CN112479982B - Preparation method of chiral indole-2,3-octatomic carbocyclic compound - Google Patents

Preparation method of chiral indole-2,3-octatomic carbocyclic compound Download PDF

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CN112479982B
CN112479982B CN202011448322.4A CN202011448322A CN112479982B CN 112479982 B CN112479982 B CN 112479982B CN 202011448322 A CN202011448322 A CN 202011448322A CN 112479982 B CN112479982 B CN 112479982B
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贾义霞
张禹
钟超
梁仁校
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses a preparation method of a chiral indole-2,3-octatomic carbocyclic compound, which comprises the following steps: palladium is used as a catalyst, and the corresponding chiral indole-2,3-octamembered carbocyclic compound is generated by the combined action of a ligand and a silver salt in an organic solvent at the temperature of room temperature to 100 ℃. The invention takes easily prepared 2- (2-iodoarylamino) cycloocta-1-ene-1-carboxylic ester derivative as a raw material, and realizes the rapid construction of the chiral indole-2,3-octatomic carbocyclic compound by constructing a ring and a chemical bond in one step and establishing a chiral center on the indole C2 benzyl position. The method has the advantages of mild reaction conditions, simple and convenient operation, easily obtained reaction raw materials, wide substrate applicability, excellent yield and enantioselectivity, easy separation of target products and the like.

Description

Preparation method of chiral indole-2,3-octatomic carbocyclic compound
Technical Field
The invention belongs to the technical field of asymmetric catalytic synthesis, and relates to a preparation method of a chiral indole-2,3-octatomic carbocyclic compound, in particular to a method for synthesizing a chiral indole-2,3-octatomic carbocyclic compound by palladium catalysis of 2- (2-iodoarylamino) cycloocta-1-ene-1-carboxylic ester through olefin isomerization/intramolecular asymmetric arylation.
Background
Indole 2,3-fused ring structure compounds are ubiquitous in natural products and bioactive molecules, and have attracted much attention in the fields of medicines, pesticides, dyes, biology, etc., and several compounds having the structure represented by formula (1) have been one of the subjects of research by organic synthetic chemists. In recent years, many literature reports have been made on the synthesis of chiral indole 2,3-fused ring compounds using different reaction strategies. Wherein, the asymmetric cycloaddition, asymmetric aromatic hydrogenation or asymmetric allylation reaction of branched-chain substituted indole catalyzed by transition metal or organic micromolecule is a general method for synthesizing chiral 2,3-cycloindole. For example, using the strategy of asymmetric cycloaddition, prolinol catalyzes the asymmetric Diels-Alder reaction of 2-alkenyl indole and trans-cinnamaldehyde; the asymmetric aromatic hydrogenation reaction of the 1-methyl-2- (4-pentenyl) -indole derivative catalyzed by the optically pure platinum-BIPHEP complex is realized by utilizing the strategy of asymmetric aromatic hydrogenation reaction; and an asymmetric allylation reaction strategy is utilized to realize the asymmetric allylation alkylation reaction catalyzed by palladium acetate-chiral phosphite ester.
Figure GDA0003851070020000021
Unfortunately, in the literature, branched substituted indole is generally used as a substrate, the nucleophilic property of an indole ring is utilized, the construction of an indole-2,3-fused ring compound is realized through strategies such as asymmetric hydrogenation, asymmetric cycloaddition, asymmetric allylation and the like, most of the obtained chiral indole fused ring derivatives are indole-2,3-fused six-membered ring or-fused five-membered ring compounds, and the synthesis of chiral indole-2,3-fused eight-membered ring cannot be realized through similar strategies.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a preparation method of a chiral indole-2,3-octatomic carbocyclic compound, which utilizes easily prepared reaction raw materials to synthesize the chiral indole-2,3-octatomic carbocyclic compound containing a C2 benzyl chiral center in one step with high efficiency through a palladium-catalyzed enamine isomerization/intramolecular asymmetric arylation reaction process.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized in that 2- (2-iodoarylamino) cycloocta-1-ene-1-carboxylic ester shown in the formula (1) is used as a raw material, the raw material reacts in an organic solvent at the temperature of room temperature to 100 ℃ under the combined action of a ligand and a silver salt in the presence of a palladium catalyst, and after the reaction is finished, the chiral indole-2,3-octatomic carbocyclic compound shown in the formula (2) is obtained through post-treatment, and the reaction general formula is as follows:
Figure GDA0003851070020000022
in the formula: r 1 One selected from alkyl, alkoxy or halogen; r 2 Is an alkyl group.
The preparation method of the chiral indole-2,3-octamembered carbocyclic compound is characterized in that R 1 、R 2 The alkyl in (A) is selected from C1-C10 straight-chain or branched-chain alkane; r 1 The alkoxy in (1) is selected from C1-C10 linear or branched chain alkoxy; r 1 The halogen in (A) is selected from one or two of fluorine, chlorine or bromine.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized in that the organic solvent is selected from tetrahydrofuran, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, toluene, m-xylene, dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, and the volume ratio of the organic solvent to the 2- (2-iodoarylamino) cycloocta-1-ene-1-carboxylic ester derivative is 1-100: volume is in ml and amount of substance is in mmol.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized in that a palladium catalyst is selected from any one of palladium bis (dibenzylideneacetone), palladium tris (dibenzylideneacetone), palladium acetate, allyl palladium chloride dimer, diacetonitrile palladium dichloride, palladium chloride, palladium iodide and palladium acetylacetonate.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized in that a ligand is selected from any one of (S) -BINAP, (S) -SegPhos, (S) -SynPhos, (S) -MeO-BIPHEP, (S) -DTBM-SegPhos, (S) -SDP and (S) -DiFluorPhos.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized in that the silver salt is any one of silver phosphate, silver carbonate, silver acetate, silver trifluoromethanesulfonate, silver tetrafluoroborate and silver nitrate.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized in that the molar ratio of 2- (2-iodoarylamino) cycloocta-1-ene-1-carboxylate to palladium catalyst, ligand and silver salt is 1:0.1 to 0.4:0.1 to 0.4:1 to 5.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized in that the reaction temperature is 40-80 ℃, and the reaction time is 0.1-72h, preferably 5h.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized by comprising the following post-treatment steps: after the reaction is finished, slowly dropwise adding acetic acid and ice water mixed solution under the ice bath condition until the solid is completely dissolved, then adding ethyl acetate to extract the water phase for three times, combining the organic phases, adding saturated salt solution to wash, removing the solvent by rotary evaporation, and then carrying out column chromatography separation to obtain a target product, wherein the mobile phase of the column chromatography is 20-100: 1 petroleum ether and ethyl acetate.
The preparation method of the chiral indole-2,3-octatomic carbocyclic compound is characterized in that in a mixed liquid of acetic acid and ice water, the volume ratio of the acetic acid to the ice water is 1:10-10:1, the dropping speed is 10 to 50 drops/min.
By adopting the technology, compared with the prior art, the invention has the following beneficial effects:
the chiral indole-2,3-octatomic carbocyclic compound is efficiently synthesized in one step by taking 2- (2-iodoarylamino) cycloocta-1-ene-1-carboxylic ester as a raw material and under the combined action of a palladium catalyst, a ligand, a silver salt and the like and catalyzing the 2- (2-iodoarylamino) cycloocta-1-ene-1-carboxylic ester derivative through palladium through enamine isomerization/intramolecular asymmetric arylation reaction.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto;
example 1:
2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylic acid methyl ester derivative 1a (77.0mg, 0.2mmol), diacetonitrile palladium dichloride (5.2mg, 10mol%), (S) -Difluorphos (16.4mg, 12mol%), silver phosphate (83.6 mg, 2equiv), tetrahydrofuran (2.0mL, 0.1M) were sequentially added to a reaction tube, the reaction mixture was reacted at 40 ℃ for 4 hours, after the reaction was completed, a 2/1 mixture of acetic acid and ice water was slowly added dropwise under ice bath conditions at a rate of 40 drops/min until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, washed with saturated brine, and after removing the solvent by rotary evaporation, the target compound 1 was isolated by column chromatography (petroleum ether: ethyl acetate =100 1) to give 93% yield.
The er value was 86/14 by HPLC [ Daicel Chiralpak C3 column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,1.0mL/min,254nm；t minor ＝8.6min,t major ＝9.5min]. 1 H NMR(500MHz,CDCl 3 )δ8.93(s,1H),7.52(d,J＝7.8Hz,1H),7.33(d,J＝8.0Hz,1H),7.16-7.11(m,1H),7.11-7.05(m,1H),4.12(dd,J＝12.4,4.8Hz,1H),3.79(s,3H),3.08(ddd,J＝14.7,4.7,3.6Hz,1H),2.64-2.51(m,1H),2.09-1.97(m,1H),1.89(tt,J＝13.2,4.5Hz,2H),1.67-1.55(m,2H),1.54-1.45(m,1H),1.39-1.31(m,1H),1.12-1.01(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.5,135.4,130.4,127.5,121.3,119.0,117.9,113.6,110.8,52.2,41.1,35.1,31.1,26.5,25.0,23.1.HRMS m/z(ESI+):Calculated for C 16 H 19 NNaO 2 ([M+Na] + ):280.1308Found:280.1301.
example 2:
2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylic acid methyl ester derivative 1a (77.0mg, 0.2mmol), diacetonitrile palladium dichloride (5.2mg, 10mol%), (S) -Difluorphos (16.4mg, 12mol%), silver phosphate (83.6 mg, 2equiv), tetrahydrofuran (10.0mL, 0.02M) were sequentially added to a reaction tube, the reaction mixture was reacted at 40 ℃ for 4 hours, after the reaction was completed, a 10/1 mixture of acetic acid and ice water was slowly dropped under ice bath conditions at a rate of 10 drops/minute until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, washed with saturated brine, and after removing the solvent by rotary evaporation, the target product compound 1 was isolated by column chromatography (petroleum ether: ethyl acetate =100 1), with a yield of 83%.
The er value was determined by HPLC to be 82/18 [ Daicel Chiralpak C3 column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,1.0mL/min,254nm；t minor ＝8.6min,t major ＝9.5min]. 1 H NMR(500MHz,CDCl 3 )δ8.93(s,1H),7.52(d,J＝7.8Hz,1H),7.33(d,J＝8.0Hz,1H),7.16-7.11(m,1H),7.11-7.05(m,1H),4.12(dd,J＝12.4,4.8Hz,1H),3.79(s,3H),3.08(ddd,J＝14.7,4.7,3.6Hz,1H),2.64-2.51(m,1H),2.09-1.97(m,1H),1.89(tt,J＝13.2,4.5Hz,2H),1.67-1.55(m,2H),1.54-1.45(m,1H),1.39-1.31(m,1H),1.12-1.01(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.5,135.4,130.4,127.5,121.3,119.0,117.9,113.6,110.8,52.2,41.1,35.1,31.1,26.5,25.0,23.1.HRMS m/z(ESI+):Calculated for C 16 H 19 NNaO 2 ([M+Na] + ):280.1308Found:280.1301.
example 3:
2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylic acid methyl ester derivative 2a (84.0mg, 0.2mmol), bis (dibenzylideneacetone) palladium (23.2mg, 20mol%), (S) -BINAP (30.2mg, 24mol%), silver carbonate (25.5mg, 1equ), toluene (20mL, 0.01M) were added in this order to a reaction tube, the reaction mixture was reacted at 40 ℃ for 1 hour, after the reaction was completed, a 5/1 mixture of acetic acid and ice water was slowly added dropwise under ice bath conditions at a rate of 20 drops/minute until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, washed with saturated brine, and after removing the solvent by rotary evaporation, the target product compound 2 was isolated by column chromatography (petroleum ether: ethyl acetate = 100) in a yield of 72%.
An er value of 80/20 by HPLC [ Daicel Chiralpak AD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,1.0mL/min,254nm；t minor ＝9.0min,t major ＝15.6min]. 1 H NMR(500MHz,CDCl 3 )δ9.05(s,1H),7.46(d,J＝1.9Hz,1H),7.23(d,J＝9.4Hz,1H),7.07(dd,J＝8.5,2.0Hz,1H),4.09(dd,J＝12.4,4.8Hz,1H),3.79(s,3H),3.04-2.93(m,1H),2.59-2.47(m,1H),2.09-1.98(m,1H),1.94-1.81(m,2H),1.66-1.55(m,2H),1.45(ddd,J＝15.2,8.0,2.6Hz,1H),1.34(ddd,J＝18.6,12.6,2.5Hz,1H),1.10-0.94(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.3,133.7,132.1,128.5,124.7,121.4,117.4,113.4,111.8,52.3,40.9,35.2,31.0,26.4,25.0,23.0.HRMS m/z(ESI-):Calculated for C 16 H 17 ClNO 2 ([M-H]-):290.0953,Found:290.0956.
example 4:
2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylic acid methyl ester derivative 2a (84.0mg, 0.2mmol), bis (dibenzylideneacetone) palladium (11.6 mg, 10mol%), (S) -BINAP (15.1mg, 12mol%), silver carbonate (51mg, 2equiv), tetrahydrofuran (2.0mL, 0.1M) were sequentially added to a reaction tube, the reaction mixture was reacted at 40 ℃ for 1 hour, after the reaction was completed, a 1/10 mixture of acetic acid and ice water was slowly added dropwise under an ice bath condition at a rate of 50 drops/min until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, washed with saturated brine, and after removing the solvent by rotary evaporation, the target product compound 2 was isolated by column chromatography (petroleum ether: ethyl acetate =100 1) with a yield of 75%.
The er value was determined by HPLC to be 84/16 [ Daicel Chiralpak AD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,1.0mL/min,254nm；t minor ＝9.0min,t major ＝15.6min]. 1 H NMR(500MHz,CDCl 3 )δ9.05(s,1H),7.46(d,J＝1.9Hz,1H),7.23(d,J＝9.4Hz,1H),7.07(dd,J＝8.5,2.0Hz,1H),4.09(dd,J＝12.4,4.8Hz,1H),3.79(s,3H),3.04-2.93(m,1H),2.59-2.47(m,1H),2.09-1.98(m,1H),1.94-1.81(m,2H),1.66-1.55(m,2H),1.45(ddd,J＝15.2,8.0,2.6Hz,1H),1.34(ddd,J＝18.6,12.6,2.5Hz,1H),1.10-0.94(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.3,133.7,132.1,128.5,124.7,121.4,117.4,113.4,111.8,52.3,40.9,35.2,31.0,26.4,25.0,23.0.HRMS m/z(ESI-):Calculated for C 16 H 17 ClNO 2 ([M-H] - ):290.0953,Found:290.0956.
example 5:
2- (2-iodophenylamino) cycloocta-1-ene-1-carboxylic acid methyl ester derivative 3a (80.1mg, 0.2mmol), diacetonitrile palladium dichloride (20.8mg, 40mol%), (S) -SegPhos (34.8mg, 48mol%), silver phosphate (83.6 mg, 2equiv), dichloromethane (10mL, 0.02M) were added in this order to a reaction tube, the reaction mixture was reacted at 40 ℃ for 5 hours, after the reaction was completed, a 2/1 mixture of acetic acid and ice water was slowly added dropwise under ice bath conditions at a rate of 40 drops/min until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, washed with saturated brine, and the target compound 3 was isolated by column chromatography after removal of the solvent by rotary evaporation (petroleum ether: ethyl acetate =100 1) in a yield of 70%.
An er value of 78/22 was determined by HPLC [ Daicel ChiralpakAD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,1.0mL/min,254nm；t minor ＝9.0min,t major ＝15.6min]. 1 H NMR(500MHz,CDCl 3 )δ8.75(s,1H),7.22(s,1H),7.14(d,J＝8.6Hz,1H),6.91-6.83(dd,J＝8.1,0.6Hz,1H),4.02(dd,J＝12.3,4.8Hz,1H),3.70(s,3H),3.03-2.91(m,1H),2.53-2.42(m,1H),2.37(s,3H),1.94(ddd,J＝11.4,7.9,4.4Hz,1H),1.80(ddd,J＝12.8,9.0,4.9Hz,2H),1.60-1.47(m,2H),1.40(td,J＝12.8,6.6Hz,1H),1.33-1.20(m,1H),0.98(ddd,J＝17.4,11.0,7.1Hz,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.5,133.7,130.5,128.1,127.6,122.8,117.6,113.1,110.5,52.1,41.1,35.1,31.1,26.5,25.0,23.1,21.5.HRMS m/z(ESI+):Calculated for C 17 H 21 NNaO 2 ([M+Na] + ):294.1465,Found:294.1462.
example 6:
to a reaction tube were added in this order 2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylic acid methyl ester derivative 3a (80.1mg, 0.2mmol), diacetonitrile palladium dichloride (5.2mg, 10mol%), (S) -SegPhos (7.3mg, 12mol%), silver phosphate (83.6 mg, 2equiv), tetrahydrofuran (2.0ml, 0.1m), and the reaction mixture was reacted at 40 ℃ for 5 hours, after the reaction was completed, a 1/1 mixture of acetic acid and ice water was slowly added dropwise under ice bath conditions at a rate of 45 drops/min until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, washed with saturated brine, and after removing the solvent by rotary evaporation, the target product compound 3 was isolated by column chromatography (petroleum ether: ethyl acetate =100 1) with 74% yield.
An er value of 84/16 by HPLC [ Daicel ChiralpakAD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,1.0mL/min,254nm；t minor ＝9.0min,t major ＝15.6min]. 1 H NMR(500MHz,CDCl 3 )δ8.75(s,1H),7.22(s,1H),7.14(d,J＝8.6Hz,1H),6.91-6.83(dd,J＝8.1,0.6Hz,1H),4.02(dd,J＝12.3,4.8Hz,1H),3.70(s,3H),3.03-2.91(m,1H),2.53-2.42(m,1H),2.37(s,3H),1.94(ddd,J＝11.4,7.9,4.4Hz,1H),1.80(ddd,J＝12.8,9.0,4.9Hz,2H),1.60-1.47(m,2H),1.40(td,J＝12.8,6.6Hz,1H),1.33-1.20(m,1H),0.98(ddd,J＝17.4,11.0,7.1Hz,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.5,133.7,130.5,128.1,127.6,122.8,117.6,113.1,110.5,52.1,41.1,35.1,31.1,26.5,25.0,23.1,21.5.HRMS m/z(ESI+):Calculated for C 17 H 21 NNaO 2 ([M+Na] + ):294.1465,Found:294.1462.
example 7:
the methyl 2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylate derivative 4a (83.0 mg, 0.2mmol), bis (dibenzylideneacetone) (11.6 mg,10 mol%), (S) -SDP (7.1mg, 12 mol%), silver acetate (32.1mg, 2 equiv), toluene (0.2ml, 1 m) were added to the reaction tube in this order, and the reaction mixture was reacted at 60 ℃ for 10 hours, and after the reaction was completed, a 2/1 mixture of acetic acid and ice water was slowly added dropwise at a rate of 40 drops/min until the solid was completely dissolved, and the organic phase was combined, washed with saturated brine, and separated by column chromatography using a method of column chromatography (petroleum ether: ethyl acetate = 100).
The er value was 77/23 by HPLC [ Daicel Chiralpak AD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝80/20,0.7mL/min,254nm；t minor ＝13.3min,t major ＝20.7min]. 1 H NMR(500MHz,CDCl 3 )δ8.81(s,1H),7.20(d,J＝8.6Hz,1H),6.95(d,J＝2.1Hz,1H),6.78(dd,J＝8.7,2.4Hz,1H),4.07(dd,J＝12.3,4.8Hz,1H),3.84(s,3H),3.76(s,3H),3.07-2.88(m,1H),2.65-2.46(m,1H),2.00(tt,J＝10.9,4.0Hz,1H),1.87(ddd,J＝16.9,10.5,6.8Hz,2H),1.65-1.55(m,2H),1.47(td,J＝12.7,6.6Hz,1H),1.38-1.26(m,1H),1.13-1.00(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.4,153.8,131.3,130.6,127.8,113.3,111.4,111.1,100.0,55.8,52.1,41.1,35.1,31.0,26.5,25.0,23.1.HRMS m/z(ESI+):Calculated for C 17 H 22 NO 3 ([M+H] + ):288.1594,Found:288.1604.
example 8:
to a reaction tube were added successively methyl 2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylate derivative 4a (83.0mg, 0.2mmol), bis (dibenzylideneacetone) palladium (11.6 mg, 10mol%), (S) -SDP (7.1mg, 12mol%), silver acetate (32.1mg, 2equiv), toluene (2.0ml, 0.1m), and the reaction mixture was reacted at 60 ℃ for 10 hours, after the reaction was completed, a 2/1 mixture of acetic acid and ice water was slowly added dropwise under ice bath conditions at a rate of 40 drops/min until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, washed with saturated brine, and after removing the solvent by rotary evaporation, the target product compound 4 was isolated by column chromatography (petroleum ether: ethyl acetate = 100) in a yield of 81%.
An er value of 80/20 by HPLC [ Daicel Chiralpak AD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝80/20,0.7mL/min,254nm；t minor ＝13.3min,t major ＝20.7min]. 1 H NMR(500MHz,CDCl 3 )δ8.81(s,1H),7.20(d,J＝8.6Hz,1H),6.95(d,J＝2.1Hz,1H),6.78(dd,J＝8.7,2.4Hz,1H),4.07(dd,J＝12.3,4.8Hz,1H),3.84(s,3H),3.76(s,3H),3.07-2.88(m,1H),2.65-2.46(m,1H),2.00(tt,J＝10.9,4.0Hz,1H),1.87(ddd,J＝16.9,10.5,6.8Hz,2H),1.65-1.55(m,2H),1.47(td,J＝12.7,6.6Hz,1H),1.38-1.26(m,1H),1.13-1.00(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.4,153.8,131.3,130.6,127.8,113.3,111.4,111.1,100.0,55.8,52.1,41.1,35.1,31.0,26.5,25.0,23.1.HRMS m/z(ESI+):Calculated for C 17 H 22 NO 3 ([M+H] + ):288.1594,Found:288.1604.
example 9:
to a reaction tube were sequentially added 2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylic acid methyl ester derivative 5a (87.4 mg,0.2 mmol), diacetonitrile palladium dichloride (5.2 mg, 10mol%), (S) -DiFluorPhos (16.4 mg, 12mol%), silver phosphate (83.6 mg, 2eq.), N-dimethylformamide (0.5 ml, 0.2m), and the reaction mixture was reacted at 80 ℃ for 5 hours, after the reaction was completed, a 2/1 mixture of acetic acid and ice water was slowly dropped under ice bath conditions at a rate of 40 drops/min until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, washed with saturated brine, and after removing the solvent by column chromatography separation (petroleum ether: ethyl acetate = 100) was isolated to give the target product compound 5 in 77% yield.
The er value was measured by HPLC to be 87/13 [ Daicel Chiralpak AD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,0.8mL/min,254nm；t minor ＝5.7min,t major ＝6.4min]. 1 H NMR(500MHz,CDCl 3 )δ9.20(s,1H),7.25(d,J＝1.6Hz,1H),6.86(dd,J＝10.6,1.7Hz,1H),4.09(dd,J＝12.4,4.8Hz,1H),3.81(s,3H),3.01-2.88(m,1H),2.59-2.47(m,1H),2.12-2.03(m,1H),1.97-1.81(m,2H),1.68-1.56(m,2H),1.51-1.40(m,1H),1.40-1.31(m,1H),1.09-0.96(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.0,149.7,147.7,132.9,131.3(d,J＝6.2Hz),124.0(d,J＝8.6Hz),122.1(d,J＝12.8Hz),114.3(d,J＝2.1Hz),113.5(d,J＝3.4Hz),107.5(d,J＝20.2Hz),52.4,41.0,35.3,30.9,26.4,25.0,23.2.HRMS m/z(ESI-):Calculated for C 16 H 16 ClFNO 2 ([M-H]-):308.0859,Found:308.0858.
example 10:
to a reaction tube were sequentially added 2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylic acid methyl ester derivative 5a (87.4 mg,0.2 mmol), diacetonitrile palladium dichloride (5.2 mg, 10mol%), (S) -DiFluorPhos (16.4 mg, 12mol%), silver phosphate (83.6 mg, 2eq.), tetrahydrofuran (2.0ml, 0.1m), and the reaction mixture was reacted at 80 ℃ for 5 hours, after the reaction was completed, a 2/1 mixture of acetic acid and ice water was slowly added dropwise under ice bath conditions at a rate of 40 drops/min until the solid was completely dissolved, then ethyl acetate was added to extract the aqueous phase three times, the organic phase was combined, saturated brine was added to wash, and the column chromatography was performed after the solvent was evaporated to obtain the target compound 5 in 83% yield.
The er value was measured by HPLC to be 87/13 [ Daicel Chiralpak AD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,0.8mL/min,254nm；t minor ＝5.7min,t major ＝6.4min]. 1 H NMR(500MHz,CDCl 3 )δ9.20(s,1H),7.25(d,J＝1.6Hz,1H),6.86(dd,J＝10.6,1.7Hz,1H),4.09(dd,J＝12.4,4.8Hz,1H),3.81(s,3H),3.01-2.88(m,1H),2.59-2.47(m,1H),2.12-2.03(m,1H),1.97-1.81(m,2H),1.68-1.56(m,2H),1.51-1.40(m,1H),1.40-1.31(m,1H),1.09-0.96(m,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.0,149.7,147.7,132.9,131.3(d,J＝6.2Hz),124.0(d,J＝8.6Hz),122.1(d,J＝12.8Hz),114.3(d,J＝2.1Hz),113.5(d,J＝3.4Hz),107.5(d,J＝20.2Hz),52.4,41.0,35.3,30.9,26.4,25.0,23.2.HRMS m/z(ESI-):Calculated for C 16 H 16 ClFNO 2 ([M-H] - ):308.0859,Found:308.0858.
example 11:
the methyl 2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylate derivative 6a (80.6 mg, 0.2mmol), bis (dibenzylideneacetone) palladium (11.6 mg, 10mol%), (S) -BINAP (15.1mg, 12mol%), silver acetate (32.1mg, 2equiv), dichloromethane (2.0 ml, 0.1m) were added to the reaction tube in this order, and the reaction mixture was reacted at 100 ℃ for 10 hours, and after the reaction was completed, a 2/1 mixture of acetic acid and ice water was slowly added dropwise under ice-bath conditions at a rate of 40 drops/min until the solid was completely dissolved, followed by adding ethyl acetate to extract the aqueous phase three times, combining the organic phases, washing with saturated brine, and separating by column chromatography after removing the solvent by rotary evaporation (petroleum ether: ethyl acetate =100 1) to obtain the objective compound 6 in 81% yield.
The er value was determined by HPLC to be 79/21 [ Daicel Chiralpak OD-H column (25 cm. Times.0.46 cm ID), n hexane/ i PrOH＝90/10,0.7mL/min,254nm；t major ＝5.9min,t minor ＝9.5min]. 1 H NMR(500MHz,CDCl 3 )δ9.10(s,1H),7.27(d,J＝7.9Hz,1H),6.97(td,J＝7.9,4.7Hz,1H),6.84(dd,J＝11.2,7.8Hz,1H),4.11(dd,J＝12.4,4.8Hz,1H),3.80(s,3H),3.12-2.98(m,1H),2.65-2.51(m,1H),2.12-2.00(m,1H),1.90(tt,J＝13.0,4.6Hz,2H),1.71-1.57(m,2H),1.48(tdd,J＝10.0,6.4,3.5Hz,1H),1.41-1.31(m,1H),1.05(tdd,J＝13.0,8.7,4.1Hz,1H)； 13 C NMR(125MHz,CDCl 3 )δ175.2,149.5(d,J＝243.6Hz),131.4,131.3(d,J＝5.6Hz),123.6(d,J＝12.8Hz),119.2(d,J＝6.2Hz),114.5(d,J＝2.0Hz),113.7(d,J＝3.2Hz),106.3(d,J＝16.3Hz),52.3,41.1,35.2,31.1,26.5,25.1,23.3.HRMS m/z(ESI-):Calculated for C 16 H 17 FNO 2 ([M-H] - ):274.1249,Found:274.1244.
examples 1-11 relate to the synthesis of specific fused ring 1-H indoles with C2 benzylic chirality and the results are listed in table 1:
TABLE 1 copper catalyzed indolinone Synthesis reaction results [a]
Figure GDA0003851070020000151
Figure GDA0003851070020000161
[a] The reaction conditions are shown in the examples; [b] the isolation yield.
The foregoing is merely a few specific embodiments of the present invention, which are described in detail and specific, but the scope of the present invention is not limited thereto. Any changes or substitutions that may be easily made by those skilled in the art within the technical scope of the present disclosure are intended to be included within the scope of the present disclosure. Therefore, the protection scope of the present invention should be subject to the appended claims.

Claims (4)

1. A preparation method of chiral indole-2,3-octatomic carbocyclic compound is characterized in that 0.2mmol of 2- (2-iodophenylamino) cycloocta-1-ene-1-methyl formate derivative, 10mol% of diacetonitrile palladium dichloride, (S) -Difluorphos 12mol%, 2equiv of silver phosphate, 2.0mL of tetrahydrofuran and 0.1M are sequentially added into a reaction tube, a reaction mixture reacts for 4 hours at 40 ℃, after the reaction is finished, a 2/1 mixture of acetic acid and ice water is slowly and dropwise added under an ice bath condition until a solid is completely dissolved, then ethyl acetate is added to extract an aqueous phase for three times, an organic phase is combined, saturated common salt water is added to wash the aqueous phase, a column chromatography separation method is adopted after a solvent is removed by rotary evaporation, and petroleum ether: ethyl acetate =100, and the target product compound chiral indole-2,3-octatomic carbocyclic compound is obtained by separation with a yield of 93%, wherein the structural formula of the 2- (2-iodophenylamino) cycloocta-1-ene-1-methyl formate derivative is shown as formula (1 a), and the structural formula of the chiral indole-2,3-octatomic carbocyclic compound is shown as formula (1):
Figure FDA0003851070010000011
2. a preparation method of chiral indole-2,3-octatomic carbocyclic compound is characterized in that 0.2mmol of 2- (2-iodophenylamino) cycloocta-1-ene-1-methyl formate derivative, 10mol% of bis (dibenzylidene acetone) palladium, (S) -SDP 12mol%, 2equiv of silver acetate, 2.0mL of toluene and 0.1M are sequentially added into a reaction tube, a reaction mixture reacts for 10 hours at 60 ℃, after the reaction is finished, a 2/1 mixture of acetic acid and ice water is slowly added dropwise under an ice bath condition at a speed of 40 drops/minute until a solid is completely dissolved, then ethyl acetate is added to extract an aqueous phase for three times, an organic phase is combined, saturated common salt solution is added to wash the aqueous phase, and a column chromatography separation method is adopted after a solvent is removed through rotary evaporation, petroleum ether: the target product compound 4 is obtained by separating ethyl acetate =100, and the yield is 81%, wherein the structural formula of the 2- (2-iodophenylamino) cycloocta-1-ene-1-methyl formate derivative is shown as a formula (4 a), and the structural formula of the chiral indole-2,3-octamembered carbocyclic compound is shown as a formula (4):
Figure FDA0003851070010000012
3. a preparation method of chiral indole-2,3-octatomic carbocyclic compound is characterized in that 0.2mmol of 2- (2-iodophenylamino) cycloocta-1-ene-1-methyl formate derivative, 10mol% of diacetonitrile palladium dichloride, (S) -DiFluorPhos 12mol%, 2eq of silver phosphate, 2.0mL of tetrahydrofuran and 0.1M are sequentially added into a reaction tube, a reaction mixture reacts for 5 hours at 80 ℃, after the reaction is finished, a 2/1 mixture of acetic acid and ice water is slowly dropped into the reaction tube under the ice bath condition, the speed is 40 drops/minute until the solid is completely dissolved, then ethyl acetate is added to extract an aqueous phase for three times, an organic phase is combined, saturated saline is added to wash the aqueous phase, and a column chromatography separation method is adopted after a solvent is removed by rotary evaporation, petroleum ether: ethyl acetate =100, and the target product compound 5 is obtained by separation with a yield of 83%, wherein the structural formula of the 2- (2-iodophenylamino) cycloocta-1-ene-1-methyl formate derivative is shown as formula (5 a), and the structural formula of the chiral indole-2,3-octamembered carbocyclic compound is shown as formula (5):
Figure FDA0003851070010000021
4. a preparation method of chiral indole-2,3-octatomic carbocyclic compound is characterized in that 0.2mmol of 2- (2-iodophenylamino) cycloocta-1-ene-1-methyl formate derivative, 10mol% of bis (dibenzylidene acetone) palladium, (S) -BINAP 12mol%, silver acetate 2equiv, dichloromethane 2.0mL and 0.1M are sequentially added into a reaction tube, a reaction mixture reacts for 10 hours at 100 ℃, after the reaction is finished, a 2/1 mixture of acetic acid and ice water is slowly added dropwise under an ice bath condition until a solid is completely dissolved, then ethyl acetate is added to extract an aqueous phase for three times, an organic phase is combined, saturated common salt water is added to wash the aqueous phase, a column chromatography separation method is adopted after a solvent is removed through rotary evaporation, and petroleum ether: ethyl acetate =100, and the target product compound 6 is obtained by separation with a yield of 81%, wherein the structural formula of the methyl 2- (2-iodophenylamino) cyclooct-1-ene-1-carboxylate derivative is shown in formula (6 a), and the structural formula of the chiral indole-2,3-octamembered carbocyclic compound is shown in formula (6):
Figure FDA0003851070010000022
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