Background
Heterocyclic compounds, especially nitrogen-containing heterocyclic compounds, are very important compounds which are generally important molecular skeletons of natural substances and pharmaceutical molecules. The nitrogen-containing heterocyclic compound has wide application in medicine and pesticide chemistry. For example, physostigmine is used primarily in the treatment of glaucoma, and can constrict the pupil and lower intraocular pressure. The clemastine is mainly used for the phenomena of skin redness and itching caused by various anaphylactic reactions, and rhinorrhea, sneezing, eye redness and itching and the like caused by pollen allergy and cold. Argatroban is an anticoagulant and is mainly used for ischemic cerebral infarction within 48 hours of attack and improvement of nervous symptoms (motor paralysis) of patients in acute stage. Prasugrel is mainly used for treating cardiovascular and cerebrovascular diseases such as heart failure, stroke, unstable angina pectoris and the like. In addition, the nitrogen-containing heterocycle is also applied to the aspects of metal catalytic materials and fuel sensitized solar cells due to the characteristics that the nitrogen-containing heterocycle is easy to carry out structural modification and is convenient for introducing various groups. Therefore, the formation of C-N bond to construct the nitrogen-containing heterocyclic compound skeleton is of crucial importance in synthetic chemistry. Transition metal catalyzed C-H bond functionalization has been an effective, versatile method of constructing complex molecules for the last few decades. The targeting, also called Ligand-Directed (Ligand-Directed) or complexation-Directed (Coordination-Directed), is that a molecule requiring C-H activation and a transition metal can form a relatively stable cyclic metal intermediate by virtue of the complexation between the Ligand and the transition metal through an existing group having Coordination ability in the molecule, so that a C-M bond is formed at an expected position, and a functionalization reaction further occurs. Among many reports, C — H bond activation with the aid of a directing group has attracted considerable attention due to its good selection and functional group tolerance.
At present, many synthetic methods for synthesizing indoline derivatives have been reported. In 2008, Yu project group first discovered a targeting group of trifluoroformamide, which can be applied to ortho-iodination of phenylethylamine to achieve selective functionalization of C — H bond. On this basis, they further succeeded in synthesizing indoline derivatives (Li, j. -j.; Mei, t. -s.; Yu, j. -q.angelw.chem.int.ed.2008, 47,6452.). After a while, the Yu topic group reported a breakthrough development. They use Ce (SO)4)2Or F+As strong oxidizing agents instead of copper salts[15]The phenethylamine protected by the trifluoroformamide is taken as a substrate to be directly synthesized in one stepIndoline derivatives are provided. However, 10 to 15 mol% of palladium (II) and a large amount of oxidizing agent (Mei, T. -S.; Wang, X.; Yu, J. -Q.J.Am.chem.Soc.2009,131,10806.) are required to achieve this conversion.
In 2011, Chen and Daugulis project groups reported picolinamide-directed palladium-catalyzed C (sp), respectively2) -H and C (sp)3) Intramolecular ammoniation reaction of-H, all using PhI (OAc)2As an oxidant, a series of azetidine and pyrroline derivatives ((a) He, G.; ZHao, Y.; Zhang, S.; Lu, C.; Chen, G.J.Am.Chem.Soc.2012,134,3.(b) Nadres, E.T.; Daugulis, O.J.Am.Chem.Soc.2012,134,7.) are synthesized through five-membered ring palladium transition states and six-membered ring palladium transition states respectively, so that C-N bonding of a challenging aliphatic amine substrate is realized. Subsequently, Chen subject group found that oxygen has a certain inhibitory effect on cyclization reaction of amine substrates (He, G.; Lu C.; Zhao, Y.; Nack, W.A.; Chen, G.Org.Lett.2012,14,2944.), and they succeeded in synthesizing nitrogen-containing heterocyclic derivatives by modifying experimental conditions using argon as a reaction atmosphere, and under the reaction conditions, the catalyst dosage is less and the temperature is lower.
2012, the Shi topic group Pd (OAc)2Is catalyst, PhI (OAc)2As an oxidant, 1,2, 3-triazole formamide is a guide group, and an intramolecular C-N bond forming reaction is realized (Ye, X.; He, Z.; Ahmed, T.; Weise, K.; Akhmedov, N.G.; Petersen, J.L.; Shi, X.Chem.Sci.2013,4,3712.). In 2013, the Ma project group uses 2-methoxyiminoacetamide as a positioning group to realize amination reaction of 2-esterphenethylamine derivatives (He, Y-P.; Zhang, C.; Fan, M.; Wu, Z.; Ma, D.org.Lett.2015,17,496.). In this system, when PhI (OAc) is used2When used as an oxidizing agent, the reaction is not good in yield and by-products of the acyl oxidation are also present.
In 2014, Shi subject group realized palladium-catalyzed ammoniation reactions of phenethylamines, amphetamines and aliphatic amines with oxamides as targeting groups, forming five-and six-membered heterocycles ((a) Wang, Q.; Han, J.; Wang, C.; Zhang, J.Y; Huang, Z.B.; Shi, D.Q.; Zhao, Y.S.Chem.Sci.2014,5,4962.(b) Han, J.; Liu, P.; Wang, C.; Wang, Q.; Zhang, J.Y; Zhao, Y.W.; Shi, D.Q.; Huang Z.B.; Zhao, Y.S.O.; Wang, Z.B.rg.lett.2014,16,5682.). Despite the many advantages of this method, PhI (OAc)2Expensive and not readily available, so that the reaction can still be improved, the invention utilizes cheap and easily available peroxide TBPB instead of expensive PhI (OAc)2As the oxidizing agent, also can well realize palladium catalyzed oxamide induced intramolecular C-N bond forming reaction, so as to synthesize the indoline derivative.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing indoline derivatives, which utilizes a small amount of catalyst and under mild reaction conditions, reduces reaction steps, shortens reaction time and improves yield. In order to solve the technical problems, the technical scheme of the invention is as follows: an indoline derivative, which is characterized in that: has a structure shown in formula IV:
wherein R is preferably-CH3、-OCH3Any one of-F, -Br or-Cl.
The invention provides a method for synthesizing indoline derivatives, which takes oxamide derivatives as raw materials, adds a catalyst, and realizes an oxamide-induced intramolecular C-N bond forming reaction under the conditions of a solvent, a peroxide oxidant and an additive to synthesize the indoline derivatives shown in formula IV.
The preferred synthesis method of the invention is that the molar ratio of the oxamide derivative to the catalyst is 1: 0.025.
In the preferred synthesis method of the present invention, the solvent is preferably one of 1, 2-dichloroethane, chlorobenzene, toluene, m-xylene, mesitylene, dimethyl sulfoxide, 1, 4-dioxane, tert-amyl alcohol and hexafluoroisopropanol. More preferably hexafluoroisopropanol.
In the preferable synthesis method of the invention, the catalyst is one of palladium chloride, palladium acetate, cobalt acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, cobalt acetylacetonate, ferric acetylacetonate, nickel chloride or copper acetate. Palladium acetate is preferred.
In the preferred synthesis method of the invention, the peroxide oxidant is one of cumyl hydroperoxide, di-tert-butyl peroxide, tert-butyl peroxybenzoate, dicumyl peroxide and tert-butyl peroxide. Tert-butyl peroxybenzoate is preferred.
In the preferred synthesis method of the invention, the additive is one of silver carbonate, benzoquinone, potassium persulfate, cuprous chloride, ferric chloride or N-methylmorpholine oxide. Potassium persulfate is preferred.
In the preferable synthesis method, the reaction temperature is 80-120 ℃, and the reaction time is 8-16 h; the preferred reaction temperature is 100 ℃ and the reaction time is 12 h.
The method for realizing the invention is listed as follows: the method for synthesizing indoline derivatives comprises the steps of taking compounds of an amine derivative formula I and a formula II as raw materials, taking triethylamine as a catalyst to synthesize an oxamide derivative formula III, taking the compound of the formula III as the raw material, adding the catalyst, and under the conditions of a solvent, a peroxide oxidant and an additive, realizing an oxamide-induced intramolecular C-N bonding reaction to synthesize indoline and derivatives thereof, namely an indoline derivative formula IV, wherein the specific synthetic route is as follows:
the invention has the advantages that: the synthesis process of the invention utilizes a C-H activation/cyclization method and uses palladium acetate as a catalyst to realize oxamide-induced intramolecular C-N bond forming reaction to synthesize the indoline derivative. Wherein the compounds N, N-diisopropyl-2- (4-bromoindol-1-yl) -2-oxyacetamide (IVa), N-diisopropyl-2- (4-fluoroindol-1-yl) -2-oxyacetamide (IVb), N-diisopropyl-2- (5-methoxyindol-1-yl) -2-oxyacetamide (IVc), N-diisopropyl-2- (5-bromoindol-1-yl) -2-oxyacetamide (IVd), N-diisopropyl-2- (6-methylindol-1-yl) -2-oxyacetamide (IVe), N, N-diisopropyl-2- (4, 6-dichloroindol-1-yl) -2-oxyacetamide (IVf) having the following structure:
Detailed Description
Example 1
Will N1,N1-diisopropyl-N2Adding (0.2mmol) of- (2-bromophenylethyl) oxamide into a reaction tube, adding a palladium acetate catalyst (2.5 mol%) and tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after a solid is separated out, purifying by using a silica gel column chromatography, and taking ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (4-bromoindol-1-yl) -2-oxyacetamide (IVa): the yield is 81%; 1H NMR (400MHz, CDCl3) δ:8.12(d, J ═ 8.4Hz,0.77H),7.22-7.01(m,2.22H),4.19-4.10(m,2H),3.94-3.90(m,1H),3.55-3.52(m,1H),3.20-3.13(m,2H),1.56-1.50(m,6H),1.26-1.15(m,6H).13C NMR(100MHz,CDCl3)δ:163.7,162.8,132.5,129.5,129.1,127.6,127.1,119.5,116.0,51.1,50.7,47.5,46.2,46.0,29.7,28.3,21.0,20.7,20.2,20.0.
Example 2
Following the procedure of example 1, N1,N1-diisopropyl-N2Adding (0.2mmol) of- (2-fluorophenethyl) oxamide into a reaction tube, adding a palladium acetate catalyst (2.5mol percent), tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after a solid is separated out, purifying by silica gel column chromatography by using ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (4-fluoroindol-1-yl) -2-oxyacetamide (IVb): the yield is 84%;1H NMR(400MHz,CDCl3)δ:7.96(d,J=8.4Hz,0.67H),7.23-7.21(m,1.24H),7.14-7.10(m,0.24H),6.97-6.95(m,0.24H),6.82-6.75(m,0.85H),4.23-4.13(m,2H),3.95-3.72(m,1H),3.58-3.20(m,1H),3.24-3.16(m,2H),1.57-1.50(m,6H),1.27-1.16(m,6H).13C NMR(100MHz,CDCl3)δ:164.1,163.7,162.4,160.2,157.7,144.2,144.1,129.6,129.6,129.3,129.3,118.2,117.9,113.1,113.0,111.6,111.4,111.1,110.9,109.0,109.0,51.0,50.6,48.4,47.2,46.1 45.91,24.5,23.0,20.9,20.6,20.1,19.9.
example 3
Following the procedure of example 1, N1,N1-diisopropyl-N2Adding (0.2mmol) of- (3-methoxyphenethyl) oxamide into a reaction tube, adding a palladium acetate catalyst (2.5mol percent), tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after solid is separated out, purifying by silica gel column chromatography by taking ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (5-methoxyindol-1-yl) -2-oxyacetamide (IVc): the yield is 71%;1H NMR(400MHz,CDCl3)δ:8.05(d,J=8.8Hz,0.75H),7.06(d,J=9.2Hz,0.26H),6.75-6.69(m,1H),4.12-4.03(m,2H),3.95-3.88(m,1H),3.75-3.73(m,3H),3.53-3.47(m,1H),3.15-3.04(m,2H),1.54-1.46(m,6H),1.22-1.10(m,6H).13C NMR(100MHz,CDCl3)δ:164.6,164.1,161.9,161.8,157.1,156.9,135.4,134.6,133.5,133.3,117.8,113.9,112.3,112.1,111.5,111.0,55.7,55.6,50.9,50.5,48.1,46.9,45.9,45.8,28.3,27.0,20.9,20.6,20.1,19.9.
example 4
Following the procedure of example 1, N1,N1-diisopropyl-N2- (3-bromochlorophenylethyl) oxamide (0.2mmol) is added into a reaction tube, then a palladium acetate catalyst (2.5mol percent), tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent) are added, hexafluoroisopropanol (0.5mL) is added, the reaction tube is sealed, the mixture is put into an oil bath and stirred at 100 ℃ for reaction for 12 hours, after the reaction is finished, the reaction system is cooled to room temperature, and after solids are precipitated, suction filtration is carried out,Performing rotary evaporation and drying, performing silica gel column chromatography, and purifying by using ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (5-bromoindol-1-yl) -2-oxyacetamide (IVd): the yield is 66%;1H NMR(400MHz,CDCl3)δ:7.79(d,J=7.6Hz,0.72H),7.31-7.19(m,2H),6.99(d,J=8.8Hz,0.26H),4.12-4.04(m,2H),3.89-3.84(m,1H),3.66-3.48(m,1H),3.17-3.09(m,2H),1.52-1.45(m,6H),1.22-1.11(m,6H).13C NMR(100MHz,CDCl3)δ:164.1,163.6,162.4,140.9,139.0,135.3,134.2,130.4,130.2,128.8,127.9,118.4,117.1,116.8,114.5,51.0,50.6,48.0,46.8,46.0,45.9,27.9,26.5,20.9,20.6,20.1,19.9.
example 5
Following the procedure of example 1, N1,N1-diisopropyl-N2Adding (0.2mmol) of (4-methylphenylethyl) oxamide into a reaction tube, adding a palladium acetate catalyst (2.5mol percent), tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after solid is separated out, purifying by silica gel column chromatography by taking ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (6-methylindol-1-yl) -2-oxyacetamide (IVe): the yield is 79 percent;1H NMR(400MHz,CDCl3)δ:8.04(s,0.61H),7.11-7.04(m,1.27H),6.91-6.83(m,0.92H),4.19-4.06(m,2H),3.97-3.71(m,1H),3.56-3.51(m,1H),3.16-3.08(m,2H),2.35-2.28(m,3H),1.60-1.50(m,6.40H),1.25-1.07(m,5.79H).13C NMR(100MHz,CDCl3)δ:164.5,164.0,162.4,162.3,141.8,139.8,137.5,137.3,129.8,128.9,125.4,125.2,125.0,124.4,117.8,113.9,50.9,50.5,48.3,46.9,45.9,45.7,27.7,26.3,21.5,21.3,20.8,20.5,20.1,19.8.
example 6
Following the procedure of example 1, N1,N1-diisopropyl-N2- (2, 4-Dichlorophenethyl) oxamide (0.2mmol) was added to the reaction tube, followed by palladium acetate catalyst (2.5 mol%) and tert-butyl peroxybenzoate (3 equiv.) to give a solutionAnd potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after a solid is separated out, purifying by silica gel column chromatography to obtain a target product N, N-diisopropyl-2- (4, 6-dichloroindol-1-yl) -2-oxyacetamide (IVf) by taking ethyl acetate and petroleum ether (1:15) as eluent: the yield is 69%;1H NMR(400MHz,CDCl3)δ:8.13-8.12(m,0.6H),7.26-7.25(m,0.39H),7.08-7.03(m,1H),4.21-4.13(m,2H),3.93-3.88(m,1H),3.70-3.52(m,1H),3.19-3.12(m,2H),1.61-1.49(m,6H),1.26-1.17(m,6H).13C NMR(100MHz,CDCl3)δ:163.8,163.3,162.8,162.4,143.7,141.9,134.3,131.8,130.9,130.1,129.0,124.4,123.8,115.9,112.2,51.2,50.8,48.2,46.9,46.4,46.1,27.3,25.9,21.0,20.8,20.2,19.9.
after screening of reaction conditions for many times, considering the effect of the reaction and the principle of green chemistry, as the optimization, hexafluoroisopropanol is determined as a solvent, palladium acetate is determined as a catalyst, and the oxamide derivative and the catalyst are reacted for 12 hours at the reaction temperature of 100 ℃ according to the molar ratio of 1:0.025, so that the yield of the obtained target product is highest.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed.