CN108863894B - Method for directly synthesizing indole from nitrile - Google Patents

Method for directly synthesizing indole from nitrile Download PDF

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CN108863894B
CN108863894B CN201810909255.8A CN201810909255A CN108863894B CN 108863894 B CN108863894 B CN 108863894B CN 201810909255 A CN201810909255 A CN 201810909255A CN 108863894 B CN108863894 B CN 108863894B
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iodotoluene
nitrile
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indole
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CN108863894A (en
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康彦彪
单祥欢
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University of Science and Technology of China USTC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—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
    • 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
    • C07D471/04—Ortho-condensed systems

Abstract

The invention discloses a method for directly synthesizing indole from nitrile, which is characterized in that 2-iodotoluene derivatives are used as substrates, anhydrous copper sulfate, potassium tert-butoxide, benzonitrile derivatives and 2-iodotoluene derivatives are reacted for 4-48h at 60-105 ℃ in a solvent according to the mol ratio of 0.02-0.1: 2-4: 5-20: 1, petroleum ether/dichloromethane/ethyl acetate are mixed according to the volume ratio of 20-5: 10:1 to be used as an eluent, and the target product is obtained through silica gel column separation. The method has the advantages of simple operation, mild conditions and high yield, and is a green and novel synthesis method.

Description

Method for directly synthesizing indole from nitrile
Technical Field
The invention belongs to the technical field of indole compound synthesis by nitrile, and particularly relates to a method for directly synthesizing indole by an aryl side chain C-H bond.
Background
There are many synthetic methods for indoles, the classical method being the Fischer indole synthesis (Fischer, e., Jourdan, f.be. dtsch. chem. ges.1883,16,2241). Most indole synthesis methods are methods for synthesizing indole from aniline and derivatives thereof and methods for synthesizing indole from nitro compounds, one example being Bartoli indole synthesis methods (Bartoli, g.; Palmieri, g.; Bosco, m.; Dalpozz, r. tetrahedron lett.1989,30,212). However, this method has the disadvantage that the indole must be substituted in position 7 in order to react.
Disclosure of Invention
The invention aims to provide a method for directly synthesizing indole by nitrile.
The invention relates to a method for directly synthesizing indole from nitrile, which is characterized by comprising the following steps: taking a 2-iodotoluene derivative as a substrate, reacting anhydrous copper sulfate, potassium tert-butoxide and a nitrile derivative with the 2-iodotoluene derivative in a molar ratio of 0.02-0.1: 2-4: 5-20: 1 in an argon atmosphere at 60-105 ℃ for 4-48h, mixing petroleum ether/dichloromethane/ethyl acetate in a volume ratio of 20-5: 10:1 to serve as an eluent, and separating by using a silica gel column to obtain a target product.
The 2-iodotoluene derivative may be 2-iodotoluene, 1-benzyl-2-iodobenzene, 5-bromo-2-iodotoluene, 5-chloro-2-iodotoluene, 2-bromo-6-iodotoluene, 5-methoxy-2-iodotoluene, 4-iodo-3-methylphenol, 3-iodo-4-methylbenzoic acid, 2-bromo-3-methylpyridine, 1- (phenoxy) benzyl-2-iodobenzene, 1- (phenylthio) benzyl-2-iodobenzene or 1- (phenylthio) benzyl-5-methoxy-2-iodobenzene.
The nitrile derivative may be benzonitrile, 4-methoxybenzonitrile, 3, 5-dimethoxybenzonitrile, 4-n-butoxybenzonitrile, 3-bromobenzonitrile, 4-iodobenzonitrile, 3-cyanopyridine, 2-naphthonitrile, 3-cyanobiphenyl, 4-tert-butylbenzonitrile, 3-methylbenzonitrile, isovaleronitrile or cyclopropylnitrile.
The solvent can be a mixed solvent of tert-butyl alcohol and 1, 4-dioxane or a mixed solvent of tert-butyl alcohol and n-octane.
The invention discloses an indole synthesis method by using nitrile as a nitrogen source for the first time, which overcomes the defect of single nitrogen source in the existing method for synthesizing indole. The method has the advantages of simple operation, mild conditions and high yield, and is a green and novel synthesis method.
Detailed Description
Example 1: synthesis of 2-phenylindoles
Figure GDA0002404356520000011
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalent of benzonitrile and 2mmol of 2-iodotoluene under the argon (or nitrogen) atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 15 hours at 90 ℃. After the reaction is finished, filtering and concentrating to remove the solvent, and performing column chromatography separation, wherein the eluent is petroleum ether/dichloromethane-
Ethyl acetate (v: v: v ═ 20:10:1) to give a white solid, 2-phenylindole; the yield thereof was found to be 81%.
The white solid was analyzed by chemical shift and fragmentation by hydrogen nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) as 2-phenylindole.
1H NMR(400MHz,CDCl3)8.26(s,1H),7.64-7.61(m,3H),7.44-7.36(m,3H),7.31(td,J＝7.2,1.2Hz,1H),7.21-7.17(m,1H),7.14-7.10(m,1H),6.82(dd,J＝2.0,1.2Hz,1H).13C NMR(100MHz,CDCl3)137.9,136.8,132.4,129.3,129.1,127.8,125.2,122.4,120.7,120.3,111.0,100.0.
Example 2: synthesis of 5-bromo-2-phenylindole
Figure GDA0002404356520000021
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalent of benzonitrile and 2mmol of 5-bromo-2-iodotoluene under the argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 27 hours at 60 ℃. After the reaction is finished, filtering and concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluent is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1), so as to obtain 5-bromo-2-phenylindole white solid; the yield thereof was found to be 84%.
1H NMR(400MHz,CDCl3)8.34(s,1H),7.74(s,1H),7.63(d,J＝7.2Hz,2H),7.44(t,J＝7.2Hz,2H),7.34(t,J＝7.2Hz,1H),7.26(s,2H),6.75(s,1H).13C NMR(100MHz,CDCl3)139.1,135.4,131.8,131.0,129.1,128.2,125.3,125.1,123.1,113.4,112.3,99.4.
Example 3: synthesis of 5-chloro-2-phenylindole
Figure GDA0002404356520000022
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalent of benzonitrile and 2mmol of 5-chloro-2-iodotoluene under the argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 12 hours at 90 ℃. After the reaction is finished, filtering and concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluent is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1), so as to obtain 5-chloro-2-phenylindole white solid; the yield thereof was found to be 84%.
1H NMR(400MHz,CDCl3)8.32(s,1H),7.64-7.62(m,2H),7.58(t,J＝2.0Hz,1H),7.044(t,J＝7.6Hz,2H),7.34(tt,J＝7.2,1.2Hz,1H),7.29(d,J＝8.8Hz,1H),7.13(dd,J＝8.4,2.0Hz,1H),6.75(dd,J＝2.4,0.8Hz,1H).13C NMR(100MHz,CDCl3)139.3,135.1,131.9,130.3,129.1,128.2,125.9,125.3,122.6,120.0,111.9,99.6.
Example 4: synthesis of 4-bromo-2-phenylindole
Figure GDA0002404356520000031
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalents of benzonitrile and 2mmol of 2-bromo-6-iodotoluene under the argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 40 hours at 60 ℃. After the reaction is finished, filtering and concentrating to remove the solvent, and carrying out column chromatography separation, wherein an eluent is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1), so as to obtain white solid 4-bromo-2-phenylindole; the yield thereof was found to be 92%.
1H NMR(400MHz,CDCl3)8.35(s,1H),7.61(d,J＝7.2Hz,2H),7.41(t,J＝7.6Hz,2H),7.34-7.26(m,3H),7.01(t,J＝7.6Hz,1H),6.85(d,J＝2.4Hz,1H).13C NMR(100MHz,CDCl3)138.5,136.9,131.7,130.0,129.2,128.3,125.3,123.2,114.6,110.1,100.2
Example 5: synthesis of 5-methoxy-2-phenylindole
Figure GDA0002404356520000032
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalent of benzonitrile and 2mmol of 5-methoxy-2-iodotoluene under the argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 30 hours at 90 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed with petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 5-methoxy-2-phenylindole as a white solid. The yield thereof was found to be 85%.
1H NMR(400MHz,CDCl3)8.23(s,1H),7.60(d,J＝7.2Hz,2H),7.39(t,J＝7.6Hz,2H),7.29(t,J＝7.2Hz,1H),7.23(d,J＝8.8Hz,1H),7.08(d,J＝2.4Hz,1H),6.84(dd,J＝8.8,2.4Hz,1H),6.74(d,J＝1.6Hz,1H),3.84(s,3H).13C NMR(100MHz,CDCl3)154.5,138.7,132.4,132.0,129.8,129.0,127.7,125.1,112.6,111.7,102.3,99.8,55.9.
Example 6: synthesis of 6-carboxy-2-phenylindole
Figure GDA0002404356520000033
Adding 1 equivalent of potassium tert-butoxide into a 25mL Schlenk reaction tube, adding 2mL of toluene under the argon atmosphere, stirring for 30min, removing the solvent, adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalent of potassium tert-butoxide, vacuum drying for 15 min, sequentially adding 3mL of benzonitrile and 1mL of tert-butanol and 2mmol of 3-iodo-4-methylbenzoic acid under the argon atmosphere, adding a polytetrafluoroethylene plug on the reaction tube, putting the reaction tube into an oil bath, and reacting for 24h at 90 ℃. After completion of the reaction, 4 equivalents of formic acid were added, filtered and concentrated to remove the solvent, and separated by column chromatography eluting with petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 5:10:1) to give 6-carboxy-2-phenyl-1H-indole as a white solid. The yield thereof was found to be 92%.
1H NMR(400MHz,DMSO-d6)12.61(s,1H),11.94(s,1H),8.11(s,1H),7.93(d,J＝7.2Hz,2H),7.68(d,J＝7.6Hz,1H),7.62(d,J＝8.4Hz,1H),7.51(t,J＝7.6Hz,2H),7.39(t,J＝7.6Hz,1H),7.01(s,1H).13C NMR(100MHz,DMSO-d6)168.8,141.5,136.9,132.6,132.0,129.5,128.6,125.9,124.0,121.0,120.1,113.8,99.6.
Example 7: synthesis of 2-phenyl-7-azaindole
Figure GDA0002404356520000041
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalents of benzonitrile and 2mmol of 2-bromo-3-methylpyridine under argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 6 hours at 90 ℃. After the reaction is completed, the solvent is removed by filtration and concentration, and column chromatography separation is performed, and the eluent is petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 5:10:1), so that 2-phenyl-7-azaindole white solid is obtained. The yield thereof was found to be 83%.
1H NMR(400MHz,CDCl3)12.95(s,1H),8.30(d,J＝3.2Hz,1H),7.98-7.91(m,3H),7.53(t,J＝7.2Hz,2H),7.40(t,J＝6.8Hz,1H),7.11(dd,J＝7.2,4.8Hz,1H),6.80(s,1H).13C NMR(100MHz,CDCl3)150.1,142.1,139.7,132.5,129.1,128.8,128.2,126.0,122.4,116.1,97.4.
Example 8: synthesis of 2, 3-diphenylindole
Figure GDA0002404356520000042
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalents of benzonitrile and 2mmol of 1-benzyl-2-iodobenzene under the argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 20 hours at 60 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2, 3-diphenylindole as a colorless liquid. The yield thereof was found to be 72%.
1H NMR(400MHz,CDCl3)8.13(s,1H),7.68(d,J＝8.0Hz,1H),7.44-7.34(m,7H),7.32-7.19(m,5H),7.16-7.12(m,1H).13C NMR(100MHz,CDCl3)135.9,135.1,134.1,132.7,130.2,128.8(two peaks),128.6,128.2,127.8,126.3,122.8,120.5,119.8,115.1,111.0.
Example 9: synthesis of 3-phenoxy-2-phenylindole
Figure GDA0002404356520000043
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalents of benzonitrile and 2mmol of 1- (phenoxy) benzyl-2-iodobenzene under the argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 4.5 hours at 90 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed with petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 3-phenoxy-2-phenylindole as a yellow solid. The yield thereof was found to be 71%.
1H NMR(400MHz,CDCl3)7.99(s,1H),7.73(d,J＝7.6Hz,2H),7.38(t,J＝8.0Hz,3H),7.29-7.18(m,5H),7.06-6.98(m,4H).13C NMR(100MHz,CDCl3)158.6,133.9,131.1,130.7,129.6,129.0,127.6,126.1,125.7,123.2,122.4,122.0,120.1,118.5,115.8,111.4.
Example 10: synthesis of 2-phenyl-3- (phenylthio) indoles
Figure GDA0002404356520000051
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalents of benzonitrile and 2mmol of 1- (phenylthio) benzyl-2-iodobenzene under the argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 11 hours at 60 ℃. After the reaction was complete, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2-phenyl-3- (phenylthio) -1H-indole as a yellow liquid. The yield thereof was found to be 93%.
1H NMR(CDCl3,400MHz):8.05(d,J＝8.4Hz,2H),7.72(d,J＝8.4Hz,2H),2.64(s,3H)；13C NMR(CDCl3,100MHz):196.9,139.7,134.4(q,J＝32.4Hz),128.6,125.7(q,J＝3.9Hz),124.9,122.2,26.7.
Example 11: synthesis of 2- (4-methoxyphenyl) -3- (phenylthio) indole
Figure GDA0002404356520000052
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of 1, 4-dioxane and 1mL of tert-butyl alcohol, 5.0 equivalents of 4-methoxybenzonitrile and 1mmol of 1- (phenylthio) benzyl-2-iodobenzene under argon atmosphere, adding a polytetrafluoroethylene plug on the reaction tube, putting the reaction tube into an oil bath, and reacting for 12 hours at 100 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2- (4-methoxyphenyl) -3- (phenylthio) indole as a yellow liquid. The yield thereof was found to be 96%.
1H NMR(400MHz,CDCl3)8.46(s,1H),7.67(td,J＝8.8,2.4Hz,2H),7.61(d,J＝8.0Hz,1H),7.41(d,J＝8.4Hz,1H),7.27-7.23(m,1H),7.17-7.14(m,3H),7.10-7.02(m,3H),6.94(td,J＝8.8,2.4Hz,2H),3.81(s,3H).13C NMR(100MHz,CDCl3)160.0,142.2,139.5,135.7,131.3,129.5,128.9,125.5,124.6,123.9,123.1,121.1,119.8,114.3,111.1,98.3,55.4.
Example 12: synthesis of 5-methoxy-2- (4-methoxyphenyl) -3- (phenylthio) indole
Figure GDA0002404356520000061
0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide are added into a 25mL Schlenk reaction tube, vacuum drying is carried out for 15 minutes, 1.5mL of 1, 4-dioxane and 1mL of tert-butanol, 5.0 equivalents of 4-methoxybenzonitrile and 1mmol of 1- (phenylthio) benzyl-5-methoxy-2-iodobenzene are sequentially added under the atmosphere of argon, a polytetrafluoroethylene plug is added on the reaction tube, and then the mixture is put into an oil bath pot and reacted for 15 hours at 100 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 5-methoxy-2- (4-methoxyphenyl) -3- (phenylthio) -1H-indole as a yellow liquid. The yield thereof was found to be 95%.
1H NMR(400MHz,CDCl3)8.40(s,1H),7.65-7.61(m,2H),7.28(d,J＝8.8Hz,1H),7.18-7.14(m,2H),7.10-7.02(m,4H),6.93-6.87(m,3H),3.79(s,3H),3.77(s,3H).13C NMR(100MHz,CDCl3)159.9,155.2,142.8,139.5,132.2,130.6,129.3,128.9,125.4,124.6,124.0,114.2,113.4,112.0,101.0,97.8,55.8,55.4.HRMS(ESI)calcd for C22H19NNaO2S[M+H]+384.1029,found 384.1034.
Example 13: synthesis of 2- (3, 5-dimethoxyphenyl) -3- (phenylthio) -1H-indole
Figure GDA0002404356520000062
0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide are added into a 25mL Schlenk reaction tube, vacuum drying is carried out for 15 minutes, 1.5mL of 1, 4-dioxane and 1mL of tert-butanol, 5.0 equivalents of 3, 5-dimethoxybenzonitrile and 1mmol of 1- (phenylthio) benzyl-2-iodobenzene are sequentially added under the argon atmosphere, a polytetrafluoroethylene plug is added on the reaction tube, and then the mixture is put into an oil bath pot and reacted for 4 hours at 100 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2- (3, 5-dimethoxyphenyl) -3- (phenylthio) -1H-indole as a yellow liquid. The yield thereof was found to be 98%.
1H NMR(400MHz,CDCl3)8.57(s,1H),7.67(d,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.26(td,J＝8.0,1.2Hz,1H),7.19-7.07(m,5H),7.04-7.00(m,1H),6.86(d,J＝2.4Hz,2H),6.46(d,J＝2.0Hz,1H),3.65(s,6H).13C NMR(100MHz,CDCl3)161.0,142.0,139.7,135.7,133.2,131.6,128.9,125.6,124.7,123.6,121.3,120.0,111.3,106.2,101.2,99.5,55.4.
Example 14: synthesis of 2- (4-n-butoxyphenyl) -3- (phenylthio) indole
Figure GDA0002404356520000071
0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide are added into a 25mL Schlenk reaction tube, vacuum drying is carried out for 15 minutes, 1.5mL of 1, 4-dioxane and 1mL of tert-butanol are sequentially added under the argon atmosphere, 5.0 equivalents of 4-n-butoxy benzonitrile and 1mmol of 1- (phenylthio) benzyl-2-iodobenzene are added into the reaction tube, a polytetrafluoroethylene plug is added into the reaction tube, and the reaction tube is put into an oil bath pot and reacted for 4 hours at 100 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2- (4-n-butoxyphenyl) -3- (phenylthio) indole as a yellow liquid. The yield thereof was found to be 88%.
1H NMR(400MHz,CDCl3)8.41(s,1H),7.64-7.59(m,3H),7.37(dt,J＝8.4,0.8Hz,1H),7.25-7.20(m,1H),7.16-7.07(m,5H),7.04-7.00(m,1H),6.92-6.89(m,2H),3.94(t,J＝6.4Hz,2H),1.78-1.71(m,2H),1.52-1.42(m,2H),0.96(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)159.7,142.4,139.6,135.8,131.4,129.5,128.9,125.6,124.7,123.7,123.1,121.2,119.8,114.9,111.1,98.3,67.9,31.4,19.3,14.0
Example 15: synthesis of 2- (3-bromophenyl) -3- (phenylthio) -1H-indole
Figure GDA0002404356520000072
0.02 equivalent of anhydrous copper sulfate and 3.0 equivalents of potassium tert-butoxide are added into a 25mL Schlenk reaction tube, vacuum drying is carried out for 15 minutes, 1.5mL of 1, 4-dioxane and 1mL of tert-butanol are sequentially added under the atmosphere of argon, 5.0 equivalents of 3-bromoxynil and 0.5mmol of 1- (phenylthio) benzyl-2-iodobenzene are added, a polytetrafluoroethylene plug is added on the reaction tube, and then the mixture is put into an oil bath pot and reacts for 24 hours at 60 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2- (3-bromophenyl) -3- (phenylthio) indole as a yellow liquid. The yield thereof was found to be 91%.
1H NMR(400MHz,CDCl3)8.44(s,1H),7.83(t,J＝2.0Hz,1H),7.67(td,J＝8.0,1.2Hz,1H),7.63(d,J＝8.0Hz,1H),7.45(ddd,J＝8.0,1.6,0.8Hz,1H),7.39(d,J＝8.0Hz,1H),7.28-7.23(m,2H),7.18-7.12(m,3H),7.09-7.01(m,3H).13C NMR(100MHz,CDCl3)140.2,138.9,136.0,133.5,131.7,131.2,130.9,130.4,129.0,127.0,125.9,125.0,123.9,122.9,121.5,120.3,111.4,100.9.
Example 16: synthesis of 2- (4-iodophenyl) -3- (phenylthio) indole
Figure GDA0002404356520000081
0.02 equivalent of anhydrous copper sulfate and 3.0 equivalents of potassium tert-butoxide are added into a 25mL Schlenk reaction tube, vacuum drying is carried out for 15 minutes, 1.5mL of 1, 4-dioxane and 1mL of tert-butanol, 5.0 equivalents of 4-iodobenzonitrile and 0.5mmol of 1- (phenylthio) benzyl-2-iodobenzene are sequentially added under the argon atmosphere, a polytetrafluoroethylene plug is added on the reaction tube, and then the mixture is put into an oil bath pot and reacts for 14 hours at the temperature of 60 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2- (4-iodophenyl) -3- (phenylthio) indole as a yellow liquid. The yield thereof was found to be 65%.
1H NMR(400MHz,CDCl3)8.44(s,1H),7.71(d,J＝8.4Hz,2H),7.62(d,J＝8.0Hz,1H),7.43(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,1H),7.26(t,J＝8.0Hz,1H),7.17-7.12(m,3H),7.07-7.02(m,3H).13C NMR(100MHz,CDCl3)140.9,139.0,138.0,136.0,131.3,130.9,129.8,129.0,125.7,124.9,123.8,121.5,120.2,111.4,100.2,94.9.
Example 17: synthesis of 2- (3-pyridyl) -3- (phenylthio) indole
Figure GDA0002404356520000082
0.02 equivalent of anhydrous copper sulfate and 3.0 equivalents of potassium tert-butoxide are added into a 25mL Schlenk reaction tube, vacuum drying is carried out for 15 minutes, 1.5mL of 1, 4-dioxane and 1mL of tert-butanol, 5.0 equivalents of 3-cyanopyridine and 0.5mmol of 1- (phenylthio) benzyl-2-iodobenzene are sequentially added under the atmosphere of argon, a polytetrafluoroethylene plug is added on the reaction tube, and then the mixture is put into an oil bath pot and reacts for 14 hours at 60 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 5:10:1) as eluent to give 2- (3-pyridyl) -3- (phenylthio) indole as a white solid. The yield thereof was found to be 94%.
1H NMR(400MHz,DMSO-d6)12.30(s,1H),9.02(d,J＝1.2Hz,1H),8.60(dd,J＝4.8,1.6Hz,1H),8.21(td,J＝8.0,2.0Hz,1H),7.68-7.52(m,2H),7.48(d,J＝8.0Hz,1H),7.29-7.20(m,3H),7.15-7.07(m,2H),7.03-7.01(m,2H).13C NMR(100MHz,DMSO-d6)149.2,148.7,139.2,138.6,136.5,135.4,130.3,129.1,127.2,125.0,123.6,123.2,120.8,118.8,112.2,97.7.
Example 18: synthesis of 2- (2-naphthyl) indole
Figure GDA0002404356520000083
Adding 0.1 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1.5mL of n-octane and 1mL of tert-butanol, 5.0 equivalents of 2-naphthonitrile and 0.5mmol of 2-iodotoluene under the argon atmosphere, adding a polytetrafluoroethylene plug on the reaction tube, putting the reaction tube into an oil bath, and reacting for 40 hours at 90 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as an eluent to give 2- (2-naphthyl) -1H-indole as a white solid. The yield thereof was found to be 63%.
1H NMR(400MHz,CDCl3)8.42(s,1H),8.02(s,1H),7.89-7.78(m,4H),7.65(d,J＝7.2Hz,1H),7.52-7.45(m,2H),7.41(dd,J＝8.0,0.8Hz,1H),7.23-7.19(m,1H),7.16-7.12(m,1H),6.94(dd,J＝2.0,0.8Hz,1H).13C NMR(100MHz,CDCl3)137.9,137.1,133.6,132.9,129.7,129.4,128.8,128.0,127.9,126.7,126.2,123.8,123.1,122.6,120.8,120.4,111.0,100.7.
Example 19: synthesis of 2- (3-biphenyl) indole
Figure GDA0002404356520000091
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 0.75mL of n-octane and 0.5mL of tert-butanol, 5.0 equivalents of 3-cyanobiphenyl and 0.5mmol of 2-iodotoluene under the argon atmosphere, adding a polytetrafluoroethylene plug on the reaction tube, putting the reaction tube into an oil bath, and reacting for 15 hours at 100 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as an eluent to give 2- (3-biphenyl) -1H-indole as a white solid. The yield thereof was found to be 75%.
1H NMR(400MHz,CDCl3)8.38(s,1H),7.86(s,1H),7.66-7.63(m,4H),7.55-7.46(m,4H),7.42-7.38(m,2H),7.21(t,J＝8.0Hz,1H),7.13(t,J＝7.2Hz,1H),6.89(d,J＝1.2Hz,1H).13C NMR(100MHz,CDCl3)142.2,140.9,137.8,136.9,132.9,129.5,129.3,128.9,127.7,127.3,126.6,124.1,122.5,120.8,120.4,111.0,100.3.
Example 20: synthesis of 2- (4-tert-butyl) phenylindole
Figure GDA0002404356520000092
Adding 0.02 equivalent of anhydrous copper sulfate and 4.0 equivalent of potassium tert-butoxide into a 25mL Schlenk reaction tube, vacuum-drying for 15 minutes, sequentially adding 1mL of 4-tert-butylbenzonitrile and 1mL of tert-butanol under argon atmosphere, and 1mmol of 2-iodotoluene, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 15 hours at 90 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2- (4-tert-butyl) phenylindole as a yellow solid. The yield thereof was found to be 69%.
1H NMR(400MHz,CDCl3)8.30(s,1H),7.63-7.57(m,3H),7.48-7.45(m,2H),7.41-7.34(m,1H),7.20-7.16(m,1H),7.13-7.09(m,1H),6.79(dd,J＝2.0,0.8Hz,1H),1.36(s,9H).13C NMR(100MHz,CDCl3)150.9,138.0,136.7,129.6,129.4,126.0,124.9,122.1,120.6,120.2,110.9,99.5,34.7,31.3.
Example 21: synthesis of 5-bromo-2- (3-methylphenyl) indole
Figure GDA0002404356520000101
0.02 equivalent of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide are added into a 25mL Schlenk reaction tube, vacuum drying is carried out for 15 minutes, 0.75mL of n-octane and 0.5mL of tert-butanol, 5.0 equivalent of 3-methylbenzonitrile and 1mmol of 5-bromo-2-iodotoluene are sequentially added under the argon atmosphere, a polytetrafluoroethylene plug is added on the reaction tube, and then the reaction tube is put into an oil bath kettle and reacts for 40 hours at 60 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 5-bromo-2- (3-methylphenyl) indole as a white solid. The yield thereof was found to be 61%.
1H NMR(400MHz,CDCl3)8.34(s,1H),7.43(s,1H),7.46-7.43(m,2H),7.33(t,J＝7.6Hz,1H),7.25(s,2H),7.16(d,J＝7.6Hz,1H),6.73(d,J＝2.0Hz,1H),2.42(s,3H).13CNMR(100MHz,CDCl3)139.3,138.8,135.3,131.7,131.0,129.0(two peaks),126.0,125.0,123.0,122.4,113.4,112.3,99.3,21.6.
Example 22: synthesis of 2-isobutyl-3- (phenylthio) indoles
Figure GDA0002404356520000102
Adding 0.1 part of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, drying for 15 minutes in vacuum, sequentially adding 2mL of isopentonitrile and 1mL of tert-butanol and 1mmol of 1- (phenylthio) benzyl-2-iodobenzene under the argon atmosphere, adding a polytetrafluoroethylene plug on the reaction tube, putting the reaction tube into an oil bath, and reacting for 30 hours at 105 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as eluent to give 2-isobutyl-3- (phenylthio) indole as a yellow liquid. The yield thereof was found to be 71%.
1H NMR(400MHz,CDCl3)8.17(s,1H),7.53(d,J＝7.2Hz,1H),7.33(td,J＝8.0,0.8Hz,1H),7.21-7.17(m,1H),7.14-7.09(m,3H),7.04-6.99(m,3H),2.76(d,J＝7.6Hz,2H),2.05-1.92(m,1H),0.91(d,J＝6.4Hz,6H).13C NMR(100MHz,CDCl3)144.7,139.6,135.6,130.3,128.7,125.6,124.5,122.3,120.8,119.3,110.9,99.7,35.7,29.3,22.6.
Example 23: synthesis of 2-cyclopropyl-3- (phenylthio) indole
Figure GDA0002404356520000103
Adding 0.1 part of anhydrous copper sulfate and 4.0 equivalents of potassium tert-butoxide into a 25mL Schlenk reaction tube, drying for 15 minutes in vacuum, sequentially adding 2mL of cyclopropanecarbonitrile and 1mL of tert-butanol and 1mmol of 1- (phenylthio) benzyl-2-iodobenzene under argon atmosphere, adding a polytetrafluoroethylene plug into the reaction tube, putting the reaction tube into an oil bath, and reacting for 20 hours at 90 ℃. After completion of the reaction, the solvent was removed by filtration and concentration, and column chromatography was performed using petroleum ether/dichloromethane/ethyl acetate (v: v: v ═ 20:10:1) as an eluent to give 2-cyclopropyl-3- (phenylthio) indole as a yellow liquid. The yield thereof was found to be 82%.
1H NMR(400MHz,CDCl3)7.82(s,1H),7.52(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.16-7.05(m,6H),7.01(t,J＝7.2Hz,1H),2.33-2.26(m,1H),1.02-0.97(m,2H),0.84-0.80(m,2H).13C NMR(100MHz,CDCl3)146.1,139.5,135.0,130.8,128.8,125.5,124.6,122.2,120.8,118.7,110.8,99.1,8.3,8.0.
The above examples summarize that: the method for directly synthesizing indole from nitrile uses 2-iodotoluene derivatives as a substrate, and comprises the steps of enabling the molar ratio of anhydrous copper sulfate to 2-iodotoluene derivatives to be 0.02-0.1: 1 in an argon atmosphere (or other inert atmospheres such as nitrogen), enabling the molar ratio of potassium tert-butoxide to 2-iodotoluene derivatives to be 2-4: 1, enabling the molar ratio of nitrile derivatives to 2-iodotoluene derivatives to be 5-20: 1, enabling the mixture to react for 4-48h at 60-105 ℃ in a solvent, mixing petroleum ether/dichloromethane/ethyl acetate according to the volume ratio of 20-5: 10:1 to serve as an eluent, and separating through a silica gel column to obtain a target product. The solvent is preferably tert-butyl alcohol, or a mixed solvent of tert-butyl alcohol and 1, 4-dioxane, or a mixed solvent of tert-butyl alcohol and n-octane (different solvents can be selected from different substrates, and one of tert-butyl alcohol, 1, 4-dioxane or n-octane can be used alone for reaction, but the indole yield is low).
The method is an indole synthesis method which directly synthesizes indole by catalyzing the activation of C-H bond of aryl side chain and uses nitrile as nitrogen source for the first time, has simple operation, mild condition and higher yield, and is a green and novel synthesis method.

Claims (2)

1. A method for directly synthesizing indole from nitrile is characterized by comprising the following steps: taking a 2-iodotoluene derivative as a substrate, reacting anhydrous copper sulfate, potassium tert-butoxide and a nitrile derivative with the 2-iodotoluene derivative in a molar ratio of 0.02-0.1: 2-4: 5-20: 1 in a solvent at 60-105 ℃ for 4-48h in an argon atmosphere, mixing petroleum ether/dichloromethane/ethyl acetate in a volume ratio of 20-5: 10:1 to obtain an eluent, and separating by using a silica gel column to obtain a target product;
the 2-iodotoluene derivative is 2-iodotoluene, 1-benzyl-2-iodobenzene, 5-bromo-2-iodotoluene, 5-chloro-2-iodotoluene, 2-bromo-6-iodotoluene, 5-methoxy-2-iodotoluene, 4-iodo-3-methylphenol, 3-iodo-4-methylbenzoic acid, 2-bromo-3-methylpyridine, 1- (phenoxy) benzyl-2-iodobenzene, 1- (phenylthio) benzyl-2-iodobenzene or 1- (phenylthio) benzyl-5-methoxy-2-iodobenzene;
the nitrile derivative is cyanophenyl, 4-methoxy cyanophenyl, 3, 5-dimethoxy cyanophenyl, 4-n-butoxy cyanophenyl, 3-bromoxynil, 4-iodocyanophenyl, 3-cyanopyridine, 2-naphthonitrile, 3-cyanobiphenyl, 4-tert-butylbenzonitrile, 3-methylbenzonitrile, isopentyl nitrile or cyclopropyl nitrile.
2. The method for directly synthesizing indole from nitrile according to claim 1, wherein the solvent is selected from the group consisting of a mixed solvent of t-butanol and 1, 4-dioxane, and a mixed solvent of t-butanol and n-octane.
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