,J=7.9,1.1Hz,1H),7.85(t,J=8.0Hz,1H),7.74(dd,J=8.0,1 .1Hz,1H),3.39–3.19(m,1H),2.67–2.53(m,1H),2.33–2.20(m,7H),1.73–1.58(m,4H),1.58–1.30(m,3H).

[0128] Example 16

[0129]

[0130] 1H NMR (400MHz, CDCl3) δ8.54(br,1H),8.10(dd,J=8.0,1.1Hz,1H),7.83(dd,J=7.9,1.1Hz,1H),7.77 (t,J=8.0Hz,1H),3.42(dt,J=10.0,7.6Hz,1H),2.51–2.47(m,1H),2.38(s,6H),1.68–1.25(m,7H).

[0131] Example 17

[0132]

[0133] 1 H NMR (400MHz, CDCl3) δ8.48(br,1H),8.33–8.25(m,1H),7.96(dd,J=8.0,1.2Hz,1H),7.90(dd,J=8.0,1.2Hz,1H),7.83(t,J=8.0Hz,1H),7.54(t,J=7.4 Hz,1H),7.51–7.44(m,1H),3.40(dt,J=10.0,7.6Hz,1H),2.58(s,6H),2.54 –2.49(m,1H),2.21(s,6H),2.05(dt,J=7.6,5.6Hz,1H),1.70–1.32(m,7H).

[0134] Example 18

[0135]

[0136] 1 H NMR(400MHz, CDCl3)δ8.30(br,1H),8.03(dd,J=7.7,1.3Hz,1H),7.93–7.79(m,2H),7.21–7.13(m,1H),7.13–7.06(m,2H), 7.03–6.93(m,2H),4.14(s,2H),3.60–3.43(m,1H),2.63–2.47(m,1H),2.29(s,6H),2.09–1.99(m,1H),1.72–1.31(m,7H).

[0137] Example 19

[0138]

[0139] 1H NMR(400MHz, CDCl3)δ8.35(br,1H),8.08–8.00(m,1H),7.87–7.81(m,2H),7.44–7.39(m,4H),7.33–7.28(m,4H),7.24 –7.15(m,2H),5.18(s,1H),3.53–3.34(m,1H),2.54–2.40(m,1H),2.13(s,6H),2.06–1.96(m,1H),1.73–1.30(m,7H).

[0140] Example 20

[0141]

[0142] Step 1: Add EDCI (30 mmol) and DMAP (20 mmol) to a 50 mL solution of compound S3 (12 mmol) and compound S2 (10 mol) in dichloromethane. Stir the reaction at room temperature for 24 hours, then quench with water. Separate the organic layer, dry, filter, and concentrate under vacuum. Purify the residue obtained by silica gel column chromatography to give product S4 (75% yield).

[0143] Step 2: Intermediate S4 (5 mmol), compound S5 (5–8 mmol, preferably 7 mmol), tetratetraphenylphosphine palladium (0.20–0.60 mmol, preferably 0.40 mmol), and potassium carbonate (10–20 mmol, preferably 15 mmol) were placed in a 100 mL sealed tube, purged with argon three times, and 30 mL of tetrahydrofuran and 5 mL of deionized water were added. The mixture was then stirred at 80–120 °C (preferably 100 °C) for 24–72 hours, and monitored by TLC until compound S4 was completely eliminated. Post-treatment: After cooling to room temperature, water and ethyl acetate were added, the organic layer was separated, dried, filtered, and concentrated under vacuum. The residue obtained was purified by silica gel column chromatography to give the product (50–80% yield).

[0144] Compounds 20–37 were synthesized using the method described above.

[0145]

[0146] 1H NMR (400MHz, CDCl3) δ8.79(d,J=2.4Hz,1H),8.31(s,1H),8.24(d,J=8.2Hz,1H),8.00(dd,J=8.4,2.2Hz,1H),7.60(d,J= 7.6Hz,2H),7.53–7.37(m,3H),3.98–3.77(m,1H),2.66–2.39(m,2H),2.34(s,6H),2.02–1.65(m,3H),1.45–1.12(m,4H).

[0147] Example 21

[0148]

[0149] 1 H NMR (400MHz, CDCl3) δ8.79(d,J=2.2Hz,1H),8.28(d,J=6.8Hz,1H),8.23(d,J=8.1Hz,1H),8.00(dd,J=8.1,2.2Hz,1H),7.54(q,J=8.5Hz,4H) ,3.85(tdd,J=10.7,6.7,4.0Hz,1H),2.59–2.42(m,2H),2.30(s,6H),1.98–1.81(m,2H),1.76–1.67(m,1H),1.37(s,9H),1.32–1.08(m,4H).

[0150] Example 22

[0151]

[0152] 1 H NMR (400MHz, CDCl3) δ8.69(d,J=2.0Hz,1H),8.30(d,J=6.7Hz,1H),8.25(d,J=8.0Hz,1H),8.08(dd,J=8.0,2.2Hz,1H),7.58–7.51(m,3H), 3.79(tdd,J=10.6,6.8,4.0Hz,1H),2.54–2.40(m,2H),2.35(s,6H),1.99–1.83(m,2H),1.73–1.64(m,1H),1.35(s,9H),1.28–1.06(m,4H).

[0153] Example 23

[0154]

[0155] 1H NMR (400MHz, CDCl3) δ8.92(d,J=1.3Hz,1H),8.38(s,1H),8.28(dd,J=8.0,1.2Hz,1H),8.07(d,J=8.0Hz,1H),7.93–7.84(m,2H),7.74–7.67(m,2H), 7.60–7.55(m,2H),7.53–7.46(m,2H),7.43–7.33(m,1H),3.93–3.72(m,1 H),2.62–2.32(m,2H),2.31(s,6H),2.06–1.69(m,3H),1.41–1.15(m,4H).

[0156] Example 24

[0157]

[0158] 1 H NMR (400MHz, CDCl3) δ8.85(d,J=1.3Hz,1H),8.43(s,1H),8.30(dd,J=7.9,1.3Hz,1H),8.15–8.05(m,3H),8.02(dd,J=7.5,1.5Hz,1 H),7.93–7.83(m,3H),7.72–7.53(m,5H),3.99–3.78(m,1H),2.66–2.36(m,2H),2.37(s,6H),2.11–1.74(m,3H),1.47–1.12(m,4H).

[0159] Example 25

[0160]

[0161] 1 H NMR (400MHz, CDCl3) δ8.74 (d, J=2.0Hz, 1H), 8.31 (dd, J=8.1, 1.3Hz, 1H), 8.26 (s, 1H ),8.15–8.05(m,2H),8.05–7.92(m,3H),7.84(dd,J=7.5,1.6Hz,1H),7.63(td,J=7. 5,1.5Hz,1H),7.55(td,J=7.5,1.6Hz,1H),3.80(tdd,J=10.6,6.7,4.0Hz,1H),2.53 –2.40(m,2H),2.35(s,6H),1.92–1.75(m,2H),1.72–1.63(m,1H),1.36–1.13(m,4H).

[0162] Example 26

[0163]

[0164] 1 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 1.6 Hz, 1H), 8.45 (s, 1H), 8.40–8.30 (m, 2H), 8.26 (d, J = 8.0, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.05–7.90 (m, 3H), 7.60–7.50 (m, 2H), 3.94–

[0165] 3.80 (m, 1H), 2.62–2.53 (m, 2H), 2.40 (s, 6H), 2.07–1.75 (m, 3H), 1.53–1.26 (m, 4H).

[0166] Example 27

[0167]

[0168] 1 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.14 (dd, J = 8.0, 2.2 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 8.00–7.83 (m, 3H), 7.72 (dd, J = 8.3, 1.9 Hz, 1H), 7.58–7.48 (m, 2H), 4.04–3.91 (m, 1H), 2.67–2.55 (m, 2H), 2.42 (s, 6H), 2.08–1.80 (m, 3H), 1.55–1.20 (m, 4H).

[0169] Example 28

[0170]

[0171] 1 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J = 7.7 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.92 (dd, J = 7.9, 2.1 Hz, 1H), 7.59–7.44 (m, 4H), 7.42–7.34 (m, 2H), 4.01–3.86 (m, 1H), 2.64–2.51 (m, 2H), 2.35 (s, 6H), 2.01–1.71 (m, 3H), 1.50–1.23 (m, 4H).

[0172] Example 29

[0173]

[0174] 1 H NMR(400MHz, CDCl3) δ8.79(d,J=1.3Hz,1H),8.45(d,J=7.5Hz,1H),8.39(s,1H),8. 33–8.22(m,2H),8.16–8.10(m,3H),8.09–8.01(m,4H),7.96(d,J=7.5Hz,1H),3.89–

[0175] 3.76(m,1H),2.60–2.41(m,2H),2.40(s,6H),2.06–1.79(m,3H),1.55–1.27(m,4H).

[0176] Example 30

[0177]

[0178] 1 H NMR (400MHz, CDCl3) δ8.90(d,J=2.1Hz,1H),8.33(d,J=6.7Hz,1H),8.30(d,J=8.1Hz,1H),8.12(dd,J=8.1,2.3Hz,1H),7.86(t,J =1.7Hz,1H),7.78(d,J=1.7Hz,2H),7.72–7.66(m,4H),7.50(dd,J=8.4,6.8Hz,4H),7.45–7.38(m,2H),3.93–3.78(m,1H),2.62–

[0179] 2.45(m,2H),2.31(s,6H),1.98–1.69(m,3H),1.46–1.19(m,4H).

[0180] Example 31

[0181]

[0182] 1H NMR (400MHz, CDCl3) δ8.78(d,J=1.8Hz,1H),8.45(s,1H),8.35(d,J=7.4,1.6Hz,2H),8. 25(dd,J=7.9,1.3Hz,1H),8.16(dd,J=7.4,1.6Hz,2H),8.07(d,J=8.0Hz,1H),8.01–7.89 (m,7H),7.77(t,J=7.5Hz,2H),7.56(t,J=7.5,1.6Hz,2H),7.43(t,J=7.5,1.6Hz,2H),3 .90–3.70(m,1H),2.59–2.41(m,2H),2.36(s,6H),1.92–1.63(m,3H),1.48–1.24(m,4H).

[0183] Example 32

[0184]

[0185] 1 H NMR (400MHz, CDCl3) δ8.85(d,J=1.6Hz,1H),8.39(s,1H),8.33(dd,J=8.0,1.2Hz,1H),8.08(d,J=8.1Hz,1H),7.94–7.86(m,3H),7.55(s, 2H),7.49(s,4H),4.03–3.81(m,1H),2.62–2.46(m,2H),2.40(s,6H),2.07–1.72(m,3H),1.43(s,18H),1.35(s,18H),1.30–1.12(m,4H).

[0186] Example 33

[0187]

[0188] 1H NMR (400MHz, CDCl3) δ8.90 (dd, J=2.2, 0.8Hz, 1H), 8.34 (d, J=6.6Hz, 1H), 8.29 ( dd,J=8.0,0.8Hz,1H),8.11(dd,J=8.1,2.3Hz,1H),7.86(t,J=1.6Hz,1H),7.76( d,J=1.7Hz,2H),7.67–7.58(m,4H),7.56–7.49(m,4H),3.94–3.75(m,1H),2.64 –2.43(m,2H),2.31(s,6H),2.04–1.62(m,3H),1.39(s,18H),1.34–1.16(m,4H).

[0189] Example 34

[0190]

[0191] 1 H NMR (400MHz, CDCl3) δ8.87(d,J=1.8Hz,1H),8.41(dd,J=8.1,1.3Hz,1H),8.35(s,1H),8.22(dd,J=7.3,1.6Hz,4H),8.15(s,3H),8.11–8.06(m,5H), 7.68–7.62(m,4H),7.61–7.49(m,13H),7.42–7.35(m,2H),3.90–3.62(m,1 H),2.65–2.48(m,2H),2.43(s,6H),2.02–1.57(m,3H),1.30–1.20(m,4H).

[0192] Example 35

[0193]

[0194] 1 H NMR (400MHz, CDCl3) δ8.75(d,J=1.2Hz,1H),8.53(s,2H),8.42(s,1H),8.39(dd,J=8.1,1.3Hz,1H),8.20–8.05(m,12H),7.6 5–7.56(m,4H),7.53–7.41(m,4H),3.83–3.55(m,1H),2.73–2.46(m,2H),2.49(s,6H),2.13–1.67(m,3H),1.35–1.25(m,4H).

[0195] Example 36

[0196]

[0197] 1 H NMR (400MHz, CDCl3) δ8.93(d,J=1.3Hz,1H),8.78(dd,J=7.4,1.6Hz,2H),8.54(dd,J=7.3,1.7Hz,2H),8.38(s,1H),8.28(dd,J=8.1,1.3Hz,1H),8 .20–8.15(m,4H),8.02–7.87(m,6H),7.74–7.58(m,8H),3.72–3.45(m,1H ),2.63–2.35(m,2H),2.39(s,6H),2.02–1.62(m,3H),1.33–1.20(m,4H).

[0198] Example 37

[0199]

[0200] 1 H NMR(400MHz, CDCl3)δ8.72(d,J=1.6Hz,1H),8.24(dd,J=8.1,1.3Hz,1H),8.09(d,J=8.0Hz,1H),8.00(s,3H),7.98–7.95(m,2H), 7.97(d,J=2.0Hz,4H),7.91(t,J=2.0Hz,2H),7.75–7.68(m,8H),7.52–7.45(m,8H),7.42–7.35(m,4H),3.90–3.76(m,1H),2.59–

[0201] 2.40(m,2H),2.38(s,6H),1.96–1.63(m,3H),1.42–1.15(m,4H).

[0202] Example 38

[0203]

[0204] EDCI (20–60 mmol, preferably 30 mmol) and DMAP (15–30 mmol, preferably 20 mmol) were added to a 50 mL solution of compound S1 (10–15 mmol, preferably 12 mmol) and compound S6 (10 mol) in dichloromethane. The reaction was stirred at room temperature for 24 hours and then quenched with water. The organic layer was separated, dried, filtered, and concentrated under vacuum. The residue obtained was purified by silica gel column chromatography to give the product (60–80% yield).

[0205] Compounds 38–43 were synthesized using the method described above.

[0206]

[0207] 1 H NMR (400MHz, CDCl3) δ8.85(dd,J=5.0,1.3Hz,1H),8.20(br,1H),8.13(dd,J=7.9,1.1Hz,1H),7.92(ddd,J=8.0,5.0,1.1Hz,1H),7.87(t d,J=8.0,1.3Hz,1H),3.88–3.74(m,1H),2.68(dd,J=12.4,7.0Hz,1H),2.39(dd,J=12.4,7.0Hz,1H),2.20(s,6H),1.27(d,J=6.1Hz,3H).

[0208] Example 39

[0209]

[0210] 1 H NMR(400MHz, CDCl3)δ8.85(dd,J=5.1,1.3Hz,1H),8.10(br,1H),8.04(dd,J=8.1,1.1Hz,1H),7.98–7.90(m,1H),7.80(td,J=8.0,1.3Hz,1H),3 .70(dt,J=10.6,2.9Hz,1H),2.93(dd,J=12.4,2.9Hz,1H),2.48–2.36(m,1H),2.34(dd,J=12.4,2.9Hz,1H),2.10(s,6H),0.90(d,J=6.4Hz,6H).

[0211] Example 40

[0212]

[0213] 1 H NMR (400MHz, CDCl3) δ8.85(dd,J=4.9,1.3Hz,1H),8.15(br,1H),8.00(dd,J=8.1,1.1Hz,1H),7.95–7.90(m,1H),7.83(t d,J=7.9,1.3Hz,1H),3.53(t,J=6.9Hz,1H),2.81(dd,J=12.4,6.8Hz,1H),2.38–2.27(m,1H),2.15(s,6H),1.02(s,9H).

[0214] Example 41

[0215]

[0216] 1 H NMR (400MHz, CDCl3) δ8.66(d,J=6.7Hz,1H),8.62–8.56(m,1H),8.15(dt,J=7.8,1.1Hz,1H),7.82(td,J=7.7,1.7Hz,1H),7.46 –7.30(m,5H),7.26–7.22(m,1H),5.23–5.12(m,1H),2.84(dd,J=12.7,9.9Hz,1H),2.57(dd,J=12.7,5.3Hz,1H),2.32(s,6H).

[0217] Example 42

[0218]

[0219] 1 H NMR (400MHz, CDCl3) δ8.53(dt,J=4.8,1.3Hz,1H),8.17(dt,J=7.7,1.2Hz,1H),8.07(d,J=8.3Hz,1H),7.83(td,J=7.7,1.7Hz,1H),7.50–7.3 5(m,1H),7.32–7.12(m,5H),4.63–4.36(m,1H),3.17–2.89(m,2H),2.47(dd,J=12.4,8.3Hz,1H),2.34(dd,J=12.4,6.2Hz,1H),2.26(s,6H).

[0220] Example 43

[0221]

[0222] 1H NMR (400MHz, CDCl3) δ8.85 (dd, J=2.3, 0.8Hz, 1H), 8.28 (dd, J=8.1, 0.8Hz, 1H), 8.11 (dd, J=8.2, 2.1Hz, 2H),7.86(t,J=1.7Hz,1H),7.75(d,J=1.7Hz,2H),7.67–7.60(m,4H),7.56–7.50(m,4H),7.34–7.26(m, 4H),7.25–7.19(m,1H),4.51(ddt,J=14.2,8.0,6.0Hz,1H),3.10(dd,J=13.7,5.7Hz,1H),3.01(dd,J=1 3.7, 6.2Hz, 1H), 2.49 (dd, J = 12.4, 8.1Hz, 1H), 2.37 (dd, J = 12.4, 6.4Hz, 1H), 2.29 (s, 6H), 1.40 (s, 18H).

[0223] Example 44

[0224] The ligands of the present invention are applied to the radical asymmetric cross-coupling reaction of tertiary alkyl chlorohydrocarbons and terminal alkynes.

[0225]

[0226] Copper trifluoromethanesulfonate (10 mol% equivalent), ligand L (15 mol%), phenylacetylene (1.5 equivalent), and cesium carbonate (3.0 equivalent) were added to a Schlenk tube equipped with a magnetic stir bar and dried in an oven. Argon gas was purged three times, followed by the addition of trifluorotoluene (1.0 mL). The reaction was then carried out at room temperature for 36 h. After the reaction was complete (monitored by TLC), the precipitate was filtered off and washed with solvent. The solution was then evaporated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain the product in 75% yield and 86% ee.

[0227] Product characterization data: pale yellow solid; HPLC conditions: Chiralcel IA (n-hexane / isopropanol = 98 / 2, flow rate 0.4 mL / min, λ = 254 nm); t R (minor) = 24.7min,t R (major) = 28.3 min.

[0228] 1H NMR(400MHz, CDCl3)δ8.41(s,1H),7.83–7.74(m,2H),7.64–7.56(m,2H),7.55–7.48(m,2H),7.44–7.35(m,5H),7.34 –7.27(m,3H),7.14–7.05(m,1H),2.53(dq,J=13.5,7.3Hz,1H),2.19(dq,J=13.5,7.3Hz,1H),1.08(t,J=7.3Hz,3H).

[0229] 13 C NMR (100MHz, CDCl3) δ168.9,139.8,137.7,131.7,129.0,128.9,128.6,128.5,127.66,126.62,124.4,122.2,119.7,89.9,88.7,55.3,33.3,10.2.

[0230] HRMS(ESI) m / z Precision Mass C 24 H 22 NO[M+H] + 340.1696, measured value 340.1691.

[0231] The reaction results are shown in the table below (L1 represents the ligand of Example 1, and so on):

[0232]

[0233]

[0234] As can be seen, the ligands of the present invention can be used as catalysts with copper salts for asymmetric cross-coupling reactions of terminal alkynes and tertiary alkyl chloroalkanes to construct all-carbon chiral quaternary carbon centers, with good yields and excellent enantioselectivity.

[0235] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A tridentate nitrogen ligand, characterized in that, It has the structure of general formula I: ； Among them, R 1 Selected from C1-C4 alkyl, phenyl, benzyl and R 2 It is hydrogen; R 3 It is quinolinyl, isoquinolinyl or ; R 5 Selected from C1-C4 alkyl, C1-C4 alkoxy, benzyl, Ph2CH-, fluorine, chlorine, bromine, trifluoromethyl, naphthyl, anthraceneyl, phenanthryl, pyrene, and substituted phenyl groups; The substituted phenyl group is , R 6 The compound is selected from hydrogen, C1-C4 alkyl, phenyl, 4-tert-butylphenyl, 3,5-di-tert-butylphenyl, 3,5-diphenylphenyl, naphthyl, anthraceneyl, phenanthryl, and 9-phenylanthryl; wherein m is 1 or 2; R 4 It can be methyl or ethyl.

2. The tridentate nitrogen ligand according to claim 1, characterized in that, The R 1 Selected from methyl, ethyl, isopropyl, tert-butyl, phenyl, benzyl and R 2 It is hydrogen.

3. The tridentate nitrogen ligand according to claim 1, characterized in that, The R 5 Selected from methyl, ethyl, isopropyl, tert-butyl, methoxy, benzyl, Ph2CH-, fluorine, chlorine, bromine, trifluoromethyl, naphthyl, anthraceneyl, phenanthryl, pyrene, and substituted phenyl groups; The substituted phenyl group is , R 6 The m is selected from hydrogen, tert-butyl, phenyl, 4-tert-butylphenyl, 3,5-di-tert-butylphenyl, 3,5-diphenylphenyl, naphthyl, anthracene, phenanthryl, and 9-phenylanthryl; wherein m is 1 or 2.

4. The tridentate nitrogen ligand according to claim 1, characterized in that, The R 5 Selected from naphthyl, anthraceneyl, phenanthryl, pyrene, and substituted phenyl groups; The substituted phenyl group is , R 6 The m is selected from hydrogen, C1-C4 alkyl, phenyl, 4-tert-butylphenyl, 3,5-di-tert-butylphenyl, 3,5-diphenylphenyl, naphthyl, anthraceneyl, phenanthryl, and 9-phenylanthryl; m is 1 or 2.

5. The tridentate nitrogen ligand according to claim 1, characterized in that, The R 5 Selected from , R 6 The m is selected from hydrogen, C1-C4 alkyl, phenyl, 4-tert-butylphenyl, 3,5-di-tert-butylphenyl, 3,5-diphenylphenyl, naphthyl, anthraceneyl, phenanthryl, and 9-phenylanthryl; m is 1 or 2.

6. A method for preparing the tridentate nitrogen ligand according to any one of claims 1 to 5, characterized in that, Includes the following steps: In the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine, compounds S1 and S2 react as follows: ； Among them, R 1 Selected from C1-C4 alkyl, phenyl, benzyl and R 2 It is hydrogen; R 3 It is quinolinyl, isoquinolinyl or ; R 5 Selected from C1-C4 alkyl, C1-C4 alkoxy, benzyl, Ph2CH-, fluorine, chlorine, bromine, and trifluoromethyl; R 4 It can be methyl or ethyl.

Images