CN109369497B - Synthesis method of N-pyrrolylpiperidine compound - Google Patents
Synthesis method of N-pyrrolylpiperidine compound Download PDFInfo
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- CN109369497B CN109369497B CN201811414675.5A CN201811414675A CN109369497B CN 109369497 B CN109369497 B CN 109369497B CN 201811414675 A CN201811414675 A CN 201811414675A CN 109369497 B CN109369497 B CN 109369497B
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a synthetic method of an N-pyrrolylpiperidine compound, belonging to the technical field of organic synthesis. Adding N-substituted piperidine 1 into a solvent, and heating and reacting in oxygen in the presence of copper acetate, 4-dimethylaminopyridine and an additive to obtain an iodopyrrole compound 2; and secondly, mixing the compound 2, copper salt, ligand, alkali and piperidine, and heating for reaction to obtain the N-pyrrolylpiperidine compound 3. The method synthesizes iodo-pyrrole compounds through a series of series reactions of oxidative ring shrinkage, decarbonylation, dehydrogenation, aromatization, beta-iodo substitution and the like of N-substituted piperidine compounds, and then obtains the N-pyrrolyl piperidine compounds through the coupling reaction of iodo-pyrrole and piperidine, has the advantages of simple raw materials, simple and convenient operation, mild conditions, wide substrate application range and the like, and provides a novel method which is economical, practical, green and environment-friendly for the synthesis of the N-pyrrolyl piperidine compounds.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of an N-pyrrolylpiperidine compound.
Background
Pyrrole and piperidine, two important nitrogen-containing heterocyclic structural units, are ubiquitous in natural products and are effective components of many Chinese herbal medicines. In addition, many artificially designed and synthesized pyrrole and piperidine derivatives have become widely used drugs (such as tolmetin, sunitinib, atorvastatin, tropicamide and irinotecan) in clinic, and make important contributions to human health and civilization progress. Therefore, the synthesis and application research of pyrrole and piperidine compounds is an important research content in the fields of synthetic chemistry, pharmaceutical chemistry, biochemistry and the like.
On the other hand, different kinds of heterocycles such as pyrrole are introduced to the piperidine ring, that is, a hybrid of two or more nitrogen-containing heterocycles is synthesized, and the improvement and adjustment of the biological activity and the luminescence property of the original parent heterocyclic compound are finally realized through introducing a new dominant structure and changing the polarity, the electrical property and the solubility property of the original heterocycle. In addition, the introduction of a new heterocyclic ring can provide a new reaction site, so that the reaction performance of the piperidine compound is further enriched. It should be noted that although N-pyrrolylpiperidine compounds have important application value, the current methods for synthesizing the compounds are very limited, and the methods often have the problems of poor regioselectivity, complicated operation, use of expensive metal catalysts and the like. Therefore, research and development of a novel method for synthesizing the N-pyrrolylpiperidine compound by using a simple and easily available reagent as a raw material through relatively simple and convenient operation steps have important theoretical significance and important application value.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method of an N-pyrrolylpiperidine compound, which comprises the steps of synthesizing an iodopyrrole compound through a series of series reactions of oxidative ring shrinkage, decarbonylation, dehydrogenation, aromatization, beta-position iodine substitution and the like of an N-substituted piperidine compound, and obtaining the N-pyrrolylpiperidine compound through the coupling reaction of iodopyrrole and piperidine. Has the advantages of simple and convenient operation, mild condition, wide substrate application range and the like, and is suitable for industrial production.
The invention adopts the following technical scheme for solving the technical problems, and the synthesis method of the N-pyrrolylpiperidine compound is characterized by comprising the following steps:
firstly, adding N-substituted piperidine 1 into a solvent, and heating in oxygen in the presence of copper acetate, 4-Dimethylaminopyridine (DMAP) and an additive to react to generate iodopyrrole compound 2. The reaction equation is:
and secondly, mixing the compound 2, copper salt, ligand, alkali and piperidine, and heating for reaction to obtain the N-pyrrolylpiperidine compound 3. The reaction equation is:
wherein: r1Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine or C1-4One or more of alkyl or alkoxy, R2Is hydrogen, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine or C1-4One or more of alkyl or alkoxy.
Further, in the first step, the solvent for the reaction serves to dissolve the raw materials, and acetonitrile, dichloroethane, 1, 4-dioxane, N-dimethylformamide, or dimethylsulfoxide is preferable.
Further, in the first step, the additive is elemental iodine or an iodinated metal salt. The metal iodide salt is lithium iodide, sodium iodide or potassium iodide. Elemental iodine and potassium iodide are preferred.
Further, in the first step, the reaction is carried out under an oxygen atmosphere of 1 to 2 atm.
Further, in the first step and the second step, the reaction temperature is 40-100 ℃.
Further, in the first step, the ratio of the amount of the N-substituted piperidine 1, the copper acetate, the additive and the 4-dimethylamino pyridine is 1:1-2:0.25-1: 0.5-2.
Further, in the second step, the copper salt is CuI, CuBr or CuCl. The ligand is L-proline.
Further, in the second step, the reaction is carried out in a solvent selected from DMF, DMSO or 1, 4-dioxane.
Further, in the second step, the base is cesium fluoride or cesium carbonate.
Compared with the prior art, the invention has the following advantages: (1) the synthesis process is simple and efficient; (2) the raw materials are simple, cheap and easily available; (3) the reaction condition is mild, and the operation is simple and convenient; (4) the application range of the substrate is wide. Therefore, the invention provides a novel method which is economical, practical, green and environment-friendly for the synthesis of the N-pyrrolylpiperidine compound.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and 4-dimethylaminopyridine (DMAP,0.5mmol,61mg) were added in this order to a 10mL Schlenk's tube, and after vacuum and oxygen charging (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (87mg, 65%). 2a (0.3mmol,81mg), CuI (0.03mmol,5.7mg), L-proline (0.03mmol,3.5mg) and cesium fluoride (0.6mmol,91mg) were placed in a 10mL Schlenk tube, evacuated and charged with nitrogen, then piperidine (0.6mmol,51mg) and DMSO (3mL) were added to the system, warmed to 50 ℃ and reacted for 24 h. The reaction system was worked up to give the desired product 3a (43mg, 63%). Characterization data for compound 2a are as follows:1H NMR(400MHz,CDCl3)δ6.42(t,J＝1.2Hz,1H),6.96(t,J＝2.0Hz,1H),7.13(t,J＝2.0Hz,1H),7.28(t,J＝7.2Hz,1H),7.34(d,J＝7.6Hz,2H),7.43(t,J＝7.6Hz,2H).13C NMR(100MHz,CDCl3)δ62.0,117.6,120.6,121.2,124.2,126.4,129.7,139.9.MS(EI):269[M]+.
example 2
1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.125mmol,32mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum-charging oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (34mg, 25%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 3
1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum-charging oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (69mg, 51%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 4
1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum-charging oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (61mg, 45%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 5
To a 10mL Schlenk tube were added 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), potassium iodide (0.5mmol,83mg) and DMAP (0.25mmol,31mg) in this order, and after evacuation and charging with oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (41mg, 30%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 6
To a 10mL Schlenk tube were added 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), potassium iodide (0.5mmol,83mg) and DMAP (0.5mmol,61mg) in this order, and after evacuation and charging with oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (54mg, 40%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 7
To a 10mL Schlenk tube were added 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), potassium iodide (0.5mmol,83mg) and DMAP (1mmol,122mg) in this order, and after applying vacuum and charging oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (53mg, 39%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 8
1a (0.5mmol,81mg), dichloroethane (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were sequentially added to a 10mL Schlenk's tube, and after vacuum-pumping and oxygen-charging (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (17mg, 13%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 9
1a (0.5mmol,81mg), 1, 4-dioxane (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were sequentially added to a 10mL Schlenk's tube, and after vacuum evacuation and oxygen charging (1atm), it was placed in an 80 ℃ oil bath and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (20mg, 15%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 10
1a (0.5mmol,81mg), N-dimethylformamide (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk's tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (23mg, 17%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 11
1a (0.5mmol,81mg), dimethyl sulfoxide (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine simple substance (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum evacuation and oxygen charging (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (23mg, 17%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 12
To a 10mL Schlenk tube, 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order, and after evacuation and charging of oxygen (1atm), they were placed in a 40 ℃ oil bath and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (11mg, 8%).
Example 13
To a 10mL Schlenk tube, 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order, and after vacuum-charging oxygen (1atm), the mixture was placed in a 100 ℃ oil bath and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (15mg, 11%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 14
To a 10mL Schlenk tube, 1a (0.5mmol,81mg), acetonitrile (5mL), anhydrous copper acetate (0.5mmol,91mg), iodine (0.25mmol,64mg) and DMAP (0.5mmol,61mg) were added in this order, and after vacuum and nitrogen gas charging, they were placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2a (17mg, 13%). In accordance with the method of example 1, 2a can be converted to 3 a.
Example 15
1b (0.5mmol,90mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 100/1) gave product 2b as a brown solid (95mg, 66%). According to the method of example 1, 2b can be converted to 3b in 60% yield. Characterization data for compound 2b are as follows:1H NMR(400MHz,CDCl3)δ6.33(d,J＝1.6Hz,1H),6.80(t,J＝2.4Hz,1H),6.97(s,1H),7.02-7.06(m,2H),7.20-7.23(m,2H).13C NMR(150MHz,CDCl3)δ62.0,116.5(d,2JC-F＝23.1Hz),117.7,121.5,122.5(d,3JC-F＝8.9Hz),124.5,136.3(d,4JC-F＝2.3Hz),161.0(d,1JC-F＝245.1Hz).19F NMR(376MHz,CDCl3)δ-115.78.MS(EI):287[M]+.
example 16
1c (0.5mmol,98g), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and column separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2c (103mg, 68%). 2c can be converted to 3c according to the method of example 1. Characterization data for compound 2c are as follows:1H NMR(600MHz,CDCl3)δ6.42(d,J＝0.6Hz,1H),6.91(t,J＝2.4Hz,1H),7.08(s,1H),7.27(d,J＝8.4Hz,2H),7.39(d,J＝9.0Hz,2H).13C NMR(150MHz,CDCl3)δ62.5,118.0,121.1,121.7,124.1,129.8,131.9,138.4.
example 17
1d (0.5mmol,120mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtering, and carrying out spin-drying,separation on silica gel column (petroleum ether/ethyl acetate 100/1) gave compound 2d (106mg, 61%). 2d can be converted to 3d according to the method of example 1. Characterization data for compound 2d are as follows:1H NMR(600MHz,CDCl3)δ6.42(s,1H),6.91(s,1H),7.09(s,1H),7.21(d,J＝7.2Hz,2H),7.54(d,J＝7.8Hz,2H).13C NMR(100MHz,CDCl3)δ62.6,118.1,119.5,121.0,122.0,124.0,132.8,138.8.
example 18
1e (0.5mmol,88mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2e (83mg, 59%). 2e (0.5mmol,141mg), CuI (0.05mmol,9.5mg), L-proline (0.05mmol,5.8mg) and cesium fluoride (1mmol,152mg) were placed in a 10mL Schlenk tube, evacuated and charged with nitrogen, then piperidine (1mmol,85mg) and DMSO (5mL) were added to the system, warmed to 50 ℃ and reacted for 24 h. The reaction system was worked up to give the desired product 3e (73mg, 61%). Characterization data for compound 2e are as follows:1H NMR(600MHz,CDCl3)δ2.37(s,3H),6.39(dd,J1＝3.0Hz,J2＝1.2Hz,1H),6.91(t,J＝2.4Hz,1H),7.08(d,J＝1.8Hz,1H),7.22(s,4H).13C NMR(100MHz,CDCl3) δ 20.9,61.5,117.3,120.5,121.3,124.2,130.2,136.2,137.6 characterization data for compound 3e are as follows:1H NMR(600MHz,CDCl3)δ1.45-1.49(m,2H),1.63-1.67(m,4H),2.27(s,3H),2.88(t,J＝5.4Hz,4H),6.02(t,J＝2.4Hz,1H),6.46(t,J＝1.8Hz,1H),6.85(t,J＝2.4Hz,1H),7.10(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,2H).13C NMR(150MHz,CDCl3)δ20.8,24.2,25.7,52.1,101.9,103.4,118.1,119.4,130.0,134.3,138.7,142.5.HRMS calcd for C16H20N2Na:263.1519[M+Na]+,found:263.1521.
example 19
1f (0.5mmol,95mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2f (92mg, 62%). 2f can be converted to 3f according to the methods of example 1 and example 18. Characterization data for compound 2f are as follows:1H NMR(600MHz,CDCl3)δ1.25(t,J＝7.8Hz,3H),2.67(q,J＝7.8Hz,2H),6.40(t,J＝1.8Hz,1H),6.92(d,J＝2.4Hz,1H),7.09(s,1H),7.24(s,4H).13C NMR(150MHz,CDCl3)δ15.6,28.3,61.5,117.3,120.7,121.3,124.3,129.0,137.8,142.6.
example 20
To a 10mL Schlenk tube were added 1g (0.5mmol,96mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) in this order, and after evacuation and charging of oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave 2g (75mg, 50%). According to the method of example 1 and example 18, 2g can be converted to 3g with a yield of 58%. Characterization data for compound 2g is as follows:1H NMR(600MHz,CDCl3)δ3.76(s,3H),6.32(dd,J1＝3.0Hz,J2＝1.2Hz,1H),6.79(t,J＝2.4Hz,1H),6.87(dd,J1＝6.6Hz,J2＝1.8Hz,2H),6.96(t,J＝1.8Hz,1H),7.18(d,J＝6.6Hz,2H).13C NMR(100MHz,CDCl3)δ55.6,61.1,114.7,117.1,121.6,122.3,124.5,133.6,158.2.
example 21
To a 10mL Schlenk tube were added 1h (0.5mmol,90mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) in this order, and after evacuation and charging of oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 10 h. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 100/1) gave compound 2h (85mg, 59%). In accordance with the methods of example 1 and example 18, 2h can be converted to 3 h. Characterization data for compound 2h are as follows:1H NMR(600MHz,CDCl3)δ6.43(s,1H),6.95-6.99(m,2H),7.06(d,J＝9.6Hz,1H),7.13-7.14(m,2H),7.37-7.41(m,1H).13C NMR(150MHz,CDCl3)δ62.7,107.9(d,2JC-F＝25.2Hz),113.1(d,2JC-F＝20.9Hz),115.8(d,4JC-F＝3.3Hz),118.1,121.0,124.1,131.0(d,3JC-F＝9.9Hz),141.2(d,3JC-F＝9.9Hz),163.3(d,1JC-F＝246.0Hz).19F NMR(376MHz,CDCl3)δ-110.55.
example 22
To a 10mL Schlenk tube were added 1i (0.5mmol,120mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), elemental iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) in this order, followed by vacuum extractionAfter being charged with oxygen (1atm), the mixture was placed in an oil bath at 80 ℃ and stirred for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and column separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2i (104mg, 60%). In accordance with the methods of example 1 and example 18, 2i can be converted to 3 i. Characterization data for compound 2i are as follows:1H NMR(400MHz,CDCl3)δ6.35(s,1H),6.86(t,J＝2.4Hz,1H),7.04(s,1H),7.19-7.23(m,2H),7.32-7.34(m,1H),7.44(s,1H).13C NMR(100MHz,CDCl3)δ62.8,118.2,118.9,121.0,123.2,123.6,124.0,129.3,131.0,140.9.
example 23
1j (0.5mmol,88mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2j (89mg, 63%). 2j can be converted to 3j according to the methods of example 1 and example 18. Characterization data for compound 2j are as follows:1H NMR(400MHz,CDCl3)δ2.31(s,3H),6.32(s,1H),6.85(s,1H),7.00(d,J＝7.2Hz,1H),7.03-7.06(m,3H),7.21(t,J＝7.6Hz,1H).13C NMR(100MHz,CDCl3)δ21.5,61.8,117.4,117.7,121.2,121.3,124.2,127.1,129.5,139.8,139.9.
example 24
To a 10mL Schlenk tube were added 1k (0.5mmol,88mg), acetonitrile (5mL), anhydrous copper acetate in that order(1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg), which were placed in an oil bath at 80 ℃ for stirring reaction for 10 hours after vacuum charging with oxygen (1 atm). Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2k (85mg, 60%). Following the procedures of example 1 and example 18, 2k can be converted to 3k in 55% yield. Characterization data for compound 2k are as follows:1H NMR(400MHz,CDCl3)δ2.13(s,3H),6.31(t,J＝2.4Hz,1H),6.59(t,J＝2.4Hz,1H),6.76(t,J＝2.0Hz,1H),7.12-7.13(m,1H),7.15-7.23(m,3H).13C NMR(150MHz,CDCl3)δ17.7,60.1,116.2,123.9,126.6,126.7,128.1,131.2,133.8,139.7.
example 25
1l (0.5mmol,96mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave 2l (76mg, 51%). In accordance with the methods of example 1 and example 18, 2l can be converted to 3 l. Characterization data for compound 2l are as follows:1H NMR(600MHz,CDCl3)δ3.77(s,3H),6.30(s,1H),6.79(t,J＝2.4Hz,1H),6.92-6.96(m,3H),7.16-7.18(m,1H),7.20-7.23(m,1H).13C NMR(100MHz,CDCl3)δ55.8,60.4,112.3,116.1,121.0,123.9,125.6,126.7,128.1,129.3,152.6.
example 26
1m (0.5mmol,95mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were added in this order to a 10mL Schlenk tube, and after vacuum charging with oxygen (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2m (81mg, 54%). In accordance with the methods of example 1 and example 18, 2m can be converted to 3 m. Characterization data for compound 2m are as follows:1H NMR(600MHz,CDCl3)δ2.35(s,6H),6.39(s,1H),6.91-6.95(m,4H),7.10(s,1H).13C NMR(100MHz,CDCl3)δ21.4,61.5,117.2,118.4,121.2,124.2,128.0,139.5,139.9.
example 27
1n (0.5mmol,119mg), acetonitrile (5mL), anhydrous copper acetate (1mmol,181mg), iodine (0.5mmol,127mg) and DMAP (0.5mmol,61mg) were sequentially added to a 10mL Schlenk tube, and after vacuum charging (1atm), it was placed in an oil bath at 80 ℃ and stirred for reaction for 10 hours. Then, the reaction was quenched by addition of 10mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 100/1) gave compound 2n (83mg, 48%). 2n can be converted to 3n according to the methods of example 1 and example 18. Characterization data for compound 2n are as follows:1H NMR(400MHz,CDCl3)δ6.55(d,J＝3.2Hz,1H),7.16(d,J＝3.2Hz,1H),7.27-7.32(m,1H),7.39-7.51(m,7H),7.60-7.63(m,2H).13C NMR(100MHz,CDCl3)δ70.9,111.6,126.57,126.62,127.4,128.16,128.24,128.5,128.9,132.1,136.4,141.3。
the foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (6)
1. A synthetic method of an N-pyrrolylpiperidine compound is characterized by comprising the following steps: firstly, adding N-substituted piperidine 1 into a solvent, and heating in oxygen in the presence of copper acetate, 4-dimethylaminopyridine and an additive to react to obtain an iodopyrrole compound 2; secondly, mixing the compound 2, copper salt, ligand, alkali and piperidine, and heating for reaction to obtain an N-pyrrolylpiperidine compound 3, wherein the reaction equation is as follows:
wherein: r1Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine or C1-4One or more of alkyl or alkoxy, R2Is hydrogen, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine or C1-4One or more of alkyl or alkoxy; in the first step, the additive is selected from elementary iodine or metal iodide salt; the metal iodide salt is lithium iodide, sodium iodide or potassium iodide; in the second step, the copper salt is selected from cuprous iodide, cuprous bromide or cuprous chloride; the ligand is selected from L-proline; the base is selected from cesium fluoride or cesium carbonate.
2. The method for synthesizing an N-pyrrolylpiperidine compound according to claim 1, wherein: the first-step reaction solvent is selected from acetonitrile, dichloroethane, 1, 4-dioxane, N-dimethylformamide or dimethyl sulfoxide.
3. The method for synthesizing an N-pyrrolylpiperidine compound according to claim 1, wherein: the first step reaction is carried out under 1-2atm of oxygen atmosphere.
4. The method for synthesizing an N-pyrrolylpiperidine compound according to claim 1, wherein: in the first step and the second step, the heating reaction temperature is selected from 40-100 ℃.
5. The method for synthesizing an N-pyrrolylpiperidine compound according to any one of claims 1 to 4, wherein: in the first step, the ratio of the amount of N-substituted piperidine 1, copper acetate, additive and 4-dimethylamino pyridine is 1:1-2:0.25-1: 0.5-2.
6. The method for synthesizing an N-pyrrolylpiperidine compound according to claim 1, wherein: in the second step, the reaction is carried out in a solvent selected from DMF, DMSO or 1, 4-dioxane.
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| Title |
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| C(sp3)–H dehydrogenation and C(sp2)–H alkoxy carbonylation of inactivated cyclic amines towards functionalized N-heterocycles;Xuesen Fan et al.;《Chem. Commun.》;20170320;第53卷;4002-4005 * |
| FeCl3–Catalyzed Cascade Reactions of Cyclic Amines with 2-Oxo-2-arylacetic Acids toward Furan-2(5H)-one Fused N,O-Bicyclic Compounds;Xuesen Fan et al.;《Adv. Synth. Catal.》;20181106;第360卷;261-266 * |
| Regioselective Synthesis of AcylatedN‑Heterocycles via the Cascade Reactions of Saturated Cyclic Amines with 2‑Oxo-2-arylacetic Acids;Xuesen Fan et al.;《J. Org. Chem.》;20180514;第83卷;6524-6533 * |
| Synthesis of α-Formylated N-Heterocycles and Their 1,1-Diacetates from Inactivated Cyclic Amines Involving an Oxidative Ring Contraction;Xuesen Fan et al.;《Org. Lett.》;20180118;第20卷;864-867 * |
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