CN110669046B - Polysubstituted tetrahydro-gamma-carboline derivative with multiple chiral centers and preparation method of stereo diversity of polysubstituted tetrahydro-gamma-carboline derivative - Google Patents

Polysubstituted tetrahydro-gamma-carboline derivative with multiple chiral centers and preparation method of stereo diversity of polysubstituted tetrahydro-gamma-carboline derivative Download PDF

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CN110669046B
CN110669046B CN201910854466.0A CN201910854466A CN110669046B CN 110669046 B CN110669046 B CN 110669046B CN 201910854466 A CN201910854466 A CN 201910854466A CN 110669046 B CN110669046 B CN 110669046B
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王春江
徐士茗
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2419—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member
    • B01J31/2428—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member with more than one complexing phosphine-P atom
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    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2461—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring
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Abstract

The invention discloses a polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers, which is synthesized by taking part in allylic carbonate derived from methyleneamine ylide and indole through a novel copper/iridium concerted catalyzed allylation/isopictet-Spengler reaction, and the synthesis method comprises the following steps: in an organic solvent, under the protection of inert gas, taking indole 2-derived allyl carbonate and amino acid-derived imine as raw materials, taking a copper complex and an iridium complex as a co-catalyst, adding diisopropylethylamine or cesium carbonate, reacting at room temperature, performing aftertreatment, and performing column chromatography purification to obtain the target compound. By changing the collocation mode of the chiral ligand used in the reaction, a plurality of stereoisomers of the same compound can be respectively synthesized with high stereoselectivity.

Description

Polysubstituted tetrahydro-gamma-carboline derivative with multiple chiral centers and preparation method of stereo diversity of polysubstituted tetrahydro-gamma-carboline derivative
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers and a preparation method of the stereospecificity of the polysubstituted tetrahydro-gamma-carboline derivative.
Background
The tetrahydro-gamma-carboline structural unit of the multi-chiral center is widely existed in natural products and drug molecules with important biological activity, particularly in the aspect of regulating the nervous system, the compound has particularly outstanding therapeutic capability on depression and Alzheimer's disease, and has attracted extensive attention in the aspect of medical pharmacy in recent years. Therefore, the synthesis method of the chiral polysubstituted tetrahydro-gamma-carboline compound, which is efficient, universal, mild in condition and easy to use, is a hot research field in the synthesis chemistry recently. In practical application, various stereoisomers of the same substance can present different physiological activities, and multiple stereoisomers can be simultaneously measured in the screening and testing processes of the medicine, so that the method has more advantages. The synthesis method of the three-dimensional diversity can obtain various isomers with different three-dimensional structures only by adjusting the collocation of a catalytic system, and is more economical and practical from the synthesis angle. (Dai, J; Dan, W; Zhang, Y; Wang, J.Eur.J.Med.Chem.2018,157,447 (B) Khorana, N; Smith, C; Herrich-Davis, K; Purohit, A; Teitler, M; Grella, B; Dukat, M; Glennon, R.A.J.Med.Chem.2003,46,3930, (C) Wang, S; Wang, Y; Liu, W; Liu, N; Zhang, Y; Dong, G; Liu, Y; Li, Z; X; Miao, Z; Yao, J; Li, J; Zhang, W; Sheng, C.ACSMed.Lett.Chem.865, 5,506. yad; Abhar, Z; Yao, J; Li, J; Zhang, W; Sheng, W; Sheng, C.ACSMed.Chett.Chett.Chett.5, 27. J; Cherok, J.27, J; Cherok, J.23; Cherov.23; Cherov.7, J.7; Cherov.7, J.11; Cherok, J.7; Cherok.7, J.7; Cherok.7, J.J.J.J.;. J. Chen. J.;. J.;. Zo. J. Chen. J.;. Zo. J. K).
Disclosure of Invention
The invention discloses a polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers, which is synthesized by taking part in allylic carbonate derived from methyleneamine ylide and indole through a novel copper/iridium concerted catalyzed allylation/isopictet-Spengler reaction, and the synthesis method comprises the following steps: in an organic solvent, under the protection of inert gas, taking indole 2-derived allyl carbonate and amino acid-derived imine as raw materials, taking a copper complex and an iridium complex as a co-catalyst, adding diisopropylethylamine or cesium carbonate, reacting at room temperature, performing aftertreatment, and performing column chromatography purification to obtain the target compound. By changing the collocation mode of the chiral ligand used in the reaction, a plurality of stereoisomers of the same compound can be respectively synthesized with high stereoselectivity.
The invention provides a method for preparing polysubstituted tetrahydro-gamma-carboline derivatives with a plurality of chiral centers in a three-dimensional diversity manner, which comprises the following steps: under the existence of an iridium catalyst and a ligand L1, a copper catalyst and a ligand L2, and alkali, carrying out catalytic reaction on a substrate-1 and a substrate-2, and preparing a polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers shown in a formula I at room temperature;
the reaction formula of the preparation method of the polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers is as follows:
Figure BDA0002197908600000011
wherein R is1Is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, chain alkyl or alkenyl; the substituted or unsubstituted unsaturated heterocyclic aryl contains a heteroatom of O or S; the substituent of the substituted aryl is alkyl, alkoxy and halogen;
R2is H or phenyl;
R3is H, chain alkyl, benzyl or ester substituent;
R4is methyl, tert-butyl or cyclic lactone group;
R5is H, methyl or halogen;
R6is methyl or benzyl;
LG is OCO2Me、OBoc、OP(O)(OEt)2Or OP (O)iPr)2。
The synthesis steps of the catalytic reaction are as follows: reacting a substrate-1, a substrate-2, an iridium complex and a copper complex in a solvent at 15-50 ℃ for 12-24 hours in the presence of 1-10 equivalents of alkali; the concentrations of the substrate-1 and the substrate-2 are respectively 0.001-3.0M; the molar ratio of the substrate-1 to the substrate-2 is 1: 10-10: 1; the dosage of the iridium catalyst is 0.0001-10 mol% of the lower concentration of the substrate-1 or the substrate-2; the dosage of the ligand L1 is 0.0001-10 mol% of the lower concentration of the substrate-1 or the substrate-2; the dosage of the copper catalyst is 0.001-30 mol% of the lower concentration of the substrate-1 or the substrate-2; the dosage of the ligand L2 is 0.001-30 mol% of the lower concentration of the substrate-1 or the substrate-2.
The solvent is at least one of methanol, ethanol, isopropanol, tert-butyl alcohol, sec-butyl alcohol, ethyl acetate, isobutyl acetate, isopropyl acetate, N-hexane, cyclohexane, N-heptane, acetone, butanone, diethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, methyl tetrahydrofuran, acetonitrile, dichloromethane, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, toluene or dioxane.
In the preparation method of the polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers, the base is any one of alkali metal salt of alcohol, alkali metal salt of amine, alkali metal carbonate, alkali metal hydroxide or organic base;
the alkali metal salt of the alcohol is potassium tert-butoxide, sodium tert-butoxide, potassium isopropoxide or sodium isopropoxide;
the alkali metal salt of the amine is lithium diisopropylamide, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide or potassium bistrimethylsilyl amide;
the alkali metal carbonate is potassium carbonate, sodium carbonate or cesium carbonate;
the alkali metal hydroxide is potassium hydroxide or sodium hydroxide;
the organic base is 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 1, 4-diazabicyclo [2.2.2] octane, diisopropylethylamine or triethylamine.
According to the preparation method of the polysubstituted tetrahydro-gamma-carboline derivative with the plurality of chiral centers, the temperature of the catalytic reaction is 15-35 ℃.
In the preparation method of the polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers, the acid used in the post-treatment under the weak acidic condition is any one of citric acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, sulfuric acid, hydroxylamine hydrochloride or hydroxylamine acetate; the dosage of the acid is 1-10 times of that of the substrate-1 or the substrate-2 with lower concentration.
The post-treatment time under the weak acid condition is 5 minutes to 3 hours, and the temperature is room temperature.
The structure of the polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers is shown as a formula I:
Figure BDA0002197908600000021
wherein R is1Is H, phenyl, p-methylphenyl, m-methylphenyl, o-methylphenyl, p-methoxyphenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, p-bromophenyl, 2-naphthyl, 2-furyl, 2-thienyl, styryl or n-butyl;
R2is H or phenyl;
R3is H, methyl, ethyl, benzyl or-CH2CH2CO2Me；
R4Is methyl or tert-butyl;
wherein is represented by R3And R4Jointly form a cyclic lactone group
Figure BDA0002197908600000031
R5Is H, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 5-chloro or 5-bromo;
R6is methyl or benzyl.
The polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers is applied to the preparation of antidepressant drugs, antitumor drugs or natural products.
Placing the polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers prepared by any one of the preparation methods in a dichloromethane solvent, adding an ether solution of diazomethane at the temperature of-20 ℃, and adding Pd (OAc)2The first derivative compound obtained after cyclopropane is used as a catalyst
Figure BDA0002197908600000032
Putting the polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers prepared by the preparation method in a methanol solvent, adding hydrogen with the pressure of 1 atmosphere at room temperature by taking Pd/C as a catalyst, and hydrogenating to obtain a second derivative compound
Figure BDA0002197908600000033
Putting the polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers prepared by the preparation method in a tetrahydrofuran solvent, adding a diisobutylaluminum hydride solution at-40 ℃, and reducing to obtain a third derivative compound
Figure BDA0002197908600000034
Putting the polysubstituted tetrahydro-gamma-carboline derivative with a plurality of chiral centers prepared by any one of the preparation methods in a dichloromethane solvent, and adding [ Ir (COD) Cl]2The fourth derivative compound is obtained by adding pinacol borane into a catalyst system of/dppm and hydroborating
Figure BDA0002197908600000041
The following preferences may be made for the above synthetic method:
1) the organic solvent is dichloromethane.
2) The molar ratio of the above-mentioned substrate-1 to substrate-2 was 1.5: 1.
3) The iridium catalyst is [ Ir (COD) Cl]2、[Ir(DBCOT)Cl]2Or [ Ir (COD) OMe]2Is preferably [ Ir (COD) Cl]2。
4) The preferred ligand L1 is of the formula:
Figure BDA0002197908600000042
5) the copper catalyst is Cu (MeCN)4BF4、Cu(MeCN)4ClO4Or Cu (MeCN)4PF6Is preferably Cu (MeCN)4BF4。
6) The preferred ligand L2 is of the formula:
Figure BDA0002197908600000043
7) the preferred iridium catalyst and ligand L1 complexes described above are prepared as follows:
at 50 ℃, dissolving the metal iridium salt and the ligand L1 in an organic solvent according to the mole number of the metal iridium salt not more than the mole number of the ligand L1, adding organic alkali, and reacting to obtain the iridium complex ligand.
8) The preferred copper catalyst and ligand L2 complexes described above were prepared as follows:
at room temperature, the metal copper salt and the ligand L2 are dissolved in an organic solvent according to the mole number of the metal copper salt not more than that of the ligand L2, and the metal copper salt and the ligand L2 are obtained through reaction.
9) The preferred base is diisopropylethylamine or cesium carbonate, depending on the type of methyleneamine ylide used.
10) The acid used for the work-up was 1 mol/l hydrochloric acid.
11) The column chromatography uses silica gel as a filling material, uses a mixed solvent of petroleum ether and ethyl acetate as an eluent, and comprises the following steps: the volume ratio of the petroleum ether to the ethyl acetate is 10:1 to 3: 1.
Compared with the prior art, the invention has the following characteristics:
1) the method has the advantages of simple synthesis, low cost and high yield, the diastereoselectivity and the corresponding selectivity of the obtained reaction target compound are good, the yield is 75-99%, and the ratio of the majority of the diastereoselectivities is more than 20: 1, the vast majority corresponds to a selectivity excess of > 99%.
2) The method of the invention adopts the copper complex and the iridium complex as the co-catalyst, and has the advantages of high catalytic reaction speed, low catalyst consumption, mild conditions and the like in the reaction.
3) The invention can realize the specific synthesis of various stereoisomers by adjusting the collocation of the chiral catalytic system, and has outstanding characteristics and advantages in the aspects of catalytic synthesis and practical application.
Detailed Description
In order that the invention may be better understood, the invention will now be further described with reference to the following examples.
Ligands (R, R) used in the following examplesa) -L1 has the formula
Figure BDA0002197908600000051
Ligands (S, S) useda) -L1 has the formula
Figure BDA0002197908600000052
The ligand (S, S, S) -L1 has the structural formula
Figure BDA0002197908600000053
The ligand (R, R, R) -L1 used in the following examples has the formula
Figure BDA0002197908600000054
The ligand (rac) -L1 used in the following examples has the formula
Figure BDA0002197908600000055
Ligands (S, S) usedp) -L2 has the formula
Figure BDA0002197908600000056
Ligands (R, R) usedp) -L2 has the formula
Figure BDA0002197908600000057
The structural formula of the adopted achiral ligand DPEphos is shown in the specification
Figure BDA0002197908600000058
Examples 1 to 1
Figure BDA0002197908600000059
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water and oxygen removalTHF and 0.5mL of deoxygenated n-propylamine were reacted at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to obtain an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol (p-chlorobenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in sequence at 25 ℃, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid (the concentration is reduced to 0.5M when sulfuric acid is used and is increased to 2M when acetic acid is used) is added for quenching reaction for 5 minutes (the concentration of acid is increased and the quenching time is prolonged when gram-level reaction is quenched), liquid separation is carried out after standing, the aqueous phase is subjected to back extraction by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 6:1) to obtain a white solid with the yield of 98 percent, the melting point of 68-70 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AD-H, i-propanol/hexane. RTM. 2/98, flow rate 1.0 mL/min. lamda. 282nm) tr＝15.53 and 18.77min；[α]20 D＝+52.4(c 0.5,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.4Hz,2H),7.29-7.23(m,3H),7.15-7.11(m,1H),6.91-6.85(m,1H),6.82(d,J＝8.0Hz,1H),6.23(ddd,J＝17.2,10.0,6.4Hz,1H),5.40(s,1H),5.31(d,J＝10.0Hz,1H),5.12(d,J＝17.2Hz,1H),4.21(d,J＝6.4Hz,1H),3.92(d,J＝2.4Hz,1H),3.71(s,3H),3.66(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 172.75,142.21,138.67,137.22,133.46,133.15,130.00,128.55,124.96,121.23,119.07,118.98,117.75,110.02,108.78,60.26,54.15,52.34,38.90,29.24 HRMS (ESI +) C22H22ClN2O2([M+H]+): 381.1364, measurement 381.1360. Comparative example 1: only dichloromethane is replaced by ethyl acetate, other conditions are the same as the above, the yield is 78%, and the diastereoselectivity proportion and the enantioselectivity excess of the product are not greatly different; the yield was 37% with only dichloromethane replaced by toluene and other conditions were the same as above, the diastereoselective ratio and the enantiomer of the productThe selectivity excess is not very different; the conversion of only dichloromethane to tetrahydrofuran was carried out under otherwise the same conditions as described above, giving a yield of 84%, and the diastereoselective ratio and the enantioselective excess of the product did not differ greatly. Comparative example 2: replacement of diisopropylethylamine only with 1, 8-diazabicyclo [5.4.0]]Undec-7-ene, otherwise identical, in 21% yield, with a diastereoselective ratio of 1: 1, enantioselective excesses of 18% and 21%; only diisopropylethylamine was replaced by triethylamine, other conditions were the same as above, the yield was 85%, the diastereoselective ratio of the product was 10:1, enantioselective excess 97%. Comparative example 3: only the ligand (R, R)a) -L1 for (S, S) -L1, otherwise identical conditions as above, in 95% yield, with a diastereoselective ratio of product of 1: 1, enantioselectivity excess 93% and 89%.
Examples 1 to 2
Figure BDA0002197908600000061
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-chlorobenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, after standing and separating, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 95%, the melting point is 68-70 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselectivity of the product in excess of 99%, HPLC (Chiralpak AD-H, i-propanol/hexane. RTM. 2/98, flow rate) 1.0mL/min,λ＝282nm)tr＝15.53 and 18.77min；[α]20 D＝-50.3(c 0.7,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.4Hz,2H),7.29-7.23(m,3H),7.15-7.11(m,1H),6.91-6.85(m,1H),6.82(d,J＝8.0Hz,1H),6.23(ddd,J＝17.2,10.0,6.4Hz,1H),5.40(s,1H),5.31(d,J＝10.0Hz,1H),5.12(d,J＝17.2Hz,1H),4.21(d,J＝6.4Hz,1H),3.92(d,J＝2.4Hz,1H),3.71(s,3H),3.66(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 172.75,142.21,138.67,137.22,133.46,133.15,130.00,128.55,124.96,121.23,119.07,118.98,117.75,110.02,108.78,60.26,54.15,52.34,38.90,29.24 HRMS (ESI +) C22H22ClN2O2([M+H]+): 381.1364, measurement 381.1360.
Examples 1 to 3
Figure BDA0002197908600000071
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-chlorobenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, liquid separation is carried out after standing, the water phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and a white solid is obtained by silica gel column chromatography (petroleum ether/ethyl acetate 6:1), the yield is 92 percent, the melting point is 86-88 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.282 nm); t is tr＝25.07 and 28.05min；[α]20 D＝+146.3(c 1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.36-7.32(m,2H),7.31-7.25(m,2H),7.17-7.10(m,1H),6.91-6.84(m,1H),6.73(d,J＝8.0Hz,1H),6.02(ddd,J＝17.2,10.0,7.2Hz,1H),5.32(d,J＝10.4Hz,1H),5.22(s,1H),5.17-5.08(m,1H),4.14(d,J＝3.6Hz,1H),3.99(dd,J＝6.0,4.0Hz,1H),3.79(s,3H),3.64(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 171.37,141.19,137.24,135.12,135.02,133.42,130.03,128.64,124.51,121.33,119.69,119.24,119.12,111.06,108.79,60.83,57.69,52.12,40.02,28.98 HRMS (ESI +) C22H22ClN2O2([M+H]+): 381.1364, measurement 381.1369.
Examples 1 to 4
Figure BDA0002197908600000072
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-chlorobenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, liquid separation is carried out after standing, the water phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and a white solid is obtained by silica gel column chromatography (petroleum ether/ethyl acetate 6:1), the yield is 96 percent, the melting point is 86-88 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.282 nm); t is tr＝25.07 and 28.05min；[α]20 D＝-156.0(c 0.8,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.36-7.32(m,2H),7.31-7.25(m,2H),7.17-7.10(m,1H),6.91-6.84(m,1H),6.73(d,J＝8.0Hz,1H),6.02(ddd,J＝17.2,10.0,7.2Hz,1H),5.32(d,J＝10.4Hz,1H),5.22(s,1H),5.17-5.08(m,1H),4.14(d,J＝3.6Hz,1H),3.99(dd,J＝6.0,4.0Hz,1H),3.79(s,3H),3.64(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 171.37,141.19,137.24,135.12,135.02,133.42,130.03,128.64,124.51,121.33,119.69,119.24,119.12,111.06,108.79,60.83,57.69,52.12,40.02,28.98 HRMS (ESI +) C22H22ClN2O2([M+H]+): 381.1364, measurement 381.1369.
Example 2
Figure BDA0002197908600000081
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (o-chlorobenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, liquid separation is carried out after standing, the water phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and a white solid is obtained by silica gel column chromatography (petroleum ether/ethyl acetate 6:1), the yield is 82%, the melting point is 64-66 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AD-H, i-propanol/hexane. RTM. 2/98, flow rate 1.0 mL/min. lamda. 234nm) tr＝9.40 and 10.13min；[α]20 D＝+52.3(c 1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.46-7.41(m,1H),7.29(d,J＝8.4Hz,1H),7.23-7.12(m,3H),7.12-7.05(m,1H),6.89(t,J＝7.2Hz,1H),6.82(d,J＝7.6Hz,1H),6.24(ddd,J＝17.2,10.0,6.8Hz,1H),5.96(s,1H),5.30(d,J＝10.4Hz,1H),5.13(d,J＝16.8Hz,1H),4.24(d,J＝6.4Hz,1H),3.95(d,J＝1.6Hz,1H),3.74(s,3H),3.68(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 172.77,140.24,138.63,137.29,134.10,134.02,130.37,129.33,128.72,127.19,124.89,121.21,119.30,118.97,117.72,109.32,108.77,60.37,52.35,50.66,38.75,29.29 HRMS (ESI +) C22H22ClN2O2([M+H]+): 381.1364, measurement 381.1366.
Example 3-1
Figure BDA0002197908600000082
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (benzylidene amino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12h at 18 ℃, 2.0mL1N hydrochloric acid is added to quench the reaction for 5min, after standing and separating liquid, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 99%, the melting point is 52-54 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 232nm) tr＝13.33 and 15.82min；[α]20 D＝-7.3(c 1.4,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.41(dd,J＝8.0,1.6Hz,2H),7.33-7.25(m,4H),7.12(ddd,J＝8.0,6.4,1.6Hz,1H),6.89-6.80(m,2H),6.25(ddd,J＝17.2,10.0,6.8Hz,1H),5.41(s,1H),5.31(d,J＝10.0Hz,1H),5.14(d,J＝17.2Hz,1H),4.22(d,J＝6.4Hz,1H),3.94(d,J＝2.0Hz,1H),3.72(s,3H),3.66(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 172.86,143.54,138.77,137.22,133.40,128.59,128.40,127.56,125.16,121.08,119.26,118.84,117.72,110.54,108.67,60.36,54.83,52.31,38.91,29.23 HRMS (ESI +) C22H22N2O2([M+H]+): 347.1754, measurement 347.1754.
Examples 3 to 2
Figure BDA0002197908600000091
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (benzylidene amino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12h at 18 ℃, 2.0mL1N hydrochloric acid is added to quench the reaction for 5min, after standing and separating liquid, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 98%, the melting point is 52-54 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 232nm) tr＝13.33 and 15.82min；[α]20 D＝+6.9(c 0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.41(dd,J＝8.0,1.6Hz,2H),7.33-7.25(m,4H),7.12(ddd,J＝8.0,6.4,1.6Hz,1H),6.89-6.80(m,2H),6.25(ddd,J＝17.2,10.0,6.8Hz,1H),5.41(s,1H),5.31(d,J＝10.0Hz,1H),5.14(d,J＝17.2Hz,1H),4.22(d,J＝6.4Hz,1H),3.94(d,J＝2.0Hz,1H),3.72(s,3H),3.66(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 172.86,143.54,138.77,137.22,133.40,128.59,128.40,127.56,125.16,121.08,119.26,118.84,117.72,110.54,108.67,60.36,54.83,52.31,38.91,29.23 HRMS (ESI +) C22H22N2O2([M+H]+): 347.1754, measurement 347.1754.
Examples 3 to 3
Figure BDA0002197908600000092
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (benzylidene amino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12h at 18 ℃, 2.0mL1N hydrochloric acid is added to quench the reaction for 5min, after standing and separating liquid, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 96%, the melting point is 62-64 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 232 nm); t is tr＝29.80 and 34.58min；[α]20 D＝+89.2(c 0.2,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.43-7.38(m,2H),7.34-7.26(m,4H),7.15-7.09(m,1H),6.87-6.82(m,1H),6.73(d,J＝8.0Hz,1H),6.03(ddd,J＝17.2,10.4,7.2Hz,1H),5.33(d,J＝10.4Hz,1H),5.25(s,1H),5.13(d,J＝17.2Hz,1H),4.17(d,J＝4.0Hz,1H),4.02-3.98(m,1H),3.78(s,3H),3.64(s,3H).13C NMR(101MHz,CDCl3) Calculated δ 171.48,142.58,137.22,135.17,134.89,128.62,128.47,127.78,124.70,121.19,119.69,119.43,118.98,111.61,108.68,60.91,58.37,52.05,39.99,28.95 HRMS (ESI +) C22H22N2O2([M+H]+): 347.1754, measurement 347.1756.
Examples 3 to 4
Figure BDA0002197908600000101
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (benzylidene amino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12h at 18 ℃, 2.0mL1N hydrochloric acid is added to quench the reaction for 5min, after standing and separating liquid, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 94%, the melting point is 62-64 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 232 nm); t is tr＝29.80 and 34.58min；[α]20 D＝-88.9(c 0.8,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.43-7.38(m,2H),7.34-7.26(m,4H),7.15-7.09(m,1H),6.87-6.82(m,1H),6.73(d,J＝8.0Hz,1H),6.03(ddd,J＝17.2,10.4,7.2Hz,1H),5.33(d,J＝10.4Hz,1H),5.25(s,1H),5.13(d,J＝17.2Hz,1H),4.17(d,J＝4.0Hz,1H),4.02-3.98(m,1H),3.78(s,3H),3.64(s,3H).13C NMR(101MHz,CDCl3) Calculated δ 171.48,142.58,137.22,135.17,134.89,128.62,128.47,127.78,124.70,121.19,119.69,119.43,118.98,111.61,108.68,60.91,58.37,52.05,39.99,28.95 HRMS (ESI +) C22H22N2O2([M+H]+): 347.1754, measurement 347.1756.
Example 4-1
Figure BDA0002197908600000102
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-methylbenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, after standing and liquid separation, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 82%, the melting point is 54-56 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AD-H plusAD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.238 nm) tr＝28.13 and 33.35min；[α]20 D＝+16.8(c 1.5,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.30-7.25(m,3H),7.14-7.08(m,3H),6.89-6.83(m,2H),6.24(ddd,J＝16.8,10.0,6.8Hz,1H),5.38(s,1H),5.30(d,J＝10.0Hz,1H),5.13(d,J＝17.2Hz,1H),4.21(d,J＝6.0Hz,1H),3.93(d,J＝2.0Hz,1H),3.71(s,3H),3.66(s,3H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ172.89,140.48,138.79,137.21,137.07,133.43,129.07,128.43,125.22,121.04,119.34,118.79,117.69,110.67,108.64,60.36,54.45,52.29,38.97,29.23,21.17 HRMS (ESI +) calcd for C23H25N2O2([M+H]+): 361.1911, measurement 361.1910.
Example 4 to 2
Figure BDA0002197908600000111
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-methylbenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12h at 18 ℃, 2.0mL1N hydrochloric acid is added to quench the reaction for 5min, after standing and separating, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 78%, the melting point is 54-56 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AD-H plusAD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.238 nm) tr＝28.13 and 33.35min；[α]20 D＝-17.4(c 1.2,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.30-7.25(m,3H),7.14-7.08(m,3H),6.89-6.83(m,2H),6.24(ddd,J＝16.8,10.0,6.8Hz,1H),5.38(s,1H),5.30(d,J＝10.0Hz,1H),5.13(d,J＝17.2Hz,1H),4.21(d,J＝6.0Hz,1H),3.93(d,J＝2.0Hz,1H),3.71(s,3H),3.66(s,3H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ172.89,140.48,138.79,137.21,137.07,133.43,129.07,128.43,125.22,121.04,119.34,118.79,117.69,110.67,108.64,60.36,54.45,52.29,38.97,29.23,21.17 HRMS (ESI +) calcd for C23H25N2O2([M+H]+): 361.1911, measurement 361.1910.
Examples 4 to 3
Figure BDA0002197908600000112
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-methylbenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and a white solid is obtained by silica gel column chromatography (petroleum ether/ethyl acetate 6:1), the yield is 76%, the melting point is 50-52 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselectivity excess of the product 99%, HPLC (Chiralpak AD-H plusAD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.238 nm); t is tr＝48.58 and 46.05min；[α]20 D＝+73.9(c 1.1,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.30-7.26(m,3H),7.14-7.09(m,3H),6.86(t,J＝7.6Hz,1H),6.76(d,J＝8.0Hz,1H),6.01(ddd,J＝16.8,10.0,7.2Hz,1H),5.32(d,J＝10.0Hz,1H),5.22(s,1H),5.12(d,J＝16.8Hz,1H),4.16(d,J＝3.6Hz,1H),4.02-3.96(m,1H),3.78(s,3H),3.63(s,3H),2.34(s,3H).13C NMR(101MHz,CDCl3)δ171.52,139.55,137.33,137.18,135.14,134.84,129.14,128.44,124.74,121.15,119.68,119.51,118.92,111.71,108.64,60.88,57.93,52Calculated values of 03,39.94,28.94,21.18 HRMS (ESI +) C23H25N2O2([M+H]+): 361.1911, measurement 361.1912.
Examples 4 to 4
Figure BDA0002197908600000121
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-methylbenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, after standing and liquid separation, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 80%, the melting point is 50-52 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselectivity excess of the product 99%, HPLC (Chiralpak AD-H plusAD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.238 nm); t is tr＝48.58 and 46.05min；[α]20 D＝-72.8(c 0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.30-7.26(m,3H),7.14-7.09(m,3H),6.86(t,J＝7.6Hz,1H),6.76(d,J＝8.0Hz,1H),6.01(ddd,J＝16.8,10.0,7.2Hz,1H),5.32(d,J＝10.0Hz,1H),5.22(s,1H),5.12(d,J＝16.8Hz,1H),4.16(d,J＝3.6Hz,1H),4.02-3.96(m,1H),3.78(s,3H),3.63(s,3H),2.34(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 171.52,139.55,137.33,137.18,135.14,134.84,129.14,128.44,124.74,121.15,119.68,119.51,118.92,111.71,108.64,60.88,57.93,52.03,39.94,28.94,21.18 HRMS (ESI +) C23H25N2O2([M+H]+): 361.1911, measurement 361.1912.
Example 5
Figure BDA0002197908600000131
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (m-methylbenzylideneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, after standing and liquid separation, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 85 percent, the melting point is 58-60 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AD-H plusAD-H, i-propanol/hexane. RTM. 2/98, flow rate 1.0mL/min,. lamda. 234nm) tr＝21.94 and 23.41min；[α]20 D＝+33.6(c 0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.27(d,J＝8.4Hz,1H),7.24-7.17(m,3H),7.14-7.09(m,1H),7.09-7.06(m,1H),6.88-6.83(m,2H),6.25(ddd,J＝17.2,10.0,6.8Hz,1H),5.37(s,1H),5.32(d,J＝10.0Hz,1H),5.14(d,J＝17.2Hz,1H),4.22(d,J＝6.4Hz,1H),3.94(d,J＝2.0Hz,1H),3.72(s,3H),3.66(s,3H),2.30(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 172.84,143.39,138.80,137.90,137.20,133.36,129.28,128.34,128.23,125.58,125.22,121.03,119.35,118.80,117.71,110.56,108.62,60.38,54.83,52.30,38.90,29.21,21.45 HRMS (ESI +) C23H25N2O2([M+H]+): 361.1911, measurement 361.1912.
Example 6
Figure BDA0002197908600000132
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (o-tolylmethyleneamino) methyl acetate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, after standing and separating, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 78%, the melting point is 50-52 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AD-H plusAD-H, i-propanol/hexane. RTM. 2/98, flow rate 1.0mL/min,. lamda. 234nm) tr＝16.94 and 18.81min；[α]20 D＝+74.7(c 0.7,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.0Hz,1H),7.22(d,J＝8.4Hz,1H),7.18(dd,J＝7.2,1.2Hz,1H),7.16-7.10(m,2H),7.04(t,J＝7.2Hz,1H),6.88-6.82(m,1H),6.71(d,J＝7.6Hz,1H),6.23(ddd,J＝17.2,10.0,6.8Hz,1H),5.65(brs,1H),5.32-5.27(m,1H),5.13(d,J＝17.2Hz,1H),4.22(d,J＝6.4Hz,1H),3.94(d,J＝2.0Hz,1H),3.73(s,3H),3.67(s,3H),2.60(brs,3H).13C NMR(101MHz,CDCl3) Calculated delta 172.76,140.53,138.60,137.19,133.73,130.32,128.64,127.33,126.18,125.02,121.07,119.35,118.80,117.80,110.65,108.65,60.50,52.28,38.76,29.25,19.09 HRMS (ESI +)C23H25N2O2([M+H]+): 361.1911, measurement 361.1914.
Example 7-1
Figure BDA0002197908600000141
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of methyl 2- (p-chlorobenzylideneamino) propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back-extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 80 percent, the melting point is 84-86 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 0.5 mL/min. lamda. 282nm) tr＝11.25 and 13.41min；[α]20 D＝+125.7(c 1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.37-7.32(m,2H),7.30-7.25(m,2H),7.24(t,J＝8.0Hz,1H),7.10(ddd,J＝8.0,6.8,1.2Hz,1H),6.88-6.81(m,1H),6.78(d,J＝7.6Hz,1H),6.07(ddd,J＝17.2,10.0,8.8Hz,1H),5.35(s,1H),5.29(m,2H),4.11(d,J＝8.8Hz,1H),3.66(s,3H),3.65(s,3H),1.38(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.12,142.72,137.47,136.83,135.71,133.10,130.02,128.56,124.85,121.06,119.03,118.83,118.34,109.09,108.77,62.45,55.24,52.41,43.40,28.98,25.27 HRMS (ESI +) C23H24ClN2O2([M+H]+): 395.1521, measurement 395.1524. Comparative example: cesium carbonate was replaced with sodium tert-butoxide, otherwise the conditions were the same as above, in 52% yield and the product was found to have a diastereoselective ratio of 3:1, enantioselective excesses 82% and 79%; cesium carbonate was replaced by potassium hydroxide under otherwise the same conditions as above in 31% yield and the product diastereoselective ratio was 14: 1, enantioselective excess 92%.
Example 7-2
Figure BDA0002197908600000142
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of methyl 2- (p-chlorobenzylideneamino) propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back-extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 77%, the melting point is 84-86 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 0.5 mL/min. lamda. 282nm) tr＝11.25 and 13.41min；[α]20 D＝-118.0(c 0.7,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.37-7.32(m,2H),7.30-7.25(m,2H),7.24(t,J＝8.0Hz,1H),7.10(ddd,J＝8.0,6.8,1.2Hz,1H),6.88-6.81(m,1H),6.78(d,J＝7.6Hz,1H),6.07(ddd,J＝17.2,10.0,8.8Hz,1H),5.35(s,1H),5.29(m,2H),4.11(d,J＝8.8Hz,1H),3.66(s,3H),3.65(s,3H),1.38(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.12,142.72,137.47,136.83,135.71,133.10,130.02,128.56,124.85,121.06,119.03,118.83,118.34,109.09,108.77,62.45,55.24,52.41,43.40,28.98,25.27 HRMS (ESI +) C23H24ClN2O2([M+H]+): 395.1521, measurement 395.1524.
Examples 7 to 3
Figure BDA0002197908600000151
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of methyl 2- (p-chlorobenzylideneamino) propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back-extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, wherein the yield is 76%, the melting point is 46-48 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.282 nm); t is tr＝6.85 and 8.55min；[α]20 D＝+252.2(c 0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.38-7.33(m,2H),7.32-7.25(m,3H),7.14(ddd,J＝8.4,7.2,1.2Hz,1H),6.93-6.85(m,1H),6.78(d,J＝8.0Hz,1H),5.94(ddd,J＝17.2,10.0,7.2Hz,1H),5.28-5.22(m,1H),5.17(s,1H),5.11-5.03(m,1H),3.75(s,3H),3.72(d,J＝6.8Hz,1H),3.63(s,3H),1.59(s,3H).13C NMR(101MHz,CDCl3)δ174.36,141.15,137.39,136.47,134.56,133.35,130.22,128.68,124.55,121.16,119.30,119.06,119.04,108.81,108.77,63.13,53.81,52.18,45.19,28.95,22.06.HRMS (ESI +) calculated value C23H24ClN2O2([M+H]+): 395.1521, measurement 395.1519.
Examples 7 to 4
Figure BDA0002197908600000152
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of methyl 2- (p-chlorobenzylideneamino) propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back-extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, wherein the yield is 75%, the melting point is 46-48 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.282 nm); t is tr＝6.85 and 8.55min；[α]20 D＝-268.3(c 1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.38-7.33(m,2H),7.32-7.25(m,3H),7.14(ddd,J＝8.4,7.2,1.2Hz,1H),6.93-6.85(m,1H),6.78(d,J＝8.0Hz,1H),5.94(ddd,J＝17.2,10.0,7.2Hz,1H),5.28-5.22(m,1H),5.17(s,1H),5.11-5.03(m,1H),3.75(s,3H),3.72(d,J＝6.8Hz,1H),3.63(s,3H),1.59(s,3H).13C NMR(101MHz,CDCl3)δ174.36,141.15,137.39,136.47,134.56,133.35,130.22,128.68,124.55,121.16,119.30,119.06,119.04,108.81,108.77,63.13,53.81,52.18,45.19,28.95,22.06.HRMS (ESI +) calculated value C23H24ClN2O2([M+H]+): 395.1521, measurement 395.1519.
Example 8
Figure BDA0002197908600000161
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of methyl 2- (m-chlorobenzylideneamino) propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, wherein the yield is 86%, the melting point is 56-58 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 0.5 mL/min. lamda. 234nm) tr＝10.67 and 12.02min；[α]20 D＝+124.5(c 1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.42(s,1H),7.32-7.29(m,1H),7.25-7.21(m,3H),7.10(ddd,J＝8.0,6.8,1.6Hz,1H),6.88-6.83(m,1H),6.83-6.79(m,1H),6.08(ddd,J＝17.2,10.0,8.8Hz,1H),5.35(s,1H),5.30(m,2H),4.11(d,J＝8.8Hz,1H)3.66(s,3H),3.64(s,3H),1.38(s,3H).13C NMR(101MHz,CDCl3)δ176.06,146.32,137.41,136.77,135.64,134.04,129.63,128.76,127.69,126.86,124.80,121.02,118.95,118.83,118.36,108.84,108.75,62.39,55.55,52.38,43.37,28Calculated values of HRMS (ESI +) C of 94,25.2323H24ClN2O2([M+H]+): 395.1521, measurement 395.1518.
Example 9
Figure BDA0002197908600000171
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of methyl 2- (o-chlorobenzylideneamino) propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 82%, the melting point is 58-60 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 0.5 mL/min. lamda. 234nm) tr＝9.51 and 10.65min；[α]20 D＝+170.0(c 1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.45-7.39(m,1H),7.26(d,J＝8.0Hz,1H),7.21-7.15(m,2H),7.14-7.07(m,2H),6.90-6.83(m,1H),6.78(d,J＝8.0Hz,1H),6.11-5.98(m,1H),5.93(s,1H),5.29(s,1H),5.28-5.23(m,1H),4.12(d,J＝8.4Hz,1H),3.68(s,3H),3.67(s,3H),1.39(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.16,140.64,137.44,136.78,136.39,133.78,130.55,129.16,128.57,127.26,124.79,121.01,119.26,118.80,118.20,108.75,108.27,62.44,52.34,51.39,43.34,28.99,25.12 HRMS (ESI +) C23H24ClN2O2([M+H]+): 395.1521, measurement 395.1522.
Example 10
Figure BDA0002197908600000172
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of methyl 2- (p-bromophenylmethyleneamino) propionate, 0.20mmol of N-methylindole-2-allylmethyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back-extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 79%, the melting point is 60-62 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 1.0 mL/min. lamda. 234nm) tr＝5.44 and 6.73min；[α]20 D＝+112.9(c 0.8,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.45-7.40(m,2H),7.31-7.27(m,2H),7.24(d,J＝8.4Hz,1H),7.10(ddd,J＝8.0,7.2,1.2Hz,1H),6.87-6.82(m,1H),6.78(d,J＝8.0Hz,1H),6.06(ddd,J＝17.2,10.0,8.8Hz,1H),5.34(s,1H),5.32-5.24(m,2H),4.11(d,J＝8.8Hz,1H),3.66(s,3H),3.65(s,3H),1.38(s,3H).13C NMR(101MHz,CDCl3) Calculated delta 176.09,143.21,137.42,136.78,135.69,131.49,130.38,124.80,121.27,121.05,119.00,118.82,118.35,108.96,108.76,62.41,55.26,52.41,43.36,28.96,25.25 HRMS (ESI +) C23H24BrN2O2([M+H]+): 439.1016, measurement 439.1022。
Example 11
Figure BDA0002197908600000181
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then 0.30mmol of 2- (benzylideneamino) methyl propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12h at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5min, after standing and liquid separation, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 10:1), a white solid is obtained, the yield is 93%, the melting point is 54-56 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 0.5 mL/min. lamda. 234nm) tr＝12.05 and 13.98min；[α]20 D＝+118.2(c0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.41(dd,J＝8.0,1.6Hz,2H),7.33-7.21(m,4H),7.08(ddd,J＝8.0,6.4,1.6Hz,1H),6.85-6.80(m,1H),6.79-6.77(m,1H),6.10(ddd,J＝17.2,10.0,8.8Hz,1H),5.36(s,1H),5.31-5.25(m,2H),4.12(d,J＝8.8Hz,1H),3.66(s,3H),3.66(s,3H),1.38(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.23,144.07,137.44,136.99,135.63,128.64,128.39,127.51,125.04,120.89,119.19,118.67,118.19,109.59,108.65,62.46,55.91,52.35,43.42,28.95,25.31 HRMS (ESI +) C23H25N2O2([M+H]+): 361.1911, measurement 361.1914.
Example 12
Figure BDA0002197908600000182
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then 0.30mmol2- (p-methyl benzylidene amino) methyl propionate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12h at 25 ℃, 2.0mL1N hydrochloric acid is added to quench the reaction for 5min, after standing and liquid separation, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 10:1), a white solid is obtained, the yield is 84%, the melting point is 50-52 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 1.0 mL/min. lamda. 234nm) tr＝4.51 and 5.38min；[α]20 D＝+116.5(c1.1,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.29(d,J＝8.0Hz,2H),7.22(d,J＝8.4Hz,1H),7.12-7.05(m,3H),6.86-6.79(m,2H),6.08(ddd,J＝17.2,10.0,8.8Hz,1H),5.33(s,1H),5.30-5.23(m,2H),4.11(d,J＝8.8Hz,1H),3.65(s,3H),3.64(s,3H),2.31(s,3H),1.37(s,3H).13C NMR(101MHz,CDCl3) Calculated delta 176.22,141.02,137.39,136.99,135.62,129.05,128.41,125.05,120.83,119.23,118.59,118.10,109.62,108.60,62.42,55.45,52.30,43.40,28.90,25.27,21.14 HRMS (ESI +) C24H27N2O2([M+H]+): 375.2067, measurement 375.2070.
Example 13
Figure BDA0002197908600000191
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (m-methylbenzylideneamino) methyl propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is subjected to back extraction by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 80%, the melting point is 60-62 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 0.5 mL/min. lamda. 234nm) tr＝9.55 and 11.24min；[α]20 D＝+121.9(c1.1,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.26-7.22(m,2H),7.21-7.17(m,2H),7.09(ddd,J＝8.4,6.0,2.4Hz,2H),6.86-6.78(m,2H),6.10(ddd,J＝17.2,10.0,8.8Hz,1H),5.32-5.24(m,3H),4.12(d,J＝8.8Hz,1H),3.67(s,3H),3.66(s,3H),2.31(s,3H),1.38(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.23,143.90,137.88,137.41,137.02,135.63,129.29,128.31,128.26,125.65,125.10,120.84,119.29,118.64,118.18,109.59,108.62,62.48,55.89,52.35,43.41,28.95,25.33,21.47 HRMS (ESI +) C24H27N2O2([M+H]+): 375.2067, measurement 375.2071.
Example 14
Figure BDA0002197908600000192
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (o-tolylmethyleneamino) methyl propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is subjected to back extraction by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, wherein the yield is 84%, the melting point is 54-56 ℃, and the diastereoselectivity ratio of the product is more than 20: the product was in 99% enantioselective excess, HPLC (Chiralpak IC plus IA, i-propanol/hexane. RTM. 1/99, flow rate 0.5 mL/min. lamda. 234nm) tr＝19.46 and 20.38min；[α]20 D＝+232.7(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.25(d,J＝8.4Hz,2H),7.16(t,J＝6.8Hz,2H),7.12-7.04(m,2H),6.82(t,J＝7.6Hz,1H),6.67(d,J＝7.6Hz,1H),6.07(ddd,J＝17.2,10.0,8.8Hz,1H),5.64(brs,1H),5.30-5.22(m,2H),4.12(d,J＝8.8Hz,1H),3.67(s,3H),3.67(s,3H),2.63(brs,3H),1.37(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.23,141.15,137.39,136.88,135.98,135.77,130.14,128.84,127.22,126.38,124.89,120.86,119.23,118.64,118.15,109.65,108.64,62.46,52.30,50.66,43.29,28.99,25.35,19.06.HRMS (ESI +) C24H27N2O2([M+H]+): 375.2067, measurement 375.2073.
Example 15
Figure BDA0002197908600000201
The preparation of (1):
0.003mmol of [ I ] was added to a 25mL reaction tuber(COD)Cl]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then 0.30mmol2- (p-methoxybenzylideneamino) methyl propionate, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12h at 40 ℃, 2.0mL1N hydrochloric acid is added for quenching reaction for 5min, after standing and liquid separation, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 10:1), a white solid is obtained, the yield is 88%, the melting point is 56-58 ℃, and the diastereoselectivity ratio of the product is more than 20: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 0.5 mL/min. lamda. 234nm) tr＝22.14 and 26.23min；[α]20 D＝+91.8(c0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.35-7.32(m,1H),7.32-7.30(m,1H),7.23(d,J＝8.8Hz,1H),7.09(ddd,J＝8.4,6.4,2.0Hz,1H),6.86-6.78(m,4H),6.08(ddd,J＝17.2,10.0,8.4Hz,1H),5.32(d,J＝0.8Hz,1H),5.31-5.23(m,2H),4.11(d,J＝8.4Hz,1H),3.77(s,3H),3.65(s,3H),3.65(s,3H),1.37(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.23,158.88,137.40,137.00,136.26,135.58,129.60,125.06,120.85,119.25,118.61,118.14,113.71,109.80,108.62,62.44,55.16,55.12,52.32,43.36,28.93,25.30 HRMS (ESI +) C24H27N2O3([M+H]+): 391.2016, measurement 391.2021.
Example 16
Figure BDA0002197908600000202
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra)-L1、0.5mL of dehydrated oxygen-removed THF and 0.5mL of oxygen-removed n-propylamine were reacted at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to obtain an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (2-naphthylmethyleneamino) methyl propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is subjected to reverse extraction by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 75%, the melting point is 136-: the enantioselectivity of the product was 99% excess, HPLC (Chiralpak AS-H, i-propanol/hexane. RTM. 2/98, flow rate 1.0 mL/min. lamda. 254nm) tr＝5.54 and 6.78min；[α]20 D＝-10.2(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.88-7.83(m,1H),7.81-7.77(m,1H),7.72(d,J＝8.4Hz,1H),7.50-7.41(m,3H),7.23(d,J＝8.4Hz,1H),7.06(ddd,J＝8.0,6.4,1.6Hz,1H),6.79-6.70(m,2H),6.16(ddd,J＝16.4,10.8,8.8Hz,1H),5.54(s,1H),5.34(s,1H),5.33-5.28(m,1H),4.16(d,J＝8.4Hz,1H),3.68(s,6H),1.40(s,3H).13C NMR(101MHz,CDCl3) Calculated delta 176.27,141.58,137.44,137.01,135.71,133.30,133.15,128.36,127.86,127.67,127.28,126.67,125.77,125.61,125.05,120.93,119.15,118.73,118.22,109.31,108.65,62.46,56.08,52.41,43.51,29.00,25.34 HRMS (ESI +) C27H27N2O2([M+H]+): 411.2067, measurement 411.2071.
Example 17
Figure BDA0002197908600000211
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra)-L1、05mL of dehydrated oxygen-removed THF and 0.5mL of oxygen-removed n-propylamine were reacted at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to obtain an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then 0.30mmol of 2- (2-furylmethyleneamino) methyl propionate, 0.20mmol of N-methylindole-2-allylmethyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, after standing and liquid separation, the aqueous phase is back-extracted with dichloromethane, the organic phase is combined and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 10:1), a white solid is obtained with the yield of 83 percent and the melting point of 52-54 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 234 nm); t is tr＝5.78 and 6.61min；[α]20 D＝+258.9(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.34(dd,J＝1.6,0.8Hz,1H),7.25(d,J＝8.4Hz,1H),7.16-7.09(m,2H),6.97-6.91(m,1H),6.34-6.27(m,2H),6.05(ddd,J＝17.2,10.0,8.4Hz,1H),5.58(s,1H),5.29(dd,J＝11.6,0.8Hz,1H),5.23(d,J＝17.2Hz,1H),4.10(d,J＝8.4Hz,1H),3.64(s,3H),3.63(s,3H),1.41(s,3H).13C NMR(101MHz,CDCl3) Calculated delta 175.96,156.06,142.07,137.33,136.10,135.63,124.93,121.09,118.94,118.88,118.81,109.95,108.79,107.19,106.94,62.33,52.42,48.84,43.10,28.91,25.13 HRMS (ESI +) C21H23N2O3([M+H]+): 351.1703, measurement 351.1698.
Example 18
Figure BDA0002197908600000212
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of THF (deoxygenated by removal of water) and 0.5mL of n-propylamine (deoxygenated) and reacted at 50 deg.CAfter 30 minutes, the solvent was distilled off under reduced pressure to obtain an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (2-thiophene methylene amino) methyl propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, the mixture is kept stand and separated, the water phase is subjected to back extraction by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 84%, the melting point is 56-58 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 234 nm); t is tr＝5.86 and 6.84min；[α]20 D＝+209.8(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.25-7.21(m,2H),7.19(d,J＝5.2Hz,1H),7.14-7.09(m,1H),7.05(d,J＝8.0Hz,1H),6.95(dd,J＝5.2,3.6Hz,1H),6.90(t,J＝7.2Hz,1H),6.09(ddd,J＝17.2,10.0,8.8Hz,1H),5.77(s,1H),5.30(dd,J＝10.0,1.2Hz,1H),5.28-5.23(m,1H),4.08(d,J＝8.8Hz,1H),3.64(s,3H),3.63(s,3H),1.39(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.10,149.42,137.39,136.45,135.16,125.83,125.25,125.18,125.07,121.03,118.92,118.84,118.50,109.50,108.76,62.50,52.40,50.80,43.42,28.91,25.11 HRMS (ESI +) C21H23N2O2S([M+H]+): 367.1475, measurement 367.1473.
Example 19
Figure BDA0002197908600000221
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of deoxygenated THF with removal of water and 0.5mL of n-propylamine with removal of oxygen, reaction at 50 ℃ for 30 minutes and evaporation of the solvent under reduced pressureThe agent gives iridium complexes. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then 0.30mmol of 2- (styrylmethyleneamino) methyl propionate, 0.20mmol of N-methylindole-2-allylmethyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in sequence at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back-extracted with dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 89%, the melting point is 60-62 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 254 nm); t is tr＝5.08 and 5.98min；[α]20 D＝+219.8(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.48(d,J＝8.0Hz,1H),7.42(d,J＝7.2Hz,2H),7.31-7.18(m,4H),7.17-7.12(m,1H),6.99-6.94(m,1H),6.87(d,J＝15.6Hz,1H),6.25(dd,J＝15.6,8.4Hz,1H),6.00(ddd,J＝17.2,10.0,8.4Hz,1H),5.28(dd,J＝10.0,1.6Hz,1H),5.19(d,J＝17.2Hz,1H),5.01(d,J＝8.4Hz,1H),4.07(d,J＝8.8Hz,1H),3.63(s,3H),3.62(s,3H),1.40(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.22,137.40,136.93,136.42,134.97,132.95,131.47,128.41,127.38,126.53,125.28,121.01,119.18,118.83,118.45,108.75,108.21,61.93,54.08,52.33,43.19,28.92,25.16 HRMS (ESI +) C25H27ClN2O2([M+H]+): 387.2067, measurement 387.2072.
Example 20
Figure BDA0002197908600000231
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of THF (deoxygenated by removal of water) and 0.5mL of n-propylamine (deoxygenated) and reacted at 50 ℃ for 30 minutes, followed by vacuum stripThe solvent was distilled off under vacuum to obtain an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then 0.30mmol of 2- (n-butylmethyleneamino) methyl propionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back extracted by dichloromethane, the organic phase is combined and dried to obtain a crude product, and a yellow oily liquid is obtained by silica gel column chromatography (petroleum ether/ethyl acetate 10:1), the yield is 83%, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak ID, i-propanol/hexane: 2/98, flow rate 0.5mL/min,. lambda.: 254 nm); t is tr＝9.14 and 9.70min；[α]20 D＝+387.8(c1.1,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.51(d,J＝7.6Hz,1H),7.26(d,J＝8.0Hz,1H),7.19-7.13(m,1H),7.08-7.01(m,1H),5.95(ddd,J＝17.2,10.0,8.8Hz,1H),5.23(dd,J＝10.0,1.6Hz,1H),5.15(d,J＝17.2Hz,1H),4.42(dd,J＝8.0,1.6Hz,1H),4.01(d,J＝8.4Hz,1H),3.60(s,3H),3.55(s,3H),2.12-2.03(m,1H),1.82-1.71(m,1H),1.50-1.38(m,2H),1.37(s,3H),1.34-1.25(m,2H),0.90(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.43,137.46,136.77,135.28,125.01,120.72,119.03,118.53,118.14,110.24,108.84,61.96,52.15,50.26,43.51,36.34,28.81,27.24,25.26,22.98,14.11 HRMS (ESI +) C21H29N2O2([M+H]+): 341.2224, measurement 341.2223.
Example 21
Figure BDA0002197908600000232
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of deoxygenated THF with removal of water and 0.5mL of deoxygenated n-propylamine, after 30 minutes of reaction at 50 ℃ under reduced pressureThe solvent is distilled off under the conditions to obtain the iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (p-chlorobenzylideneamino) propionic acid tert-butyl ester, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is subjected to back extraction by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 87%, the melting point is 46-48 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak OD-H, i-propanol/hexane: 2/98, flow rate 0.5mL/min,. lambda.238 nm); t is tr＝9.26 and 10.47min；[α]20 D＝+97.2(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.36-7.31(m,2H),7.29-7.25(m,2H),7.23(d,J＝8.4Hz,1H),7.09(ddd,J＝8.0,6.8,1.2Hz,1H),6.87-6.80(m,1H),6.78(d,J＝7.6Hz,1H),6.07(ddd,J＝17.2,10.0,8.4Hz,1H),5.35(s,1H),5.30-5.21(m,2H),4.03(d,J＝8.4Hz,1H),3.66(s,3H),1.35(s,3H),1.30(s,9H).13C NMR(101MHz,CDCl3) Calculated values of δ 174.65,142.89,137.36,137.23,136.24,132.98,129.95,128.52,124.89,120.86,118.88,118.71,117.93,108.83,108.61,81.22,62.67,55.31,43.45,28.82,27.89,24.76 HRMS (ESI +) C26H30ClN2O2([M+H]+): 437.1990, measurement 437.1997.
Example 22
Figure BDA0002197908600000241
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. In the other placeA25 mL reaction tube was charged with 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (p-chlorobenzylideneamino) n-butyric acid methyl ester, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is subjected to back extraction by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 85 percent, the melting point is 78-80 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.236 nm); t is tr＝4.75 and 5.49min；[α]20 D＝+96.9(c1.3,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.4Hz,2H),7.26(d,J＝8.4Hz,2H),7.23(d,J＝8.4Hz,1H),7.12-7.05(m,1H),6.84(t,J＝7.2Hz,1H),6.77(d,J＝7.6Hz,1H),6.06(ddd,J＝17.2,10.0,9.2Hz,1H),5.35-5.21(m,3H),4.15(d,J＝8.8Hz,1H),3.67(s,3H),3.63(s,3H),1.83(dq,J＝14.8,7.6Hz,1H),1.64(dq,J＝14.8,7.6Hz,1H),0.91(t,J＝7.6Hz,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 174.84,142.79,137.46,136.72,135.74,133.05,130.03,128.51,124.83,120.97,118.93,118.78,117.82,109.26,108.75,66.37,55.29,52.04,41.77,30.69,28.96,7.72 HRMS (ESI +) C24H26ClN2O2([M+H]+): 409.1677, measurement 409.1682.
Example 23
Figure BDA0002197908600000242
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. At the other oneA25 mL reaction tube was charged with 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (p-chlorobenzylideneamino) methyl phenylpropionate, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are sequentially added at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is subjected to back extraction by dichloromethane, the organic phase is combined and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid with the yield of 86 percent and the melting point of 74-76 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak IE, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.236 nm); t is tr＝7.40 and 8.79min；[α]20 D＝+11.2(c1.1,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.4Hz,2H),7.29-7.20(m,6H),7.11-7.05(m,3H),6.87-6.77(m,2H),6.23(dt,J＝17.2,9.6Hz,1H),5.41(d,J＝9.2Hz,1H),5.37(s,1H),5.31(s,1H),4.22(d,J＝9.2Hz,1H),3.65(s,3H),3.43(s,3H),3.08(d,J＝13.2Hz,1H),2.94(d,J＝13.2Hz,1H).13C NMR(101MHz,CDCl3) Calculated values of δ 174.32,143.15,137.49,137.16,135.58,135.10,132.92,130.13,129.68,128.44,128.39,127.17,124.83,121.10,118.97,118.81,118.40,109.50,108.76,66.95,55.16,51.71,44.51,43.96,28.98 HRMS (ESI +) C29H28ClN2O2([M+H]+): 471.1834, measurement 471.1830.
Example 24
Figure BDA0002197908600000251
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (p-chlorobenzylideneamino) -4- (methoxycarbonyl) n-butyric acid methyl ester, 0.20mmol of N-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, the mixture is separated after standing, the water phase is back extracted by dichloromethane, the organic phases are combined, dried and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, wherein the yield is 82%, the melting point is 76-78 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak IE, i-propanol/hexane: 5/95, flow rate 1.0mL/min,. lambda.236 nm); t is tr＝13.91 and 16.61min；[α]20 D＝+100.2(c0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.37-7.32(m,2H),7.30-7.25(m,2H),7.38(d,J＝8.4Hz,1H),7.13-7.07(m,1H),6.88-6.81(m,1H),6.78(d,J＝8.0Hz,1H),6.07(ddd,J＝17.2,10.0,9.2Hz,1H),5.33(m,3H),4.13(d,J＝8.8Hz,1H),3.66(s,3H),3.66(s,3H),3.63(s,3H),2.50-2.40(m,1H),2.39-2.30(m,1H),2.16-2.08(m,1H),2.03-1.94(m,1H).13C NMR(101MHz,CDCl3) Calculated values of δ 174.30,172.91,142.49,137.49,136.36,135.14,133.16,130.01,128.55,124.74,121.16,119.01,118.88,118.43,109.25,108.79,65.03,55.16,52.36,51.78,42.25,32.34,28.98,28.14 HRMS (ESI +) C26H28ClN2O4([M+H]+): 467.1732, measurement 467.1734.
Example 25
Figure BDA0002197908600000252
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol Cu(CH3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol2- (p-chlorobenzylideneamino) -gamma-butyrolactone, 0.20mmol N-methylindole-2-allyl methyl carbonate, 0.3mmol cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL1N hydrochloric acid is added for quenching reaction for 5 minutes, after standing, liquid separation is carried out, the aqueous phase is back extracted by dichloromethane, the organic phases are combined, dried and dried to obtain a crude product, and a white solid is obtained by silica gel column chromatography (petroleum ether/ethyl acetate 3:1), the yield is 81%, the melting point is 60-62 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 8/92, flow rate 1.0mL/min,. lambda.: 254 nm); t is tr＝28.69 and 34.54min；[α]20 D＝+58.3(c1.2,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.37-7.31(m,2H),7.31-7.27(m,2H),7.26(d,J＝8.4Hz,1H),7.14-7.07(m,1H),6.89-6.81(m,1H),6.69(d,J＝8.0Hz,1H),6.03(ddd,J＝17.6,10.0,8.0Hz,1H),5.35(dd,J＝10.0,0.8Hz,1H),5.25(s,1H),5.19(d,J＝13.2Hz,1H),4.40(td,J＝9.6,6.0Hz,1H),4.29(td,J＝8.4,2.4Hz,1H),3.62(s,3H),3.56(d,J＝7.6Hz,1H),2.46(ddd,J＝13.6,9.6,8.4Hz,1H),1.98(ddd,J＝13.6,6.0,2.4Hz,1H).13C NMR(101MHz,CDCl3) Calculated values of δ 174.88,141.15,137.38,135.68,133.53,133.40,130.17,128.74,124.59,121.07,119.39,119.31,118.94,109.70,108.78,64.88,60.68,55.03,41.42,36.21,29.24 HRMS (ESI +) C23H22ClN2O2([M+H]+): 393.1364, measurement 393.1358.
Example 26
Figure BDA0002197908600000261
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of THF and 0.5mL of n-propylamine, which were deoxygenated by removal of water and oxygen, reacted at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to obtain iridium complexA compound (I) is provided. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-chlorobenzylideneamino) methyl acetate, 0.20mmol N-methyl-5-methylindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12 hours at 18 ℃, 2.0mL1N hydrochloric acid is added for quenching reaction for 5 minutes, after standing, liquid separation is carried out, the water phase is back extracted by dichloromethane, the organic phases are combined, dried and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 92%, the melting point is 46-48 ℃, and the diastereoselectivity ratio of the product is 12: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 226 nm); t is tr＝10.57 and 14.27min；[α]20 D＝+97.1(c1.2,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.36-7.32(m,2H),7.29-7.24(m,2H),7.16(d,J＝8.4Hz,1H),6.96(dd,J＝8.4,1.2Hz,1H),6.62(s,1H),6.21(ddd,J＝17.2,10.0,6.8Hz,1H),5.38(s,1H),5.30(d,J＝10.0Hz,1H),5.11(d,J＝17.2Hz,1H),4.18(dd,J＝6.8,1.2Hz,1H),3.89(d,J＝2.4Hz,1H),3.70(s,3H),3.63(s,3H),2.26(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 172.72,142.25,138.65,135.64,133.55,133.06,129.95,128.53,128.24,125.16,122.77,118.69,117.73,109.38,108.49,60.16,54.12,52.29,39.03,29.28,21.32 HRMS (ESI +) C23H24ClN2O2([M+H]+): 395.1521, measurement 395.1515.
Example 27
Figure BDA0002197908600000271
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. At the other 250.01mmol of Cu (CH) was added to a mL reaction tube3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then at 25 ℃, 0.30mmol (p-chlorobenzylideneamino) methyl acetate, 0.20mmol N-methyl-5-chloroindole-2-allyl methyl carbonate, 0.3mmol diisopropylethylamine and the iridium complex are added in turn, after stirring for 12h at 18 ℃, 2.0mL1N hydrochloric acid is added for quenching reaction for 5min, after standing, liquid separation is carried out, the water phase is back extracted by dichloromethane, the organic phases are combined, dried and dried to obtain a crude product, and after silica gel column chromatography (petroleum ether/ethyl acetate 6:1), a white solid is obtained, the yield is 96%, the melting point is 56-58 ℃, and the diastereoselectivity ratio of the product is 14: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 238 nm); t is tr＝17.37 and 30.53min；[α]20 D＝+54.3(c1.1,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.34-7.31(m,2H),7.30-7.27(m,2H),7.17(d,J＝8.4Hz,1H),7.07(dd,J＝8.8,2.0Hz,1H),6.77(d,J＝2.0Hz,1H),6.22(ddd,J＝16.8,10.4,6.4Hz,1H),5.33(d,J＝10.4Hz,2H),5.12(d,J＝16.8Hz,1H),4.19(d,J＝6.4Hz,1H),3.91(d,J＝2.0Hz,1H),3.72(s,3H),3.64(s,3H).13C NMR(101MHz,CDCl3) Calculated δ 172.66,141.71,138.33,135.68,134.95,133.41,129.85,128.72,125.91,124.73,121.48,118.36,117.94,109.81,109.76,60.14,53.97,52.39,39.01,29.45 HRMS (ESI +) values C22H21Cl2N2O2([M+H]+): 415.0975, measurement 415.0977.
Example 28
Figure BDA0002197908600000272
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (p-chlorobenzylideneamino) methyl propionate, 0.20mmol of N-methyl-4-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, standing is carried out, liquid separation is carried out, the water phase is subjected to reverse extraction by dichloromethane, the organic phase is combined, drying and spin-drying are carried out, a crude product is obtained, and a white solid is obtained by silica gel column chromatography (petroleum ether/ethyl acetate 10:1), the yield is 85%, the melting point is 76-78 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 238 nm); t is tr＝5.24 and 6.64min；[α]20 D＝+131.0(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.28-7.21(m,2H),7.20-7.16(m,2H),7.11(d,J＝8.0Hz,1H),7.05-7.00(m,1H),6.66(d,J＝7.2Hz,1H),6.01(ddd,J＝17.2,10.0,8.4Hz,1H),5.68(s,1H),5.23-5.31(m,2H),4.09(d,J＝8.4Hz,1H),3.65(s,3H),3.62(s,3H),1.88(s,3H),1.34(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 175.90,145.14,137.86,136.45,136.37,132.89,130.38,129.40,128.74,124.54,121.45,120.64,118.64,108.70,106.46,62.31,55.89,52.39,43.89,28.93,24.95,21.06.HRMS (ESI +) C24H26ClN2O2([M+H]+): 409.1677, measurement 409.1679.
Example 29
Figure BDA0002197908600000281
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p)-L2, under the protection of nitrogen, 1mL of dichloromethane is added, and the mixture is stirred at room temperature for half an hour. Then, 0.30mmol of 2- (p-chlorobenzylideneamino) methyl propionate, 0.20mmol of N-methyl-5-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn at 25 ℃, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, standing is carried out, liquid separation is carried out, the water phase is subjected to back extraction by dichloromethane, the organic phase is combined, dried and dried in a spinning manner to obtain a crude product, and a white solid is obtained by silica gel column chromatography (petroleum ether/ethyl acetate 10:1), the yield is 84%, the melting point is 72-74 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 238 nm); t is tr＝4.53 and 5.32min；[α]20 D＝+141.3(c0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),7.12(d,J＝8.4Hz,1H),6.92(d,J＝8.4Hz,1H),6.56(s,1H),6.13-5.99(m,1H),5.33(s,1H),5.31-5.20(m,2H),4.08(d,J＝8.4Hz,1H),3.63(s,3H),3.62(s,3H),2.24(s,3H),1.36(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.07,142.84,136.84,135.88,135.79,133.00,129.97,128.54,128.03,125.04,122.57,118.67,118.24,108.46,108.43,62.42,55.21,52.33,43.42,28.95,25.22,21.32 HRMS (ESI +) C24H26ClN2O2([M+H]+): 409.1677, measurement 409.1682.
Example 30
Figure BDA0002197908600000282
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. However, the device is not suitable for use in a kitchenThen at 25 ℃, 0.30mmol of 2- (p-chlorobenzylideneamino) methyl propionate, 0.20mmol of N-methyl-6-methylindole-2-allyl methyl carbonate, 0.3mmol of cesium carbonate and the iridium complex are added in turn, after stirring for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added for quenching reaction for 5 minutes, the mixture is kept stand and separated, the aqueous phase is back extracted by dichloromethane, the organic phases are combined and dried, and a crude product is obtained, and the crude product is chromatographed by a silica gel column (petroleum ether/ethyl acetate 10:1) to obtain a white solid, the yield is 88%, the melting point is 70-72 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 238 nm); t is tr＝4.66 and 5.71min；[α]20 D＝+113.3(c1.3,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.38-7.31(m,2H),7.30-7.23(m,2H),7.04(s,1H),6.72-6.62(m,2H),6.06(ddd,J＝17.2,10.0,8.8Hz,1H),5.34(s,1H),5.32-5.21(m,2H),4.09(d,J＝8.8Hz,1H),3.64(s,3H),3.62(s,3H),2.41(s,3H),1.37(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.12,142.81,137.87,136.92,135.09,133.03,130.93,129.99,128.53,122.69,120.44,118.65,118.22,108.94,108.91,62.45,55.21,52.36,43.36,28.88,25.26,21.76 HRMS (ESI +) C24H26ClN2O2([M+H]+): 409.1677, measurement 409.1676.
Example 31
Figure BDA0002197908600000291
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then 0.30mmol of 2- (p-chlorobenzylideneamino) propionic acid methyl ester, 0.20mmol of N-methyl-7 are added in that order at 25 DEG C-methylindole-2-allyl methyl carbonate, 0.3mmol cesium carbonate and the iridium complex, stirring at 25 ℃ for 12h, adding 2.0mL1N hydrochloric acid to quench the reaction for 5min, standing, separating the liquid, back-extracting the aqueous phase with dichloromethane, combining the organic phases, drying and spin-drying to obtain a crude product, and performing silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid with a yield of 95% and a melting point of 70-72 ℃, wherein the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 238 nm); t is tr＝5.24 and 6.13min；[α]20 D＝+40.9(c0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.4Hz,2H),7.25(d,J＝8.4Hz,2H),6.78(d,J＝6.8Hz,1H),6.69(t,J＝7.6Hz,1H),6.59(d,J＝8.0Hz,1H),6.06(ddd,J＝17.2,10.0,8.4Hz,1H),5.35-5.21(m,3H),4.08(d,J＝8.4Hz,1H),3.92(s,3H),3.65(s,3H),2.73(s,3H),1.37(s,3H).13C NMR(101MHz,CDCl3) Calculated δ 176.09,142.76,136.84,136.29,136.19,133.03,130.01,128.54,125.62,124.26,120.73,118.91,118.40,117.12,109.10,62.53,55.15,52.37,43.39,32.04,25.28,20.34 HRMS (ESI +) C24H26ClN2O2([M+H]+): 409.1677, measurement 409.1677.
Example 32
Figure BDA0002197908600000292
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then 0.30mmol of 2- (p-chlorobenzylideneamino) propionic acid methyl ester, 0.20mmol of N-methyl-5-chloroindole-2-allylcarbonic acid methyl ester, 0.3mmol of cesium carbonate and the above iridium were added in that order at 25 deg.CAnd (2) after the complex is stirred for 12 hours at 25 ℃, 2.0mL of 1N hydrochloric acid is added to quench the reaction for 5 minutes, the mixture is kept stand and separated, the water phase is back-extracted by dichloromethane, the organic phase is combined, dried and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain a white solid, wherein the yield is 93%, the melting point is 54-56 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 248 nm); t is tr＝5.82 and 7.05min；[α]20 D＝+181.9(c1.2,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.35-7.30(m,2H),7.30-7.26(m,2H),7.14(d,J＝8.8Hz,1H),7.04(dd,J＝8.8,2.0Hz,1H),6.73(d,J＝2.0Hz,1H),6.06(ddd,J＝17.2,10.0,8.8Hz,1H),5.32(dd,J＝10.0,1.2Hz,1H),5.29-5.24(m,2H),4.09(d,J＝8.8Hz,1H),3.65(s,3H),3.64(s,3H),1.37(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 176.00,142.22,137.18,136.48,135.90,133.35,129.86,128.72,125.79,124.56,121.30,118.62,118.30,109.78,108.81,62.40,55.05,52.43,43.54,29.14,25.11 HRMS (ESI +) C23H23Cl2N2O2([M+H]+): 429.1131, measurement 429.1132.
Example 33
Figure BDA0002197908600000301
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(R,Ra) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (S, S)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (p-chlorobenzylideneamino) propionic acid methyl ester, 0.20mmol of N-methyl-5-bromoindole-2-allylcarbonic acid methyl ester, 0.3mmol of cesium carbonate and the above iridium complex were added in this order at 25 ℃ and, after stirring at 25 ℃ for 12 hours, 2.0mL of 1N salt was addedQuenching reaction with acid for 5min, standing, separating, back-extracting water phase with dichloromethane, mixing organic phases, drying, and spin-drying to obtain crude product, and performing silica gel column chromatography (petroleum ether/ethyl acetate 10:1) to obtain white solid with yield of 80%, melting point of 66-68 deg.C, and diastereoselectivity ratio of product of > 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AS-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 246 nm); t is tr＝5.81 and 7.19min；[α]20 D＝+395.6(c0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.35-7.30(m,2H),7.30-7.26(m,2H),7.16(dd,J＝8.8,2.0Hz,1H),7.09(d,J＝8.8Hz,1H),6.89(d,J＝2.0Hz,1H),6.05(ddd,J＝17.2,10.0,8.8Hz,1H),5.32(dd,J＝10.0,1.6Hz,1H),5.30-5.23(m,2H),4.09(d,J＝8.7Hz,1H),3.65(s,3H),3.63(s,3H),1.37(s,3H).13C NMR(101MHz,CDCl3) Calculated values of δ 175.96,142.19,137.04,136.43,136.15,133.33,129.83,128.70,126.44,123.86,121.32,118.64,112.15,110.25,108.72,62.38,55.01,52.42,43.50,29.11,25.08 HRMS (ESI +) C23H23BrClN2O2([M+H]+): 473.0626, measurement 473.0625.
Example 34
Figure BDA0002197908600000302
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2、0.006mmol(S,Sa) L1, 0.5mL of water-and oxygen-scavenging THF and 0.5mL of oxygen-scavenging n-propylamine, the reaction was carried out at 50 ℃ for 30 minutes, and then the solvent was distilled off under reduced pressure to give an iridium complex. To a 25mL reaction tube was added 0.01mmol of Cu (CH)3CN)4BF4And 0.011mmol (R, R)p) L2, 1mL dichloromethane was added under nitrogen, and the mixture was stirred at room temperature for half an hour. Then, 0.30mmol of 2- (p-chlorobenzylideneamino) methyl propionate, 0.20mmol of N-methyl-5-bromoindole-2-allylmethyl carbonate, 0.3mmol of cesium carbonate and the above iridium complex were added in this order at 25 ℃ and stirred at 25 ℃ for 12 hours, 2.0mL of 2N hydrochloric acid was added, stirring was continued at room temperature for 3 hours, and after standing, liquid separation was carried outThe aqueous phase is back-extracted with dichloromethane, the organic phases are combined, dried and dried to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 8:1) to obtain a white solid with the yield of 46 percent, the melting point of 56-58 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 226 nm); t is tr＝5.68 and 16.35min；[α]20 D＝-166.3(c0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.60(d,J＝7.2Hz,2H),7.36-7.24(m,4H),7.21-7.16(m,3H),7.11(t,J＝7.6Hz,1H),7.09-7.03(m,2H),6.81(t,J＝7.6Hz,1H),6.60(d,J＝8.0Hz,1H),5.76(ddd,J＝18.0,10.0,8.4Hz,1H),5.24-5.13(m,2H),4.12(t,J＝8.4Hz,1H),3.70(s,3H),3.64(s,3H),3.61(d,J＝8.4Hz,1H).13C NMR(101MHz,CDCl3) Calculated δ 172.69,146.33,144.40,137.61,137.06,135.00,128.99,128.59,127.99,127.88,127.10,127.01,126.20,120.95,120.50,119.27,118.54,116.21,108.65,65.20,59.94,52.01,41.26,30.70 HRMS (ESI +) C28H26N2O2([M+H]+): 423.2067, measurement 423.2061.
Example 35
Figure BDA0002197908600000311
The preparation of (1):
0.2mmol of the chiral poly-substituted tetrahydro-gamma-carboline obtained in example 1-1 and 2mLCH were added to a 25mL reaction tube2N2Solution (0.5mol/L ether solution), 0.002mmol of Pd (OAc) was added at-20 deg.C2As a catalyst, the reaction mixture was allowed to stand at room temperature after 1 hour and reacted overnight. After the reaction is finished, the solvent is evaporated under the reduced pressure to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 6:1) to obtain a white solid with the yield of 94 percent and the melting point of 62-64 ℃, wherein the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.282 nm); t is tr＝16.28 and 21.08min；[α]20 D＝+11.8(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.4Hz,2H),7.29-7.25(m,3H),7.12(t,J＝7.2Hz,1H),6.86(t,J＝7.2Hz,1H),6.78(d,J＝8.0Hz,1H),5.44(s,1H),4.12(d,J＝1.2Hz,1H),3.75(s,3H),3.65(s,3H),2.87(d,J＝9.2Hz,1H),2.27(brs,1H),1.46-1.38(m,1H),0.83-0.72(m,2H),0.71-0.62(m,1H),0.37(td,J＝10.0,5.2Hz,1H).13C NMR(101MHz,CDCl3) Calculated values of δ 173.33,142.79,137.33,136.37,133.08,129.99,128.58,125.05,121.13,119.02,118.93,109.04,108.85,61.48,54.47,52.16,38.96,30.09,17.27,6.75,3.77 HRMS (ESI +) C23H24ClN2O2([M+H]+): 395.1521, measurement 395.1513.
Example 36
Figure BDA0002197908600000312
The preparation of (1):
0.2mmol of the chiral poly-substituted tetrahydro- γ -carboline obtained in example 1-1 and 0.002mmol of Pd/C catalyst (10% Pd content) were added to a 25mL reaction tube, and 2mL of methanol was added thereto as a solvent, and hydrogen gas at 1 atm was substituted and added thereto at room temperature, and the reaction was terminated after 6 hours. The Pd/C catalyst is removed by suction filtration with kieselguhr, the solvent is evaporated under reduced pressure to obtain a crude product, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate 6:1) to obtain a white solid, wherein the yield is 98 percent, the melting point is 56-58 ℃, and the diastereoselectivity ratio of the product is more than 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak IE, i-propanol/hexane: 2/98, flow rate 1.0mL/min,. lambda.: 232 nm); t is tr＝9.86 and 10.79min；[α]20 D＝-30.6(c0.8,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.0Hz,2H),7.27(d,J＝8.0Hz,2H),7.24(s,1H),7.10(t,J＝7.6Hz,1H),6.85(t,J＝7.6Hz,1H),6.77(d,J＝8.0Hz,1H),5.41(s,1H),3.97(s,1H),3.70(s,3H),3.68(s,3H),3.37(d,J＝9.2Hz,1H),2.09-2.01(m,1H),1.94-1.85(m,1H),1.16(t,J＝7.6Hz,3H).13C NMR(101MHz,CDCl3)δ173.98,142.89,137.20,136.94,133.03,129.99,128.52,125.06,120.95,118.91,118.90,108.84,108.71,57.47,54.27,52.18,36.02,29.19,27Calculated values of HRMS (ESI +). 32,12.5322H23ClN2O2([M+H]+): 383.1521, measurement 383.1506.
Example 37
Figure BDA0002197908600000321
The preparation of (1):
0.2mmol of chiral poly-substituted tetrahydro-gamma-carboline obtained in example 1-1 was added to a 25mL reaction tube, 2mL of anhydrous tetrahydrofuran was added thereto as a solvent, the system was cooled to-40 ℃, 0.6mmol of diisobutylaluminum hydride (1.5mol/L toluene solution) was added thereto as a reducing agent, and the reaction was terminated after 3 hours at room temperature. Quenching the reaction system with ice water, separating the extracts, collecting the organic phases, combining the phases, evaporating the solvent under reduced pressure to obtain a crude product, which is subjected to silica gel column chromatography (pure ethyl acetate) to obtain a white solid with a yield of 97%, a melting point of 52-54 ℃ and a diastereoselectivity ratio of > 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak AD-H, i-propanol/hexane: 15/85, flow rate 1.0mL/min,. lambda.282 nm); t is tr＝12.37 and 17.49min；[α]20 D＝+113.0(c1.4,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.31-7.23(m,5H),7.20-7.14(m,1H),6.98-6.90(m,2H),5.95(ddd,J＝17.2,10.0,7.2Hz,1H),5.28(d,J＝10.0Hz,1H),5.24(s,1H),5.06(d,J＝17.2Hz,1H),3.70-3.64(m,2H),3.60(s,3H),3.47-3.40(m,1H),3.13-3.04(m,1H).13C NMR(101MHz,CDCl3) Calculated values of δ 141.19,138.60,137.20,134.88,133.16,129.85,128.57,124.98,121.30,119.16,118.91,118.16,109.94,108.82,62.19,57.23,52.94,39.12,29.71 HRMS (ESI +) C29H28ClN2O2([M+H]+): 353.1415, measurement 353.1400.
Example 38
Figure BDA0002197908600000322
The preparation of (1):
0.003mmol of [ Ir (COD) Cl was added to a 25mL reaction tube]2And 0.006mmol of bis (diphenylphosphino) methane (dppm) and 2mL of anhydrous dichloromethane, and after stirring for 30 minutes, 0.2mmol of the chiral poly-substituted tetrahydro- γ -carboline obtained in example 1-1 and 0.4mmol of pinacolborane (HBpin) were added thereto, and the reaction was terminated after 12 hours at room temperature. The reaction was quenched with 2mL of methanol, the solvent was evaporated under reduced pressure to give the crude product, which was chromatographed on silica gel (petroleum ether/ethyl acetate 3:1 with 1% methanol added) to give a white solid in 86% yield, melting point 68-70 ℃, diastereoselectivity ratio of product > 20: 1, enantioselective excess of product 99%, HPLC (Chiralpak OD-H, i-propanol/hexane: 5/95, flow rate 1.0mL/min,. lambda.: 228 nm); t is tr＝9.62 and 15.53min；[α]20 D＝-32.3(c 0.9,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.38-7.33(m,2H),7.28-7.25(m,2H),7.24(d,J＝8.0Hz,1H),7.09(ddd,J＝8.0,6.8,1.2Hz,1H),6.84(ddd,J＝8.0,6.8,1.2Hz,1H),6.74(dt,J＝8.0,0.8Hz,1H),5.41(d,J＝1.2Hz,1H),3.99(d,J＝2.0Hz,1H),3.75(s,3H),3.66(s,3H),3.45(ddd,J＝8.8,3.6,1.6Hz,1H),2.12-2.04(m,1H),2.03-1.96(m,1H),1.27(s,12H).13C NMR(101MHz,CDCl3) Calculated values of δ 174.02,142.89,137.22,137.07,132.99,130.04,128.50,125.05,120.86,118.88,118.82,108.74,108.68,83.26,57.10,54.26,52.10,36.07,29.16,28.32,24.94,24.79 HRMS (ESI +) C28H35BClN2O4([M+H]+): 509.2373, measurement 509.2381.

Claims (1)

1. A preparation method of polysubstituted tetrahydro-gamma-carboline derivatives with a plurality of chiral centers is characterized in that: the method comprises the following steps: under the conditions of an iridium catalyst and a ligand L1, a copper catalyst and a ligand L2, and in the presence of alkali, carrying out catalytic reaction on a substrate-1 and a substrate-2 to obtain a polysubstituted tetrahydro-gamma-carboline derivative shown in a formula I;
the synthesis steps of the catalytic reaction are as follows: reacting a substrate-1, a substrate-2, an iridium catalyst and ligand L1, a copper catalyst and ligand L2 in a solvent at 15-50 ℃ for 12-24 hours in the presence of 1-10 equivalent of alkali; the concentrations of the substrate-1 and the substrate-2 are respectively 0.001-3.0M; the molar ratio of the substrate-1 to the substrate-2 is 1: 10-10: 1; the dosage of the iridium catalyst is 0.0001-10 mol% of the lower concentration of the substrate-1 or the substrate-2; the dosage of the ligand L1 is 0.0001-10 mol% of the lower concentration of the substrate-1 or the substrate-2; the dosage of the copper catalyst is 0.001-30 mol% of the lower concentration of the substrate-1 or the substrate-2; the dosage of the ligand L2 is 0.001-30 mol% of the lower concentration of the substrate-1 or the substrate-2;
the reaction formula of the preparation method of the polysubstituted tetrahydro-gamma-carboline derivative is as follows:
Figure DEST_PATH_IMAGE001
wherein R is1Is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, chain alkyl or alkenyl; the substituted or unsubstituted unsaturated heterocyclic aryl contains a heteroatom of O or S; the substituent of the substituted aryl is alkyl, alkoxy and halogen;
R2is H or phenyl;
R3is H, chain alkyl, benzyl or ester substituent;
R4is methyl, tert-butyl or cyclic lactone group;
R5is H, methyl or halogen;
R6is methyl or benzyl;
LG is OCO2Me、OBoc、OP(O)(OEt)2Or OP (O) i Pr)2；
The ligand L1 has a structural formula as follows:
Figure DEST_PATH_IMAGE003
、
Figure 503521DEST_PATH_IMAGE004
or
Figure DEST_PATH_IMAGE005
；
The structural formula of the chiral ligand L2 is as follows:
Figure DEST_PATH_IMAGE007
、
Figure DEST_PATH_IMAGE009
、
Figure DEST_PATH_IMAGE011
；
the copper catalyst can be Cu (MeCN)4BF4、Cu(MeCN)4ClO4Or Cu (MeCN)4PF6Any one of the above;
the iridium catalyst is [ Ir (COD) Cl]2、[Ir(DBCOT)Cl]2Or [ Ir (COD) OMe]2Any one of the above;
the alkali is any one of alkali metal salt of alcohol, alkali metal salt of amine, alkali metal carbonate, alkali metal hydroxide or organic alkali.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048175A1 (en) * 2001-12-01 2003-06-12 Eidgenössische Technische Hochschule Zürich Ethz Ligands for use in catalytic processes
WO2015137496A1 (en) * 2014-03-14 2015-09-17 武田薬品工業株式会社 Process for producing heterocyclic compound
CN109836457A (en) * 2017-11-24 2019-06-04 中国科学院大连化学物理研究所 A kind of high steric-hindrance amino chirality P, N, N ligand and its preparation method and application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048175A1 (en) * 2001-12-01 2003-06-12 Eidgenössische Technische Hochschule Zürich Ethz Ligands for use in catalytic processes
CN1599743A (en) * 2001-12-01 2005-03-23 苏黎世联邦理工学院 Ligands for use in catalytic processes
WO2015137496A1 (en) * 2014-03-14 2015-09-17 武田薬品工業株式会社 Process for producing heterocyclic compound
CN106458897A (en) * 2014-03-14 2017-02-22 武田药品工业株式会社 Process for producing heterocyclic compound
CN109836457A (en) * 2017-11-24 2019-06-04 中国科学院大连化学物理研究所 A kind of high steric-hindrance amino chirality P, N, N ligand and its preparation method and application

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Cu(I)-Catalyzed Chemoselective and Stereoselective [3 + 3] Cycloaddition of Azomethine Ylides with 2‑Indolylnitroethylenes: Facile Access to Highly Substituted Tetrahydro-γ-Carbolines;Wu-Lin Yang等;《ACS Catal.》;20160727;第6卷;5685-5690 *
Stereodivergent Synthesis of α,α-Disubstituted α‑Amino Acids via Synergistic Cu/Ir Catalysis;Liang Wei等;《J. Am. Chem. Soc.》;20180105;第140卷;1508-1513 *
Wu-Lin Yang等.Cu(I)-Catalyzed Chemoselective and Stereoselective [3 + 3] Cycloaddition of Azomethine Ylides with 2‑Indolylnitroethylenes: Facile Access to Highly Substituted Tetrahydro-γ-Carbolines.《ACS Catal.》.2016,第6卷 *

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