CN107955020B - Method for synthesizing benzimidazol oxazinone compound by copper salt catalysis in one pot - Google Patents
Method for synthesizing benzimidazol oxazinone compound by copper salt catalysis in one pot Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
The invention relates to a method for synthesizing benzimidazol oxazinone compounds by catalyzing copper salt in one pot, which comprises the following steps: adding a compound shown as a general formula I, a compound shown as a general formula II, a catalyst and TEMPO into a reaction tube, then adding pyridine and an organic solvent to carry out a series-dehydrogenation reaction, cooling and removingRemoving the solvent, and purifying to obtain a product III; the method has the advantages of simple and easily obtained raw materials, greatly simplified reaction steps, mild and easily controlled reaction conditions, avoidance of the use of precious or toxic metals and strong oxidants, and effective obtaining of a plurality of benzimidazol oxazinone compounds.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a method for synthesizing benzimidazol oxazinone compounds in one pot under catalysis of copper salt.
Background
The structure of benzimidazole compounds is widely present in pharmaceutical chemistry, functional materials and natural products. In addition, the oxazinone compounds show wide biological activity, and the 6-bromo-3, 4-dihydro-1, 4-benzoxazine has good curative effects on inflammation and depression. Therefore, the establishment of a scheme for effectively synthesizing the oxazinone is of great significance to the field of pharmaceutical chemistry. So far, there are few methods for synthesizing oxazinones reported in literature, and representative methods include:
(1) the target product is obtained in the presence of carbon dichlorosulfide (cf. synthesis 1975,5, 325-326).
(2) The desired product was obtained in the presence of o-hydroxybenzoyl chloride (see Pharmaceutical chemistry journal 2000,34, 353-355).
(3) The oxazinone product is synthesized from 2-hydroxybenzamide and ketone as raw materials with a yield of 28% -92% (see J. org. chem.1981,46, 3240-3342).
(4) 2-hydroxy-4-methylbenzamide and aldehyde are used as raw materials and react in toluene to obtain the oxazinone product with the yield of 50-90% (see Angew Chem Int Ed 2010,49, 9749-.
The above synthetic methods all have many defects and shortcomings:
1) most raw materials cannot be directly obtained, need to be prepared by self, and have no high efficiency.
2) The catalyst used in the reaction needs to be prepared by itself, and the process is complicated and difficult to prepare.
3) The starting materials for the reaction are hazardous and unsuitable for large-scale preparation.
4) The side reaction is more, and the by-product has no use.
Therefore, there is a need to improve the existing methods for synthesizing oxazinones, and to obtain a method for synthesizing oxazinones with low synthesis cost, mild reaction conditions, easily available principle, and using cheap metal.
Disclosure of Invention
In order to solve the above problems and in accordance with the principles of green chemistry and economics, the present invention aims to provide copper salt catalyzed C-N acylation and sp under mild conditions2C-O dehydrogenation reaction to synthesize the oxazinone compound with a novel structure.
In order to achieve the purpose, the invention provides the following technical scheme:
the method for synthesizing the benzimidazol oxazinone compound by catalyzing copper salt in one pot comprises the following steps: adding a compound shown as a general formula I, a compound shown as a general formula II, a catalyst and TEMPO into a reaction tube, then adding pyridine and an organic solvent to carry out a series-dehydrogenation reaction, cooling, removing the solvent and purifying to obtain a product III;
the chemical reaction formula is as follows:
R1、R2is hydrogen, R3Is hydrogen, methyl, methoxy or halogen; or R1Is methyl, methoxy, ester or halogen, R2Is hydrogen, R3Is hydrogen; or R1、R2Is methyl or halogen, R3Is hydrogen.
Further, the organic solvent is p-xylene, and the catalyst is Cu (OAc)2·H2O，CuCl，CuCl2，CuBr，CuBr2Or CuI.
Further, the conditions of the series-dehydrogenation reaction were that the reaction was performed with condensing reflux at 120 ℃ in air for 36 hours.
Further, the purification is that silica gel is added and then is dried in a spinning mode, then the silica gel with the size of 300-400 meshes is used for passing through a column, and a developing agent is a mixed solution of petroleum ether and ethyl acetate.
Further, the developing agent is a mixed solution of petroleum ether and ethyl acetate according to a volume ratio of 16: 1-6: 1.
Further, in the tandem-dehydrogenation reaction, the compound represented by the general formula I is in excess.
Further, in the tandem-dehydrogenation reaction, the molar ratio of the compound represented by the general formula I to the compound represented by the general formula II is 0.4: 0.2.
further, the amount of the catalyst added was 1/5 which corresponded to the molar amount of the compound of the formula II.
Further, the compound shown in the general formula I is benzimidazole, 5, 6-dimethylbenzimidazole, 5-methylbenzimidazole, 5-ethylbenzimidazole, 5-fluorobenzimidazole, 5-chlorobenzimidazole, 5-bromobenzimidazole, 5, 6-difluorobenzimidazole or 5, 6-chlorobenzimidazole; the compound shown in the general formula II is salicylic acid, 3-methyl salicylic acid, 4-methyl salicylic acid, 5-methyl salicylic acid, 6-methyl salicylic acid, 3-methoxy salicylic acid, 5-fluoro salicylic acid, 5-chloro salicylic acid or 5-bromo salicylic acid.
The invention has the beneficial effects that: the synthesis method of the copper salt catalyzed oxazinone compound disclosed by the invention uses benzimidazole, substituted benzimidazole and the like and salicylic acid as raw materials, is easy to obtain, adopts a one-pot method to complete C-N coupling and C-O dehydrogenation reaction, has mild reaction conditions, is environment-friendly and saves cost, uses CuBr as a catalyst, does not use precious and toxic metals, strong oxidants or strong bases, and further reduces the production cost, and in addition, the oxazinone compound obtained by the method has multiple varieties and the yield can reach 81%.
Detailed Description
The preferred embodiments of the present invention will be described in detail below.
EXAMPLE 1 preparation of 12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-1)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), salicylic acid 28mg (0.2mmol) and paraxylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature at 120 ℃, condensing, refluxing, stirring, reacting for 36 hours, cooling to room temperature, transferring all into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin-drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining the compound III-138 mg with the yield of 81% by taking ethyl acetate as 16: 1-6: 1; a white solid; the melting point of the white solid is 210-211 ℃;1H NMR(600MHz,CDCl3)＝8.38(d,J＝8.0Hz,1H),8.35(d,J＝7.8Hz,1H),7.83(t,J＝7.8Hz,1H),7.74(d,J＝7.9Hz,1H),7.56(d,J＝8.4Hz,1H),7.53–7.45(m,2H),7.42(t,J＝7.7Hz,1H)ppm。
example 2, preparation of 8, 9-dimethyl-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-2)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), compound 5.6-dimethyl benzimidazole 59mg (0.4mmol), salicylic acid 28mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol) to the tube, controlling the temperature at 120 ℃, condensing, refluxing, stirring, reacting for 36 hours, cooling to room temperature, transferring all the materials into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel, spinning to dry, and passing through a column by 300-mesh 400-mesh silica gel using a developing agentPetroleum ether: obtaining the compound III-230 mg with a yield of 57% by taking ethyl acetate as 16: 1-6: 1; a white solid; the melting point of the white solid is 224-225 ℃;1H NMR(600MHz,CDCl3)＝8.32(d,J＝7.8Hz,1H),8.13(s,1H),7.80(t,J＝7.8Hz,1H),7.53(d,J＝8.4Hz,1H),7.50–7.44(m,2H),2.42(s,3H),2.39(s,3H)ppm；13C NMR(151MHz,CDCl3)156.3,153.3,150.5,137.7,136.1,135.0,132.8,128.1,126.9,125.3,119.4,117.3,115.3,114.3,20.4,20.3ppm；HRMS:[M+H]+calculated for C16H12N2O2+H+:265.0977,found 265.0978；IR(KBr)υ2921,1721,1635,1570,1464,1388,1354,1290,1264,1169,754cm-1。
EXAMPLE 3 preparation of 9-methyl-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one and 8-methyl-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-3-1 and Compound III-3-2)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), compound 5-methylbenzimidazole 53mg (0.4mmol), salicylic acid 28mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature to be 120 ℃, condensing, refluxing and stirring for reaction for 36 hours, cooling to room temperature, transferring all the mixture into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-332 mg with a yield of 64% in a ratio of 1:1, wherein ethyl acetate is 16: 1-6: 1; a light yellow solid; the melting point of the light yellow solid is 200-201 ℃;1H NMR(600MHz,CDCl3)＝8.32(d,J＝7.1Hz,1H),8.22–8.14(m,1H),7.81(t,J＝7.7Hz,1H),7.52(ddd,J＝25.0,23.6,7.7Hz,3H),7.24(dd,J＝35.8,7.7Hz,1H),2.52(d,J＝15.8Hz,3H)ppm；13C NMR(151MHz,CDCl3)156.5,156.2,155.7,153.3,153.3,151.0,150.6,139.7,137.2,136.3,136.2,136.2,133.9,128.8,128.2,128.1,127.2,126.5,125.4,125.4,124.9,119.2,118.6,117.3,115.1,114.5,114.3,114.3,21.8,21.7ppm；HRMS:[M+H]+calculated for C15H10N2O2+H+:251.0821,found 251.0825；IR(KBr)υ3437,1717,1629,1570,1466,1392,1350,1290,1284,1127,699cm-1。
EXAMPLE 4 preparation of 9-methoxy-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one and 8-methoxy-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-4-1 and Compound III-4-2)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), compound 5-methoxybenzimidazole 60mg (0.4mmol), salicylic acid 28mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature to be 120 ℃, condensing, refluxing and stirring for reaction for 36 hours, cooling to room temperature, transferring all the materials into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: ethyl acetate 16: 1-6: 1 to obtain compound III-427 mg in 51% yield at a ratio of 1: 1; a light yellow solid; the melting point of the light yellow solid is determined to be 180-181 ℃;1H NMR(600MHz,CDCl3)＝8.32(ddd,J＝7.8,4.5,1.5Hz,2H),8.23(d,J＝8.8Hz,1H),7.93(d,J＝2.5Hz,1H),7.84–7.79(m,2H),7.60(d,J＝8.8Hz,1H),7.54(t,J＝8.0Hz,2H),7.49(dt,J＝13.5,6.7Hz,2H),7.23(s,1H),7.06(dd,J＝8.7,2.6Hz,1H),6.99(dd,J＝8.8,2.4Hz,1H),3.92(s,3H),3.89(s,3H)ppm；13C NMR(151MHz,CDCl3)158.6,156.9,156.6,156.0,153.3,153.1,151.4,150.0,140.7,136.3,136.1,133.7,129.1,128.1,128.1,125.5,125.3,122.7,119.5,117.3,117.3,115.5,114.5,114.3,114.1,112.0,102.9,99.4,56.0,55.8ppm；HRMS:[M+Na]+calculated for C15H10N2O3+Na+:289.0589,found 289.0588；IR(KBr)υ3419,1894,1719,1628,1574,1469,1392,1293,1199,1097,954cm-1。
example 5 preparation of Ethyl 12-oxo-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazine-9-carboxylic acid and Ethyl 12-oxo-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazine-8-carboxylic acid (Compounds III-5-1 and III-5-2)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), compound 5-ethyl benzimidazole 76mg (0.4mmol), salicylic acid 28mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature to be 120 ℃, condensing, refluxing and stirring for reaction for 36 hours, cooling to room temperature, transferring all the mixture into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-532 mg with a yield of 52% in a ratio of 1:1 when ethyl acetate is 16: 1-6: 1; a light yellow solid; the pale yellow solid measured melting point of 230-;1H NMR(600MHz,CDCl3)＝8.99(t,J＝4.1Hz,1H),8.48–8.24(m,4H),8.20–8.11(m,1H),8.10(dd,J＝8.4,1.4Hz,1H),7.85(ddd,J＝8.4,7.2,1.6Hz,2H),7.71(d,J＝8.3Hz,1H),7.60–7.34(m,4H),4.62–4.13(m,4H),1.57–1.30(m,6H)ppm；13C NMR(151MHz,CDCl3)166.3,166.2,156.2,156.0,153.2,153.1,152.7,151.7,143.1,139.3,136.7,136.6,131.7,130.7,128.5,128.3,128.3,127.7,126.2,125.9,125.7,125.3,120.8,118.8,118.7,117.4,116.7,114.6,114.2,114.1,61.2,61.1,14.4,14.3ppm；HRMS:[M+H]+calculated for C17H12N2O4+H+:309.0875,found 309.0876；IR(KBr)υ3436,1910,1713,1635,1587,1470,1392,1294,1264,1151,749cm-1.
EXAMPLE 6 preparation of 9-fluoro-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one and 8-fluoro-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-6-1 and Compound III-6-2)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), compound 5-fluorobenzimidazole 55mg (0.4mmol), salicylic acid 28mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature to be 120 ℃, condensing, refluxing and stirring for reaction for 36 hours, cooling to room temperature, transferring all the materials into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin drying, and then passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-615 mg with a yield of 30% and a ratio of 7:8, wherein ethyl acetate is 16: 1-6: 1; a light yellow solid; the pale yellow solid measured a melting point of 240-241 ℃;1H NMR(600MHz,CDCl3)＝8.38–8.28(m,3H),8.10(dd,J＝8.2,2.5Hz,1H),7.84(dd,J＝11.1,4.5Hz,2H),7.66(dd,J＝8.7,4.6Hz,1H),7.56(t,J＝7.7Hz,2H),7.51(dd,J＝14.3,7.0Hz,2H),7.41(dd,J＝8.8,2.3Hz,1H),7.21(td,J＝9.3,2.5Hz,1H),7.14(td,J＝9.2,2.4Hz,1H)ppm；13C NMR(151MHz,CDCl3)162.0,160.4,160.4,158.8,156.3,156.1,153.3,153.2,152.0,136.6,136.5,128.3,128.2,125.7,125.6,125.0,119.8,119.8,117.4,115.8,115.8,114.2,114.0,113.8,111.6,111.5,106.1,105.9,102.8,102.6ppm；HRMS:[M+H]+calculated for C14H7N2O2F+H+:255.0570,found 255.0572；IR(KBr)υ3437,1857,1724,1637,1580,1483,1357,1288,1150,1017,958cm-1.
EXAMPLE 7 preparation of 9-chloro-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-7-1)
A25 mL Schlenk reaction tube was charged with CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), the compound 5-chlorobenzimidazole 61mg (0.4mmol), salicylic acid 28mg (0.2mmol), p-xylene (0.5mL), and then pyridine 33. mu.L (0.4mmol) was added thereto, the mixture was condensed at 120 ℃ and refluxed for reaction for 36 hours, cooled to room temperature, transferred to a 25mL flask, and evaporated on a rotary evaporatorRemoving the solvent by spinning, adding a proper amount of silica gel for spin drying, and then passing through a column by using 300-mesh 400-mesh silica gel, wherein the developing agent is petroleum ether: obtaining compound III-7-19 mg with a yield of 17% by taking ethyl acetate as 16: 1-6: 1; a light yellow solid; the light yellow solid measured a melting point of 220-;1H NMR(600MHz,CDCl3)＝8.35(dd,J＝7.9,1.4Hz,1H),8.30(d,J＝8.6Hz,1H),7.88–7.83(m,1H),7.72(d,J＝1.8Hz,1H),7.57(d,J＝8.4Hz,1H),7.53(t,J＝7.6Hz,1H),7.39(dd,J＝8.6,1.9Hz,1H)ppm；13C NMR(151MHz,CDCl3)156.1,153.3,151.8,140.5,136.6,131.8,128.3,127.2,125.8,124.2,119.3,117.5,115.8,114.1ppm；HRMS:[M+H]+calculated for C14H7N2O2Cl+H+:271.0274,found271.0275；IR(KBr)υ3697,1943,1864,1722,1610,1566,1468,1398,1284,1148,959cm-1。
EXAMPLE 8 preparation of 8-chloro-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-7-2)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), compound 5-chlorobenzimidazole 61mg (0.4mmol), salicylic acid 28mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature at 120 ℃, condensing, refluxing, stirring and reacting for 36 hours, cooling to room temperature, transferring all into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin-drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining the compound III-7-210 mg with a yield of 19% by taking ethyl acetate as 16: 1-6: 1; a light yellow solid; the light yellow solid measured a melting point of 218-;1H NMR(600MHz,CDCl3)＝8.41(d,J＝1.9Hz,1H),8.35(dd,J＝7.8,1.3Hz,1H),7.88–7.84(m,1H),7.65(d,J＝8.5Hz,1H),7.57(d,J＝8.4Hz,1H),7.53(t,J＝7.6Hz,1H),7.45(dd,J＝8.5,1.9Hz,1H)ppm；13C NMR(151MHz,CDCl3)156.2,153.3,151.3,138.1,136.7,129.4,129.0,128.3,126.6,125.7,119.9,117.5,115.3,114.1ppm；HRMS:[M+H]+calculated for C14H7N2O2Cl+H+:271.0274,found271.0277；IR(KBr)υ3695,1723,1631,1575,1469,1389,1283,1150,1059,956,895cm-1.
example 9 preparation of 9-bromo-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one and 8-bromo-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-8-1 and Compound III-8-2)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), compound 5-bromobenzimidazole 78mg (0.4mmol), salicylic acid 28mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol) to the solution, controlling the temperature at 120 ℃, condensing, refluxing, stirring and reacting for 36 hours, cooling to room temperature, transferring the solution to a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: and (3) obtaining the compound III-820 mg with a yield of 32% by taking ethyl acetate as 16: 1-6: 1, wherein the ratio of the ethyl acetate to the compound III is 7: 2; a light yellow solid; the pale yellow solid measured a melting point of 224-225 ℃;1H NMR(600MHz,CDCl3)＝8.56(s,1H),8.35(d,J＝9.1Hz,2H),8.25(d,J＝8.5Hz,1H),7.86(dd,J＝17.9,9.4Hz,2H),7.61–7.55(m,5H),7.53(dd,J＝13.4,5.8Hz,3H)ppm；13C NMR(151MHz,CDCl3)156.2,156.1,153.2,151.6,151.2,140.8,138.5,136.7,136.6,129.4,129.4,128.3,128.3,127.6,126.9,125.8,125.7,122.2,120.5,120.3,119.2,118.1,117.5,117.4,116.6,116.1,114.1,114.0ppm；HRMS:[M+Na]+calculated for C14H7N2O2Br+Na+:336.9589,found 336.9588；IR(KBr)υ3449,1939,1864,1736,1633,1564,1469,1284,1147,1043,957cm-1。
EXAMPLE 10, preparation of 8, 9-difluoro-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-9)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), compound 5, 6-difluorobenzimidazole 62mg (0.4mmol), salicylic acid 28mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol) to the solution, controlling the temperature at 120 ℃, condensing, refluxing, stirring and reacting for 36 hours, cooling to room temperature, transferring the solution to a 25mL flask, spinning off the solvent on a rotary evaporator, adding a proper amount of silica gel, spinning to dry, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-926 mg with a yield of 48% when ethyl acetate is 16: 1-6: 1; a white solid; the melting point of the white solid is 255-256 ℃;1H NMR(600MHz,CDCl3)＝8.34(dd,J＝7.9,1.5Hz,1H),8.23(dd,J＝9.5,7.3Hz,1H),7.87(ddd,J＝8.7,7.4,1.6Hz,1H),7.58(d,J＝8.3Hz,1H),7.53(dd,J＝9.3,6.8Hz,1H)ppm；13C NMR(151MHz,CDCl3)156.1,153.1,151.6,150.5,136.8,135.4,135.3,130.7,128.3,125.8,123.7,123.6,117.5,113.9,107.5,107.4,104.2,104.0ppm；HRMS:[M+H]+calculated for C14H6N2O2F2+H+:273.0476,found 273.0475；IR(KBr)υ3070,1835,1726,1641,1585,1472,1399,1232,1202,1150,962cm-1。
EXAMPLE 11 preparation of 8, 9-dichloro-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-10)
Adding 6mg (0.04mmol) of CuBr, 5mg (0.03mmol) of TEMPO, 74mg (0.4mmol) of compound 5, 6-dichlorobenzimidazole, 28mg (0.2mmol) of salicylic acid and 0.5mL of p-xylene into a 25mL Schlenk reaction tube, adding 33 μ L (0.4mmol) of pyridine, controlling the temperature at 120 ℃, condensing, refluxing, stirring and reacting for 36 hours, cooling to room temperature, transferring all the materials into a 25mL flask, spinning off a solvent on a rotary evaporator, adding a proper amount of silica gel, spinning to dry, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: ethyl acetate 16: 1-61, obtaining the compound III-1020 mg with the yield of 33 percent; a white solid; the melting point of the white solid is 205-206 ℃;1H NMR(600MHz,CDCl3)＝8.51(s,1H),8.35(dd,J＝7.9,1.4Hz,1H),7.89–7.85(m,1H),7.83(s,1H),7.58(d,J＝8.4Hz,1H),7.54(dd,J＝11.5,4.1Hz,1H)ppm；13C NMR(151MHz,CDCl3)156.0,153.3,152.0,139.0,136.9,130.4,128.4,127.8,127.60(s),126.0,120.6,117.5,116.5,114.0ppm；HRMS:[M+Na]+calculated forC14H6N2O2Cl2+Na+:326.9704,found 326.9703；IR(KBr)υ3098,1823,1724,1635,1588,1469,1379,1280,1196,1092,959cm-1。
EXAMPLE 12 preparation of 4-methyl-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-11)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 3-methyl salicylic acid 31mg (0.2mmol) and paraxylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature to be 120 ℃, condensing, refluxing and stirring for reaction for 36 hours, cooling to room temperature, transferring all the components into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin-drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-1132 mg with the yield of 64% by taking ethyl acetate as 16: 1-6: 1; a white solid; the melting point of the white solid is 228-;1H NMR(600MHz,CDCl3)＝8.35(s,1H),8.14(s,1H),7.71(t,J＝6.4Hz,1H),7.63(s,1H),7.50–7.31(m,3H),2.57(d,J＝4.6Hz,3H)ppm；13C NMR(151MHz,CDCl3)156.7,151.6,151.1,139.5,137.5,128.6,127.1,126.0,125.7,125.0,123.7,119.0,115.0,114.0,15.5ppm；HRMS:[M+H]+calculated for C15H10N2O2+H+:251.0821,found 251.0823；IR(KBr)υ3059,1722,1627,1568,1483,1398,1287,1194,1097,1004,928cm-1。
EXAMPLE 13 preparation of 3-methyl-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-12)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 4-methyl salicylic acid 31mg (0.2mmol) and paraxylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature to be 120 ℃, condensing, refluxing and stirring for reaction for 36 hours, cooling to room temperature, transferring all the components into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin-drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-1235 mg with a yield of 70% by taking ethyl acetate as 16: 1-6: 1; a white solid; the melting point of the white solid is 258-259 ℃;1H NMR(600MHz,CDCl3)＝8.35(d,J＝8.0Hz,1H),8.18(d,J＝8.0Hz,1H),7.71(d,J＝7.9Hz,1H),7.45(t,J＝7.7Hz,1H),7.39(t,J＝7.7Hz,1H),7.33(s,1H),7.27(d,J＝9.0Hz,1H),2.53(s,3H)ppm；13C NMR(151MHz,CDCl3)156.4,153.4,151.2,148.4,139.5,128.7,127.9,126.8,125.9,123.7,119.0,117.3,115.0,111.8,22.0ppm；HRMS:[M+H]+calculated for C15H10N2O2+H+:251.0821,found 251.0823；IR(KBr)υ3062,1709,1620,1568,1455,1394,1288,1161,1043,1003,954cm-1。
example 14 preparation of 2-methyl-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-13)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 5-methyl salicylic acid 31mg (0.2mmol) and p-xylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), condensing, refluxing and stirring at 120 deg.C for reaction for 36h, and cooling to room temperatureAnd (3) transferring the mixture into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin-drying, and then passing the silica gel through a column by using 300-400-mesh silica gel, wherein the developing agent is petroleum ether: obtaining compound III-1334 mg with a yield of 68% when ethyl acetate is 16: 1-6: 1; a white solid; the melting point of the white solid is 251-252 ℃;1H NMR(600MHz,CDCl3)＝8.35(d,J＝7.9Hz,1H),8.08(s,1H),7.71(d,J＝7.9Hz,1H),7.59(d,J＝10.3Hz,1H),7.46–7.35(m,3H),2.48(s,3H)ppm；13C NMR(151MHz,CDCl3)156.5,151.4,151.3,139.5,137.3,135.6,128.7,127.7,126.0,123.6,119.0,117.1,115.1,113.8,20.8ppm；HRMS:[M+Na]+calculated forC15H10N2O2+Na+:273.0640,found 273.0641；IR(KBr)υ3056,1728,1624,1567,1486,1384,1285,1167,1047,1002,962cm-1。
example 15 preparation of 1-methyl-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-14)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 6-methyl salicylic acid 31mg (0.2mmol) and paraxylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature to be 120 ℃, condensing, refluxing and stirring for reaction for 36 hours, cooling to room temperature, transferring all the components into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin-drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-1415 mg with a yield of 30% when ethyl acetate is 16: 1-6: 1; a white solid; the melting point of the white solid is measured to be 256-257 ℃;1H NMR(600MHz,CDCl3)＝8.36(d,J＝8.0Hz,1H),7.71(d,J＝7.9Hz,1H),7.63(t,J＝7.9Hz,1H),7.45(t,J＝7.6Hz,1H),7.38(t,J＝7.4Hz,2H),7.24(d,J＝7.5Hz,1H),2.94(s,3H)ppm；13C NMR(151MHz,CDCl3)157.1,154.6,150.8,143.4,139.7,135.1,128.9,128.5,125.9,123.5,118.9,115.4,115.0,112.5,22.6ppm；HRMS:[M+Na]+calculated for C15H10N2O2+Na+:273.0640,found 273.0643；IR(KBr)υ3097,1712,1629,1573,1456,1391,1284,1147,1030,1003,972cm-1。
EXAMPLE 16 preparation of 4-methoxy-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-15)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 3-methoxysalicylic acid 34mg (0.2mmol) and paraxylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature to be 120 ℃, condensing, refluxing and stirring for reaction for 36 hours, cooling to room temperature, transferring all the components into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin-drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-157 mg with a yield of 14% by taking ethyl acetate as 16: 1-6: 1; a white solid; the melting point of the white solid is 230-231 ℃;1H NMR(600MHz,CDCl3)＝8.38(d,J＝7.9Hz,1H),7.89(d,J＝7.9Hz,1H),7.75(d,J＝7.9Hz,1H),7.48(t,J＝7.6Hz,1H),7.41(dd,J＝13.0,7.9Hz,2H),7.35(d,J＝7.8Hz,1H),4.04(s,3H)ppm；13C NMR(151MHz,CDCl3)156.5,151.0,148.2,143.5,139.6,128.7,126.0,125.2,123.7,119.2,118.7,118.1,115.1,115.0,56.8ppm；HRMS:[M+H]+calculated for C15H10N2O3+H+:267.0770,found 267.0771；IR(KBr)υ3056,1723,1665,1594,1497,1355,1285,1182,1079,1030,920cm-1。
EXAMPLE 17 preparation of 2-methoxy-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-16)
To a 25mL Schlenk reaction tube was added CuBr 6mg (0.0)4mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 5-methoxysalicylic acid 34mg (0.2mmol), p-xylene (0.5mL), pyridine 33. mu.L (0.4mmol) is added, the mixture is cooled to room temperature and is transferred into a 25mL flask, the solvent is removed by a rotary evaporator, silica gel is added to the flask, the mixture is dried by spin drying, and the silica gel is filtered through a 300-mesh 400-mesh silica gel column by using a developing agent which is petroleum ether: obtaining compound III-1633 mg with a yield of 62% by taking ethyl acetate as 16: 1-6: 1; a white solid; the white solid measured a melting point of 240-241 ℃;1H NMR(600MHz,CDCl3)＝8.35(d,J＝7.9Hz,1H),8.08(s,1H),7.71(d,J＝7.9Hz,1H),7.59(d,J＝10.3Hz,1H),7.46–7.35(m,3H),2.48(s,3H)ppm；13C NMR(151MHz,CDCl3)157.0,156.5,151.1,147.6,139.6,128.6,126.0,125.1,123.6,119.0,118.6,115.0,114.5,108.6,56.1ppm；HRMS:[M+Na]+calculated forC15H10N2O3+Na+:289.0589,found 289.0588；IR(KBr)υ3450,2116,1936,1855,1713,1626,1597,1451,1354,1202,935cm-1。
EXAMPLE 18 preparation of 2-fluoro-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-17)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 5-fluorosalicylic acid 32mg (0.2mmol) and paraxylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature at 120 ℃, condensing, refluxing, stirring and reacting for 36 hours, cooling to room temperature, transferring all the materials into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-1725 mg with a yield of 50% by taking ethyl acetate as 16: 1-6: 1; a white solid; the melting point of the white solid is measured to be 256-257 ℃;1H NMR(600MHz,CDCl3)＝8.36(d,J＝8.0Hz,1H),7.99(dd,J＝7.6,2.5Hz,1H),7.74(d,J＝7.9Hz,1H),7.56(dd,J＝8.2,3.7Hz,2H),7.49(t,J＝7.7Hz,1H),7.42(t,J＝7.7Hz,1H)ppm；13C NMR(151MHz,CDCl3)160.2,158.6,155.5,150.7,149.4,139.5,128.4,126.3,124.2,124.0,124.0,119.4,119.3,119.2,115.4,115.4,115.1,113.8,113.6ppm；HRMS:[M+H]+calculated for C14H7N2O2F+H+:255.0570,found 255.0572；IR(KBr)υ3056,1893,1726,1637,1574,1483,1386,1283,1196,1001,949cm-1。
EXAMPLE 19 preparation of 2-chloro-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-18)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 5-chlorosalicylic acid 35mg (0.2mmol) and paraxylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature at 120 ℃, condensing, refluxing, stirring and reacting for 36 hours, cooling to room temperature, transferring all the materials into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-1829 mg with a yield of 54% when ethyl acetate is 16: 1-6: 1; a white solid; the melting point of the white solid is 234-;1H NMR(600MHz,CDCl3)＝8.36(d,J＝6.8Hz,1H),8.30(s,1H),7.76(dd,J＝20.3,7.3Hz,2H),7.56–7.45(m,2H),7.43(d,J＝6.4Hz,1H)ppm；13C NMR(151MHz,CDCl3)1155.3,151.6,150.6,139.4,136.4,131.3,128.6,127.6,126.4,124.1,119.3,119.0,115.4,115.1ppm；HRMS:[M+H]+calculated for C14H7N2O2Cl+H+:271.0274,found 271.0272；IR(KBr)υ3084,1723,1634,1579,1472,1382,1269,1197,1080,1002,932cm-1。
EXAMPLE 20 preparation of 2-bromo-12H-benzo [ e ] benzo [4,5] imidazo [2,1-b ] [1,3] oxazin-12-one (Compound III-19)
Adding CuBr 6mg (0.04mmol), TEMPO 5mg (0.03mmol), benzimidazole 47mg (0.4mmol), 5-bromosalicylic acid 43mg (0.2mmol) and paraxylene (0.5mL) into a 25mL Schlenk reaction tube, adding pyridine 33 μ L (0.4mmol), controlling the temperature at 120 ℃, condensing, refluxing, stirring and reacting for 36 hours, cooling to room temperature, transferring all the materials into a 25mL flask, removing the solvent by a rotary evaporator, adding a proper amount of silica gel for spin drying, and passing through a column by using 300-mesh 400-mesh silica gel, wherein a developing agent is petroleum ether: obtaining compound III-1930 mg with a yield of 48% when ethyl acetate is 16: 1-6: 1; a white solid; the melting point of the white solid is 228-;1H NMR(600MHz,CDCl3)＝8.45(d,J＝2.4Hz,1H),8.36(d,J＝7.9Hz,1H),7.91(dd,J＝8.8,2.4Hz,1H),7.74(d,J＝7.9Hz,1H),7.50–7.40(m,3H)ppm；13C NMR(151MHz,CDCl3)155.2,152.1,150.6,139.4,139.3,130.7,128.6,126.4,124.1,119.3,119.2,118.4,115.8,115.1ppm；HRMS:[M+Na]+calculated for C14H7N2O2Br+Na+:336.9589,found 336.9588；IR(KBr)υ3432,1899,1721,1684,1579,1470,1380,1270,1194,1086,932cm-1。
finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (6)
1. The method for synthesizing the benzimidazol oxazinone compound by catalyzing one pot with the copper salt is characterized by comprising the following steps: adding a compound shown as a general formula I, a compound shown as a general formula II, a catalyst and TEMPO into a reaction tube, then adding pyridine and an organic solvent to carry out a series-dehydrogenation reaction, cooling, removing the solvent and purifying to obtain a product III;
the chemical reaction formula is as follows:
the organic solvent is p-xylene, and the catalyst is Cu (OAc)2·H2O，CuCl，CuCl2，CuBr，CuBr2Or CuI;
the conditions of the series-dehydrogenation reaction are that the reaction is carried out for 36 hours in the air at 120 ℃ by condensation, reflux and stirring;
the compound shown in the general formula I is benzimidazole, 5, 6-dimethylbenzimidazole, 5-methylbenzimidazole, 5-ethylbenzimidazole, 5-fluorobenzimidazole, 5-chlorobenzimidazole, 5-bromobenzimidazole, 5, 6-difluorobenzimidazole or 5, 6-dichlorobenzimidazole; the compound shown in the general formula II is salicylic acid, 3-methyl salicylic acid, 4-methyl salicylic acid, 5-methyl salicylic acid, 6-methyl salicylic acid, 3-methoxy salicylic acid, 5-fluoro salicylic acid, 5-chloro salicylic acid or 5-bromo salicylic acid.
2. The copper salt-catalyzed one-pot synthesis method of benzimidazol oxazinones according to claim 1, wherein the copper salt-catalyzed one-pot synthesis method comprises the following steps: the purification is that after silica gel is added, the silica gel is dried in a spinning mode, then silica gel of 300-400 meshes is used for passing through a column, and a developing agent is a mixed solution of petroleum ether and ethyl acetate.
3. The copper salt-catalyzed one-pot synthesis method of benzimidazol oxazinones according to claim 2, wherein the copper salt-catalyzed one-pot synthesis method comprises the following steps: the developing agent is a mixed solution of petroleum ether and ethyl acetate according to a volume ratio of 16: 1-6: 1.
4. The copper salt-catalyzed one-pot synthesis method of benzimidazol oxazinones according to claim 1, wherein the copper salt-catalyzed one-pot synthesis method comprises the following steps: in the tandem-dehydrogenation reaction, the compound represented by the general formula I is in excess.
5. The copper salt catalyzed one-pot synthesis method of benzimidazol oxazinones according to claim 1, wherein: in the tandem-dehydrogenation reaction, the molar ratio of the compound represented by the general formula I to the compound represented by the general formula II is 0.4: 0.2.
6. the copper salt catalyzed one-pot synthesis method of benzimidazol oxazinones according to claim 1, wherein: the catalyst is added in an amount corresponding to 1/5 moles of the compound of formula II.
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