A method for synthesizing chiral dihydroquinoline spirocyclic compounds by rhodium-catalyzed asymmetric dearomatization and cyclization.
By employing a rhodium-catalyzed asymmetric dearomatization and cyclization synthesis method, using rhodium chiral bisphosphine complexes and a base catalytic system, the problems of long synthesis steps and low yields in the synthesis of chiral dihydroquinoline spirocyclic compounds in the prior art have been solved, achieving a highly efficient, simple, and enantioselective synthesis.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- DALIAN INSTITUTE OF CHEMICAL PHYSICS CHINESE ACADEMY OF SCIENCES
- Filing Date
- 2024-11-25
- Publication Date
- 2026-05-26
AI Technical Summary
Existing techniques for synthesizing chiral dihydroquinoline spirocyclic compounds involve lengthy steps, low yields, large catalyst requirements, and difficulty in controlling enantioselectivity.
A rhodium-catalyzed asymmetric dearomatization cyclization synthesis method was adopted, using a rhodium chiral bisphosphine complex and a base as the catalytic system, and alkynylquinoline salts and arylboronic acids as substrates to synthesize chiral dihydroquinoline spirocyclic compounds via asymmetric dearomatization cyclization.
This method enables the synthesis of chiral dihydroquinoline spirocyclic compounds with simple operation, high yield, and high enantioselectivity. The products are specific, easy to separate, readily available catalysts, and mild reaction conditions, exhibiting atom economy and environmental friendliness.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of asymmetric catalytic synthesis technology, specifically relating to a method for the synthesis of chiral dihydroquinoline spirocyclic compounds via rhodium-catalyzed asymmetric dearomatization and cyclization. Background Technology
[0002] Chiral dihydroquinoline spirocyclic skeletons are important structural units of alkaloids, widely found in natural products and physiologically active molecules. For example, chiral tetrahydroquinoline spiroindolone is a potent tumor inhibitor with significant inhibitory effects on human tumor cells such as MCF, SKBR-3, PC3, and HeLa (References: Kouznetsov VV; Arenas D.RM; Arvelo F.; Forero, JSB; Sojo, F.; Munoz, A. Lett. Drug Des. Discovery 2010, 7, 632). Currently, most synthetic routes for chiral dihydroquinoline spirocyclic compounds suffer from drawbacks such as long steps, low yields, large catalyst requirements, and difficulty in controlling enantioselectivity. Therefore, developing a simple, efficient, high-yield, and highly enantioselective method for synthesizing chiral dihydroquinoline spirocyclic compounds is a highly attractive research direction. Summary of the Invention
[0003] The purpose of this invention is to provide a method for synthesizing chiral dihydroquinoline spirocyclic compounds by rhodium-catalyzed asymmetric dearomatization cyclization. This invention has the advantages of simple operation, practicality, readily available raw materials, short synthesis steps, high enantioselectivity, high yield, high atom economy, and environmental friendliness.
[0004] To achieve the above objectives, the present invention provides the following technical solution:
[0005] This invention provides a method for synthesizing chiral dihydroquinoline spirocyclic compounds by rhodium-catalyzed asymmetric dearomatization cyclization. The method uses a chiral bisphosphine complex of rhodium and a base as the catalytic system, and alkynylquinoline salt compound 1 and arylboronic acid 2 as substrates to synthesize chiral dihydroquinoline spirocyclic compound 3 by asymmetric dearomatization cyclization.
[0006] The reaction formula is as follows:
[0007]
[0008] In the formula:
[0009] Ar is selected from phenyl, naphthyl, substituted phenyl, and thiophene-2-yl; Ar' is selected from phenyl, naphthyl, and substituted phenyl; R is selected from C1 to C2. 10The alkyl, phenyl, naphthyl, substituted phenyl, thiophene-2-yl groups; X is selected from iodine, bromine, trifluoromethanesulfonate, hexafluorophosphate, tetrafluoroborate; the substituents of the substituted phenyl groups are independently selected from C1 to C6 alkyl, halogen, methoxy, and phenyl groups;
[0010] The chiral bisphosphine ligand in the rhodium chiral bisphosphine complex is at least one of (S)-BINAP, (S)-SynPhos, (S)-DifluorPhos, (R)-(S)-JosiPhos, (R)-PhanePhos, (S)-SDP, and (S)-Xyl-SDP.
[0011] Based on the above technical solution, further, the alkali is one or more of sodium bicarbonate, sodium acetate, sodium carbonate, potassium acetate, potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide, triethylamine, and diisopropylethylamine; the molar ratio of the alkali to the alkynylquinoline salt compound 1 is 1.5:1 to 4.0:1, preferably 2.5:1.
[0012] Based on the above technical solution, the molar ratio of arylboronic acid 2 and alkynylquinoline salt compound 1 is further 1.5:1 to 4.0:1, preferably 2.5:1.
[0013] Based on the above technical solution, further, the molar ratio of the rhodium and alkynylquinoline salt compound 1 is 0.005:1 to 0.025:1, preferably 0.01:1.
[0014] Based on the above technical solution, further, the reaction temperature is 30-70℃, for example 30, 50, 70℃; the reaction time is 12-72h, preferably 18-30h, and more preferably 24h.
[0015] Based on the above technical solution, furthermore, the reaction solvent is one or more of the following: tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane (1,4-Dioxane), toluene, chlorobenzene (PhCl), trifluorotoluene (PhCF3), ethyl acetate (EtOAc), dichloromethane (DCM), 1,2-dichloroethane (DCE), methanol (MeOH), and ethanol (EtOH), preferably tetrahydrofuran, ethyl acetate, or 1,4-dioxane.
[0016] Based on the above technical solution, the chiral dihydroquinoline spirocyclic compound is further selected from one of the following 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l;
[0017]
[0018] Based on the above technical solution, the method further includes the following steps:
[0019] The rhodium precursor and chiral bisphosphine ligand were added to a solvent and stirred at room temperature for 20–60 minutes. The above system was then added to alkynylquinoline salt compound 1 and arylboronic acid 2. A base was added, and the mixture was stirred at 30–70 °C for 12–72 h. The chiral dihydroquinoline spirocyclic compound was then obtained by column chromatography.
[0020] Based on the above technical solution, further, the molar ratio of the rhodium precursor to the chiral bisphosphine ligand is 1:1 to 1:4, preferably 1:2; the molar ratio of the rhodium precursor to the alkynylquinoline salt compound 1 is 0.005:1 to 0.025:1, preferably 0.01:1.
[0021] Based on the above technical solution, further, the amount of solvent used is 0.5 to 5 mL of solvent per 0.2 mmol of alkynylquinoline salt compound 1, preferably 3 mL of solvent.
[0022] Based on the above technical solution, further, the alkynylquinoline salt compound 1 is phenyl-substituted alkynylquinoline trifluoromethanesulfonate, the arylboronic acid 2 is phenylboronic acid, the rhodium precursor is dichloro(vinyl)rhodium dimer, the chiral bisphosphine ligand is (S)-SDP, the base is sodium carbonate, the solvent is tetrahydrofuran, the reaction temperature is 50-70℃, the yield is over 97%, and the enantiomeric excess is over 98%.
[0023] Compared with the prior art, the present invention has the following advantages:
[0024] 1. The present invention has high reactivity and enantioselectivity, complete reaction, specific product, convenient separation, and can obtain pure products with high enantiomeric excess (enantiomeric excess can reach 98%).
[0025] 2. This invention can yield various types of chiral dihydroquinoline spirocyclic compounds.
[0026] 3. The catalyst of this invention is readily available, and the reaction operation is simple and practical.
[0027] 4. The cyclization reaction conditions of the present invention are mild, and the reaction can be carried out at 30°C.
[0028] 5. Compared with traditional synthesis methods, this invention can obtain a large number of chiral dihydroquinoline spirocyclic compounds with a small amount of chiral catalyst, achieving chiral enhancement. Moreover, the reaction steps are short, and chiral dihydroquinoline spirocyclic compounds with diverse structures can be synthesized in a single step with high yield and a wide range of substrates. Detailed Implementation
[0029] The present invention is described in detail below through embodiments; however, the present invention is not limited to the embodiments described below.
[0030] The synthesis of the substituted alkynylquinoline trifluoromethanesulfonate in the examples is described in references Robinson, DJ; Spurlin, SP; Gorden, JD; Karimov, RRACS Catal. 2020, 10, 51;
[0031] In the examples, the chiral bisphosphine ligands were purchased from Strem or Leyen.
[0032] Example 1: Condition Optimization
[0033] Weighed dichlorovinylrhodium dimer (1 mol%, 0.001 mmol) and chiral bisphosphine ligand L* (2 mol%, 0.002 mmol) were added to an ampoule. The mixture was stirred at room temperature for 30 minutes with 0.5 mL of solvent. The mixture was then rinsed with 1.0 mL of solvent into a 15 mL sealed tube containing phenyl-substituted alkynylquinoline trifluoromethanesulfonate 1a (0.1 mmol) and phenylboronic acid 2a (0.25 mmol). A base (2.5 equivalents, 0.25 mmol) was added. The tube was then sealed and reacted at 30–70 °C for 24 hours. After cooling to room temperature, the solvent was removed by rotary evaporation, and the product was directly separated by column chromatography (eluent: petroleum ether, ethyl acetate, volume ratio 20:1) to obtain the pure product. The structure and reaction formula of chiral bisphosphine ligand L* are as follows:
[0034]
[0035] The yield was NMR yield, and the enantiomeric excess (ee value) of the product was determined by chiral liquid chromatography. The reaction conditions and results are shown in Table 1.
[0036] Table 1. Screening of chiral ligands, solvents, bases, and reaction temperatures
[0037]
[0038]
[0039] Based on the yields and enantiomeric excess results of dihydroquinoline spirocyclic compounds in Experiments 1-4, the preferred chiral bisphosphine ligands are L1, L3, and L4, with L4 being particularly preferred. Based on the yields and enantiomeric excess results of dihydroquinoline spirocyclic compounds in Experiments 4-8, the preferred bases are K2CO3, Na2CO3, NaHCO3, and Et3N, with K2CO3, Na2CO3, and Et3N being particularly preferred. Based on the yields and enantiomeric excess results of dihydroquinoline spirocyclic compounds in Experiments 4, 9-13, the preferred organic solvents are THF, Dioxane, Toluene, EtOAc, and DCE. Based on the yields and enantiomeric excess results of dihydroquinoline spirocyclic compounds in Experiments 4, 14-15, the preferred reaction temperature is 30–70 °C.
[0040] Example 2: Rhodium-catalyzed asymmetric dearomatization cyclization of alkynylquinoline trifluoromethanesulfonate with arylboronic acid to synthesize chiral dihydroquinoline spirocyclic compounds.
[0041] Weighed dichlorovinylrhodium dimer (1 mol%, 0.002 mmol) and chiral bisphosphine ligand (S)-SDP (2 mol%, 0.004 mmol) were added to an ampoule. 1.0 mL of tetrahydrofuran was added and stirred for 30 minutes. The system was then rinsed with 2.0 mL of tetrahydrofuran into a 15 mL sealed tube containing substituted alkynylquinoline trifluoromethanesulfonate 1 (0.2 mmol) and arylboronic acid 2 (0.5 mmol). Sodium carbonate (2.5 equivalents, 0.5 mmol) was added. The tube was then sealed and reacted at 50 °C for 24 hours. After cooling to room temperature, the solvent was removed by rotary evaporation, followed by direct column chromatography (eluent: petroleum ether, ethyl acetate, volume ratio 20:1) to obtain the pure product. The reaction equation and experimental results are as follows:
[0042]
[0043] The yield was the separation yield, and the enantiomeric excess of the product was determined by chiral liquid chromatography.
[0044] This invention synthesizes chiral dihydroquinoline spirocyclic compounds via rhodium-catalyzed asymmetric dearomatization cyclization of alkynylquinoline trifluoromethanesulfonate and arylboronic acid, achieving an enantiomeric excess of up to 98%. This invention is simple and practical, with short reaction steps, high enantioselectivity, good yield, and advantages such as atom economy and environmental friendliness.
[0045] The chiral dihydroquinoline spirocyclic compound prepared in the above embodiments has a chiral dihydroquinoline spirocyclic structure as its core skeleton. Currently, the existing effective tumor inhibitor, chiral tetrahydroquinoline spiroindolineone, has a chiral dihydroquinoline spirocyclic structure as its core skeleton. Therefore, the chiral dihydroquinoline spirocyclic compound prepared in the embodiments of the present invention has the potential to be used to prepare tumor inhibitors.
[0046] The characterization data of the compounds in the examples are as follows:
[0047] (+)-(S,E)-4-Benzylidene-1'-methyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinolin
[0048] 6.59(t,J=7.3Hz,1H),6.47(d,J=8.2Hz,1H),6.23(d,J=9.8Hz,1H),5.69(d,J=9.9Hz,1H),2.95(dt,J=14. 7,4.2Hz,1H),2.78-2.68(m,1H),2.55(s,3H),2.25(dt,J=13.0,4.3Hz,1H),2.13(td,J=13.1,4.1Hz,1H). 13 C NMR (100MHz, CDCl3) δ145.0,142.5,137.9,136.7,135.8,129.8,129.6,129.5,128.9,128.4,128.4,12 7.3,126.9,126.8,124.6,124.5,122.2,120.1,116.2,109.7,63.6,35.0,33.6,23.9.HPLC: Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol=98 / 2, flow=0.8mL / min, retention time 9.1min(major)and 9.5min.HRMS Calculated for C 26 H 24 N[M+H] + 350.1903, found: 350.1901.
[0049] (+)-(E)-4-Benzylidene-1',7-dimethyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3b): 70.3 mg, 97% yield, colorless oily liquid, new compound, R f =0.65 (petroleum ether / ethyl acetate)
[0050] 14.8,4.3Hz,1H),2.78-2.69(m,1H),2.57(s,3H),2.33(s,3H),2.24(dt,J=12.8,4.3Hz,1H),2.12(td,J=13.1,4.1Hz,1H). 13 C NMR (100MHz, CDCl3) δ145.0,142.4,138.4,138.1,136.7,133.2,130.2,129.6,129.5,129.1,128.4,128. 4,126.9,126.7,124.6,123.6,122.2,120.2,116.1,109.7,63.6,34.8,33.7,23.8,21.5.HPLC: Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol=98 / 2, flow=0.8mL / min, retention time 8.2min (major) and 8.6min.HRMS Calculated for C 27 H 26 N[M+H] + 364.2060, found: 364.2059.
[0051] (+)-(E)-4-Benzylidene-1',6-dimethyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3c): 69.1 mg, 95% yield, colorless oily liquid, new compound, R f =0.65 (petroleum ether / ethyl acetate) 2.99(dt,J=14.7,4.2Hz,1H),2.82-2.72(m,1H),2.60(s,3H),2.42(s,3H),2.29(dt,J=13.0,4.2Hz,1H),2.17(td,J=13.1,4.1Hz,1H). 13C NMR (100MHz, CDCl3) δ145.1,139.8,138.0,136.9,135.6,129.8,129.5,129.5,129.5,129.0,128.4,1 26.8,126.8,124.9,124.3,122.1,120.1,116.1,109.6,63.3,35.2,33.5,23.9,21.4.HPLC: Chiralpak AD-Hcolumn, 254nm, 30℃, n-hexane / isopropanol=98 / 2, flow=0.8mL / min, retention time 7.5min (major) and 8.6min.HRMS Calculated for C 27 H 26 N[M+H] + 364.2060, found: 364.2068.
[0052] (-)-(E)-4-Benzylidene-1',5-dimethyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3d): 44.5 mg, 61% yield, colorless oily liquid, new compound, R f =0.60 (petroleum ether / ethyl acetate)
[0053] 2.76-2.68(m,1H),2.66(s,3H),2.61(s,3H),2.39-2.21(m,2H). 13 C10 NMR (100MHz, CDCl3) δ 145.0, 143.9, 137.9, 137.0, 136.6, 134.5, 130.6, 129.9, 129.5, 129.2, 129.1, 128.4, 127.2, 127.0, 126.8, 121.5, 119.9, 116.0, 109.3, 64.2, 37.3, 33.6, 25.4, 22.5. HPLC: Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol = 98 / 2, flow = 0.8mL / min, retention time 7.3min and 9.1min (major). HRMS calculated for C10 NMR. 27 H 26 N[M+H] + 364.2060, found: 364.2069.
[0054] (+)-(E)-4-Benzylidene-1',6'-dimethyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3e): 69.0 mg, 95% yield, pale yellow oily liquid, novel compound, R f =0.70 (petroleum ether / ethyl acetate)
[0055] 2.94(dt,J=14.7,4.2Hz,1H),2.78-2.68(m,1H),2.53(s,3H),2.28-2.18(m,4H),2.12(td,J=13.1,4.1Hz,1H). 13 C10 NMR (100MHz, CDCl3) δ 142.9, 142.6, 138.0, 136.8, 135.9, 129.9, 129.8, 129.5, 129.3, 128.4, 127.6, 127.3, 126.8, 125.2, 124.6, 124.5, 122.3, 120.2, 109.8, 63.4, 34.4, 33.6, 23.9, 20.3. HPLC: Chiralcel OD-H column, 254nm, 30℃, n-hexane / isopropanol = 98 / 2, flow = 0.8mL / min, retention time 6.5min (major) and 7.4min. HRMS calculated for C10 NMR. 27 H 26 N[M+H] + 364.2060, found: 364.2061.
[0056] (+)-(E)-4-Benzylidene-6'-methoxy-1'-methyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3f): 73.2 mg, 96% yield, yellow oily liquid, new compound, R f =0.65 (petroleum ether / ethyl acetate)
[0057] Hz,1H),6.27(d,J=9.8Hz,1H),5.80(d,J=9.8Hz,1H),3.80(s,3H),2.99(dt,J=14.8,4.4Hz,1H),2.78(ddd d,J=14.9,12.9,4.3,2.1Hz,1H),2.58(s,3H),2.25(dt,J=13.0,4.4Hz,1H),2.16(td,J=13.0,4.1Hz,1H). 13 C10 NMR (100MHz, CDCl3) δ 151.2, 142.4, 139.6, 137.9, 136.8, 136.0, 130.7, 129.7, 129.5, 128.4, 128.3, 127.3, 126.8, 124.6, 124.5, 122.2, 121.3, 114.3, 113.1, 110.5, 63.2, 56.0, 33.8, 33.7, 23.9. HPLC: Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol = 90 / 10, flow = 0.8mL / min, retention time 10.4min (major) and 11.3min. HRMS Calculated for C10 NMR. 27 H 26 NO[M+H] + 380.2009, found: 380.2003.
[0058] (+)-(E)-1'-Methyl-4-(4-methylbenzylidene)-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3g): 69.9mg, 96% yield, white solid, melting range 40-41℃, new compound, R f =0.60
[0059]
[0060] 145.1, 142.4, 136.6, 136.0, 135.9, 135.0, 129.8, 129.6, 129.4, 129.1, 128.9, 128.3, 127.3, 126.9, 124.6, 124.5, 122.2, 120.1, 116.2, 109.7, 63.6, 34.9, 33.6, 23.9, 21.4. HPLC: Chiralcel OD-3 column, 254 nm, 30 °C, n-hexane / isopropanol = 99 / 1, flow = 0.6 mL / min, retention time 11.7 min and 14.8 min (major). HRMS Calculated for C 27 H 26 N[M + H] + 364.2060, found: 364.2069.
[0061] (+)-(E)-1'-Methyl-4-(3-methylbenzylidene)-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-
[0062]
[0063] 2.79 - 2.69 (m, 1H), 2.56 (s, 3H), 2.38 (s, 3H), 2.26 (dt, J = 12.9, 4.2 Hz, 1H), 2.14 (td, J = 13.1, 4.1 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 145.1, 142.5, 137.9, 137.9, 136.6, 135.9, 130.2, 129.8, 129.6, 128.9, 128.4, 128.3, 127.6, 127.3, 126.9, 126.5, 124.6, 124.6, 122.2, 120.1, 116.2, 109.7, 63.6, 35.0, 33.6, 23.9, 21.6. HPLC: Chiralcel OD-3 column, 254 nm, 30 °C, n-hexane / isopropanol = 99 / 1, flow = 0.6 mL / min, retention time 10.3 min (major) and 11.0 min. HRMS Calculated for C 27 H 26 N[M + H] + 364.2060, found: 364.2058.
[0064] (+)-(E)-1'-Methyl-4-(2-methylbenzylidene)-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3i): 66.3 mg, 91% yield, white solid, melting range 127-128 °C, new compound, R f =0.60 (petroleum ether / ethyl acetate 50 / 1), 95% ee, [α] 20 D = +125.34 (c 0.57, CHCl3). 1 H NMR (400MHz, 136.7, 135.8, 130.1, 130.0, 129.6, 129.4, 129.0, 128.4, 127.3, 127.2, 126.9, 125.6, 124.5, 123.4, 122.1, 120.1, 116.2, 109.6, 63.7, 35.3, 33.6, 23.9, 20.3. HPLC: Chirapak AD-3 column, 254 nm, 30 °C, n-hexane / isopropanol = 99 / 1, flow = 0.6 mL / min, retention time 13.0 min and 16.6 (major) min. HRMS calculated for C 27 H 26 N[M+H] + 364.2060, found: 364.2057.
[0065] (+)-(E)-4-(4-Chlorobenzylidene)-1'-methyl-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3j): 69.7 mg, 91% yield, white solid, melting range 53-54 °C, new compound, R f =0.60 (petroleum ether / ethyl acetate 50 / 1), 98% ee, [α] 20 D = +158.34 (c 1.27, CHCl3). 1 H
[0066] 130.7, 129.8, 129.6, 128.7, 128.6, 128.5, 127.4, 126.9, 124.6, 123.2, 122.4, 120.1, 116.3, 109.7, 63.5, 34.8, 33.6, 23.8. HPLC: Chiralpak AS-H + Chiralpak AS-H column, 254 nm, 30 °C, n-hexane / isopropanol = 99 / 1, flow = 0.6 mL / min, retention time 21.2 min (minor) and 22.1 min (major). HRMS Calculated for C 26 H 23 ClN[M + H] + 384.1514( 35 Cl) and 386.1495( 37 Cl), found: 384.1519( 35 Cl) and 386.1490( 37 Cl).
[0067] 1H), 3.81 (s, 3H), 2.94 (dt, J = 14.8, 4.2 Hz, 1H), 2.78 - 2.68 (m, 1H), 2.55 (s, 3H), 2.24 (dt, J = 13.0, 4.2 Hz, 1H), 2.13 (td, J = 13.1, 4.2 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 158.5, 145.1, 142.3, 136.0, 135.2, 130.7, 130.5, 129.7, 129.6, 128.9, 128.1, 127.3, 126.9, 124.5, 124.2, 122.2, 120.1, 116.1, 113.8, 109.6, 63.6, 55.4, 34.9, 33.6, 23.8. The HPLC: Chiralcel OD-3 column, 254 nm, 30 °C, n-hexane / isopropanol = 99 / 1, flow = 0.6 mL / min, retention time 12.2 min (major) and 13.7 min. HRMS Calculated for C 27 H 26 NO[M + H] + 380.2009, found: 380.2009.
[0068] (+)-(E)-1'-Methyl-4-(thiophen-2-ylmethylene)-3,4-dihydro-1'H,2H-spiro[naphthalene-1,2'-quinoline](3l): 58.3 mg, 82% yield, white solid, melting range 45-46 °C, new compound, R f =0.60(hexanes / ethyl acetate 50 / 1),97%ee,[α] 20 D = +128.24 (c 0.98, CHCl3). 1 HNMR (400MHz, CDCl3) δ 145.1, 142.5, 141.2, 135.4, 133.9, 129.6, 129.2, 128.3, 128.1, 127.9, 127.3, 127.2, 126.9, 125.8, 124.2, 122.8, 120.1, 118.1, 116.3, 109.7, 63.4, 33.6, 33.5, 24.1. HPLC: Chiralcel OD-H + Chiralpak AD-H column, 254nm, 30℃, n-hexane / isopropanol = 95 / 5, flow = 1.0mL / min, retention time 14.0min (major) and 16.6min. HRMS Calculated for C 24 H 22 NS[M+H] + 356.1467, found: 356.1468.
[0069] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; modifications or equivalent substitutions may be made to the technical solutions described in the foregoing embodiments, and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for synthesizing chiral dihydroquinoline spirocyclic compounds by rhodium-catalyzed asymmetric dearomatization cyclization, characterized in that, Using a rhodium chiral bisphosphine complex and a base as a catalytic system, and alkynylquinoline salt compound 1 and arylboronic acid 2 as substrates, a chiral dihydroquinoline spirocyclic compound 3 was synthesized. The reaction formula is as follows: In the formula: Ar is selected from phenyl, naphthyl, substituted phenyl, and thiophene-2-yl; Ar' is selected from phenyl, naphthyl, and substituted phenyl; R is selected from C1 to C2. 10 The alkyl, phenyl, naphthyl, substituted phenyl, thiophene-2-yl groups; X is selected from iodine, bromine, trifluoromethanesulfonate, hexafluorophosphate, tetrafluoroborate; the substituents of the substituted phenyl groups are independently selected from C1 to C6 alkyl, halogen, methoxy, and phenyl groups; The chiral bisphosphine ligand in the rhodium chiral bisphosphine complex is at least one of (S)-BINAP, (S)-SynPhos, (S)-DifluorPhos, (R)-(S)-JosiPhos, (R)-PhanePhos, (S)-SDP, and (S)-Xyl-SDP.
2. The method as described in claim 1, characterized in that, The alkali is one or more of sodium bicarbonate, sodium acetate, sodium carbonate, potassium acetate, potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide, triethylamine, and diisopropylethylamine; the molar ratio of the alkali to the alkynylquinoline salt compound 1 is 1.5:1 to 4.0:1, preferably 2.5:
1.
3. The method as described in claim 1, characterized in that, The molar ratio of arylboronic acid 2 to alkynylquinoline salt compound 1 is 1.5:1 to 4.0:1, preferably 2.5:1; the molar ratio of rhodium to alkynylquinoline salt compound 1 is 0.005:1 to 0.025:1, preferably 0.01:
1.
4. The method as described in claim 1, characterized in that, The reaction temperature is 30–70°C; the reaction time is 12–72 h, preferably 18–30 h, and more preferably 24 h.
5. The method as described in claim 1, characterized in that, The reaction solvent is one or more of the following: tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane (1,4-Dioxane), toluene, chlorobenzene (PhCl), trifluorotoluene (PhCF3), ethyl acetate (EtOAc), dichloromethane (DCM), 1,2-dichloroethane (DCE), methanol (MeOH), and ethanol (EtOH), preferably tetrahydrofuran, ethyl acetate, or 1,4-dioxane.
6. The method as described in claim 1, characterized in that, The chiral dihydroquinoline spirocyclic compound is selected from one of the following 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l; 7. The method according to any one of claims 1-6, characterized in that, The method includes the following steps: The rhodium precursor and chiral bisphosphine ligand were added to a solvent and stirred at room temperature for 20–60 minutes. The above system was then added to alkynylquinoline salt compound 1 and arylboronic acid 2. A base was added, and the mixture was stirred at 30–70 °C for 12–72 h. The chiral dihydroquinoline spirocyclic compound was then obtained by column chromatography.
8. The method as described in claim 7, characterized in that, The molar ratio of the rhodium precursor to the chiral bisphosphine ligand is 1:1 to 1:4, preferably 1:2; the molar ratio of the rhodium precursor to the alkynylquinoline salt compound 1 is 0.005:1 to 0.025:1, preferably 0.01:
1.
9. The method as described in claim 7, characterized in that, The amount of solvent used is 0.5 to 5 mL of solvent per 0.2 mmol of alkynylquinoline salt compound 1, preferably 3 mL of solvent.
10. The method as described in claim 7, characterized in that, The alkynylquinoline salt compound 1 is a phenyl-substituted alkynylquinoline trifluoromethanesulfonate, the arylboronic acid 2 is phenylboronic acid, the rhodium precursor is dichloro(vinyl)rhodium dimer, the chiral bisphosphine ligand is (S)-SDP, the base is sodium carbonate, the solvent is tetrahydrofuran, the reaction temperature is 50-70℃, the yield is over 97%, and the enantiomeric excess is over 98%.