A method for synthesizing tetrahydroquinoline compounds having CB bonds

Abstract

The invention discloses a method for synthesizing a tetrahydroquinoline compound with a C-B bond, comprising the following steps: mixing an Rh-type catalyst, a phosphorus ligand or an NHC ligand and a solvent, adding borane, quinoline or a derivative thereof, reacting, cooling to 0-5°C, adding an acylating agent and a base, warming to room temperature, reacting again, and obtaining a tetrahydroquinoline compound with a C-B bond. The synthetic method of the present invention is a two-step one-pot method, using metal Rh as a catalyst, and in the absence of the need for pre-substrate activation, performing two dearomatization reduction reactions of quinoline with high chemical selectivity, high regio- and stereoselectivity under mild conditions, and realizing two hydroborations of quinoline in one step, and obtaining a tetrahydroquinoline compound with a C-B bond. The substrate of the method is widely applicable, and the functional group has good tolerance, and the corresponding tetrahydroquinoline compound containing a chiral C-B bond can be obtained by using a chiral ligand.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing a tetrahydroquinoline compound with a CB bond. Background Art

[0002] Nitrogen heterocyclic substances represented by pyridine and quinoline are abundant in nature and diverse in variety. Due to their special chemical properties and biological activities, nitrogen heterocyclic substances are widely used in fields such as chemistry and pharmacy, especially the reductive dearomatization products of pyridine and its derivatives, such as dihydropyridine, dihydroquinoline, and tetrahydroquinoline, which are widely concerned by researchers as important intermediates and organic reducing agents for the synthesis of natural products and drugs. For example, 1,2-dihydropyridine is used as a starting material in the synthesis of the antiviral drug oseltamivir; 1,4-dihydropyridine is used as a calcium channel blocker and as a synthetic module for drugs for the treatment of hypertension, coronary heart disease, Alzheimer's disease, cancer and other diseases. Most existing studies focus on obtaining dearomatous dihydroquinoline rings through a one-step reduction reaction using borane or silane, and the double bonds of the resulting dihydroquinoline can be further chemically transformed. A few research groups have successfully achieved the synthesis of tetrahydroquinolines with (chiral) CX molecules using a step-by-step approach, involving 1,2-dearomatization of quinoline followed by (enantioselective) hydrogenation functionalization of the 1,2-dihydro intermediate under metal (Cu, Ni) catalysis. Although this step-by-step reaction strategy enables the installation of various functional groups at the 3 or 4 position, a large amount of salt waste is generated during the two-step synthesis, and the reaction intermediates in the first step are unstable and difficult to store. Using tri(pentafluorophenyl)borane (BCF) as a catalyst can achieve a one-pot method to obtain a two-step reduction product, but the reaction has the following defects: 1. BCF as a catalyst has poor tolerance to functional groups. For example, substrates containing ether groups, ester groups and fluorine groups are not suitable for this catalytic system; 2. Chirality control cannot be achieved. The structural characteristics of BCF in the BCF reaction system and the reaction mechanism are Out-sphere, which determines that it is impossible to introduce chiral inducing factors to perform asymmetric reactions to obtain chiral products; 3. The reaction temperature is high and the energy consumption is high. The reaction temperature of hydrosilation needs to reach 100°C, and the temperature of hydroboration needs to reach 85°C.

[0003] Prior art (paper) references:

[0004] a

[0005]

[0006] b

[0007]

[0008] c

[0009]

[0010] (1)E.Kim,HJJeon,S.Park,S.Chang,Adv.Synth.Catal.2020,362,308-313.

[0011] (2)N.Gandhamsetty,S.Park,S.Chang,J.Am.Chem.Soc.2015,137,15176-15184.

[0012] (3)H.Ito, et al.J.Am.Chem.Soc.2016,138,4338-4341.

[0013] (4)H.Ito,et al.Adv.Synth.Catal.2016,358,2379-2384.

[0014] (5)J.Zhang, et al.J.Org.Chem.2018,83,1924-1932.

[0015] (6)S.-L.You,et al.Org.Lett.2019,21,5357-5362.

[0016] (7)S.-L.You,et al.Org.Lett.2020,22,1530-1534.

[0017] (8)X.Fang,et al.Org.Lett.2020,22,8566-8571. Summary of the invention

[0018] The primary purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art and provide a method for synthesizing a tetrahydroquinoline compound having a CB bond. The synthesis method of the present invention is a two-step one-pot method, using Rh as a catalyst, and performing two dearomatization reduction reactions of quinoline with high chemical selectivity, high regio- and stereoselectivity under mild conditions without the need for pre-activation of the substrate, and achieving two hydroborations of quinoline in one step to obtain a tetrahydroquinoline compound having a CB bond. The reaction substrate of the method is widely applicable, has good functional group tolerance, and can obtain the corresponding tetrahydroquinoline compound containing a chiral CB bond by using a chiral ligand.

[0019] The object of the present invention is achieved by the following technical scheme: a method for synthesizing a tetrahydroquinoline compound with a CB bond, comprising the following steps: mixing an Rh-type catalyst, a phosphorus ligand or an NHC ligand and a solvent, then adding borane, quinoline or a derivative thereof, reacting to obtain a two-step hydroboration product, cooling to 0-5°C, adding an acylating agent and a base, heating to room temperature, reacting again, washing with water, and purifying to obtain a tetrahydroquinoline compound with a CB bond.

[0020] The specific synthetic route of the synthetic method is as follows:

[0021]

[0022] Wherein, R is a saturated alkane group substituted at position 2; R' is a mono- or di-substituted alkane group, halogen, ester group, or oxyalkane at positions 6 and 7; and R" is a benzoyl group, a tert-butyloxycarbonyl group, an acetyl group, or a chloroacetyl group.

[0023] Preferably, the synthesis of the tetrahydroquinoline compound is carried out under nitrogen protection.

[0024] Preferably, the amount of the Rh-based catalyst is 1%-5% of the molar amount of quinoline or its derivatives.

[0025] Preferably, the phosphorus ligand or NHC ligand is used in an amount of 2% to 10% of the molar amount of quinoline or its derivatives.

[0026] Preferably, the solvent is a non-polar solvent, such as toluene, benzene, and n-hexane; more preferably, an oxygen-containing polar solvent, such as tetrahydrofuran and 1,4-epoxyhexacyclo, is added to the non-polar solvent; most preferably, the volume ratio of the non-polar and polar solvents is 4-8:1.

[0027] Preferably, the concentration of quinoline or its derivatives in the reaction system is 0.3-1 mol / l.

[0028] Preferably, the mixing is stirring for 5-30 min.

[0029] Preferably, the borane is pinacol borane (HBpin).

[0030] Preferably, the base is triethylamine.

[0031] Preferably, the molar ratio of borane, quinoline or its derivative, acylating agent and base is 2-5:1:1-3:1-5.

[0032] Preferably, the reaction is carried out at 25-50°C for 24-72h.

[0033] Preferably, the second reaction is carried out at room temperature for 12-24 hours.

[0034] Preferably, the purification is carried out by suction filtration followed by recrystallization or column chromatography.

[0035] Preferably, the eluent used in the column chromatography is ethyl acetate / n-hexane or dichloromethane / methanol; more preferably, the volume ratio of ethyl acetate / n-hexane is 2-4:1; the volume ratio of dichloromethane / methanol is 90-99:1-10.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] 1. The synthesis method of the present invention is a two-step one-pot method. Without the need for pre-activation of the substrate, Rh is used as a catalyst to carry out two dearomatization reduction reactions, and two hydroborations of quinoline are achieved in one step to obtain a tetrahydroquinoline compound with a CB bond at the C-4 position. The reaction conditions are mild and can be carried out at room temperature.

[0038] 2. The reaction product obtained by the synthesis method of the present invention is a brand-new product. The CB bond in the product structure can be easily chemically reacted to be converted into more than a dozen other groups such as -COOH, -F, -OH, -NH2, etc. The variability of this structure will make the substrate of great significance in the synthesis of known drugs and the research and development of new drug structures, which can greatly reduce the reaction steps and conveniently and quickly carry out the modification of the active molecular structure.

[0039] 3. The synthesis method of the present invention can achieve chirality control by using chiral ligands to control the reaction, thereby obtaining tetrahydroquinoline compounds containing chiral CB bonds, and the next step of chemical transformation can be carried out while maintaining the chirality.

[0040] 4. The synthetic method of the present invention has good functional group tolerance, and substrates containing ether groups, ester groups and fluorine groups are suitable for this synthetic method.

[0041] 5. The synthesis method of the present invention has high regio- and stereo-selectivity, and all products are 4-CB bond products. When 2-methylquinoline is used as the substrate, dr>96%. DETAILED DESCRIPTION

[0042] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0043] Example 1

[0044] Under nitrogen protection, 42 mg of Rh(COD)2OTf catalyst and 48 mg of triphenylphosphine were weighed in a reactor, 12 mL of anhydrous toluene was added and stirred for 5 min, then 3.9 mL of HBpin and 1.07 mL of quinoline were added, and the reaction was carried out at 25°C for 36 h. After the reaction was completed, the temperature was lowered to 0°C, 2.1 g of p-nitrobenzoyl chloride and 3 mL of triethylamine were added, and the temperature was slowly raised to 25°C for 24 h. After washing with water, column chromatography (eluent ethyl acetate / n-hexane, volume ratio = 4 / 1) was performed to obtain 3 g of tetrahydroquinoline compounds with a CB bond at the C-4 position, with a yield of 80%. The structural formula of the tetrahydroquinoline compound is:

[0045]

[0046] The same experimental method was used, and chiral S-Binap was used as a ligand to obtain a tetrahydroquinoline compound containing chirality and a CB bond at the C-4 position, with a yield of 75% and 80% ee. (Column chromatography conditions: chromatographic column ECOSIL Chiral CAD-H 5u 250×4.6mm; mobile phase: n-hexane / isopropanol=90 / 10, flow rate 1ml / min, peak elution time: secondary peak 11.31min, main peak 13.90min.)

[0047] 1 H NMR(400MHz, CDCl3)δ8.08(d,J=8.7Hz,2H),7.70–7.62(m,2H),7.19(dd,J=7.6, 1.5Hz,1H),7.02(td,J=7.5,1.2Hz,1H),6.78(t,J=7.6Hz,1H),6.38(s,1H),4.3 0–4.18(m,1H),3.62(ddd,J=12.8,7.0,4.0Hz,1H),2.66(t,J=5.1Hz,1H),2.47– 2.35(m,1H),1.95(dddd,J=12.9,9.6,7.0,5.8Hz,1H),1.21(d,J=4.5Hz,12H).. 13 C NMR (101MHz, CDCl3) δ167.70,148.35,142.43,137.79,130.24,128.04,125.93,125.55,125.37,123.09,84.14,44.28,26.39,25.08,24.58.

[0048] Example 2

[0049] Under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of triphenylphosphine were weighed in a reactor, 0.5 mL of anhydrous toluene was added and stirred for 5 min, then 128 uL of HBpin and 49 mg of 7-chloroquinoline were added, and the reaction was carried out at 25°C for 24 h. After the reaction was completed, the temperature was lowered to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine were added, and the temperature was slowly raised to 25°C for 24 h. After washing with water, column chromatography (eluent ethyl acetate / n-hexane, volume ratio = 4 / 1) was performed to obtain 103 mg of tetrahydroquinoline compounds with a CB bond at the C-4 position, with a yield of 78%. The structural formula of the tetrahydroquinoline compound is:

[0050]

[0051] The same experimental method was used, and chiral S-Binap was used as a ligand to obtain tetrahydroquinoline compounds containing chiral C-4 CB bonds, with a yield of 70% and 72% ee. (Column chromatography conditions: chromatographic column ECOSIL Chiral CAD-H 5u 250×4.6mm; mobile phase: n-hexane / isopropanol = 90 / 10, flow rate 1ml / min, peak elution time: secondary peak 11.01min, main peak 13.61min.)

[0052] 1 H NMR (400MHz, CDCl3) δ7.61–7.52(m,2H),7.52–7.37(m,1H),7.37–7.30(m,2H ),6.84(dd,J=8.6,2.5Hz,1H),6.59–6.52(m,1H),4.23(ddd,J=12.8,9.6,7. 0Hz, 1H), 3.71 (ddd, J=12.8, 6.8, 4.1Hz, 1H), 2.68 (t, J=5.1Hz, 1H), 2.51–2. 39(m,1H),1.99(dddd,J=12.8,9.6,6.8,5.7Hz,1H),1.30(d,J=1.6Hz,12H). 13 C NMR (101MHz, CDCl3) δ170.08,137.35,136.78,135.80,130.29,129.83,12 9.11,128.01,127.74,126.95,125.21,84.19,44.32,26.29,25.06,24.51.

[0053] Example 3

[0054] Under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of triphenylphosphine were weighed in a reactor, 0.5 mL of anhydrous toluene was added and stirred for 5 min, then 128 uL of HBpin and 44 mg of 6-fluoroquinoline were added, and the reaction was carried out at 25°C for 24 h. After the reaction was completed, the temperature was lowered to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine were added, and the temperature was slowly raised to 25°C for 24 h. After washing with water, column chromatography (eluent ethyl acetate / n-hexane, volume ratio = 4 / 1) was performed to obtain 90 mg of tetrahydroquinoline compounds with a CB bond at the C-4 position, with a yield of 70%. The structural formula of the tetrahydroquinoline compound is:

[0055]

[0056] The same experimental method was used, and chiral S-Binap was used as a ligand to obtain a tetrahydroquinoline compound containing a chiral C-4 CB bond with a yield of 55% and 39% ee. (Column chromatography conditions: chromatographic column OXH0CE-PB001, 0.46cm ID×25cm L×5μmn; mobile phase: n-hexane / ethanol / ethylenediamine=90 / 10 / 0.05 (v / v / v); flow rate 1ml / min; peak time: secondary peak 5.73min, main peak 6.21min. )

[0057] 1 H NMR (400MHz, CDCl3) δ8.10(d,J=8.4Hz,2H),7.69–7.61(m,2H),6.93(dd,J=8.8,2.8Hz,1H),6.67–5.94(m,2H),4.22(s,1H),3.59( dddd,J=12.9,6.9,4.0Hz,1H),2.63(t,J=5.1Hz,1H),2.39(s,1H),1.93(dddd,J=13.0,9.5,7.0,5.8Hz,1H),1.21(d,J=4.8Hz,12H). 13 C NMR (101MHz, CDCl3) δ167.54,161.33,158.89,148.42,142.14,133.81,130.15,127.06 ,126.98,123.21,114.94,114.72,112.43,112.20,84.33,44.16,26.18,25.10,24.55. 19 F NMR (377MHz,CDCl3)δ-116.39.

[0058] Example 4

[0059] Under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of triphenylphosphine were weighed into a reactor, 0.5 mL of anhydrous toluene was added and stirred for 5 min, then 128 uL of HBpin and 56 mg of 6-carboxymethylquinoline were added, and the reaction was carried out at 25°C for 24 h. After the reaction was completed, the temperature was lowered to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine were added, and the temperature was slowly raised to 25°C for 24 h. After washing with water, column chromatography (eluent ethyl acetate / n-hexane, volume ratio = 4 / 1) was performed to obtain 89 mg of tetrahydroquinoline compounds with a CB bond at the C-4 position, with a yield of 68%. The structural formula of the tetrahydroquinoline compound is:

[0060]

[0061] The same experimental method was used, and chiral S-Binap was used as a ligand to obtain tetrahydroquinoline compounds containing chiral C-4 CB bonds, with a yield of 70% and 77% ee. (Column chromatography conditions: chromatographic column ECOSIL Chiral CAD-H 5u 250×4.6mm; mobile phase n-hexane / isopropanol = 90 / 10, flow rate 1ml / min, peak elution time: secondary peak 22.04min, main peak 23.41min.)

[0062] 1 H NMR (400MHz, CDCl3) δ7.91(d,J=2.0Hz,2H),7.37(d,J=7.5Hz,2H),7.32–7.24(m,2H),6.60(d,J=8.4Hz,1H),4.17(ddd,J=12.8,9.9,7.0Hz,1H),3.89( s,3H),3.80–3.70(m,1H),2.73(t,J=5.0Hz,1H),2.44(ddt,J=13.2,7.0,4. 1Hz,1H),1.95(dddd,J=12.7,9.9,6.8,5.5Hz,1H),1.25(d,J=1.3Hz,11H). 13 CNMR(101MHz,CDCl3)δ170.48,166.89,143.09,135.70,134.88,130.51,129.34,1 29.17,128.05,126.56,125.80,125.58,84.16,52.01,44.64,26.24,25.05,24.52.

[0063] Example 5

[0064] Under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of triphenylphosphine were weighed into a reactor, 0.5 mL of anhydrous toluene was added and stirred for 5 min, then 128 uL of HBpin and 35.5 uL of 7-methoxyquinoline were added, and the reaction was carried out at 25°C for 24 h. After the reaction was completed, the temperature was lowered to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine were added, and the temperature was slowly raised to 25°C for 24 h. After washing with water, column chromatography (eluent ethyl acetate / n-hexane, volume ratio = 4 / 1) was performed to obtain 86 mg of tetrahydroquinoline compounds with a CB bond at the C-4 position, with a yield of 70%. The structural formula of the tetrahydroquinoline compound is:

[0065]

[0066] The same experimental method was used, and chiral S-Binap was used as a ligand to obtain tetrahydroquinoline compounds containing chiral C-4 CB bonds, with a yield of 40% and 80% ee. (Column chromatography conditions: chromatographic column ECOSIL Chiral CAD-H 5u 250×4.6mm; mobile phase: n-hexane / isopropanol = 90 / 10, flow rate 1ml / min, peak time: main peak 17.46min secondary peak 21.06min.)

[0067] 1 H NMR (400MHz, CDCl3) δ8.08(d,J=8.4Hz,2H),7.69–7.61(m,2H),6.74(d,J=2.6Hz,1H),6.46–6.01(m,2H),4.24(s,1H),3.73(s,3H),3. 57(ddd,J=12.8,7.1,3.9Hz,1H),2.60(t,J=5.1Hz,1H),2.39(s,1H),1.92(dddd,J=12.9,9.5,7.1,5.7Hz,1H),1.21(d,J=4.9Hz,12H). 13 C NMR (101MHz, CDCl3) δ167.31,157.20,148.24,142.61,130.87,130.25,12 6.75,123.07,113.19,110.69,84.16,55.33,44.08,26.32,25.10,24.59.

[0068] Example 6

[0069] Under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of triphenylphosphine were weighed in a reactor, 0.5 mL of anhydrous toluene was added and stirred for 5 min, then 128 uL of HBpin and 43 mg of 7-methylquinoline were added, and the reaction was carried out at 25°C for 24 h. After the reaction was completed, the temperature was lowered to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine were added, and the temperature was slowly raised to 25°C for 24 h. After washing with water, column chromatography (eluent ethyl acetate / n-hexane, volume ratio = 4 / 1) was performed to obtain 89 mg of tetrahydroquinoline compounds with a CB bond at the C-4 position, with a yield of 85%. The structural formula of the tetrahydroquinoline compound is:

[0070]

[0071] The same experimental method was used, and chiral S-Binap was used as a ligand to obtain tetrahydroquinoline compounds containing chiral C-4 CB bonds, with a yield of 36% and 86% ee. (Column chromatography conditions: chromatographic column ECOSIL Chiral CAD-H 5u 250×4.6mm; mobile phase: n-hexane / isopropanol = 90 / 10, flow rate 1ml / min, peak elution time: secondary peak: 8.86min, main peak 11.33min.)

[0072] 1 H NMR (400MHz, CDCl3) δ8.07(d,J=8.7Hz,2H),7.70–7.61(m,2H),6.99(d,J=1.9Hz,1H),6.57(d,J=8.1Hz,1H),6.22(s,1H),4.23(q,J=9.9Hz,1 H),3.58(ddd,J=12.9,7.1,3.8Hz,1H),2.59(t,J=5.0Hz,1H),2.46–2.34(m,1H),2.24(s,3H),1.97–1.84(m,1H),1.21(d,J=5.3Hz,12H).13C NMR (101MHz, CDCl3) δ167.54,148.28,142.59,135.30,135.18,130.24,12 8.59,126.10,125.68,123.07,84.11,44.23,26.43,25.08,24.58,20.99.

[0073] Example 7

[0074] Under nitrogen protection, 7 mg of Rh(COD)2Otf catalyst and 8 mg of triphenylphosphine were weighed in a reactor, 0.5 mL of anhydrous toluene was added and stirred for 5 min, then 128 uL of HBpin and 53 mg of 2-methylquinoline were added, and the reaction was carried out at 50°C for 48 h. After the reaction was completed, the temperature was lowered to 0°C, 100 uL of triethylamine and 67 mg of chloroacetyl chloride were added, and the temperature was slowly raised to 25°C for 24 h. After washing with water, column chromatography (eluent: dichloromethane / methanol, volume ratio = 95 / 5) was performed to obtain 90 mg of tetrahydroquinoline compounds with a CB bond at the C-4 position, with a yield of 85%. The structural formula of the tetrahydroquinoline compound is:

[0075]

[0076] The same experimental method was used, and chiral S-Binap was used as a ligand to obtain tetrahydroquinoline compounds containing chiral C-4 CB bonds with a yield of 70%, 44% ee, and a dr of 96.8:3.2. (Column chromatography conditions: chromatographic column ECOSIL ChiralCAD-H 5u 250×4.6mm; mobile phase: n-hexane / isopropanol = 90 / 10, flow rate 1ml / min, peak time: main peak 4.54min, secondary peak: 5.15min.)

[0077] 1 H NMR(400MHz, CDCl3)δ7.19(m,3H),5.14–4.59(m,1H),4.33(d,J=13.4Hz,1H),3.98–3.89(m,1H), 2.53(ddd,J=12.8,8.1,3.1Hz,1H),2.42(dd,J=5.2,3.0Hz,1H),1.41(s,1H),1.31–1.10(m,15H). 13 C NMR (101MHz, CDCl3) δ165.66,135.96,127.42,126.75,126.08,125.36,83.96,50.33,,42.94,35.80,25.10,24.50,20.65.

[0078] Example 8

[0079] Under nitrogen protection, 7 mg of Rh(COD)2Otf catalyst and 8 mg of triphenylphosphine were weighed in a reactor, 0.5 mL of anhydrous toluene was added and stirred for 5 min, then 128 uL of HBpin and 53 mg of 7-chloro-2-methylquinoline were added, and the reaction was carried out at 50°C for 48 h. After the reaction was completed, the temperature was lowered to 0°C, 100 uL of triethylamine and 67 mg of chloroacetyl chloride were added, and the temperature was slowly raised to 25°C for 24 h. After washing with water, column chromatography (eluent dichloromethane / methanol, volume ratio = 95 / 5) was performed to obtain 90 mg of tetrahydroquinoline compounds with CB bonds at the C-4 position, with a yield of 78%. The structural formula of the tetrahydroquinoline compound is:

[0080]

[0081] The same experimental method was used, using chiral S-Binap as a ligand, to obtain tetrahydroquinoline compounds containing chiral C-4 CB bonds with a yield of 69%, 47% ee, and 99% dr. Column chromatography conditions: OXH0CE-PB0010.46cm ID×25cm L×5μmn: Mobile phase: n-hexane / ethanol / ethylenediamine=90 / 10 / 0.05 (v / v / v) 1ml / min, peak time: secondary peak 5.58min, main peak: 5.97min.

[0082] 1 H NMR (400MHz, CDCl3) δ7.21–7.08(m,3H),4.73(d,J=9.5Hz,1H),4.26(d,J=13.3Hz,1H),3.92(d,J=13.3H z,1H),2.52(ddd,J=11.7,7.9,3.0Hz,1H),2.40(dd,J=5.2,3.0Hz,1H),1.39(s,1H),1.20–1.11(m,15H). 13 C NMR (101MHz, CDCl3) δ165.54,141.52,134.60,132.09,127.51,126.39,126.20,84.15,50.36,42.64,35.62,25.10,24.61,24.49,20.62.

[0083] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a tetrahydroquinoline compound having a CB bond, characterized in that: The synthesis method comprises the following steps: 42 mg of Rh(COD)2OTf catalyst and 48 mg of phosphorus ligand are weighed in a reactor under nitrogen protection, 12 mL of anhydrous toluene is added and stirred for 5 minutes, 3.9 mL of HBpin and 1.07 mL of quinoline are added, and the reaction is carried out at 25°C for 36 hours. After the reaction is completed, the temperature is lowered to 0°C, 2.1 g of p-nitrobenzoyl chloride and 3 mL of triethylamine are added, the temperature is slowly raised to 25°C and the reaction is carried out for 24 hours, and the mixture is washed with water and subjected to column chromatography, wherein the eluent is ethyl acetate / n-hexane in a volume ratio of 4 / 1, to obtain a tetrahydroquinoline compound having a CB bond at the C-4 position, wherein the phosphorus ligand is triphenylphosphine or chiral S-Binap.

2. A method for synthesizing a tetrahydroquinoline compound having a CB bond, characterized in that: The synthesis method comprises the following steps: under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of phosphorus ligand are weighed in a reactor, 0.5 mL of anhydrous toluene is added and stirred for 5 minutes, 128 uL of HBpin and 49 mg of 7-chloroquinoline are added, the temperature is reacted at 25°C for 24 hours, after the reaction is completed, the temperature is cooled to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine are added, the temperature is slowly raised to 25°C and reacted for 24 hours, after washing with water, column chromatography is performed, and the eluent is ethyl acetate / n-hexane, with a volume ratio of 4 / 1, to obtain a tetrahydroquinoline compound with a CB bond at the C-4 position, wherein the phosphorus ligand is triphenylphosphine or chiral S-Binap.

3. A method for synthesizing a tetrahydroquinoline compound having a CB bond, characterized in that: The synthesis method comprises the following steps: under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of phosphorus ligand are weighed in a reactor, 0.5 mL of anhydrous toluene is added and stirred for 5 minutes, 128 uL of HBpin and 44 mg of 6-fluoroquinoline are added, the reaction is carried out at 25°C for 24 hours, after the reaction is completed, the temperature is lowered to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine are added, the temperature is slowly raised to 25°C for reaction for 24 hours, and the mixture is washed with water and subjected to column chromatography, wherein the eluent is ethyl acetate / n-hexane, and the volume ratio is 4 / 1, to obtain a tetrahydroquinoline compound having a CB bond at the C-4 position, wherein the phosphorus ligand is triphenylphosphine or chiral S-Binap.

4. A method for synthesizing a tetrahydroquinoline compound having a CB bond, characterized in that: The synthesis method comprises the following steps: under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of phosphorus ligand are weighed in a reactor, 0.5 mL of anhydrous toluene is added and stirred for 5 min, 128 uL of HBpin and 56 mg of 6-carboxymethylquinoline are added, the temperature is reacted at 25°C for 24 h, after the reaction is completed, the temperature is cooled to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine are added, the temperature is slowly raised to 25°C and reacted for 24 h, after washing with water, column chromatography is performed, and the eluent is ethyl acetate / n-hexane, with a volume ratio of 4 / 1, to obtain a tetrahydroquinoline compound with a CB bond at the C-4 position, wherein the phosphorus ligand is triphenylphosphine or chiral S-Binap.

5. A method for synthesizing a tetrahydroquinoline compound having a CB bond, characterized in that: The synthesis method comprises the following steps: under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of phosphorus ligand are weighed in a reactor, 0.5 mL of anhydrous toluene is added and stirred for 5 minutes, 128 uL of HBpin and 35.5 uL of 7-methoxyquinoline are added, the temperature is reacted at 25°C for 24 hours, after the reaction is completed, the temperature is cooled to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine are added, the temperature is slowly raised to 25°C and reacted for 24 hours, after washing with water, column chromatography is performed, and the eluent is ethyl acetate / n-hexane, with a volume ratio of 4 / 1, to obtain a tetrahydroquinoline compound with a CB bond at the C-4 position, wherein the phosphorus ligand is triphenylphosphine or chiral S-Binap.

6. A method for synthesizing a tetrahydroquinoline compound having a CB bond, characterized in that: The synthesis method comprises the following steps: under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of phosphorus ligand are weighed in a reactor, 0.5 mL of anhydrous toluene is added and stirred for 5 minutes, 128 uL of HBpin and 43 mg of 7-methylquinoline are added, the reaction is carried out at 25°C for 24 hours, after the reaction is completed, the temperature is lowered to 0°C, 68 mg of p-nitrobenzoyl chloride and 100 uL of triethylamine are added, the temperature is slowly raised to 25°C and reacted for 24 hours, and the mixture is washed with water and subjected to column chromatography, wherein the eluent is ethyl acetate / n-hexane, and the volume ratio is 4 / 1, to obtain a tetrahydroquinoline compound having a CB bond at the C-4 position, wherein the phosphorus ligand is triphenylphosphine or chiral S-Binap.

7. A method for synthesizing a tetrahydroquinoline compound having a CB bond, characterized in that: The synthesis method comprises the following steps: under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of phosphorus ligand are weighed in a reactor, 0.5 mL of anhydrous toluene is added and stirred for 5 min, 128 uL of HBpin and 53 mg of 2-methylquinoline are added, the mixture is reacted at 50° C. for 48 h, after the reaction is completed, the temperature is lowered to 0° C., 100 uL of triethylamine and 67 mg of chloroacetyl chloride are added, the temperature is slowly raised to 25° C., the mixture is reacted for 24 h, and the mixture is washed with water and subjected to column chromatography, wherein the eluent is dichloromethane / methanol, and the volume ratio is 95 / 5, to obtain a tetrahydroquinoline compound having a CB bond at the C-4 position, wherein the phosphorus ligand is triphenylphosphine or chiral S-Binap.

8. A method for synthesizing a tetrahydroquinoline compound having a CB bond, characterized in that: The synthesis method comprises the following steps: under nitrogen protection, 7 mg of Rh(COD)2OTf catalyst and 8 mg of phosphorus ligand are weighed in a reactor, 0.5 mL of anhydrous toluene is added and stirred for 5 min, 128 uL of HBpin and 53 mg of 7-chloro-2-methylquinoline are added, the mixture is reacted at 50° C. for 48 h, after the reaction is completed, the temperature is lowered to 0° C., 100 uL of triethylamine and 67 mg of chloroacetyl chloride are added, the temperature is slowly raised to 25° C., the mixture is reacted for 24 h, and the mixture is washed with water and subjected to column chromatography, wherein the eluent is dichloromethane / methanol, and the volume ratio is 95 / 5, to obtain a tetrahydroquinoline compound having a CB bond at the C-4 position, wherein the phosphorus ligand is triphenylphosphine or chiral S-Binap.

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