Process for the synthesis of chiral non-racemic c2 symmetric bidentate bisoxazoline arylalkenyl compounds

Abstract

The application provides a synthesis method of chiral non-racemic C2-symmetric bidentate bisoxazoline arylalkenyl compounds. The method synthesizes chiral non-racemic C2-symmetric bidentate bisoxazoline arylalkenyl compounds by dehydration condensation reaction of aldehyde compounds and non-racemic C2-symmetric bidentate bisoxazoline with active methylene, is simple and efficient, fills the blank of chiral non-racemic C2-symmetric bidentate bisoxazoline arylalkenyl compounds by condensation reaction, and is of great significance for large-scale use of the compounds as ligands in transition metal catalyzed reactions.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing chiral non-racemic C2 symmetric bidentate bisoxazoline aryl alkenyl compounds. Background Technology

[0002] Chiral non-racemic C2 symmetric bidentate bisoxazoline is a very effective catalyst ligand that exhibits good enantioselectivity after coordination with metals. The chiral, non-racemic, C2-symmetric bidentate bisoxazoline aryl alkenyl compound ligands developed by Anthony J. Burke et al. form copper complexes with copper that can catalyze indole-mediated Friedel-Crafts reactions or asymmetric cyclopropanation reactions (Carreiro, EP; Burke, AJ; Ramalho, JPP; Rodrigues, AI; Arylid-OX and Arylid-BOX derived catalysts: applications in catalytic asymmetric cyclopropanation. Tetrahedron: Asymmetry 2009, 20, 1272–1278; Sun, YJ; Li, N.; Zheng, ZB; Liu, L.; Yu, YB; Qin, ZH; Fu, B., Highly Enantioselective Friedel-Crafts Reaction of Indole with Alkylidene Malonates Catalyzed by Heteroarylidene Malonate-Derived). Bis(oxazoline)Copper(II)Complexes.Adv.Synth.Catal.2009,351,3113–3117.).

[0003]

[0004] For example, in the asymmetric cyclopropanation reaction of styrene with ethyl diazonium catalyzed by ligand 3r and Cu(I), it exhibits a cis / trans isomer ratio of 62:38 and enantioselectivity of 84% ee and 77% ee (Carreiro, EdP; Chercheja, S.; Moura, NMM; Gertrudes, CSC; Burke, AJ, Arylid-Box: A new family of chiral bis-oxazoline ligands for metal mediated catalytic enantioselective synthesis. Inorg. Chem. Commun. 2006, 9, 823–826.).

[0005] For example, ligands 3n and 3o have been used in the catalytic Friedel-Crafts reaction between indole and diethyl phenylmethylmalonate, exhibiting excellent asymmetric enantioselectivity of 99.3% and 98.7%, respectively (Sun, YJ; Li, N.; Zheng, ZB; Liu, L.; Yu, YB; Qin, ZH; Fu, B., Highly Enantioselective Friedel-Crafts Reaction of Indole with Alkylidenemalonates Catalyzed by Heteroarylidene Malonate-Derived Bis(oxazoline)Copper(II) Complexes. Adv. Synth. Catal. 2009, 351, 3113–3117.). The structural formulas of 3r, 3n, and 3o are as follows:

[0006]

[0007] The catalytic reaction formula is as follows:

[0008]

[0009] However, the synthesis of such ligands as C2-symmetric bidentate bisoxazoline aryl alkenyl compounds (Formula 3) in the prior art requires multiple steps of reaction starting from the substrate malonic acid ester, which is complex, cumbersome, and has a low overall yield.

[0010]

[0011] Therefore, it is essential to develop a simple and efficient method for preparing chiral non-racemic C2-symmetric bidentate bisoxazoline aryl alkenyl compounds. Summary of the Invention

[0012] To address the problems in the prior art, this invention provides a method for synthesizing chiral non-racemic C2 symmetric bidentate bisoxazoline aryl alkenyl compounds.

[0013] The present invention adopts the following technical solution:

[0014] A method for synthesizing a chiral, non-racemic, C2-symmetric bidentate bisoxazoline aryl alkenyl compound of formula 3, prepared from compounds of formula 1 and formula 2 under basic conditions, is as follows:

[0015]

[0016] Where R is C 1-6 Alkyl or benzyl (Bn);

[0017] R' is X is O or S.

[0018] R 1 H, one or more substituted halogens, one or more substituted C 1-6 Alkyl groups, one or more substituted C 1-6 alkoxy groups, Or amide group.

[0019] According to one embodiment of the present invention, the base is selected from NaOH, t-BuOK, t-BuONa, or t-BuOLi. According to one embodiment of the present invention, the solvent is an alcohol solvent, such as ethanol or n-butanol.

[0020] According to one embodiment of the present invention, the alkali is t-BuOK, t-BuONa or t-BuOLi; preferably t-BuOLi; more preferably, the amount of t-BuOLi is 2.0-2.2 equivalents.

[0021] According to one embodiment of the present invention, the solvent used in the reaction is EtOH and / or n-BuOH; preferably EtOH.

[0022] According to one embodiment of the present invention, the amount of reaction raw material 2 is 2.0-2.5 equivalents.

[0023] According to one embodiment of the present invention, the reaction temperature is 20-60°C and the reaction time is 10-12 h.

[0024] According to one embodiment of the present invention, EtOH is used as the solvent, t-BuOLi is used as the base, the amount of t-BuOLi is 2-2.2 equivalents, the amount of raw material 2 is 2.0-2.5 equivalents, and the reaction is carried out at room temperature for 10-12 hours.

[0025] According to one embodiment of the invention, the halogen is fluorine, chlorine, bromine or iodine.

[0026] According to one embodiment of the present invention, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, or isohexyl; the C 1-6 Alkoxy groups are methoxy, ethoxy, or tert-butoxy groups.

[0027] According to one embodiment of the present invention, the R 1 The values ​​are H, 4-F, 4-Cl, 4-Br, 4-MeO, 4-NHCOCH3, 3-F, 2-F, 2-Br, 2-Me, 3,5-(CH3)2, and 3,5-(MeO)2.

[0028] According to one embodiment of the present invention, the chiral non-racemic C2 symmetrical bidentate bisoxazoline aryl alkenyl compound of formula 3 is selected from compounds 3a-3r:

[0029] (4S,4'S)-2,2'-(2-phenylethylene-1,1-diyl)bis(4-benzyl-4,5-dihydrooxazole)(3a);

[0030] (4S,4'S)-2,2'-[2-(4-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3b);

[0031] (4S,4'S)-2,2'-[2-(4-chlorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3c);

[0032] (4S,4'S)-2,2'-[2-(4-bromophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3d);

[0033] (4S,4'S)-2,2'-[2-(4-methoxyphenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3e);

[0034] N-[4-(2,2-bis((S)-4-benzyl-4,5-dihydrooxazol-2-yl)vinyl)phenyl]acetamide (3f);

[0035] (4S,4'S)-2,2'-[2-(3-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3h);

[0036] (4S,4'S)-2,2'-[2-(2-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3i);

[0037] (4S,4'S)-2,2'-[2-(2-bromophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3j);

[0038] (4S,4'S)-2,2'-[2-(o-tolyl)ethen-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3k);

[0039] (4S,4'S)-2,2'-[2-(3,5-dimethylyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3l);

[0040] (4S,4'S)-2,2'-[2-(3,4-dimethoxyphenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3m); (4S,4'S)-2,2'-[2-(furan-2-yl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3n);

[0041] (4S,4'S)-2,2'-[2-(thiophen-2-yl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3o);

[0042] (4S,4'S)-2,2'-[2-(2-((4-chlorophenyl)ethynyl)phenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3p);

[0043] (4S,4'S)-2,2'-[2-(anthracene-9-yl)ethen-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole)(3q);

[0044] (4S,4'S)-2,2'-[2-phenylethylene-1,1-diyl]bis(4-tert-butyl-4,5-dihydrooxazole)(3r).

[0045] Beneficial effects:

[0046] This invention provides a method for synthesizing chiral non-racemic C2-symmetric bidentate bisoxazoline aryl alkenyl compounds of Formula 3. The invention synthesizes chiral non-racemic C2-symmetric bidentate bisoxazoline (Formula 1) via a dehydration condensation reaction using an aldehyde compound (Formula 2) and a non-racemic C2-symmetric bidentate bisoxazoline with an active methylene group. This method is simple and efficient, filling the gap in the development of chiral non-racemic C2-symmetric bidentate bisoxazoline aryl alkenyl compounds through condensation reactions. This is of great significance for the large-scale application of these compounds as ligands in transition metal catalytic reactions. Detailed Implementation

[0047] To further illustrate the present invention and its advantages, the technical solution of the present invention will be further described below through specific embodiments. It should be understood that these embodiments are only helpful in understanding the present invention and should not be regarded as specific limitations of the present invention.

[0048] Unless otherwise specified, all parts mentioned in this invention are parts by weight, and all percentages are mass percentages.

[0049] Example 1: Preparation of chiral non-racemic C2 symmetric bidentate bisoxazoline aryl alkenyl compounds

[0050] The reaction route is as follows:

[0051]

[0052] The operating steps are as follows:

[0053] In a dry 25 mL round-bottom flask, substrate 1 (0.2 mmol), ethanol (3 mL), aldehyde 2 (0.5 mmol), and lithium tert-butoxide (0.44 mmol) were added sequentially under an argon atmosphere. The mixture was reacted for 10 hours under argon protection. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (eluting with a mixture of petroleum ether and ethyl acetate) to give product 3.

[0054] The inventors first attempted to prepare 3a by reacting a non-racemic C2-symmetric bidentate bisoxazoline ligand 1a with benzaldehyde 2a under alkaline conditions. The specific preparation route is as follows.

[0055]

[0056] The reaction conditions were investigated as shown in Table 1 below.

[0057] Using NaOH as the base and EtOH as the solvent, condensation product 3a can be generated in 14% yield (entry 1). The inventors found that by continuing to use EtOH as the solvent, the yield of the base using t-BuOK was 23%, the yield of the base using t-BuONa was 32%, and the yield of the base using t-BuOLi increased to 44%.

[0058] Using t-BuOLi as the base, the screening of solvent types revealed that when n-BuOH was used as the solvent, the yield of the target product was 35%; when DMF and DMSO were used as solvents, no product was formed (items 6-7).

[0059] Increasing or decreasing the reaction temperature had limited effect (entries 8-10). Slightly increasing the amount of t-BuOLi to 2.2 equiv improved the yield to 55% (entry 11).

[0060] Increasing the amount of reactant 2a to 2.5 equiv increased the yield to 58% (entry 12). Shortening the reaction time also improved the yield (entry 12).

[0061] The optimal reaction conditions were: EtOH as solvent, t-BuOLi as base, 2.5 equiv of aldehyde, and reaction at room temperature for 10 h.

[0062] Table 1. Investigation of Reaction Conditions a

[0063]

[0064]

[0065] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equivalence), ethanol (3.0 mL), base (2.0 equivalence), argon protection, reaction at room temperature for 12 hours.

[0066] b-yield through 1 The HNMR analysis was performed using 1,3,5-trimethoxybenzene as an internal standard.

[0067] c t-BuOLi (2.2 equivalent).

[0068] d2a (0.5 mmol, 2.5 equivalents).

[0069] Based on the determination of the optimal reaction conditions, the range of reaction substrates was explored, and the results are shown in Table 2 below.

[0070] Benzaldehyde with various substituents at the para position of the benzene ring, such as halogens 3b-d, electron-donating groups 3e-f, or carbazole with a large steric hindrance, can be successfully converted into the corresponding product, with the highest yield reaching 78%.

[0071] For benzene rings with meta-substituents, such as fluorine, the yield is 31% (3h). For benzaldehyde rings with ortho-substituents, such as 3i-k, the target product can be isolated in medium to high yields. Disubstituted benzene rings are also compatible (3l-m). In addition to aromatic aldehydes, heterocyclic aldehydes, such as 2-furan carboxaldehyde and 2-thiophene carboxaldehyde, can also participate in the reaction, with the corresponding products isolated in 73% and 82% yields, respectively.

[0072] It is worth noting that sterically hindered aldehydes, such as (2-(4-chlorophenyl)ethynyl)benzaldehyde and 9-anthracene carboxaldehyde, can also generate the corresponding products under optimal reaction conditions. Although the yields of (2-(4-chlorophenyl)ethynyl)benzaldehyde and 9-anthracene carboxaldehyde reacting with 1a are only 53%, the yield of 9-anthracene carboxaldehyde reacting with 1a is as high as 91%.

[0073] In addition, substituent R is compatible with other substituents such as benzyl and tert-butyl, and can give the corresponding product (3r) with a separation yield of 66%.

[0074] Table 2. Scope of application for substrates a

[0075]

[0076] a. Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), t-BuOLi (0.4 mmol), EtOH (3.0 mL), argon atmosphere, room temperature, 10 h.

[0077] Product structure confirmation

[0078]

[0079] (4S,4'S)-2,2'-(2-phenylethylene-1,1-diyl)bis(4-benzyl-4,5-dihydrooxazole) (3a), separated by column chromatography (petroleum ether / ethyl acetate = 3:1 → 9:1), mp = 42.7-42.9℃, yield 69%. 1 H NMR(400MHz, CDCl3)δ7.61(s,1H),7.45–7.42(m,2H),7.35–7.28(m,7H),7.24–7.20(m,6H),4.65–4.54(m,2H), 4.40–4.26(m,2H),4.14–4.07(m,2H),3.20(ddd,J=13.7,8.1,5.5Hz,2H),2.74(ddd,J=24.7,13.7,8.7Hz,2H). 13C NMR (101MHz, CDCl3) δ162.4,161.0,141.6,137.95,137.90,134.2,129.7,129.4,129.34,129.27 ,128.6,128.5,128.51,126.47,118.7,72.1,71.8,68.3,68.2,41.6,41.1.HRMS(ESI-TOF)Calcd for C 28 H 27 N2O2 + ([M+H)) + )423.2067.Found 423.2066.

[0080]

[0081] (4S,4'S)-2,2'-[2-(4-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3b), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), mp = 52.2-52.4℃, yield 51%. 1 H NMR(400MHz, CDCl3)δ7.55(s,1H),7.40(ddt,J=8.3,4.9,2.9Hz,2H),7.32–7.28(m,4H),7.25–7.20(m,6H),7.04–6.98(m,2H),4.6 5–4.54(m,2H),4.33(dt,J=38.8,8.9Hz,2H),4.13–4.07(m,2H),3.19(dt,J=13.6,5.9Hz,2H),2.76(ddd,J=37.0,13.7,8.6Hz,2H). 13 C NMR (101MHz, CDCl3) δ164.6,162.3,162.1,160.8,140.3,137.84,137.76,131.4,131.3,130.31,130.28,129.3,12 8.6,128.5,126.6,126.5,118.41,118.39,115.8,115.5,72.1,71.8,68.2,68.1,41.6,41.0.HRMS(ESI-TOF)Calcd for C 28 H 26 FN2O2 + ([M+H)) + )441.1973.Found 441.1975.

[0082]

[0083] (4S,4'S)-2,2'-[2-(4-chlorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3c), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), yield 26%. 1 H NMR(400MHz, CDCl3)δ7.54(s,1H),7.36–7.28(m,8H),7.26–7.20(m,6H),4.59(dddd,J=12.4,11.0,8.6,5.5Hz,2H), 4.32(dt,J=36.0,8.9Hz,2H), 4.13–4.07(m,2H), 3.19(dt,J=12.8,6.0Hz,2H), 2.75(ddd,J=35.8,13.7,8.6Hz,2H). 13 C NMR (101MHz, CDCl3) δ162.2,160.7,140.2,137.8,137.7,135.7,132.6,130.6,129.3,128.8, 128.6,128.5,126.6,126.5,119.2,72.1,71.9,68.3,68.2,41.6,41.0.HRMS(ESI-TOF)Calcd for C 28 H 26 ClN2O2 + ([M+H)) + )457.1677.Found 457.1678.

[0084]

[0085] (4S,4'S)-2,2'-[2-(4-bromophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3d), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), mp = 57.2-57.4℃, yield 78%. 1 H NMR(400MHz, CDCl3)δ7.52(s,1H),7.45(d,J=8.6Hz,2H),7.29(ddt,J=10.5,8.2,3.4Hz,7H),7.23–7.21(m,5H),4.66–4.54 (m,2H),4.32(dt,J=35.1,8.9Hz,2H),4.12–4.07(m,2H),3.18(dt,J=13.2,6.3Hz,2H),2.75(ddd,J=35.5,13.7,8.6Hz,2H). 13C NMR (101MHz, CDCl3) δ162.2,160.7,140.2,137.8,137.7,133.0,131.7,130.8,129.3,128.6,12 8.5,126.60,126.55,124.1,119.3,72.1,71.9,68.3,68.2,41.6,41.0.HRMS(ESI-TOF)Calcdfor C 28 H 26 BrN2O2 + ([M+H)) + )501.1172.Found 501.1179.

[0086]

[0087] (4S,4'S)-2,2'-[2-(4-methoxyphenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3e), separated by column chromatography (petroleum ether / ethyl acetate = 3:1 → 9:1), yield 68%. 1 H NMR (400MHz, CDCl3) δ7.54 (s, 1H), 7.39 (d, J = 8.7Hz, 2H), 7.30 (q, J = 6.9, 6.2H z,4H),7.23(t,J=6.6Hz,6H),6.84(d,J=8.7Hz,2H),4.59(ddt,J=25.8,14.5,7 .4Hz,2H),4.32(dt,J=50.1,8.9Hz,2H),4.10(dt,J=21.9,8.0Hz,2H),3.82(s, 3H), 3.21 (ddd, J=15.2, 10.4, 5.3Hz, 2H), 2.76 (ddd, J=51.3, 13.7, 8.8Hz, 2H). 13 C NMR (101MHz, CDCl3) δ162.7,161.4,160.9,141.2,138.0,137.9,131.3,129.3,128.6,128.5,126. 7,126.53,126.48,116.0,114.0,72.0,71.7,68.20,68.15,55.3,41.7,41.1.HRMS(ESI-TOF)Calcd for C 29 H 29 N2O3 + ([M+H)) + )453.2173.Found 453.2173.

[0088]

[0089] N-[4-(2,2-bis((S)-4-benzyl-4,5-dihydrooxazol-2-yl)vinyl)phenyl]acetamide (3f), separated by column chromatography (petroleum ether / ethyl acetate = 1:1 → 3:1), mp = 83.4-83.7℃, yield 68%. 1 H NMR(400MHz, CDCl3)δ8.20(s,1H),7.49(s,1H),7.36–7.28(m,6H),7.24–7.21 (m,7H),5.29(s,1H),4.58(tdd,J=15.8,11.1,7.4Hz,2H),4.43(t,J=9.0Hz,1H ),4.27(t,J=8.8Hz,1H),4.17(t,J=8.3Hz,1H),4.07(dd,J=8.3,7.3Hz,1H),3 .17(dt,J=13.6,5.3Hz,2H),2.76(ddd,J=56.0,13.7,8.5Hz,2H),2.09(s,3H). 13 C NMR (101MHz, CDCl3) δ168.7,162.5,161.8,141.2,139.8,137.81,137.76,130.2,129.3,129.2,128 .6,128.5,126.64,126.55,119.1,116.8,72.3,71.8,68.2,68.1,41.7,41.2.HRMS(ESI-TOF)Calcd for C 30 H 30 N3O3 + ([M+H)) + )480.2282.Found 480.2280.

[0090]

[0091] (4S,4'S)-2,2'-[2-(4-(9H-carbazole-9-yl)phenyl)vinyl-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3g), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), yield 45%. 1H NMR(400MHz, CDCl3)δ8.14(d,J=7.7Hz,2H),7.69–7.65(m,3H),7.57–7.55(m,2H),7.46–7.39(m,4H),7.34–7.27(m,7H),7.25–7.19(m,5H), 4.72–4.59(m,2H),4.39(dt,J=45.7,9.0Hz,2H),4.20–4.12(m,2H),3.23(ddd,J=13.8,5.3,2.3Hz,2H),2.81(ddd,J=36.8,13.7,8.6Hz,2H). 13 C NMR (101MHz, CDCl3) δ162.4,160.9,140.40,140.37,138.9,137.8,137.7,132.9,131.0,129.37,129.35,128.6,128.5,12 6.63,126.59,126.56,126.1,123.6,120.4,120.3,119.1,109.8,72.2,71.9,68.3,68.2,41.6,41.1.HRMS(ESI-TOF)Calcd for C 40 H 34 N3O2 + ([M+H)) + )588.2646.Found 588.2645.

[0092]

[0093] (4S,4'S)-2,2'-[2-(3-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3 h), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), mp = 52.1-52.3 °C, yield 31%. 1 H NMR(400MHz,CDDCl3)δ7.55(s,1H),7.34–7.28(m,5H),7.23–7.18(m,8H),7.07–7.00(m,1H),4.59(dtd,J=16.6,9.1,5.5H z,2H),4.33(dt,J=38.8,8.9Hz,2H),4.16–4.08(m,2H),3.20(dd,J=13.7,5.4Hz,2H),2.73(ddd,J=13.6,11.4,8.9Hz,2H). 13C NMR (101MHz, CDCl3) δ163.8,162.1,161.4,160.6,140.01,139.98,137.85,137.77,136.24,136.16,130.1,130.0,129.4,129.2, 128.6,128.5,126.6,125.5,125.4,120.1,116.7,116.5,115.8,115.6,72.3,71.9,68.3,68.2,41.5,41.2.HRMS(ESI-TOF)Calcd for C 28 H 26 FN2O2 + ([M+H)) + )441.1973.Found 441.1973.

[0094]

[0095] (4S,4'S)-2,2'-[2-(2-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3i), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), mp = 52.3-52.5℃, yield 54%. 1 H NMR(400MHz, CDCl3)δ7.74(s,1H),7.46(td,J=7.7,1.7Hz,1H),7.36–7.27(m,5H),7.24–7.18(m,6H),7.10–7.05(m,2H),4.63–4.53 (m,2H),4.32(dt,J=23.1,8.9Hz,2H),4.13–4.07(m,2H),3.19(ddd,J=19.7,13.7,5.4Hz,2H),2.73(ddd,J=13.7,10.1,8.8Hz,2H). 13 C NMR (101MHz, CDCl3) δ162.2,161.9,160.8,159.4,137.9,137.8,134.3,134.2,131.6,131.5,129.73,129.71,129.34,129.26,128.6,1 28.5,126.5,123.95,123.91,122.5,122.3,120.51,120.49,115.8,115.6,72.1,71.8,68.4,68.2,41.6,41.1.HRMS(ESI-TOF)Calcdfor C 28 H 26 FN2O2+ ([M+H)) + )441.1973.Found441.1973.

[0096]

[0097] (4S,4'S)-2,2'-[2-(2-bromophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3j), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), mp = 63.2-63.4℃, yield 49%. 1 H NMR (400MHz, CDCl3) δ7.78(s,1H),7.60(dd,J=7.7,1.4Hz,1H),7.45(dd,J=7.5,1.8Hz,1H),7.29(q,J=7.1Hz,4H),7.25–7.15(m,8H),4.6 3–4.48(m,2H),4.28(dt,J=11.8,8.9Hz,2H),4.14–3.98(m,2H),3.16(ddd,J=52.3,13.7,5.3Hz,2H),2.69(ddd,J=22.8,13.7,8.8Hz,2H). 13 C NMR (101MHz, CDCl3) δ162.0,160.5,140.9,137.8,134.9,132.9,130.7,129.9,129.34,129.28,128 .58,128.55,127.0,126.6,126.5,124.5,72.0,71.9,68.4,68.1,41.5,41.1.HRMS(ESI-TOF)Calcd for C 28 H 26 BrN2O2 + ([M+H)) + )501.1172.Found501.1174.

[0098]

[0099] (4S,4'S)-2,2'-[2-(o-tolyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3k), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), yield 72%. 1H NMR(400MHz,CDDCl3)δ7.77(s,1H),7.39(d,J=7.7Hz,1H),7.32–7.29(m,3H),7.25–7.19(m,7H),7.14(t,J=6.2Hz,3H),4.54(dtdd,J=39.0,9.0 ,7.3,5.5Hz,2H),4.30–4.25(m,2H),4.12–3.99(m,2H),3.15(ddd,J=61.7,13.7,5.4Hz,2H),2.67(ddd,J=39.2,13.7,8.9Hz,2H),2.36(s,3H). 13 C NMR (101MHz, CDCl3) δ162.2,161.0,141.0,138.0,137.9,137.3,133.7,130.2,129.5,129.4,129.2,12 8.5,128.2,126.5,126.4,125.6,119.8,72.1,71.7,68.2,68.1,41.6,41.2,20.0.HRMS(ESI-TOF)Calcd for C 29 H 29 N2O2 + ([M+H)) + )437.2224.Found437.2229.

[0100]

[0101] (4S,4'S)-2,2'-[2-(3,5-xylyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3l), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), mp = 54.4-54.6℃, yield 63%. 1 H NMR(400MHz, CDCl3)δ7.56(s,1H),7.31–7.27(m,4H),7.23–7.18(m,6H),7.11(s,2H),7.00(s,1H),4.62–4.52(m,2H),4 .31(dt,J=40.4,8.9Hz,2H),4.15–4.06(m,2H),3.21(td,J=14.2,5.4Hz,2H),2.71(dd,J=13.7,9.0Hz,2H),2.32(s,6H). 13C NMR (101MHz, CDCl3) δ162.5,161.3,142.0,138.0,137.9,134.0,131.6,129.4,129.1,128.7,128 .5,127.2,126.53,126.52,118.2,72.4,71.7,68.3,68.2,41.6,41.4,21.4.HRMS(ESI-TOF)Calcd forC 30 H 31 N2O2 + ([M+H)) + )451.2380.Found 451.2384.

[0102]

[0103] (4S,4'S)-2,2'-[2-(3,4-dimethoxyphenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3m), separated by column chromatography (petroleum ether / ethyl acetate = 3:1 → 9:1), yield 36%. 1 H NMR (400MHz, CDCl3) δ7.54(s,1H),7.32–7.28(m,4H),7.23(d,J=7.2Hz,6H),7.08(dd,J=6.4,1.9Hz,2H),6.82(d,J=8.9Hz,1H),4.64–4.53(m,2H), 4.33(dt,J=40.8,8.9Hz,2H),4.17–4.06(m,2H),3.88(d,J=16.0Hz,6H), 3.22(ddd,J=21.8,13.7,5.5Hz,2H), 2.75(ddd,J=29.3,13.7,8.7Hz,2H). 13 C NMR (101MHz, CDCl3) δ162.7,161.3,150.6,148.7,141.4,137.97,137.95,129.3,129.2,128.6,128.5,126.9 ,126.54,126.49,123.5,116.3,112.4,110.9,72.2,71.8,68.3,68.2,55.9,41.7,41.4.HRMS(ESI-TOF)Calcd for C 30 H 31 N2O4 + ([M+H)) + )483.2278.Found 483.2277.

[0104]

[0105] (4S,4'S)-2,2'-[2-(furan-2-yl)vinyl-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3n), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), yield 73%. 1 H NMR (400MHz, CDCl3) δ7.47(d,J=1.6Hz,1H),7.33–7.26(m,7H),7.22(d,J=6.7Hz,4H),6.66(d,J=3.5 Hz,1H),6.46(dd,J=3.4,1.8Hz,1H),4.67(tdd,J=8.9,7.7,5.6Hz,1H),4.56(tdd,J=8.9,7.2,5.2Hz ,1H),4.43(dd,J=9.3,8.5Hz,1H),4.28–4.18(m,2H),4.07(dd,J=8.3,7.2Hz,1H),3.29(dd,J=13.8, 5.6Hz, 1H), 3.19 (dd, J=13.7, 5.2Hz, 1H), 2.85 (dd, J=13.8, 8.8Hz, 1H), 2.70 (dd, J=13.7, 8.8Hz, 1H). 13 C NMR (101MHz, CDCl3) δ162.3,161.0,149.9,145.3,138.2,137.9,129.34,129.26,128.6,128.5,127.2, 126.49,126.47,116.6,114.2,112.4,72.3,71.8,68.32,68.25,61.5,41.6,41.5.HRMS(ESI-TOF)Calcd for C 26 H 25 N2O3 + ([M+H)) + 413.1860.Found 413.1860.

[0106]

[0107] (4S,4'S)-2,2'-[2-(thiophen-2-yl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3o), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), yield 82%. 1H NMR(400MHz, CDCl3)δ7.72(s,1H),7.46(d,J=5.1Hz,1H),7.34–7.26(m,7H),7.25–7.20(m, 4H),7.04(dd,J=5.1,3.7Hz,1H),4.75–4.67(m,1H),4.56(tdd,J=8.9,7.0,5.2Hz,1H),4.4 6(dd,J=9.6,8.5Hz,1H),4.29–4.20(m,2H),4.07(dd,J=8.4,7.0Hz,1H),3.39–3.34(m,1H) ,3.19(dd,J=13.7,5.2Hz,1H),2.89(dd,J=13.8,8.9Hz,1H),2.70(dd,J=13.7,8.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ162.3,160.7,138.1,137.9,137.1,133.9,130.8,129.3, 129.2.,128.6,128.5,127.2,126.5,114.7,72.5,71.8,68.4,68.3,41.6,41.2.

[0108] HRMS (ESI-TOF) Calculation for C 26 H 25 N2O2S + ([M+H)) + )429.1631.Found 429.1636.

[0109]

[0110] (4S,4'S)-2,2'-[2-(2-((4-chlorophenyl)ethynyl)phenyl)vinyl-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3p), separated by column chromatography (petroleum ether / ethyl acetate = 5:1 → 15:1), yield 53%. 1 H NMR (400MHz, CDCl3) δ8.11(s,1H),7.55(d,J=8.0Hz,2H),7.47–7.44(m,2H),7.35–7.27(m,8H),7.25–7.18(m,6H) ,4.65–4.53(m,2H),4.36–4.29(m,2H),4.13–4.06(m,2H),3.19(ddd,J=27.7,13.7,5.4Hz,2H),2.77–2.71(m,2H). 13C NMR (101MHz, CDCl3) δ162.4,160.8,140.1,137.92,137.86,136.1,134.6,132.8,132.2,129.34,129.28,129.0,128.7,128. 6,128.5,128.2,126.54,126.52,123.8,121.5,119.9,94.7,88.2,72.1,71.8,68.4,68.2,41.6,41.1.HRMS(ESI-TOF)Calcd for C 36 H 30 ClN2O2 + ([M+H)) + )557.1990.Found 557.1998.

[0111]

[0112] (4S,4'S)-2,2'-[2-(anthracite-9-yl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole) (3q), separated by column chromatography (petroleum ether / ethyl acetate = 3:1 → 9:1), mp = 66.2-66.4℃, yield 91%. 1 H NMR(400MHz, CDCl3)δ8.47(d,J=23.7Hz,2H),8.13–8.11(m,2H),8.01(dd,J=6.3,3.0Hz,2H),7.54–7.47(m, 4H),7.37–7.24(m,5H),7.06–7.05(m,3H),6.61–6.58(m,2H),4.70(tdd,J=9.1,7.0,4.7Hz,1H),4.42–4.37( m,1H),4.27–4.19(m,1H),4.07(tdd,J=9.1,7.1,5.9Hz,1H),3.82–3.74(m,1H),3.36–3.29(m,1H),3.24(dd, J=8.3,7.3Hz,1H),2.83(dd,J=13.6,9.0Hz,1H),2.24(dd,J=13.6,5.9Hz,1H),1.55(dd,J=13.6,9.1Hz,1H). 13C NMR (101MHz, CDCl3) δ161.6,160.5,141.2,137.9,137.8,131.1,129.4,128.9,128.7,128.6,128.2,1 27.8,126.6,126.2,125.8,125.4,124.8,71.84,71.78,68.4,67.6,41.5,40.9.HRMS(ESI-TOF)Calcd for C 36 H 31 N2O2 + ([M+H)) + 523.2380.Found 523.2385.

[0113]

[0114] (4S,4'S)-2,2'-[2-phenylvinyl-1,1-diyl]bis(4-tert-butyl-4,5-dihydrooxazole) (3r), separated by column chromatography (petroleum ether / ethyl acetate = 20:1 → 12:1), mp = 66.2-66.4℃, yield 66%. 1 H NMR (400MHz, CDCl3) δ7.55–7.51(m,1H),7.50–7.44(m,1H),7.34(s,1H),4.38–4.30(m,1H),4.30 –4.20(m,1H),4.19–4.12(m,1H),4.08–3.99(m,1H),0.97(d,J=1.8Hz,1H),0.91(d,J=1.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.84,160.52,140.50,134.14,129.50,129.47,128.45,119 .07,76.56,76.50,68.92,68.61,34.10,33.96,26.19,25.86.HRMS(ESI-TOF)Calcd forC 22 H 31 N2O2 + ([M+H)) + )355.2380.Found 355.2381.

Claims

1. A method for synthesizing a chiral, non-racemic, C2-symmetric bidentate bisoxazoline aryl alkenyl compound of formula 3, prepared from compounds of formula 1 and formula 2 under basic conditions, the synthetic route being as follows: ， in, R is C 1-6 Alkyl or benzyl groups; R' is , or X is O or S. R 1 H, one or more halogens, one or more C 1-6 alkyl, one or more C 1-6 alkoxy groups, , or amide group; the base is t -BuOLi; solvent is ethanol; reaction temperature is room temperature.

2. The method as described in claim 1, characterized in that: t -The dosage of BuOLi is 2.0-2.2 equivalents.

3. The method as described in claim 1, characterized in that: The amount of compound 2 is 2.0-2.5 equivalents.

4. The method as described in claim 1, characterized in that: The reaction time is 10-12 h.

5. The method as described in claim 1, characterized in that: Use EtOH as a solvent. t -BuOLi makes alkali t The amount of -BuOLi used was 2-2.2 equivalents; the amount of compound 2 used was 2.0-2.5 equivalents, and the reaction was carried out at room temperature for 10-12 h.

6. The method according to any one of claims 1-5, characterized in that: The halogen is fluorine, chlorine, bromine, or iodine; the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, or isohexyl; the C 1-6 Alkoxy groups are methoxy, ethoxy, or tert-butoxy groups.

7. The method according to any one of claims 1-5, characterized in that: The R 1 It can be H, 4-F, 4-Cl, 4-Br, 4-MeO, 4-NHCOCH3, 3-F, 2-F, 2-Br, 2-Me, 3,5-(CH3)2 or 3,5-(MeO)2.

8. The method according to any one of claims 1-5, characterized in that: The chiral, non-racemic, C2-symmetric bidentate bisoxazoline aryl alkenyl compound of formula 3 is selected from the following compounds: (4S,4'S)-2,2'-(2-phenylethylene-1,1-diyl)bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(4-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(4-chlorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(4-bromophenyl)ethenyl-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(4-methoxyphenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); N-[4-(2,2-bis((S)-4-benzyl-4,5-dihydrooxazol-2-yl)vinyl)phenyl]acetamide; (4S,4'S)-2,2'-[2-(3-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(2-fluorophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(2-bromophenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(o-tolyl)ethen-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(3,5-dimethylyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(3,4-dimethoxyphenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(furan-2-yl)ethen-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(thiophen-2-yl)ethen-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(2-((4-chlorophenyl)ethynyl)phenyl)ethylene-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-(anthrayl-9-yl)ethen-1,1-diyl]bis(4-benzyl-4,5-dihydrooxazole); (4S,4'S)-2,2'-[2-phenylethylene-1,1-diyl]bis(4-tert-butyl-4,5-dihydrooxazole).

Images