CN114292277A - Indoline tetrahydropyrane compound and preparation method thereof - Google Patents
Indoline tetrahydropyrane compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses indoline tetrahydropyran compounds and a preparation method thereof, belonging to the field of organic synthesis, wherein the preparation method comprises the following steps: adding Pd into a dry reaction tube2(dba)3•CHCl3Adding a ligand, adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 3-nitroindole (II) and alkenyl carbonate (III); after the reaction is finished, separating and purifying to obtain an indoline tetrahydropyran compound (I); the indoline-containing tetrahydropyran compound provided by the invention contains easily functionalized groups, is convenient for deriving and synthesizing other polycyclic compounds, and can provide more candidate molecules for research and development of new drugs and screening of drugs; the preparation method has the advantages of novelty, simplicity in operation, mild reaction conditions, high yield and the like.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to an indoline tetrahydropyran compound and a preparation method thereof.
Background
Asymmetric dearomatization is a difficulty in the field of organic synthesis, and the current main research direction is to use electron-rich aromatic compounds, such as indole and naphthol, mainly to utilize the inherent nucleophilicity of the compounds. In recent years, 3-nitroindole, as a class of electron-poor heteroaromatic hydrocarbon compounds, has attracted extensive interest to organic chemists, and has a very important position particularly in the field of palladium-catalyzed dearomatization [3+2] cycloaddition reactions.
However, only 2 cases so far have been concerned with palladium-catalyzed dearomatization [4+2] cycloaddition reactions involving 3-nitroindole, and all are the reaction of Π -allylpalladium 1,4- [ N, C ] dipolar active intermediate with 3-nitroindole (Chin. chem. Lett.,2019,30, 1512-.
Furthermore, the [4+2] cycloaddition reaction of the dipole active intermediate of pi-allylpalladium 1,4- [ O, C ] with 3-nitroindole has not been reported so far, and it is likely that the nucleophilic ability of oxygen is weaker than that of carbon and nitrogen, so that the dearomatization addition in the first step is difficult to perform.
On the other hand, alkenyl carbonate can form pi-allyl palladium 1,4- [ O, C ] dipolar active intermediate under the action of palladium, and has been successfully applied to [4+2] cycloaddition reaction, and research on dearomatization has not been reported.
Disclosure of Invention
One of the objectives of the present invention is to provide a new class of indoline tetrahydropyran compounds, so as to solve the above problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: the indoline tetrahydropyrane compound has a structure shown as the following structural formula (I):
in the above structural formula, R1The radical being an electron-withdrawing substituent R2The substituent is selected from one of hydrogen, alkyl, alkoxy, nitro or halogen.
As a preferable technical scheme, the electron-withdrawing substituent is selected from one of p-methyl benzenesulfonyl, acyl or ester group.
The invention discloses a novel indoline tetrahydropyrane compound and a preparation method thereof for the first time, wherein the compound contains easily functionalized groups, is convenient for deriving and synthesizing other chiral polycyclic compounds, and can provide more candidate molecules for research and development of new drugs and screening of drugs.
The invention realizes the dearomatization [4+2] reaction of the pi-allyl palladium 1,4- [ O, C ] dipolar active intermediate and 3-nitroindole, and has very important significance: not only is the first case that the pi-allyl palladium 1,4- [ O, C ] dipolar active intermediate is used for realizing dearomatization reaction of poor electron aromatic heterocycle, but also the generated indoline tetrahydropyrane compound is widely existed in living active molecules, has diversified biological activity and is an important source for developing new drugs.
More specifically, the application value of the compound disclosed by the invention is as follows: many of the existing indoline tetrahydropyrane compounds have good biological activity, and the compounds synthesized by the invention can be reasonably predicted to have certain biological activity, so that sufficient compound sources are provided for screening of pharmaceutical activity; in addition, more candidate molecules can be provided for the research and development of new drugs and the screening of drugs, particularly high-throughput screening, and the compound library is enriched.
The second purpose of the invention is to provide a preparation method of the indoline tetrahydropyran compound, which adopts the technical scheme that: adding Pd into a reaction tube2(dba)3·CHCl3Adding a ligand, adding a solvent, stirring for complexing, sequentially adding 3-nitroindole (II) and alkenyl carbonate (III), after the reaction is finished, separating and purifying to obtain an indoline tetrahydropyran compound (I), wherein,
the 3-nitroindole (II) has the following structure:
the alkenyl carbonate (III) has the following structure:
the reaction formula is as follows:
as a preferred technical scheme: the stirring and complexing time is 1-30min, and more preferably 5min, so that the efficiency can be ensured and the complexing can be completed.
As a preferred technical scheme: the reaction solvent is one or more of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane and chlorobenzene.
Acetonitrile is further preferable as the reaction solvent because the yield of the reaction is highest.
As a preferred technical scheme: the ligand is a phosphine ligand, and triphenylphosphine is further preferable because the yield is high and triphenylphosphine is readily available and inexpensive.
As a preferred technical scheme: the catalyst (Pd)2(dba)3·CHCl3/PPh3) The minimum amount is 1 mol%.
As a preferred technical scheme: the reaction temperature is from 0 ℃ to 50 ℃.
Further, 40 ℃ is preferable because the yield of the reaction is high and the energy consumption is low.
Compared with the prior art, the invention has the advantages that: the invention realizes the dearomatization [4+2] cycloaddition reaction of a first instance of pi-allyl palladium 1,4- [ O, C ] dipolar active intermediate and 3-nitroindole, and discloses a series of novel indoline tetrahydropyrane compounds and a synthesis method thereof for the first time, wherein the compounds contain easily functionalized groups, are convenient for deriving and synthesizing other chiral polycyclic compounds, can provide more candidate molecules for the research and development of new drugs and the screening of drugs, particularly high-throughput screening, and enrich the compound library; moreover, the method has the advantages of mild reaction conditions, easily obtained raw materials and catalyst, simple operation, low catalyst dosage (which can be as low as 1 mol%), high yield (99% yield) and the like.
Drawings
FIG. 1 is a hydrogen spectrum of I-a obtained in example 1;
FIG. 2 is a carbon spectrum of I-a obtained in example 1;
FIG. 3 is a single crystal diagram of I-a obtained in example 1.
Detailed Description
The invention will be further explained with reference to the drawings.
The raw materials, solvents, catalysts, molecular sieves and the like used in the invention are all commercially available.
Example 1: synthesis of Compound I-a
Adding Pd into a dry reaction tube2(dba)3·CHCl3Adding a ligand, adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-a and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed, the crude product is separated and purified by column chromatography to obtain a compound I-a, different reaction conditions are shown in Table 1, and the specific reaction process is as follows:
TABLE 1 different reaction conditions
In Table 1, "x" represents the catalyst Pd2(dba)3·CHCl3The amount of "y" represents the amount of ligand.
As can be seen from Table 1, Pd was used as a catalyst2(dba)3·CHCl 35 mol% and PPh3(15 mol%) and acetonitrile as a solvent, and the reaction temperature is 40 ℃ and is a more preferable embodiment.
The compound I-a obtained was a white solid with a purity of > 99% by HPLC; >20:1dr, m.p.148.4-150.2 ℃.
And (3) structural identification: hydrogen spectrum1H NMR(600MHz,CDCl3) See fig. 1: δ 7.80(d, J ═ 8.4Hz,2H),7.61(d, J ═ 8.2Hz,1H),7.42-7.38(m,1H),7.32(d, J ═ 7.6Hz,1H),7.26(d, J ═ 8.4Hz,2H),7.11-7.07(m,1H),6.51(s,1H),4.87(d, J ═ 2.3Hz,1H),4.75(d, J ═ 2.3Hz,1H),4.30(dd, J ═ 15.8,1.8Hz,1H),4.08(dd, J ═ 15.8,2.2Hz,1H),3.31(dt, J ═ 14.0,1.8Hz,1H),3.21(d, J ═ 14.0, 1.38H), 3.38H, 3.3.3H, 1H, 3H, 3.3H, 3H, 1H, and c13C NMR(151MHz,CDCl3) See FIG. 2: δ 145.1,142.6,136.8,134.7,132.5,129.9,127.7,126.0,125.1,124.6,114.5,111.9,92.7,91.6,63.0,36.2,21.7 HRMS (ESI-TOF) calcd.for C19H19N2O5S[M+H]+387.1009；found:387.1006。
Single crystal diffraction experiments:
single crystal cultivation: the compound I-a (40mg) as the main component obtained in example 1 was dissolved in 20mL of ethanol, left standing at room temperature for 7 days, to precipitate a single crystal, and the single crystal was collected to conduct a single crystal diffraction test, as shown in FIG. 3.
The test parameters are shown in table 2:
TABLE 2 Single Crystal test parameters
Example 2: synthesis of Compound I-b
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-b and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain a compound I-b.
A white solid; 35.9mg, yield 97%; >20:1 dr; m.p.174.3-175.0 ℃.
And (3) structural identification:1H NMR(300MHz,DMSO-d6)δ7.98(d,J＝7.5Hz,2H),7.75-7.68(m,1H),7.64-7.57(m,2H),7.55-7.44(m,3H),7.20-7.10(m,1H),6.52(s,1H),4.92(s,1H),4.75(s,1H),4.26(d,J＝15.7Hz,1H),3.70(d,J＝15.7Hz,1H),3.45(d,J＝14.2Hz,1H),3.33-3.26(m,1H).13C NMR(101MHz,DMSO-d6)δ141.9,137.2,137.0,134.3,132.5,129.5,127.4,126.0,125.4,124.5,113.3,111.5,91.7,90.9,62.2,33.8.HRMS(ESI-TOF)calcd.for C18H16N2NaO5S[M+Na]+395.0672；found:395.0675。
example 3: synthesis of Compounds I-c
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-c and 0.15mmol of alkenyl carbonate III-a. After the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compound I-c.
A colorless oil; 11.9mg, yield 48%; >20:1 dr; .
And (3) structural identification:1H NMR(600MHz,DMSO-d6)δ8.75(s,1H),8.15-8.10(m,1H),7.68-7.64(m,1H),7.43-7.38(m,2H),5.27(s,1H),5.05(s,2H),5.02(s,1H),4.52(s,2H),1.95(s,3H).13C NMR(151MHz,DMSO-d6)δ169.9,138.9,135.2,133.4,127.7,124.4,124.2,120.3,119.7,116.2,112.3,64.1,49.1,20.4.HRMS(ESI-TOF)calcd.for C14H15N2O4[M+H]+275.1026；found:275.1027。
example 4: synthesis of Compounds I-d
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding solvent, stirring and complexing for 5 minutes, and then adding 0.1mmol of 3-nitroindole II-d and 0.15mmol of alkenyl carbonate III-a in sequence. After the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compound I-d.
A white solid; 25.2mg, yield 88%; >20:1 dr; m.p.93.4-94.5 ℃.
And (3) structural identification:1H NMR(400MHz,DMSO-d6)δ7.81-7.67(m,1H),7.59(dd,J＝7.6,1.3Hz,1H),7.52-7.43(m,1H),7.19-7.13(m,1H),6.37(s,1H),4.97(s,1H),4.80(s,1H),4.28(dd,J＝15.3,1.4Hz,1H),3.90-3.82(m,4H),3.48(d,J＝14.2Hz,1H),3.37(dt,J＝14.2,1.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ152.4,143.0,137.5,132.1,125.6,125.2,123.8,114.6,111.4,91.8,88.5,62.8,53.3,34.4.HRMS(ESI-TOF)calcd.for C14H14N2NaO5[M+Na]+313.0795；found:313.0799。
example 5: synthesis of Compounds I-e
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15mol percent), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-e and 0.15mmol of alkenyl carbonate III-a(ii) a After the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compound I-e.
A yellow solid; 25.9mg, yield 71%; >20:1 dr; m.p.59.0-60.8 deg.C.
And (3) structural identification:1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.59(d,J＝7.0Hz,1H),7.50-7.45(m,3H),7.44-7.39(m,2H),7.36(d,J＝7.0Hz,1H),7.19-7.12(m,1H),6.45(s,1H),5.34(s,2H),4.97(s,1H),4.80(s,1H),4.29(d,J＝15.4Hz,1H),3.88(dd,J＝15.4,1.9Hz,1H),3.49(d,J＝14.2Hz,1H),3.38(dt,J＝14.2,1.9Hz,1H).13C NMR(101MHz,DMSO-d6)δ151.7,143.0,137.5,135.9,132.2,128.5,128.2,127.6,125.7,125.2,123.9,114.6,111.4,91.7,88.6,67.3,62.8,34.3.HRMS(ESI-TOF)calcd.for C20H18N2NaO5[M+Na]+389.1108；found:389.1113。
example 6: synthesis of Compounds I-f
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-f and 0.15mmol of alkenyl carbonate III-a. After the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compound I-f.
A white solid; 28.7mg, yield 86%; >20:1 dr; m.p.33.8-35.0 deg.C
And (3) structural identification:1H NMR(600MHz,DMSO-d6)δ7.83-7.59(m,1H),7.55(d,J＝7.4Hz,1H),7.48-7.43(m,1H),7.15-7.10(m,1H),6.29(s,1H),4.96(s,1H),4.79(s,1H),4.27(d,J＝15.4Hz,1H),3.88(d,J＝15.4Hz,1H),3.43(d,J＝14.3Hz,1H),3.40-3.39(m,1H),1.53(s,9H).13C NMR(151MHz,DMSO-d6)δ150.8,143.2,137.7,132.1,125.8,125.0,123.5,114.7,111.3,91.7,88.7,82.2,62.9,34.4,27.8.HRMS(ESI-TOF)calcd.for C17H20N2NaO5[M+Na]+355.1264；found:355.1274。
example 7: synthesis of Compounds I-g
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-g and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain compound I-g.
A white solid; 41.4mg, yield 98%; >20:1 dr; m.p.109.6-111.8 deg.C
And (3) structural identification:1H NMR(400MHz,DMSO-d6)δ7.87(d,J＝8.4Hz,2H),7.50-7.44(m,2H),7.42-7.37(m,2H),7.17(dd,J＝7.0,1.9Hz,1H),6.46(s,1H),4.94(d,J＝2.1Hz,1H),4.79(d,J＝2.1Hz,1H),4.40(dd,J＝16.0,1.6Hz,1H),3.96(dd,J＝16.0,2.1Hz,1H),3.53(d,J＝14.0Hz,1H),3.43-3.39(m,1H),2.36(s,3H).13C NMR(101MHz,DMSO-d6)δ145.3,144.3,136.9,134.0,133.7,130.8,130.0,127.8,125.2,123.0,112.4,111.3,92.8,91.7,62.4,32.2,21.1.HRMS(ESI-TOF)calcd.for C19H17ClN2NaO5S[M+Na]+443.0439；found:443.0444。
example 8: synthesis of Compounds I-h
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-h and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain a compound I-h.
A white solid; 46.0mg, yield 99%; >20:1 dr; m.p.69.2-71.4 deg.C;
and (3) structural identification:1H NMR(400MHz,DMSO-d6)δ7.87(d,J＝8.4Hz,2H),7.53(dd,J＝8.0,1.1Hz,1H),7.41-7.35(m,3H),7.32(dd,J＝8.0,1.1Hz,1H),6.46(s,1H),4.92(d,J＝2.2Hz,1H),4.79(d,J＝2.2Hz,1H),4.40(dd,J＝16.0,1.6Hz,1H),3.99(dd,J＝16.0,2.0Hz,1H),3.59(d,J＝14.0Hz,1H),3.40(dt,J＝14.0,2.0Hz,1H),2.36(s,3H).13C NMR(101MHz,DMSO-d6)δ145.2,144.4,136.8,133.9,133.7,129.9,128.5,127.8,124.6,119.3,112.8,111.2,93.4,91.7,62.4,32.1,21.1.HRMS(ESI-TOF)calcd.for C19H17BrN2NaO5S[M+Na]+488.9915；found:488.9918。
example 9: synthesis of Compounds I-I
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%) and then adding solvent, stirring and complexing for 5min, and then adding 0.1mmol of 3-nitroindole II-i and 0.15mmol of alkenyl carbonate III-a in sequence. After the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain a compound I-I.
A white solid; 40.6mg, yield 99%; >20:1 dr; m.p.99.3-100.5 deg.C;
and (3) structural identification:1H NMR(600MHz,DMSO-d6)δ7.84(d,J＝8.3Hz,2H),7.38(d,J＝8.3Hz,2H),7.33-7.29(m,2H),6.89(dd,J＝6.1,2.4Hz,1H),6.32(s,1H),5.02(d,J＝2.4Hz,1H),4.78(d,J＝2.4Hz,1H),4.34(d,J＝15.9Hz,1H),3.93(d,J＝15.9Hz,1H),3.40-3.37(m,2H),2.34(s,3H),2.19(s,3H).13C NMR(151MHz,DMSO-d6)δ145.0,142.8,137.5,136.9,134.3,132.1,130.0,127.7,126.8,124.2,111.1,111.0,93.5,91.6,62.8,32.9,21.1,17.8.HRMS(ESI-TOF)calcd.for C20H20N2NaO5S[M+Na]+423.0985；found:423.0992。
example 10: synthesis of Compounds I-j
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-j and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compound I-j.
A white solid; 38.3mg, yield 95%; >20:1 dr; m.p.152.4-155.2 ℃.
And (3) structural identification:1H NMR(300MHz,DMSO-d6)δ7.83(d,J＝8.1Hz,2H),7.55-7.47(m,2H),7.40(d,J＝8.1Hz,2H),7.36-7.28(m,1H),6.49(s,1H),4.93(s,1H),4.78(s,1H),4.31(d,J＝15.8Hz,1H),3.77(d,J＝15.8Hz,1H),3.45(d,J＝14.1Hz,1H),3.29(d,J＝14.1Hz,1H),2.36(s,3H)；
13C NMR(101MHz,DMSO-d6)δ158.8(d,J＝241.6Hz),145.0,138.4(d,J＝2.0Hz),136.8,134.1,130.0,127.7(d,J＝9.0Hz),127.5,119.4(d,J＝23.9Hz),115.0(d,J＝8.5Hz),113.0(d,J＝25.3Hz),111.8,91.6(d,J＝1.9Hz),91.4,62.3,33.9,21.0；
HRMS(ESI-TOF)calcd.for C19H17FN2NaO5S[M+Na]+427.0734；found:427.0740。
example 11: synthesis of Compounds I-k
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-k and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain a compound I-k.
A white solid; 40.6mg, yield 97%; >20:1 dr; m.p.113.0-115.4 ℃.
And (3) structural identification:1H NMR(300MHz,DMSO-d6)δ7.85(d,J＝8.4Hz,2H),7.70(dd,J＝1.7,0.9Hz,1H),7.55-7.47(m,2H),7.41(d,J＝8.1Hz,2H),6.49(s,1H),4.94(s,1H),4.78(s,1H),4.29(d,J＝15.8Hz,1H),3.73(d,J＝15.8Hz,1H),3.50(d,J＝14.3Hz,1H),3.29(d,J＝14.3Hz,1H),2.36(s,3H)；
13C NMR(101MHz,DMSO-d6)δ145.1,141.0,136.7,134.1,132.4,130.0,128.3,127.8,127.5,125.7,114.9,111.9,91.4,91.2,62.3,33.6,21.1；
HRMS(ESI-TOF)calcd.for C19H17ClN2NaO5S[M+Na]+443.0439；found:443.0445。
example 12: synthesis of Compounds I-l
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-l and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain a compound I-l.
A white solid; 46.4mg, yield 99%; >20:1 dr; m.p.154.8-156.4 deg.C
And (3) structural identification:1H NMR(400MHz,DMSO-d6)δ7.85(d,J＝8.3Hz,2H),7.81(d,J＝2.1Hz,1H),7.64(dd,J＝8.7,2.1Hz,1H),7.45(d,J＝8.7Hz,1H),7.41(d,J＝8.3Hz,2H),6.49(s,1H),4.94(s,1H),4.78(s,1H),4.29(d,J＝16.0Hz,1H),3.72(dd,J＝16.0,2.1Hz,1H),3.51(d,J＝14.1Hz,1H),3.28(dt,J＝14.1,2.1Hz,1H),2.36(s,3H)；
13C NMR(101MHz,DMSO-d6)δ145.1,141.4,136.7,135.2,134.1,130.0,128.4,128.1,127.5,116.0,115.3,111.9,91.4,91.2,62.3,33.5,21.1；
HRMS(ESI-TOF)calcd.for C19H17BrN2NaO5S[M+Na]+488.9915；found:488.9917。
example 13: synthesis of Compounds I-m
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-m and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain a compound I-m.
A white solid; 36.6mg, yield 89%; >20:1 dr; m.p.169.2-171.9 deg.C;
and (3) structural identification:1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝1.5Hz,1H),7.94-7.90(m,3H),7.61(d,J＝8.5Hz,1H),7.44(d,J＝8.1Hz,2H),6.61(s,1H),4.95(d,J＝2.2Hz,1H),4.78(d,J＝2.2Hz,1H),4.28(dd,J＝15.8,1.8Hz,1H),3.61(dd,J＝15.8,2.0Hz,1H),3.54(d,J＝14.2Hz,1H),3.33-3.28(m,1H),2.37(s,3H)；
13C NMR(101MHz,DMSO-d6)δ145.5,145.4,137.1,136.3,134.1,130.2,127.6,126.9,118.0,113.7,112.2,106.4,91.2,90.9,62.3,33.4,21.1；
HRMS(ESI-TOF)calcd.for C20H17N3NaO5S[M+Na]+434.0781；found:434.0784。
example 14: synthesis of Compounds I-n
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15mol percent), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-n and 0.15mm of alkenyl carbonate III-aol; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compound I-n.
A white solid; 38.9mg, yield 97%; >20:1 dr; m.p.134.0-136.2 ℃;
and (3) structural identification:1H NMR(600MHz,DMSO-d6)δ7.83(d,J＝8.4Hz,2H),7.39-7.37(m,3H),7.28(s,1H),7.26(d,J＝8.4Hz,1H),6.47(s,1H),4.92(d,J＝2.2Hz,1H),4.76(d,J＝2.2Hz,1H),4.26(dd,J＝15.7,1.9Hz,1H),3.74(dd,J＝15.7,2.2Hz,1H),3.41(s,1H),3.28(dt,J＝14.1,2.2Hz,1H),2.34(s,3H),2.22(s,3H)；
13C NMR(151MHz,DMSO-d6)δ144.8,139.8,137.1,134.3,134.0,133.0,129.9,127.5,126.2,125.3,113.3,111.5,91.9,91.1,62.2,33.9,21.0,20.3；
HRMS(ESI-TOF)calcd.for C20H20N2NaO5S[M+Na]+423.0985；found:423.0995。
example 15: synthesis of Compounds I-o
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-o and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compound I-o.
A white solid; 40.4mg, yield 96%; >20:1 dr; m.p.149.5-151.6 deg.C;
and (3) structural identification:1H NMR(400MHz,DMSO-d6)δ7.89(d,J＝8.4Hz,2H),7.56(d,J＝8.2Hz,1H),7.46-7.41(m,3H),7.22(dd,J＝8.2,1.9Hz,1H),6.54(s,1H),4.92(d,J＝2.3Hz,1H),4.77(d,J＝2.1Hz,1H),4.28(dd,J＝15.8,1.5Hz,1H),3.70(dd,J＝15.9,2.1Hz,1H),3.45(d,J＝14.1Hz,1H),3.29(dt,J＝14.0,2.0Hz,1H),2.37(s,3H)；
13C NMR(101MHz,DMSO-d6)δ145.3,143.2,136.9,136.7,134.1,130.1,127.5,127.2,125.0,124.4,113.0,111.8,91.3,91.2,62.2,33.6,21.1；
HRMS(ESI-TOF)calcd.for C19H17ClN2NaO5S[M+Na]+443.0439；found:443.0446。
example 16: synthesis of Compounds I-p
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-p and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compound I-p.
A white solid; 36.0mg, yield 90%; >20:1 dr; m.p.160.2-162.3 deg.C;
and (3) structural identification:1H NMR(600MHz,DMSO-d6)δ7.87(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),7.34(d,J＝7.8Hz,1H),7.29(s,1H),6.93(d,J＝7.8Hz,1H),6.49(s,1H),4.90(d,J＝2.4Hz,1H),4.74(d,J＝2.4Hz,1H),4.24(dd,J＝15.8,1.8Hz,1H),3.68(dd,J＝15.8,2.2Hz,1H),3.39(s,1H),3.27(dt,J＝14.0,2.0Hz,1H),2.35(s,3H),2.33(s,3H)；
13C NMR(151MHz,DMSO-d6)δ144.9,142.9,142.2,137.2,134.5,130.0,127.5,125.2,125.1,123.3,113.7,111.5,91.7,91.2,62.2,33.9,21.5,21.1；
HRMS(ESI-TOF)calcd.for C20H20N2NaO5S[M+Na]+423.0985；found:423.0989。
example 17: synthesis of Compounds I-q
Adding Pd into a dry reaction tube2(dba)3·CHCl3(5 mol%) and PPh3(15 mol%), then adding a solvent, stirring and complexing for 5 minutes, and then sequentially adding 0.1mmol of 3-nitroindole II-q and 0.15mmol of alkenyl carbonate III-a; after the reaction is completed (24h), the crude product is separated and purified by column chromatography to obtain the compounds I-q.
A white solid; 35.9mg, yield 90%; >20:1 dr; m.p.149.0-151.2 deg.C;
and (3) structural identification:1H NMR(400MHz,DMSO-d6)δ7.72(d,J＝8.3Hz,2H),7.45-7.39(m,3H),7.28(d,J＝7.5Hz,1H),7.22-7.16(m,1H),6.63(s,1H),4.90(s,1H),4.77(s,1H),4.38(d,J＝15.2Hz,1H),3.93(d,J＝15.2Hz,1H),3.37(s,2H),2.38(s,3H),2.14(s,3H)；
13C NMR(101MHz,DMSO-d6)δ144.4,142.0,136.9,136.8,135.1,130.1,129.2,127.4,126.6,126.1,123.7,111.9,92.0,91.8,63.6,35.5,21.1,20.3；
HRMS(ESI-TOF)calcd.for C20H20N2NaO5S[M+Na]+423.0985；found:423.0990。
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. The indoline tetrahydropyran compound is characterized by having a structure shown as a structural formula (I):
in the above structural formula, R1The radical being an electron-withdrawing substituent R2The substituent is selected from one of hydrogen, alkyl, alkoxy, nitro or halogen.
2. The indoline tetrahydropyran compound according to claim 1, wherein the electron-withdrawing substituent is selected from one of p-methyl benzenesulfonyl, acyl, or ester groups.
3. The method for producing an indoline tetrahydropyran compound according to claim 1 or 2, characterized by: adding Pd into a reaction tube2(dba)3·CHCl3Adding a ligand, adding a solvent, stirring for complexing, sequentially adding 3-nitroindole (II) and alkenyl carbonate (III), after the reaction is finished, separating and purifying to obtain an indoline tetrahydropyran compound (I), wherein,
the 3-nitroindole (II) has the following structure:
the alkenyl carbonate (III) has the following structure:
4. the production method according to claim 3, characterized in that: the stirring and complexing time is 1-30 min.
5. The production method according to claim 3, characterized in that: the reaction solvent is one or more of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane and chlorobenzene.
6. The method of claim 5, wherein: the reaction solvent is acetonitrile.
7. The production method according to claim 3, characterized in that: the catalyst is tris (dibenzylidene acetone) bisPalladium (Pd)2(dba)3·CHCl3) And a phosphine ligand.
8. The production method according to claim 3, characterized in that: the catalyst is used in an amount of at least 1 mol%.
9. The production method according to claim 3, characterized in that: the reaction temperature is from 0 ℃ to 50 ℃.
10. The method of claim 9, wherein: the reaction temperature of the 9 is 40 ℃.
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| WO2009075821A1 (en) * | 2007-12-12 | 2009-06-18 | Chevron Phillips Chemical Company Lp | Process for one-pot synthesis of 1,1-diphenyl-1-(3-substituted-cyclopentadienyl)-1-(2,7-di-t-butyl-fluoren-9-yl)methane type ligands |
| CN107382823A (en) * | 2017-07-11 | 2017-11-24 | 成都丽凯手性技术有限公司 | Chiral tetrahydro carbazole analog derivative and preparation method thereof |
| CN112778326A (en) * | 2021-01-13 | 2021-05-11 | 成都大学 | Synthetic method of thiophene [2,3-b ] indole compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009075821A1 (en) * | 2007-12-12 | 2009-06-18 | Chevron Phillips Chemical Company Lp | Process for one-pot synthesis of 1,1-diphenyl-1-(3-substituted-cyclopentadienyl)-1-(2,7-di-t-butyl-fluoren-9-yl)methane type ligands |
| CN107382823A (en) * | 2017-07-11 | 2017-11-24 | 成都丽凯手性技术有限公司 | Chiral tetrahydro carbazole analog derivative and preparation method thereof |
| CN112778326A (en) * | 2021-01-13 | 2021-05-11 | 成都大学 | Synthetic method of thiophene [2,3-b ] indole compound |
Non-Patent Citations (1)
| Title |
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| PEI-HAO DOU ET AL.: "Dearomatization of 3‑Nitroindoles Enabled Using Palladium-", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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