CN108707116B - 2-alkyl substituted benzimidazole derivative and preparation method thereof - Google Patents
2-alkyl substituted benzimidazole derivative and preparation method thereof Download PDFInfo
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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Abstract
A 2-alkyl substituted benzimidazole derivative and a preparation method thereof. The invention discloses a 2-alkyl benzimidazole derivative, a preparation method and a structure thereofThe structure formula is as follows:
wherein R is1Is a formate protecting group, R2Is an alkyl group. The method synthesizes the 2-alkyl benzimidazole derivative, has profound significance from the aspects of organic synthesis and medicinal chemistry, and has the advantages of easily obtained raw materials, high yield, mild reaction conditions, wide substrate range and simple and convenient post-treatment.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a 2-alkyl substituted benzimidazole derivative and a preparation method thereof.
Background
The 2-alkyl substituted benzimidazole has a plurality of important biological activities such as sterilization, anti-inflammation, antivirus and anticancer, and is widely applied to the fields of natural products, medicines, pesticides, etc. Therefore, research on new synthetic methods of 2-alkyl substituted benzimidazole compounds and analogues thereof has important application value and is concerned by researchers in related fields.
The traditional 2-alkyl substituted benzimidazole synthesis method is mainly a condensation reaction between an o-phenylenediamine compound and a synthon containing one C under harsh conditions, such as the reaction with carboxylic acid, aldehyde ketone and the like. In recent years, transition metal catalyzed ortho-haloanilines have attracted attention from organic synthesis chemists to synthesize 2-alkyl substituted benzimidazole compounds through tandem reactions. However, the above synthetic route often has the problems of many reaction steps, harsh reaction conditions, pre-activation of raw materials, poor regioselectivity and the like. Based on the structural diversity of the 2-alkyl substituted benzimidazole compound and the wide application thereof in medicines, pesticides and industries, the development of a new synthetic method has profound significance.
Disclosure of Invention
The invention aims to provide a 2-alkyl substituted benzimidazole derivative.
Another object of the present invention is to provide a process for producing the above 2-alkyl-substituted benzimidazole derivative.
The specific technical scheme of the invention is as follows:
a2-alkyl substituted benzimidazole derivative has the following structural formula:
wherein R is1Is a formate protecting group, R2Is an alkyl group.
In a preferred embodiment of the present invention, said R1Boc or Cbz.
The reaction equation of the preparation method of the 2-alkyl substituted benzimidazole derivative is as follows:
in a preferred embodiment of the present invention, the method comprises the following steps: placing the N-phenyl tert-amyl amidine, hydroxylamine protected by formate, a rhodium catalyst, an oxidant, an organic acid, an alkali and a chlorine-containing organic solvent into a reaction container in an air atmosphere, reacting at 50-120 ℃, removing the chlorine-containing organic solvent after the reaction is finished, and purifying to obtain the 2-alkyl benzimidazole derivative;
the rhodium catalyst is trivalent rhodium salt, the oxidant comprises silver salt and peroxide of silver, and the alkali comprises potassium tert-butoxide, potassium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine and diethylamine;
the molar ratio of the N-phenylalkylamidine, the formate-protected hydroxylamine, the rhodium catalyst, the oxidant, the organic acid and the base is 1: 1-4.0: 0.01-0.1: 0-2.0: 0-6: 0-1.
Further preferably, the rhodium catalyst comprises dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer.
Further preferably, the oxidant comprises silver oxide and silver carbonate.
Further preferably, the organic acid includes benzoic acid, phenylacetic acid, acetic acid and pivalic acid.
Further preferably, the chlorine-containing organic solvent includes dichloroethane, dichloromethane, chloroform and chlorobenzene. Still more preferably, the chlorine-containing organic solvent is dichloroethane.
Further preferably, the reaction temperature is 100 ℃ and the molar ratio of the N-phenylalkylamidine, the formate-protected hydroxylamine, the rhodium catalyst, the oxidizing agent, the organic acid and the base is 1:3:0.025:1:2: 0.5.
The invention has the beneficial effects that:
1. the synthesis of the 2-alkyl benzimidazole derivative has profound significance from the pharmaceutical chemistry perspective;
2. the method has the advantages of easily available raw materials, high yield, mild reaction conditions, wide substrate range and simple and convenient post-treatment.
Detailed Description
The technical solution of the present invention is further illustrated and described by the following detailed description.
Example 1
Preparation of the target product 1
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 56.1mg of the desired product 1 in 91% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.72(dd，J＝9.9，8.4Hz，2H)，7.51(dd，J＝7.6，1.6Hz，2H)，7.46-7.37(m，3H)，7.30-7.20(m，2H)，5.51(s，2H)，1.57(s，9H)；13CNMR(101MHz，CDCl3)δ162.60，150.78，141.26，134.13，134.00，129.08，128.92，128.87，124.41，124.03，119.84，114.69，69.85，36.08，28.99.HRMS m/z(ESI)calcd for C19H21N2O2(M+H)+309.1598，found 309.1598.
example 2
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5mol percent, 0.2mmol of silver acetate, 0.4mmol of pivalic acid and 50mol percent of potassium tert-butoxide are added into a reaction tube in turn, and 1.5mL of 1, 2-dichloroethane is finally added for reaction for 36h at 100 ℃ in the air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 27.7mg of the target product 1 with a yield of 45%.
Example 3
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver oxide 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and separation and purification by silica gel column chromatography to obtain 48.0mg of the target product 1 with the yield of 78%.
Example 4
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, sodium alkoxide 50 mol%, sequentially adding into a reaction tube, finally adding 1.5mL of 1, 2-dichloroethane, reacting for 36h at 100 ℃ in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 41.2mg of the target product 1 with a yield of 67%.
Example 5
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, and sodium hydroxide 50 mol%, sequentially adding into a reaction tube, finally adding 1.5mL of 1, 2-dichloroethane, and reacting at 100 deg.C for 36h in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and separation and purification by silica gel column chromatography to obtain 32.0mg of the target product 1 with the yield of 52%.
Example 6
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, triethylamine 50 mol%, were added to the reaction tube in order, and finally 1.5mL of 1, 2-dichloroethane was added and reacted at 100 ℃ for 36h in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 28.9mg of the target product 1 with a yield of 47%.
Example 7
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium carbonate 50 mol%, sequentially adding into a reaction tube, finally adding 1.5mL of 1, 2-dichloroethane, reacting for 36h at 100 ℃ in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 43.1mg of the target product 1 with a yield of 70%.
Example 8
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate0.2mmol, 0.4mmol of benzoic acid and 50 mol% of potassium carbonate are sequentially added into a reaction tube, and finally 1.5mL of 1, 2-dichloroethane is added for reaction for 36h at 100 ℃ in the air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 34.1mg of the target product 1 with a yield of 51%.
Example 9
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5mol percent, 0.2mmol of silver carbonate, 0.4mmol of acetic acid and 50mol percent of potassium carbonate are sequentially added into a reaction tube, and finally 1.5mL of 1, 2-dichloroethane is added for reaction for 36h at 100 ℃ in the air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 19.1mg of the target product 1 with a yield of 31%.
Example 10
Preparation of the target product 2
Adding N- (p-methylphenyl) tert-amylamidine 0.2mmol, hydroxylamine 0.6mmol, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 59.9mg of the corresponding desired product 2 in 93% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.91-7.86(m，1H)，7.77-7.69(m，1H)，7.42-7.36(m，5H)，7.35-7.28(m，2H)，7.25(d，J＝4.8Hz，2H)，7.21(t，J＝5.4Hz，3H)，5.39(s，2H)，4.59(s，2H)；13C NMR(101MHz，CDCl3)δ154.34，150.03，142.17，136.45，134.07，133.00，129.04，128.84，128.79，128.70，128.44，126.64，124.76，124.46，119.86，115.05，69.59，36.88.HRMS m/z(ESI)calcd for C20H22N2O2(M+H)+323.1754，found 322.323.1752
example 11
Preparation of the target product 3
0.2mmol of N- (p-fluorophenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases were combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 43.1mg of the corresponding desired product 3 in 66% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.61(dd，J＝8.7，5.1Hz，0H)，7.54-7.49(m，0H)，7.48-7.40(m，0H)，7.01(td，J＝9.0，2.5Hz，0H)，5.51(s，0H)，1.55(s，1H)；13CNMR(101MHz，CDCl3)δ163.07(d，J＝3.4Hz)，160.34(d，J＝240.5Hz)，159.15，150.36，137.57，134.24(d，J＝13.6Hz)，133.88，129.25，129.02，128.95，120.38(d，J＝10.0Hz，4H)，111.99(d，J＝24.7Hz，5H)，102.35(d，J＝30.1Hz，4H)，70.09，36.18，28.95.HRMS m/z(ESI)calcd for C19H20FN2O2(M+H)+327.1503，found 327.1502.
example 12
Preparation of the target product 4
0.2mmol of N- (p-chlorophenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 40.4mg of the corresponding desired product 4 in 59% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.75(d，J＝1.9Hz，1H)，7.59(d，J＝8.5Hz，1H)，7.52(dd，J＝7.7，1.6Hz，2H)，7.49-7.38(m，3H)，7.25(dd，J＝8.4，2.0Hz，1H)，5.52(s，2H)，1.55(s，9H)；13C NMR(101MHz，CDCl3)δ163.29，150.30，139.87，134.60，133.85，130.14，129.27，129.03，128.95，124.59，120.51，115.11，70.19，36.17，28.93.HRMS m/z(ESI)calcd for C19H20ClN2O2(M+H)+343.1208，found 343.1211.
example 13
Preparation of the target product 5
0.2mmol of N- (p-bromophenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. Stopping the reaction, and mixing the reaction mixtureCooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 63.5mg of the corresponding target 5 in 82% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.91(d，J＝1.4Hz，1H)，7.58-7.48(m，3H)，7.48-7.36(m，4H)，5.51(s，2H)，1.55(d，J＝1.3Hz，9H)；13C NMR(101MHz，CDCl3)δ163.16，150.25，140.23，134.97，133.81，129.26，129.03，128.94，127.30，120.92，117.97，117.74，70.21，36.14，28.91.HRMS m/z(ESI)calcd for C19H20BrN2O2(M+H)+387.0703，found 387.0704.
example 14
Preparation of target product 6
0.2mmol of N- (p-iodophenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 53.8mg of the corresponding desired product 6 in 62% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ8.10(d，J＝1.5Hz，1H)，7.56(dd，J＝8.4，1.6Hz，1H)，7.52(dd，J＝7.8，1.4Hz，2H)，7.49-7.39(m，4H)，5.51(s，2H)，1.54(s，9H)；13C NMR(101MHz，CDCl3)δ162.94，150.26，140.83，135.32，133.77，133.02，129.28，129.04，128.98，123.80，121.39，88.28，70.24，36.07，28.90.HRMS m/z(ESI)calcd for C19H20IN2O2(M+H)+435.0564，found 435.0564.
example 15
Preparation of the target product 7
Adding N- (p-isopropylphenyl) tert-amylamidine 0.2mmol, hydroxylamine 0.6mmol, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 47.6mg of the corresponding desired product 7 in 68% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.60(d，J＝8.2Hz，1H)，7.54(dd，J＝7.0，5.3Hz，3H)，7.48-7.39(m，3H)，7.14(d，J＝8.2Hz，1H)，5.50(s，2H)，2.91(hept，J＝6.8Hz，1H)，1.56(s，9H)，1.16(d，J＝6.9Hz，6H)；13C NMR(101MHz，CDCl3)δ162.23，150.83，145.64，139.59，134.16，134.10，129.12，129.11，128.90，123.14，119.36，112.19，69.88，36.02，34.45，29.01，24.28.HRMS m/z(ESI)calcd for C22H27N2O2(M+H)+351.2067，found 351.2067.
example 16
Preparation of the target product 8
Adding 0.2mmol of N- (p-methylthiophenyl) tert-amyl amidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4m50mol percent of potassium tert-butoxide is added into a reaction tube in turn, and 1.5mL of 1, 2-dichloroethane is finally added to react for 36h at 100 ℃ in the air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 40.4mg of the corresponding desired product 8 in 57% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.58(dd，J＝5.0，3.2Hz，2H)，7.55-7.50(m，2H)，7.49-7.38(m，3H)，7.20(dd，J＝8.4，1.7Hz，1H)，5.49(s，2H)，2.25(s，3H)，1.56(s，9H)；13C NMR(101MHz，CDCl3)6162.37，150.53，139.37，134.60，133.93，129.25，129.23，128.97，123.89，119.86，113.01，70.09，36.10，28.96，16.58.HRMS m/z(ESI)calcd for C20H23N2O2S(M+H)+355.1475，found 355.1478.
example 17
Preparation of the target product 9
Adding N- (p-methoxyphenyl) tert-amylamidine 0.2mmol, hydroxylamine 0.6mmol, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 48.0mg of the corresponding desired product 9 in 71% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.56(d，J＝8.7Hz，1H)，7.54-7.50(m，2H)，7.46-7.39(m，3H)，7.21(d，J＝2.4Hz，1H)，6.87(dd，J＝8.7，2.5Hz，1H)，5.49(s，2H)，3.60(s，3H)，1.56(s，9H)；13C NMR(101MHz，CDCl3)δ161.47，157.42，150.67，135.44，134.67，134.06，129.15，129.14，128.90，120.09，112.75，99.14，69.90，55.47，36.03，29.01.HRMS m/z(ESI)calcd for C20H23N2O3(M+H)+339.1703，found 339.1704.
example 18
Preparation of the target product 10
Adding 0.2mmol of N- (m-methylphenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 59.9mg of the corresponding desired product 10 in 93% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.64-7.56(m，1H)，7.49(d，J＝5.4Hz，3H)，7.46-7.36(m，3H)，7.04(d，J＝8.4Hz，1H)，5.49(s，2H)，2.41(s，3H)，1.57(d，J＝1.9Hz，9H)；13CNMR(101MHz，CDCl3)δ162.64，150.71，141.50，134.22，133.77，131.95，128.98，128.83，128.82，125.63，119.80，114.33，69.66，36.06，28.94，21.20.HRMS m/z(ESI)calcd for C20H23N2O2(M+H)+323.1754，found 323.1754.
example 19
Preparation of the target product 11
Adding N- (m-chlorophenyl) tert-amylamidine 0.2mmol, hydroxylamine 0.6mmol, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 58.1mg of the corresponding desired product 11 in 85% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.65(dd，J＝17.5，5.3Hz，2H)，7.49(d，J＝5.7Hz，2H)，7.42(d，J＝6.5Hz，3H)，7.18(d，J＝8.7Hz，1H)，5.50(s，2H)，1.55(s，9H)；13C NMR(101MHz，CDCl3)δ163.92，150.33，142.19，133.87，132.62，129.51，129.22，128.98，128.92，124.62，119.70，115.56，70.10，36.21，28.89.HRMS m/z(ESI)calcd for C19H20ClN2O2(M+H)+343.1208，found 343.1204.
example 20
Preparation of the target product 12
0.2mmol of N- (m-bromophenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 58.1mg of the corresponding desired product 12 in 85% yield. The combination ofCharacterization data for substances are as follows:1H NMR(400MHz，CDCl3)δ7.74(d，J＝1.8Hz，1H)，7.49(d，J＝8.8Hz，1H)，7.40(dd，J＝7.5，1.9Hz，2H)，7.37-7.30(m，3H)，7.23(dd，J＝8.8，1.9Hz，1H)，5.41(s，2H)，1.46(s，9H)；13C NMR(101MHz，CDCl3)δ163.74，150.31，142.59，133.84，133.04，129.21，128.97，128.91，127.31，122.76，116.93，115.96，70.11，36.19，28.89.HRMS m/z(ESI)calcd for C19H20BrN2O2(M+H)+387.0703，found 387.0703.
example 21
Preparation of the target product 13
0.2mmol of N- (m-iodophenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 68.6mg of the corresponding desired product 13 in 79% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ8.03(d，J＝1.0Hz，1H)，7.52-7.39(m，7H)，5.50(s，2H)，1.55(s，9H)；13C NMR(101MHz，CDCl3)δ163.36，150.33，142.84，133.83，133.70，132.98，129.21，128.96，128.91，128.89，116.43，87.28，70.11，36.13，28.89.HRMS m/z(ESI)calcd for C19H20IN2O2(M+H)+435.0564，found 435.0565.
example 22
Preparation of the target product 14
0.2mmol of N- (o-methylphenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10mL × 3), the organic phases combined, dried over anhydrous MgSO4, filtered, concentrated by rotary evaporation, and purified by silica gel column chromatography to give 62.5mg of the corresponding desired product 14 in 97% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.55(d，J＝7.9Hz，1H)，7.49(d，J＝7.5Hz，2H)，7.44-7.36(m，3H)，7.09(dt，J＝12.7，7.4Hz，2H)，5.49(s，2H)，2.61(s，3H)，1.61-1.52(m，9H)；13C NMR(101MHz，CDCl3)δ161.46，150.98，140.51，134.29，133.81，129.94，128.97，128.85，128.83，124.48，124.09，112.08，69.64，36.14，29.04，16.31.HRMS m/z(ESI)calcd for C20H23N2O2(M+H)+323.1754，found 323.1754.
example 23
Preparation of target product 15
0.2mmol of N- (o-chlorophenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), the organic phases combined, dried over anhydrous MgSO4, filtered and spunEvaporated and concentrated, and then separated and purified by silica gel column chromatography to obtain 56.8mg of the corresponding target product 15 with a yield of 83%. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.62(d，J＝8.3Hz，1H)，7.54-7.48(m，2H)，7.46-7.38(m，3H)，7.28(d，J＝7.8Hz，1H)，7.13(t，J＝8.1Hz，1H)，5.51(s，2H)，1.57(s，9H)；13C NMR(101MHz，CDCl3)δ163.19，150.48，138.64，135.18，133.85，129.21，129.02，128.91，124.82，124.74，124.03，113.20，70.17，36.30，28.96.HRMS m/z(ESI)calcd for C19H20ClN2O2(M+H)+343.1208，found 343.1208.
example 24
Preparation of target product 16
0.2mmol of N- (o-bromophenyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5mol percent, 0.2mmol of silver carbonate, 0.4mmol of pivalic acid and 50mol percent of potassium tert-butoxide are added into a reaction tube in turn, and 1.5mL of 1, 2-dichloroethane is finally added for reaction for 36h at 100 ℃ in the air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 58.8mg of the corresponding target product 16 with 76% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.66(d，J＝8.2Hz，1H)，7.54-7.47(m，2H)，7.47-7.40(m，4H)，7.07(t，J＝8.1Hz，1H)，5.51(s，2H)，1.57(s，9H)；13CNMR(101MHz，CDCl3)δ163.08，150.52，140.05，134.71，133.86，129.21，129.01，128.92，127.09，125.12，113.82，113.59，70.16，36.32，28.94.HRMS m/z(ESI)calcd for C19H20BrN2O2(M+H)+387.0703，found 387.0703.
example 25
Preparation of target product 17
Adding 0.2mmol of N- (1-naphthyl) tert-amylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 48.7mg of the corresponding target product 17 with a yield of 68%. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ8.63(d，J＝8.2Hz，1H)，7.85(t，J＝8.4Hz，2H)，7.67-7.56(m，2H)，7.56-7.37(m，6H)，5.54(s，2H)，1.62(s，9H)；13C NMR(101MHz，CDCl3)δ160.89，150.96，136.76，134.12，130.76，130.41，129.13，129.00，128.91，127.84，126.47，125.13，124.68，122.42，114.33，70.00，36.22，29.19.HRMS m/z(ESI)calcd for C23H23N2O2(M+H)+359.1754，found 359.1756.
example 26
Preparation of the target product 18
0.2mmol of N-phenylisobutylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. Stopping the reaction, cooling the reaction mixture toDiluting with ethyl acetate at room temperature, washing with 30mL of saturated brine, extracting with ethyl acetate (10 mL. times.3), combining the organic phases, anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 46.3mg of the corresponding target product 18 with a yield of 75%. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.91-7.87(m，1H)，7.73-7.68(m，1H)，7.50(dd，J＝7.4，1.4Hz，2H)，7.47-7.39(m，3H)，7.33-7.24(m，2H)，5.49(s，2H)，3.08(d，J＝7.1Hz，2H)，2.29-2.14(m，1H)，0.97(d，J＝6.6Hz，6H)；13C NMR(101MHz，CDCl3)δ155.93，150.38，142.09，134.14，132.83，129.13，128.91，128.89，124.42，124.36，119.54，114.97，69.65，39.55，27.51，22.45.HRMS m/z(ESI)calcd for C19H21N2O2(M+H)+309.1598，found 309.1598.
example 27
Preparation of the target product 19
0.2mmol of N-phenylcyclopropylamidine, 0.6mmol of hydroxylamine, [ RhCp. Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 52.6mg of the corresponding target product 19 with a yield of 90%. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.88-7.84(m，1H)，7.63-7.58(m，1H)，7.51(dd，J＝7.8，1.6Hz，2H)，7.46-7.37(m，3H)，7.29-7.21(m，2H)，5.52(s，2H)，2.83(tt，J＝8.3，5.1Hz，1H)，1.31-1.21(m，2H)，1.14-1.03(m，2H)；13C NMR(101MHz，CDCl3)δ158.33，150.74，142.12，134.33，133.05，129.02，128.87，128.70，124.36，124.03，119.23，114.78，69.50，10.52，9.47.HRMS m/z(ESI)calcd for C18H17N2O2(M+H)+293.1285，found293.1282.
example 28
Preparation of target product 20
0.2mmol of N-phenylbenzylamidine, 0.6mmol of hydroxylamine, [ RhCp Cl2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 38.3mg of the corresponding target product 20 with 56% yield. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.91-7.86(m，1H)，7.77-7.69(m，1H)，7.42-7.36(m，5H)，7.35-7.28(m，2H)，7.25(d，J＝4.8Hz，2H)，7.21(t，J＝5.4Hz，3H)，5.39(s，2H)，4.59(s，2H)；13C NMR(101MHz，CDCl3)δ154.34，150.03，142.17，136.45，134.07，133.00，129.04，128.84，128.79，128.70，128.44，126.64，124.76，124.46，119.86，115.05，69.59，36.88.HRMS m/z(ESI)calcd for C22H19N2O2(M+H)+343.1441，found 343.1441.
example 29
Preparation of the target product 21
0.2mmol of N-phenyl-tert-amylamidine, 0.6mmol of tert-butyl hydroxycarbamate, [ RhCp Cl ]2]22.5 mol%, silver carbonate 0.2mmol, pivalic acid 0.4mmol, potassium tert-butoxide 50 mol%, added to the reaction tube in turn, and finally 1.5mL of 1, 2-dichloroethane were added and reacted at 100 ℃ for 36 hours in air. The reaction was stopped, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 30mL of saturated brine, extracted with ethyl acetate (10 mL. times.3), and the organic phases were combined and anhydrous MgSO4Drying, filtering, rotary evaporation and concentration, and purification by silica gel column chromatography to obtain 53.8mg of the corresponding target product 21 with a yield of 62%. The characterization data for this compound are as follows:1H NMR(400MHz，CDCl3)δ7.77-7.68(m，2H)，7.28(dt，J＝7.8，4.2Hz，2H)，1.72(s，9H)，1.59(s，9H)；13C NMR(101MHz，CDCl3)δ162.50，149.51，141.24，134.20，124.01，123.63，119.76，114.06，85.33，35.89，29.11，28.02.HRMS m/z(ESI)calcd for C16H23N2O2(M+H)+275.1754，found 275.1753.
it will be understood by those skilled in the art that the parameters and groups of the present invention can be changed within the following ranges to obtain the same or similar technical effects as the above embodiments, and still fall within the scope of the present invention:
a2-alkyl substituted benzimidazole derivative has the following structural formula:
wherein R is1Is a formate protecting group, R2Is an alkyl group. Preferably, said R1Boc or Cbz.
The preparation method of the 2-alkyl substituted benzimidazole derivative is characterized in that: the reaction equation is as follows:
the method specifically comprises the following steps: placing the N-phenyl tert-amyl amidine, hydroxylamine protected by formate, a rhodium catalyst, an oxidant, an organic acid, an alkali and a chlorine-containing organic solvent into a reaction container in an air atmosphere, reacting at 50-120 ℃, removing the chlorine-containing organic solvent after the reaction is finished, and purifying to obtain the 2-alkyl benzimidazole derivative;
the rhodium catalyst is trivalent rhodium salt, the oxidant comprises silver salt and peroxide of silver, and the alkali comprises potassium tert-butoxide, potassium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine and diethylamine;
the molar ratio of the N-phenylalkylamidine, the formate-protected hydroxylamine, the rhodium catalyst, the oxidant, the organic acid and the base is 1: 1-4.0: 0.01-0.1: 0-2.0: 0-6: 0-1.
Preferably, the rhodium catalyst comprises dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer. The oxidant comprises silver oxide and silver carbonate. The organic acids include benzoic acid, phenylacetic acid, acetic acid and pivalic acid. The chlorine-containing organic solvent includes dichloroethane, dichloromethane, chloroform and chlorobenzene.
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, which is defined by the appended claims.
Claims (2)
1. A method for preparing 2-alkyl substituted benzimidazole derivative is characterized in that: the reaction equation is as follows:
the method specifically comprises the following steps: placing the N-phenyl tert-amyl amidine, hydroxylamine protected by formic ether, a rhodium catalyst, an oxidant, an organic acid, an alkali and a chlorine-containing organic solvent into a reaction container in an air atmosphere, reacting at 50-120 ℃, removing the chlorine-containing organic solvent after the reaction is finished, and purifying to obtain the N-phenyl tert-amyl amidine2-alkylbenzimidazole derivatives, the above R1Is Boc or Cbz, R2Is an alkyl group;
the rhodium catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer, the oxidant is silver oxide or silver carbonate, the alkali is potassium tert-butoxide, potassium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine and diethylamine, the chlorinated organic solvent is dichloroethane, and the organic acid is benzoic acid, phenylacetic acid, acetic acid or pivalic acid.
2. The method of claim 1, wherein: the reaction temperature is 100 ℃, and the molar ratio of the N-phenylalkylamidine, the formate-protected hydroxylamine, the rhodium catalyst, the oxidant, the organic acid and the base is 1:3:0.025:1:2: 0.5.
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