Chiral bis-imidazoline ligand containing cyclohexane skeleton structure and preparation method of chiral bis-imidazoline ligand

Abstract

The invention provides a chiral bis-imidazoline ligand containing a semi-rigid cyclohexane skeleton structure and a preparation method of the chiral bis-imidazoline ligand. The chiral bis-imidazoline ligand containing the semi-rigid cyclohexane skeleton structure is prepared by taking optically pure transcyclohexane-1, 2-dicarboxylic acid and monosulfonylated 1, 2-diphenylethyl-1, 2-diamine as raw materials. Reaction raw materials are easy to obtain and operation is simple. The product has specific stereoselectivity, can be used for synthesizing a sulfonylated chiral bis-imidazoline ligand with a cyclohexane skeleton structure, and is used for adjusting the coordination capability of the ligand. The synthesized compound is a very important chiral bidentate ligand, and shows a certain chiral control performance in an aziridine propanation reaction of unsaturated ketone.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a chiral bisimidazoline ligand containing a cyclohexane skeleton structure and a preparation method thereof. Background Art

[0002] Asymmetric catalysis is an important method for preparing a large number of optically active compounds, especially for preparing non-naturally occurring optically active compounds, and chiral ligands are the key to achieving asymmetric catalysis. Chiral bis-oxazoline ligands with semi-rigid cyclohexane as the skeleton have been successfully used in the copper-catalyzed aziridination of unsaturated ketones (Ma, LG; Du, DM; Xu, JX. J. Org. Chem. 2005, 70, 10155–10158; Ma, LG; Du, DM; Xu, JX Chirality 2006, 18, 575–580; Ma, LG; Jiao, P.; Zhang, QH; Du, DM; Xu, JX Tetrahedron: Asymmetry 2007, 18, 878–884.) and the asymmetric cyclocarbonylation of 2-propargyl-1,3-dione (Kato, K.; Tanaka, M.; Yamamura, S.; Yamamoto, Yasuhiro; Akita, H. Tetrahedron Lett. 2003, 44, 3089–3092). Bis-imidazolines are also a class of widely used chiral ligands, such as asymmetric hydrogen transfer reduction of ketones (Enthaler, S.; Hagemann, B.; Bhor, S.; Anilkumar, G.; Tse, MK; Bitterlich, B.; Junge, K.; Erre, G.; Beller, M. Adv. Synth. Catal. 2007, 349, 853–860) and asymmetric epoxidation of olefins (Anilkumar, G.; Bhor, S.; Tse, MK; Klawonn, M.; Bitterlich, B.; Beller, M. Tetrahedron: Asymmetry 2005, 16, 3536–3561.). However, chiral ligands with a semi-rigid cyclohexane skeleton and a combination of bis-imidazolines have not attracted much attention.

[0003] In order to enrich the types and applications of chiral ligands and bisimidazoline chiral ligands containing cyclohexane as a skeleton, it is necessary to develop new chiral ligands containing bisimidazoline structures, especially new bisimidazoline ligands containing cyclohexane skeleton structures. The present invention designs a class of chiral bisimidazoline ligands containing a semi-rigid cyclohexane skeleton structure, and prepares the chiral bisimidazoline ligands containing a cyclohexane skeleton structure by optically pure 1,2-diphenylethane-1,2-diamine and optically pure cyclohexane-1,2-dicarboxylic acid. The reaction raw materials are easy to obtain and the operation is simple. The synthesized compound is a very important chiral ligand, which exhibits excellent chiral control performance in the asymmetric aziridine reaction of unsaturated ketones. Summary of the invention

[0004] The purpose of the present invention is to provide a chiral bisimidazoline ligand containing a semi-rigid cyclohexane skeleton structure and a preparation method thereof. The compound is a very important new chiral ligand. The preparation method of the present invention uses optically pure 1,2-diphenylethane-1,2-diamine and optically pure cyclohexane-1,2-dicarboxylic acid as raw materials. The raw materials are simple and easy to obtain, and no complicated operation is required. It is a simple method suitable for large-scale preparation.

[0005] The technical solution of the present invention is as follows:

[0006] A chiral bisimidazoline ligand containing a cyclohexane skeleton structure (Formula [1]) and a preparation method thereof. A chiral bisimidazoline ligand containing a cyclohexane skeleton structure is obtained by reacting optically pure 1,2-diphenylethane-1,2-diamine (Formula [2]) with optically pure cyclohexane-1,2-dicarboxylic acid.

[0007]

[0008] In the above reaction formula:

[0009] R represents an alkyl group and an aryl group having 1 to 10 carbon atoms. The aryl group may be a cyclic ring, and a phenyl group substituted by fluorine, chlorine, bromine, alkoxy, cyano and nitro.

[0010] The alkyl group mentioned herein refers to a straight chain or branched chain alkyl group having 1 to 10 carbon atoms, for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, nonyl, decyl, etc. Preferably, the straight chain or branched chain alkyl group has 1 to 8 carbon atoms, particularly preferably, the straight chain or branched chain alkyl group has 1 to 6 carbon atoms, and most preferably, the straight chain or branched chain alkyl group has 1 to 4 carbon atoms.

[0011] The cycloalkyl group refers to a cyclic alkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl. Preferably, the cycloalkyl group has 3 to 8 carbon atoms, and particularly preferably, the cycloalkyl group has 3 to 6 carbon atoms.

[0012] The cycloalkylalkyl refers to a cyclic alkyl group having 4 to 10 carbon atoms, for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, and cycloheptylpropyl, preferably cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.

[0013] The aryl group refers to an aryl group having 6 to 10 carbon atoms, preferably phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-cyanophenyl, m-cyanophenyl, p-cyanophenyl, 1-naphthyl, 2-naphthyl, substituted naphthyl, etc.

[0014] The prepared chiral bisimidazoline ligands containing a cyclohexane skeleton structure include, for example, the following five compounds 1a to 1e:

[0015] 1a: R = Me;

[0016] 1b: R = Ph;

[0017] 1c: R = 4-MeC6H4;

[0018] 1d: R = 4-MeOC6H4;

[0019] 1e: R = 4-O2NC6H4.

[0020] The above-mentioned preparation method generally comprises the following steps: firstly protecting (1R,2R)-1,2-diphenylethane-1,2-diamine shown in formula [2] with sulfonyl chloride, then condensing it with (1S,2S)-cyclohexane-1,2-dicarboxylic acid, and then performing a cyclization reaction to prepare the compound.

[0021] In the above-mentioned preparation method, the raw material is replaced by (1S,2S)-1,2-diphenylethane-1,2-diamine as shown in formula [2], or (1S,2S)-cyclohexane-1,2-dicarboxylic acid is replaced by (1R,2R)-cyclohexane-1,2-dicarboxylic acid, and according to the above-mentioned synthesis method, a chiral bisimidazoline ligand containing a cyclohexane skeleton structure having a skeleton as shown in formula [1] but with opposite configurations of the imidazoline ring or the cyclohexane ring.

[0022] The above-mentioned preparation method comprises the following steps: monosulfonylation of (1R,2R)-1,2-diphenylethane-1,2-diamine represented by formula [2] with sulfonyl chloride in the presence of an organic base to obtain the monosulfonylated (1R,2R)-1,2-diphenylethane-1,2-diamine represented by formula [3]; the organic base used includes trimethylamine, triethylamine, tripropylamine, tributylamine, N-methyltetrahydropyrrole, N-methylpiperidine, N-methylmorpholine, pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, and mixtures thereof.

[0023] The above-mentioned preparation method comprises condensing the monosulfonylated (1R,2R)-1,2-diphenylethane-1,2-diamine shown in formula [3] with (1S,2S)-cyclohexane-1,2-dicarboxylic acid in the presence of a condensing agent to obtain a cyclohexane-1,2-dicarboxamide compound shown in formula [4]. The condensing agent used includes DCC, DIC, EDCI, BOP, BOP-Cl, PyBOP, DEPBT, HOBT, HBTU, TBTU, and mixtures thereof.

[0024] The above-mentioned preparation method comprises cyclizing the cyclohexane-1,2-dicarboxamide compound shown in formula [4] in the presence of a cyclization reagent to obtain a chiral bisimidazoline ligand containing a cyclohexane skeleton structure shown in formula [1]. The cyclization reagent used comprises trifluoromethanesulfonic anhydride, trifluoromethanesulfonic anhydride and triphenylphosphine oxide.

[0025] The above-mentioned preparation method is usually prepared by stirring the reaction under room temperature to reflux conditions.

[0026] In the above-mentioned preparation method, the solvent usually used is dichloromethane, dichloroethane, ethanol, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, chlorobenzene, trifluoromethylbenzene, etc. or a mixture thereof.

[0027] Advantages and positive effects of the present invention:

[0028] This method can simply and efficiently synthesize optically active chiral bisimidazoline ligand compounds containing a cyclohexane skeleton structure. As a new type of chiral ligand, the product exhibits excellent stereocontrol activity in asymmetric aziridine reaction. DETAILED DESCRIPTION

[0029] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0030] Embodiment 1

[0031] (1S,2S)-1,2-Bis((4R,5R)-1-(methylsulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane 1a

[0032] N-[(1R,2R)-2-Amino-1,2-diphenylethyl]methanesulfonamide

[0033] At 0°C, (1S,2S)-1,2-diphenylethane-1,2-diamine (1.06 g, 5 mmol) and Et3N (1.4 mL, 10 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran and stirred for 10 min. Sulfonyl chloride (5 mmol) dissolved in 10 mL of anhydrous tetrahydrofuran was added dropwise to the system. The temperature was gradually raised to 35°C, and the reaction was continued to stir for 12 h. The mixture was concentrated and purified by silica gel column chromatography. The product monosulfonyl-protected (1S,2S)-1,2-diphenylethane-1,2-diamine was obtained by elution with DCM / MeOH=20:1 (v / v). 0.88 g, yield: 61%, Mp109.7–110.6°C; R f =0.28 (DCM / MeOH 40:1, v / v). 1 H NMR (400MHz, CDCl3) δ: 7.37–7.29 (m, 8H, ArH), 7.29–7.22 (m, 2H, ArH), 4.56 (d, J = 5.1Hz, 1H, CH), 4.28 (d, J = 5.1Hz, 1H, CH), 2.26 (s, 3H, CH3). 13 C NMR (101MHz, CDCl3) δ: 142.0, 139.8, 128.8, 128.8, 128.0, 128.0, 127.0, 126.8, 63.6, 60.3, 40.8.

[0034] (1S,2S)-N 1 ,N 2 -Bis((1R,2R)-2-(methylsulfonamido)-1,2-diphenylethyl)cyclohexane-1,2-dicarboxamide

[0035] At 25°C, (S,S)-cyclohexyl-1,2-dicarboxylic acid (120 mg, 0.7 mmol), EDCI (403 mg, 2.1 mmol), DMAP (17 mg, 0.14 mmol) and anhydrous dichloromethane (5 mL) were added to a round-bottom flask in sequence and stirred for 50 minutes. At the same temperature, a solution of (1S,2S)-1,2-diphenylethane-1,2-diamine (1.4 mmol dissolved in 5 mL anhydrous dichloromethane) protected by a single sulfonyl group of the compound was added dropwise to the above mixed solution. The temperature was raised to 35°C and stirring was continued for 24 hours. A large amount of white solid precipitated from the solution. Petroleum ether (10 mL) was added to promote solid precipitation, and the solid was filtered and washed with petroleum ether to obtain a white solid. The obtained white solid was recrystallized from methanol and filtered to obtain a colorless crystalline cyclohexane-1,2-dicarboxamide compound.

[0036] Colorless crystals 336mg, yield: 71%, Mp 283.5–285.2℃; R f =0.25 (DCM / MeOH 20:1, v / v). =–13.55 (c = 2.0, DMSO). 1 H NMR (400MHz, DMSO-d6) δ: 7.92 (d, J = 9.7 Hz, 2H, 2NH), 7.64 (d, J = 9.9 Hz, 2H, 2NH) ),7.38(d,J=7.2Hz,4H,ArH),7.28(t,J=7.5Hz,4H,ArH),7.24–7.15(m,6H,ArH ),7.05–6.95(m,6H,ArH),5.20(dd,J=9.6,4.7Hz,2H,2CH),4.78(dd,J=10.1,4 .8Hz,2H,2CH),2.37–2.30(m,2H,2CH),2.07(s,6H,2CH3),1.62(d,J=8.5Hz,2H inCH2),1.53(d,J=12.6Hz,2H in CH2),1.20–1.09(m,2H,CH2),1.05–0.90(m,2H,CH2). 13 CNMR (101MHz, DMSO-d6) δ: 173.8, 140.3, 139.8, 127.8, 127.7, 127.03, 126.98, 126.7, 62.0, 56.3, 45.6, 40.8, 29.3, 25.1.

[0037] (1S,2S)-1,2-Bis((4R,5R)-1-(methylsulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane

[0038] At 0°C, triphenylphosphine oxide (1.67 g, 6 mmol), trifluoromethanesulfonic anhydride (0.5 mL, 3 mmol) and anhydrous dichloromethane (0.5 mmol / mL) were added to the round-bottom flask in sequence. Stir at 0°C for 30 minutes, cyclohexane-1,2-dicarboxamide (1 mmol.) was added to the system in portions, the temperature was slowly raised to room temperature and stirring was continued for 16 hours. Saturated sodium bicarbonate solution was added to the mixed solution, the liquid was separated, the aqueous phase was extracted with dichloromethane (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography, eluting with PE / EA = 10:1 (v / v) to obtain a colorless crystalline product.

[0039] Colorless crystals 350mg, yield: 51%, Mp186.2–189.4℃; R f =0.15(PE / EA 10:1,v / v) = +133.15 (c = 2.0, CHCl3). 1 H NMR(400MHz, CDCl3)δ:7.37(dd,J=8.1,6.5Hz,4H,ArH),7.33–7.27(m,5H,ArH),7.27–7.22(m,7H,ArH), 7.21–7.16(m,4H,ArH),4.88(s,4H,4CH),3.87–3.61(m,2H,2CH),2.87(s,6H,2CH3),2.73–2.65(m,2H,2H in 2CH2),1.98–1.92(m,2H,2H in 2CH2),1.61–1.53(m,4H,2CH2). 13 C NMR (101MHz, CDCl3) δ: 163.6, 142.6, 140.6, 129.2, 128.9, 128.3, 128.2, 126.9, 126.3, 78.4, 71.3, 40.9, 39.6, 33.0, 25.8.

[0040] Embodiment 2

[0041] (1S,2S)-1,2-Bis((4R,5R)-1-(phenylsulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane 1b

[0042] N-[(1R,2R)-2-Amino-1,2-diphenylethyl]benzenesulfonamide

[0043] According to the preparation method of Example 1, methanesulfonyl chloride was replaced with benzenesulfonyl chloride to obtain benzenesulfonamide product. Colorless crystal 1.30g, yield: 74%, Mp 139.7-142.0℃; R f=0.30 (DCM / MeOH 40:1, v / v). 1 H NMR (400MHz, CDCl3) δ: 7.47–7.41 (m, 2H, ArH), 7.34 (t, J = 7.4Hz, 1H, ArH), 7.22–7.08 (m, 12H, ArH), 4.41 (d, J = 5.3Hz, 1H, CH), 4.13 (d, J = 5.3Hz, 1H, CH). 13 C NMR (101MHz, CDCl3) δ: 141.5, 140.3, 139.2, 132.0, 128.63, 128.57, 128.4, 127.7, 127.6, 127.1, 126.9, 126.6, 63.4, 60.6.

[0044] (1S,2S)-N 1 ,N 2 -Bis((1R,2R)-2-(benzenesulfonylamino)-1,2-diphenylethyl)cyclohexane-1,2-dicarboxamide, colorless crystals 434 mg, yield: 77%, Mp 256.5–259.3℃; R f =0.25 (DCM / MeOH 20:1, v / v). =–30.80 (c = 2.0, DMSO). 1 H NMR (400MHz, CDCl3) δ: 7.51–7.42 (m, 4H, NH), 7.34 (d, J = 7.5Hz, 2H, ArH), 7.18 (t, J = 7.9Hz, 4H,ArH),7.15–7.00(m,6H,ArH),7.02–6.94(m,2H,ArH),6.91(t,J=7.3Hz,4H,ArH),6.88– 6.81(m,4H,ArH),6.77(d,J=7.8Hz,2H,ArH),6.73–6.66(m,4H,ArH),6.34(d,J=7.6Hz,2H, ArH),4.95(dd,J=10.0,7.7Hz,2H,2CH),4.59(dd,J=10.0,7.7Hz,2H,2CH),2.58–2.51(m,2H in CH2),2.09–1.97(m,4H,CH2CH2),1.84(d,J=9.0Hz,2H,CH2),1.45–1.38(m,2H,CH2). 13C NMR (101MHz, DMSO-d6) δ: 174.2,141.6,139.6,139.5,132.1,128.9,128.0,1 27.8,127.5,127.3,127.0,126.9,126.4,62.2,57.1,55.4,46.0,29.7,25.5.

[0045] (1S,2S)-1,2-Bis((4R,5R)-1-(phenylsulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane

[0046] Colorless crystals 458mg, yield: 57%, Mp 267.9–269.3℃; R f =0.25(PE / EA 10:1,v / v). =–19.60 (c = 2.0, CHCl3). 1 H NMR(400MHz, CDCl3)δ:7.94–7.87(m,4H,ArH),7.42–7.36(m,4H,ArH),7.35–7.29(m,2H ,ArH),7.24–7.21(m,2H,ArH),7.21–7.17(m,4H,ArH),7.09(tt,J=7.5,1.2Hz,2H,ArH) ,7.01(t,J=7.7Hz,4H,ArH),6.63–6.51(m,4H,ArH),6.49–6.38(m,4H,ArH),4.84(d,J= 6.2Hz,2H,2CH),4.24(d,J=6.2Hz,2H,2CH),4.21–4.14(m,2H,2CH),3.04–2.90(m,2H,2H in 2CH2),2.10–1.94(m,2H,2H in 2CH2),1.64(m,4H,2CH2). 13 CNMR(101MHz, CDCl3)δ:164.1,142.8,141.8,136.6,133.0,129.1(2C),128.9,128.6,128.1,127.6,127.3,126.2,80.2,71.4,41.6,34.7,26.1.

[0047] Embodiment 3

[0048] (1S,2S)-1,2-Bis((4R,5R)-1-(p-toluenesulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane 1c

[0049] N-[(1R,2R)-2-Amino-1,2-diphenylethyl]-p-toluenesulfonamide

[0050] According to the preparation method of Example 1, methanesulfonyl chloride was replaced with p-toluenesulfonyl chloride to obtain p-toluenesulfonamide product. Colorless crystal 1.12g, yield: 61%, Mp 122.4-124.1℃; R f =0.33 (DCM / MeOH 40:1, v / v). 1 H NMR (400MHz, CDCl3) δ: 7.31 (d, J=8.3Hz, 2H, ArH), 7.20–7.04 (m, 10H, ArH), 6.96 (d, J= 8.0Hz,2H,ArH),4.39(d,J=5.5Hz,1H,CH),4.15(d,J=5.5Hz,1H,CH),2.31(s,3H,CH3). 13 C NMR (101MHz, CDCl3) δ: 142.6, 141.4, 139.3, 137.3, 129.2, 128.5, 128.3, 127.6, 127.5, 127.2, 127.0, 126.7, 63.4, 60.6, 21.5.

[0051] (1S,2S)-N 1 ,N 2 -Bis((1R,2R)-2-(p-toluenesulfonamido)-1,2-diphenylethyl)cyclohexane-1,2-dicarboxamide

[0052] Colorless crystals 245mg, yield: 42%, Mp 251.3–252.7℃; R f =0.23 (DCM / MeOH 20:1, v / v). =–35.20 (c = 2.0, DMSO). 1H NMR (400MHz, CDCl3) δ: 7.36 (d, J=8.3Hz, 4H, NH), 7.04 (d, J=7.1Hz, 6H, ArH), 7.00–6.96 (m, 6H,ArH),6.92(t,J=7.5Hz,4H,ArH),6.87–6.81(m,4H,ArH),6.76(d,J=7.8Hz,2H,ArH),6.7 3–6.67(m,4H,ArH),6.25(d,J=7.7Hz,2H,ArH),4.94(dd,J=9.9,7.8Hz,2H,2CH),4.56(dd, J=9.9,7.6Hz,2H,2CH),2.53(d,J=9.9Hz,2H,2CH),2.28(s,6H,2CH3),2.02(d,J=12.7Hz,2H in 2CH2),1.81(d,J=8.7Hz,2Hin2CH2),1.54(m,2H,CH2),1.39–1.28(m,2H,CH2). 13 C NMR (101MHz, DMSO-d6) δ: 174.2,142.2,139.8,139.6,138.8,129.4,127.9,1 27.8,127.5,127.2,126.9,126.8,126.4,62.2,57.1,46.0,29.7,25.5,21.3.

[0053] (1S,2S)-1,2-Bis((4R,5R)-1-(p-toluenesulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane

[0054] Colorless crystals 300mg, yield: 36%, Mp 273.6–274.5℃; R f =0.25(PE / EA 10:1,v / v). =–78.22 (c = 0.9, CHCl3). 1H NMR(400MHz, CDCl3)δ:7.82(d,J=8.3Hz,4H,ArH),7.42–7.35(m,4H,ArH),7.35–7.24(m ,4H,ArH),7.21–7.15(m,4H,ArH),7.01(d,J=7.7Hz,2H,ArH),6.99(d,J=7.7Hz,2H,ArH ),6.38(d,J=8.0Hz,4H,ArH),6.31(d,J=8.0Hz,4H,ArH),4.83(d,J=6.1Hz,2H,2CH),4. 17(d,J=6.1Hz,4H,4CH),3.08–2.56(m,2H,2Hin2CH2),2.04(s,6H,2CH3),2.02(s,2H,2H in 2CH2),1.73–1.58(m,4H,4H in 2CH2). 13 CNMR(101MHz, CDCl3)δ:164.4,143.9,143.0,142.1,133.4,129.6,129.1,12 8.9,128.7,128.0,127.6,127.5,126.1,80.3,71.4,41.6,34.9,26.1,21.4.

[0055] Embodiment 4

[0056] (1S,2S)-1,2-Bis((4R,5R)-1-(p-methoxyphenylsulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane 1d

[0057] N-[(1R,2R)-2-Amino-1,2-diphenylethyl]-p-methoxybenzenesulfonamide

[0058] According to the preparation method of Example 1, methanesulfonyl chloride was replaced with p-methoxybenzenesulfonyl chloride to obtain p-methoxybenzenesulfonamide product. Colorless crystal 1.20g, yield: 64%, Mp 127.5-131.4℃; R f =0.17 (DCM / MeOH 40:1, v / v). 1 HNMR(400MHz, CDCl3)δ:7.40–7.31(m,2H,ArH),7.23–7.07(m,10H,ArH),6.68–6.60 (m,2H,ArH),4.36(d,J=5.4Hz,1H,CH),4.12(d,J=5.4Hz,1H,CH),3.79(s,3H,CH3). 13C NMR (101MHz, CDCl3) δ: 162.4, 141.6, 139.4, 132.0, 129.1, 128.6, 128.4, 127.7, 127.5, 127.2, 126.7, 113.8, 63.3, 60.7, 55.6.

[0059] (1S,2S)-N 1 ,N 2 -Bis((1R,2R)-2-(p-methoxybenzenesulfonamido)-1,2-diphenylethyl)cyclohexane-1,2-dicarboxamide

[0060] Colorless crystals 511 mg, yield: 87%, Mp 256.3–258.7℃; R f =0.20 (DCM / MeOH 20:1, v / v). =–13.05 (c = 2.0, DMSO). 1 H NMR (400MHz, DMSO-d6) δ: 7.88 (t, J=11.0Hz, 1H, 4H, NH), 7.18 (d, J=8.5Hz, 4H, ArH), 7.12–7.05 (m, 14H, ArH), 7.04 (d, J=8.1Hz, 2H, ArH), 6.87 (t, J=7.5Hz ,4H,ArH),6.68(d,J=8.5Hz,4H,ArH),5.05(dd,J=9.8,4.9Hz,2H,CH),4.74( dd,J=10.0,4.8Hz,2H,2CH),3.72(s,6H,2CH3),2.29(s,2H,2CH),1.61(s,2H in CH2),1.53(d,J=13.4Hz,2H in CH2),1.10(s,2H in CH2),0.92(d,J=12.6Hz,2H in CH2). 13 CNMR (101MHz, DMSO-d6) δ: 174.2, 162.0, 139.7, 133.4, 128.5, 127.9, 127. 8,127.5,127.2,127.0,126.8,114.1,62.1,57.1,55.9,46.0,29.7,25.5.

[0061] (1S,2S)-1,2-Bis((4R,5R)-1-(p-methoxyphenylsulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane

[0062] Colorless crystals 606mg, yield: 70%, Mp 214.5–216.7℃; Rf =0.13 (PE / EA 10:1, v / v). =–115.45 (c = 2.0, CHCl3). 1 H NMR(400MHz, CDCl3)δ:7.88–7.80(m,4H,ArH),7.38(dd,J=8.1,6.4Hz,4H,ArH), 7.34–7.29(m,2H,ArH),7.24–7.17(m,6H,ArH),6.99(t,J=7.7Hz,4H,ArH),6.57 –6.50(m,4H,ArH),6.16–6.08(m,4H,ArH),4.87(d,J=6.2Hz,2H,2CH),4.21(d,J =6.2Hz,2H,2CH),4.18–4.14(m,2H,2CH),3.51(s,6H,2CH3),3.03–2.93(m,2H,2H in2CH2),2.00(s,2H,2H in 2CH2),1.72–1.60(m,4H,2CH2). 13 C NMR(101MHz, CDCl3)δ:164.5,163.3,142.9,141.9,130.8,129.0,128.9,12 8.5,128.0,127.6,127.1,126.3,114.1,79.9,71.5,55.7,41.7,34.7,26.1.

[0063] Embodiment 5

[0064] (1S,2S)-1,2-Bis((4R,5R)-1-(p-nitrobenzenesulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane 1e

[0065] N-[(1R,2R)-2-Amino-1,2-diphenylethyl]-p-nitrobenzenesulfonamide

[0066] According to the preparation method of Example 1, methanesulfonyl chloride was replaced with p-nitrobenzenesulfonyl chloride to obtain p-nitrobenzenesulfonamide product. Colorless crystal 1.43g, yield: 72%, Mp 196.7-198.1℃; R f =0.30 (DCM / MeOH 40:1, v / v). 1HNMR(400MHz, CDCl3)δ:7.96(d,J=8.9Hz,2H,ArH),7.53(d,J=8.8Hz,2H,ArH),7.24–7.18 (m,5H,ArH),7.18–7.11(m,5H,ArH),4.49(d,J=4.5Hz,1H,CH),4.22(d,J=4.5Hz,1H,CH). 13 C NMR (101MHz, DMSO) δ: 148.7, 146.8, 142.4, 139.5, 127.7, 127.6, 127.5, 127.3 (2C), 126.58, 126.55, 123.8, 65.0, 60.4.

[0067] (1S,2S)-N 1 ,N 2 -Bis((1R,2R)-2-(p-nitrobenzenesulfonamido)-1,2-diphenylethyl)cyclohexane-1,2-dicarboxamide

[0068] Colorless crystal 112mg, yield: 42%, Mp>300℃ R f =0.20 (DCM / MeOH 20:1, v / v). =–13.70 (c = 1.0, DMSO). 1 H NMR (400MHz, DMSO-d6) δ: 8.47 (d, J=10.0Hz, 2H, NH), 8.01–7.96 (m, 4H, ArH), 7.93 (d, J=9.8Hz,2H,NH),7.53–7.47(m,4H,ArH),7.12–6.95(m,14H,ArH),6.91–6.78(m,6H, ArH),5.08(dd,J=9.7,5.4Hz,2H,2CH),4.77(dd,J=10.0,5.4Hz,2H,CH),2.35–2.25( m,2H,CH),1.69–1.57(m,4H,CH2CH2),1.17–1.07(m,2H,CH2),1.03–0.97(m,2H,CH2). 13 C NMR(101MHz,DMSO-d6)δ:173.7,148.7,146.5,139.0,138.7,127.6,127.49, 127.45,127.1,126.8,126.7,126.4,123.8,62.2,56.3,45.6,29.32,25.09.

[0069] (1S,2S)-1,2-Bis((4R,5R)-1-(p-nitrobenzenesulfonyl)-4,5-diphenyl-4,5-dihydro-1H-imidazolin-2-yl)cyclohexane

[0070] Colorless crystals 268mg, yield: 30%, Mp 279.2–283.8℃; R f =0.30(PE / EA 10:1,v / v). =–80.00 (c = 1.1, CHCl3). 1 H NMR(400MHz, CDCl3)δ:8.10–8.02(m,4H,ArH),7.46–7.34(m,10H,ArH),7.29–7.23(m,2H,ArH),7.21–7.17(m,4H,ArH),7.01(t,J=7.7H z,4H,ArH),6.54–6.47(m,4H,ArH),4.91(d,J=6.3Hz,2H,2CH),4.28(d,J=6.3Hz,2H,2CH),4.16–4.09(m,2H,2CH),2.97–2.85(m,2H,2H in 2CH2),2.11–1.98(m,2H,2H in 2CH2),1.73–1.59(m,4H,2CH2). 13 C NMR (101MHz, CDCl3) δ: 163.5, 150.4, 142.2, 141.8, 140.6, 129.9, 129.3, 128.7, 128.5, 126.6, 126.2, 124.1, 79.8, 71.7, 41.7, 34.5, 26.0.

Claims

1. A chiral bisimidazoline ligand containing a semi-rigid cyclohexane skeleton structure, the general structural formula of which is as follows: In formula (1): R represents an alkyl group, a cycloalkyl group, a cycloalkylalkyl group and an aryl group having 1 to 10 carbon atoms, the aryl group may be a cyclic group, and a phenyl group substituted by fluorine, chlorine, bromine, alkoxy, cyano and nitro.

2. The chiral bisimidazoline ligand containing a semi-rigid cyclohexane skeleton structure according to claim 1, characterized in that: The chiral bisimidazoline ligand containing a semi-rigid cyclohexane skeleton structure is selected from one of the following compounds 1a to 1e: 1a: R = Me; 1b: R = Ph; 1c: R = 4-MeC6H4; 1d: R = 4-MeOC6H4; 1e: R = 4-O2NC6H4.

3. The method for preparing a chiral bisimidazoline ligand containing a semi-rigid cyclohexane skeleton structure according to claim 1, wherein (1R, 2R)-1,2-diphenylethane-1,2-diamine shown in formula [2] is first protected with sulfonyl chloride, then condensed with (1S, 2S)-cyclohexane-1,2-dicarboxylic acid, and then cyclized to obtain a chiral bisimidazoline ligand containing a cyclohexane skeleton structure shown in formula [1]: in: R represents an alkyl group, a cycloalkyl group, a cycloalkylalkyl group and an aryl group having 1 to 10 carbon atoms, the aryl group may be a cyclic group, and a phenyl group substituted by fluorine, chlorine, bromine, alkoxy, cyano and nitro.

4. The method for preparing a chiral bisimidazoline ligand containing a cyclohexane skeleton structure as claimed in claim 3, characterized in that The (1R,2R)-1,2-diphenylethane-1,2-diamine shown in formula [2] can be replaced by (1S,2S)-1,2-diphenylethane-1,2-diamine, or (1S,2S)-cyclohexane-1,2-dicarboxylic acid can be replaced by (1R,2R)-cyclohexane-1,2-dicarboxylic acid, and according to the synthesis method of claim 3, a chiral bisimidazoline ligand containing a cyclohexane skeleton structure having a skeleton shown in formula [1] but with opposite configurations of the imidazoline ring or the cyclohexane ring.

5. The method for preparing a chiral bisimidazoline ligand containing a cyclohexane skeleton structure as claimed in claim 3, characterized in that The (1R,2R)-1,2-diphenylethane-1,2-diamine shown in formula [2] can be subjected to monosulfonylation with sulfonyl chloride in the presence of an organic base to obtain the monosulfonylated (1R,2R)-1,2-diphenylethane-1,2-diamine shown in formula [3]; the organic base used includes trimethylamine, triethylamine, tripropylamine, tributylamine, N-methyltetrahydropyrrole, N-methylpiperidine, N-methylmorpholine, pyridine, 2-methylpyridine, 4-methylpyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, and mixtures thereof.

6. The method for preparing a chiral bisimidazoline ligand containing a cyclohexane skeleton structure as claimed in claim 3, characterized in that The monosulfonylated (1R,2R)-1,2-diphenylethane-1,2-diamine shown in formula [3] can be condensed with (1S,2S)-cyclohexane-1,2-dicarboxylic acid in the presence of a condensing agent to obtain a cyclohexane-1,2-dicarboxamide compound shown in formula [4]; the condensing agent used includes DCC, DIC, EDCI, BOP, BOP-Cl, PyBOP, DEPBT, HOBT, HBTU, TBTU, and mixtures thereof.

7. The method for preparing a chiral bisimidazoline ligand containing a cyclohexane skeleton structure as claimed in claim 3, characterized in that The cyclohexane-1,2-dicarboxamide compound shown in formula [4] can be cyclized in the presence of a cyclization reagent to obtain a chiral bisimidazoline ligand containing a cyclohexane skeleton structure shown in formula [1]. The cyclization reagent used includes trifluoromethanesulfonic anhydride, trifluoromethanesulfonic anhydride and triphenylphosphine oxide.

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