Method for selectively preparing aminoisoquinoline derivative or arylimidazole derivative through alkali salt regulated cobalt catalysis

Abstract

According to the method, benzamidine hydrochloride or substituted benzamidine hydrochloride and iodine ylide are used as initial raw materials, and a cobalt catalyst is used for catalyzing C-H cyclization reaction, so that the amino isoquinoline derivative or the aryl imidazole derivative is prepared. An aminoisoquinoline derivative or an arylimidazole derivative is selectively prepared by adjusting the type of an alkali salt. The safer benzamidine hydrochloride or substituted benzamidine hydrochloride and iodine ylide are used as initial raw materials to synthesize the amino isoquinoline derivative or the aryl imidazole derivative, the conditions are mild, the selectivity, the yield and the safety are high, and the industrial synthesis of the amino isoquinoline derivative or the aryl imidazole derivative can be realized; the subsequent development and application of the amino isoquinoline derivative or the aryl imidazole derivative are facilitated; according to the method, the amino isoquinoline derivative or the aryl imidazole derivative is selectively prepared by regulating alkali salt and taking benzylamidine hydrochloride or substituted benzylamidine hydrochloride and iodine ylide as initial raw materials for the first time.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by regulating cobalt catalysis with alkali salt. Background Art

[0002] Isoquinoline and imidazole compounds are extremely important nitrogen-containing heterocyclic compounds with significant application value in fields such as medicine and functional materials. Aminoisoquinoline and arylimidazole derivatives are important components of these compounds, and their skeletons are widely found in natural products, bioactive molecules, and drug molecules. Furthermore, these compounds are key intermediates for synthesizing functional material molecules and are widely used. Currently, the synthesis of aminoisoquinoline and arylimidazole derivatives primarily relies on expensive transition metal-catalyzed C-H bond cleavage methods. However, these methods typically require the use of diazo compounds as carbene precursors. Diazo compounds are toxic, unstable, and prone to explosion, resulting in poor safety. The synthesis conditions and safety requirements for aminoisoquinoline and arylimidazole derivatives are very high, limiting their industrial synthesis. Therefore, there is a need to develop methods for synthesizing aminoisoquinoline and arylimidazole derivatives using safer raw materials and synthesis conditions. Summary of the Invention

[0003] Therefore, based on the above background, the present invention provides a method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by regulating cobalt catalysis with an alkali salt. The present invention uses safer benzamidine hydrochloride or substituted benzamidine hydrochloride, or iodine ylide as starting materials to synthesize aminoisoquinoline derivatives or aryl imidazole derivatives. Moreover, the present invention is the first to selectively prepare aminoisoquinoline derivatives or aryl imidazole derivatives by regulating an alkali salt with benzamidine hydrochloride or substituted benzamidine hydrochloride, or iodine ylide as starting materials.

[0004] The technical solution provided by the present invention is:

[0005] A method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by regulating cobalt catalysis with alkali salts, wherein benzamidine hydrochloride or substituted benzamidine hydrochloride and iodine ylide are used as starting materials, a cobalt catalyst is used to catalyze the C-H cyclization reaction under heating conditions, and aminoisoquinoline derivatives or aryl imidazole derivatives are selectively prepared by adjusting the type of alkali salt;

[0006] selectively preparing an alkali salt of an aminoisoquinoline derivative selected from a phosphate or a dihydrogen phosphate;

[0007] The base salt for selectively preparing the aryl imidazole derivative is selected from carbonates;

[0008] The structural formula of the aminoisoquinoline derivative is shown in the following formula (I):

[0009]

[0010] The structural formula of the aryl imidazole derivative is shown in the following formula (II):

[0011]

[0012] R is selected from one of hydrogen, alkyl, halogen, ester or trifluoromethyl;

[0013] The cobalt catalyst is selected from at least one of a II cobalt catalyst and a III cobalt catalyst.

[0014] Furthermore, the phosphate is selected from potassium phosphate, and the dihydrogen phosphate is selected from potassium dihydrogen phosphate.

[0015] Furthermore, the carbonate is selected from at least one of magnesium carbonate and calcium carbonate.

[0016] Furthermore, the para-position or meta-position of the phenyl ring of the substituted benzamidine hydrochloride is substituted by a substituent, and the substituent is selected from one of an alkyl group, a halogen group, an ester group or a trifluoromethyl group.

[0017] Furthermore, the cobalt catalyst is selected from at least one of Cp*Co(CO)I2, [Cp*Co(CH3CN)3](SbF6)2, Co(OAc)2, and CoCl2.

[0018] Furthermore, the structural formula of the iodine ylide is one of the following:

[0019]

[0020] Furthermore, the 1-aminoisoquinoline derivative of formula (I) is specifically any one of the following compounds:

[0021]

[0022]

[0023] Furthermore, the 2-aryl imidazole derivative of the structural formula (II) is specifically any one of the following compounds:

[0024]

[0025] Furthermore, it specifically includes the following steps:

[0026] 1) adding benzamidine hydrochloride or substituted benzamidine hydrochloride, iodine ylide, cobalt catalyst and alkali salt into an organic solvent and dispersing;

[0027] 2) At a temperature of 80-100℃, the reaction is stirred in a sealed tube. After the reaction, the material is separated.

[0028] Further, the molar ratio of benzamidine hydrochloride or substituted benzamidine hydrochloride, iodonium ylide and cobalt catalyst is 1:

[0029] (0.01-1):0.1;

[0030] The molar ratio of benzamidine hydrochloride or substituted benzamidine hydrochloride and base salt is 1:(1-3).

[0031] Further, the organic solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, dichloromethane, trifluoroethanol, hexafluoroisopropanol, toluene, chlorobenzene, 1,2-dichloroethane, n-hexane.

[0032] Further, the material separation in step 2) is selected from recrystallization or column chromatography. The solvents used in the recrystallization method include acetone, ethyl acetate, ethanol, isopropanol, n-hexane, tetrahydrofuran, dichloromethane; when the column chromatography method is used for product separation, silica gel or alumina is used as the stationary phase, and the developing agent is selected from a mixture of polar and non-polar solvents, such as dichloromethane-petroleum ether, ethyl acetate-petroleum ether, ethyl acetate-n-hexane, dichloromethane-acetone.

[0033] The synthetic route of the present application is as follows:

[0034]

[0035] The beneficial effects achieved by the present application are:

[0036] The present application uses benzamidine hydrochloride or substituted benzamidine hydrochloride, iodonium ylide as starting materials to synthesize aminoisoquinoline derivatives or arylimidazole derivatives, which has mild conditions, high selectivity, high yield and high safety, so that aminoisoquinoline derivatives or arylimidazole derivatives can be synthesized industrially, which is beneficial to the subsequent development and application of aminoisoquinoline derivatives or arylimidazole derivatives;

[0037] Further, the present application uses benzamidine hydrochloride or substituted benzamidine hydrochloride, iodonium ylide as starting materials,

[0038] The reaction is controlled by adjusting the base salt to selectively prepare aminoisoquinoline derivatives or arylimidazole derivatives.

[0039] Drawings of the specification

[0040] Figure 1 is the reaction mechanism diagram of the present application.

[0041] Figure 2 is the structure of the aminoisoquinoline derivative A in Example 11 H NMR spectrum.

[0042] Figure 3 is the aminoisoquinoline derivative A in Example 1 13 C NMR spectrum.

[0043] Figure 4 is the aminoisoquinoline derivative B in Example 2 1 H NMR spectrum.

[0044] Figure 5 is the aminoisoquinoline derivative B in Example 2 13 C NMR spectrum.

[0045] Figure 6 is the aminoisoquinoline derivative C in Example 3 1 H NMR spectrum.

[0046] Figure 7 is the aminoisoquinoline derivative C in Example 3 13 C NMR spectrum.

[0047] Figure 8 is the aminoisoquinoline derivative D in Example 4 1 H NMR spectrum.

[0048] Figure 9 is the aminoisoquinoline derivative D in Example 4 13 C NMR spectrum.

[0049] Figure 10 is the aminoisoquinoline derivative E in Example 5 1 H NMR spectrum.

[0050] Figure 11 is the aminoisoquinoline derivative E in Example 5 13 C NMR spectrum.

[0051] Figure 12 is the aminoisoquinoline derivative F in Example 6 1 H NMR spectrum.

[0052] Figure 13 is the aminoisoquinoline derivative F in Example 6 13 C NMR spectrum.

[0053] Figure 14 is the 6-amino-2H-pyran-[3,4-c]-isoquinolin-1(4H)-one in Example 7 1 H NMR spectrum.

[0054] Figure 15is the 6-amino-2H-pyran-[3,4-c]-isoquinolin-1(4H)-one in Example 7 13 C NMR spectrum.

[0055] Figure 16 is 6,6-dimethyl-2-phenyl-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 8 1 H NMR spectrum.

[0056] Figure 17 is 6,6-dimethyl-2-phenyl-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 8 13 C NMR spectrum.

[0057] Figure 18 is 6,6-dimethyl-2-(4-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 9 1 H NMR spectrum.

[0058] Figure 19 is 6,6-dimethyl-2-(4-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 9 13 C NMR spectrum.

[0059] Figure 20 is 6,6-dimethyl-2-(4-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 10 1 H NMR spectrum.

[0060] Figure 21 is 6,6-dimethyl-2-(4-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 10 13 C NMR spectrum.

[0061] Figure 22 is 6,6-dimethyl-2-(4-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 11 1 H NMR spectrum.

[0062] Figure 23 is 6,6-dimethyl-2-(4-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 11 13 C NMR spectrum.

[0063] Figure 24is 6,6-dimethyl-2-(3-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 12 1 H NMR spectrum.

[0064] Figure 25 is 6,6-dimethyl-2-(3-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 12 13 C NMR spectrum.

[0065] Figure 26 is 6,6-dimethyl-2-(3-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 13 1 H NMR spectrum.

[0066] Figure 27 is 6,6-dimethyl-2-(3-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 13 13 C NMR spectrum.

[0067] Figure 28 In Example 14, 6,6-dimethyl-2-(3-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one 1 H NMR spectrum.

[0068] Figure 29 is 6,6-dimethyl-2-(3-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in Example 14 13 C NMR spectrum. DETAILED DESCRIPTION

[0069] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0070] The present invention uses benzamidine hydrochloride or substituted benzamidine hydrochloride and iodine ylide as starting materials, uses a cobalt catalyst to catalyze the C—H cyclization reaction, and selectively prepares 1-aminoisoquinoline derivatives or 2-aryl imidazole derivatives by adjusting the type of alkali salt; Figure 1 As shown, analysis of the synthesis mechanism of the present invention may be seen below:

[0071] In mechanism loop 1 (left), cobalt first reacts with benzamidine hydrochloride and phosphate (or dihydrogen phosphate) to form intermediate A. Intermediate A then reacts with iodine ylide to form intermediate B. Intermediate B then inserts into the C-Co bond via 1,1-migration to form intermediate C, which undergoes proton dissociation to give intermediate D. Finally, intermediate D undergoes intramolecular nucleophilic addition to give an aminoisoquinoline derivative.

[0072] In mechanism loop 2 (right), cobalt first reacts with benzamidine hydrochloride and carbonate to form intermediate E. Intermediate E then reacts with iodine ylide to form intermediate F. Intermediate F then inserts into the C-Co bond via a 1,1-migration to form intermediate G, which undergoes a rearrangement process to give intermediate H. Intermediate H undergoes proton dissociation to give intermediate I. Intermediate I undergoes an intramolecular nucleophilic addition reaction to give intermediate J. Finally, intermediate J undergoes an isomerization process to give a benzo[d]imidazole derivative.

[0073] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods. Unless otherwise specified, the materials, reagents, etc. used in the following examples are all commercially available.

[0074] Example 1: Synthesis of aminoisoquinoline derivative A

[0075] In a 25 mL reactor, pentamethylcyclopentadienylcarbonylcobalt diiodide (0.0048 g, 0.01 mmol), benzamidine hydrochloride (0.039 g, 0.2 mmol), 5,5-dimethylcyclohexanedione iodide ylide (0.069 g, 0.2 mmol), potassium phosphate (0.0425 g, 0.2 mmol), and hexafluoroisopropanol (1 mL) as solvent were added and stirred at 80 ° C for 12 h.

[0076] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:ethyl acetate) afforded 0.040 g of aminoisoquinoline derivative A in a yield of 84%.

[0077] The CAS number of pentamethylcyclopentadienylcarbonylcobalt diiodide in the raw materials of this embodiment is 35886-64-7, purchased from Anaiji Chemical;

[0078] Benzamidine hydrochloride has a CAS number of 1670-14-0 and was purchased from Titan Technology Exploration Platform;

[0079] 5,5-Dimethylcyclohexanedione iodide ylide has a CAS number of 35024-12-5 and was purchased from West Asia Reagents.

[0080] The structural formula of 5,5-dimethylcyclohexanedione iodide is shown in formula (1).

[0081] The synthetic route of this embodiment is specifically shown below:

[0082]

[0083] The aminoisoquinoline derivative A in this example is a white solid; 1 H NMR(DMSO-d6,500MHz)δ9.35(d,J=10.0Hz,1H),8.23(d,J=10.0Hz,1H),7.82(s,2 H),7.71-7.67(m,1H),7.47-7.44(m,1H),2.82(s,2H),2.44(s,2H),1.03(s,6H); 13 C NMR (DMSO-d6, 125 MHz) δ 197.3, 162.8, 159.9, 135.1, 131.9, 128.1, 127.4, 125.2, 124.0, 115.8, 110.4, 53.3, 47.2, 32.0, 27.8 (see Figure 2 and Figure 3 ).

[0084] Example 2: Synthesis of aminoisoquinoline derivative B

[0085] In a 25 mL reactor, pentamethylcyclopentadienylcarbonylcobalt diiodide (0.0048 g, 0.01 mmol), 4-methylbenzamidine hydrochloride (0.2 mmol), 5,5-dimethylcyclohexanedione iodide ylide (0.069 g, 0.2 mmol), potassium phosphate (0.0425 g, 0.2 mmol), and hexafluoroisopropanol (1 mL) as solvent were added and stirred at 80 ° C for 12 h.

[0086] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:ethyl acetate) afforded 0.044 g of aminoisoquinoline derivative B in a yield of 86%.

[0087] The CAS number of 4-methylbenzamidine hydrochloride in this example is 6236-27-8, which was purchased from Titan Technology Exploration Platform.

[0088] The synthetic route of this embodiment is specifically shown below:

[0089]

[0090] Aminoisoquinoline derivative B, white solid; 1H NMR (DMSO-d6, 500 MHz) δ 9.17 (s, 1H), 8.12 (d, J = 10.0 Hz, 1H), 7.74 (s, 2H), 7.29 (d, J = 10.0 Hz, 1H), 2.80 (s, 2H), 2.44-2.42 (m, 5H), 1.02 (s, 6H); 13 C NMR (DMSO-d6, 125 MHz) δ 197.2, 162.9, 159.7, 141.7, 135.3, 126.8, 124.6, 124.0, 113.9, 110.2, 53.4, 47.2, 32.0 (see Figure 4 and Figure 5 ).

[0091] Example 3: Synthesis of aminoisoquinoline derivative C

[0092] In a 25 mL reactor, pentamethylcyclopentadienyl carbonyl diiodo cobalt (0.0048 g, 0.01 mmol), 4-fluorobenzamidine hydrochloride (0.2 mmol), 5,5-dimethylcyclohexanone iodonium ylide (0.069 g, 0.2 mmol), potassium phosphate (0.0425 g, 0.2 mmol), hexafluoroisopropanol (1 mL) as solvent, stirred at 80 °C for 12 h.

[0093] Column chromatography (silica gel, 200-300 mesh; eluent, petroleum ether: ethyl acetate) afforded 6-amino-9-fluoro-3,3-dimethyl-3,4-dihydrophenanthridin-l(2H)-one 0.035 g, yield 67%.

[0094] The CAS number of 4-fluorobenzamidine hydrochloride used in this example is 456-14-4, which was purchased from Titan Scientific Exploration Platform.

[0095] The synthetic route of this example is shown below:

[0096]

[0097] Aminoisoquinoline derivative C, white solid; 1 H NMR (DMSO-d6, 500 MHz) δ 9.10-9.07 (m, 1H), 8.34-8.31 (m, 1H), 7.92 (s, 2H), 7.38-7.34 (m, 1H), 2.82 (s, 2H), 2.44 (s, 2H), 1.03 (s, 6H); 13 CNMR (DMSO-d6, 125 MHz) δ 197.3, 165.3, 164.32, 163.29 (d, 1 J C-F = 246.3 Hz), 159.7, 137.2 (d,3 J C-F =11.3Hz),127.5(d, 3 J C-F =10.0Hz),114.2(d, 2 J C-F =23.8Hz),112.9,110.0,109.4(d, 2 J C-F =23.8Hz),53.1,47.2,32.0,27.8(see Figure 6 and Figure 7 ).

[0098] Example 4: Synthesis of aminoisoquinoline derivative D

[0099] In a 25 mL reactor, pentamethylcyclopentadienylcarbonylcobalt diiodide (0.0048 g, 0.01 mmol), methyl 4-carbamimidobenzoate hydrochloride (0.2 mmol), 5,5-dimethylcyclohexanedione iodide ylide (0.069 g, 0.2 mmol), potassium phosphate (0.0425 g, 0.2 mmol), and hexafluoroisopropanol (1 mL) as solvent were added and stirred at 80 ° C for 12 h.

[0100] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:ethyl acetate) gave 0.043 g of methyl 6-amino-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydrophenanthridine-9-carboxylate in a yield of 72%.

[0101] In this embodiment, the CAS number of methyl 4-carbamimidobenzoate hydrochloride is 42836-73-4, which was purchased from Titan Technology Exploration Platform.

[0102] The synthetic route of this embodiment is specifically shown below:

[0103]

[0104] Aminoisoquinoline derivative D, white solid; 1 H NMR(DMSO-d6,500MHz)δ10.00(s,1H),8.35(d,J=5.0Hz,1H),8.06(s,2H),7.9 3(dd,J=5.0,10.0Hz,1H),3.92(s,3H),2.84(s,2H),2.47(s,2H),1.04(s,6H); 13C NMR (DMSO-d6, 125 MHz) δ 197.3, 166.2, 159.6, 134.7, 132.2, 129.0, 127.8, 127.4, 124.7, 118.0, 110.4, 53.1, 52.4, 47.0, 32.0, 27.8 (see Figure 8 and Figure 9 ).

[0105] Example 5: Synthesis of aminoisoquinoline derivative E

[0106] In a 25 mL reactor, (triacetonitrile-pentamethylcyclopentadienyl)cobalt hexafluoroantimonate (0.0039 g, 0.005 mmol), 4-trifluoromethylbenzamidine hydrochloride (0.045 g, 0.2 mmol), 5,5-dimethylcyclohexanedione iodide (0.069 g, 0.2 mmol), potassium dihydrogen phosphate (0.0544 g, 0.4 mmol), and trifluoroethanol (1 mL) were added as solvent and stirred at 100 °C for 12 h.

[0107] Column chromatography (silica gel, 200-300 mesh; developing solvent, n-hexane:ethyl acetate) afforded 0.041 g of aminoisoquinoline derivative E in a yield of 67%.

[0108] The (triacetonitrile-pentamethylcyclopentadienyl)cobalt hexafluoroantimonate ([Cp*Co(CH3CN)3](SbF6)2) in this example was synthesized according to the literature (J.Am.Chem.Soc.2014,136,17722–17725).

[0109] 4-Trifluoromethylbenzamidine hydrochloride has a CAS number of 38980-96-0 and was purchased from Titan Technology Exploration Platform.

[0110] The synthetic route of this embodiment is specifically shown below:

[0111]

[0112] Aminoisoquinoline derivative E, white solid; 1 H NMR (DMSO-d6, 500MHz) δ9.78 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 8.13 (s, 2H), 7.76-7.74 (m, 1H), 2.84 (s, 2H), 2.46 (s, 2H), 1.03 (s, 6H); 13 CNMR(DMSO-d6,125MHz)δ197.5,166.7,164.5,159.7,134.7,131.6(q, 2 J C-F=31.3Hz),128.3,125.7,122.5(q, 4 J C-F =3.8Hz),120.7,117.5,109.9,53.1,47.2,32.0,27.7(see Figure 10 and Figure 11 ).

[0113] Example 6: Synthesis of aminoisoquinoline derivative F

[0114] In a 25 mL reactor, (triacetonitrile-pentamethylcyclopentadienyl)cobalt hexafluoroantimonate (0.0039 g, 0.005 mmol), 3-chlorobenzamidine hydrochloride (0.2 mmol), 5,5-dimethylcyclohexanedione iodide (0.069 g, 0.2 mmol), potassium dihydrogen phosphate (0.0544 g, 0.4 mmol), and trifluoroethanol (1 mL) were added as solvent and stirred at 100 °C for 12 h.

[0115] Column chromatography (silica gel, 200-300 mesh; developing solvent, n-hexane:ethyl acetate) afforded 0.038 g of aminoisoquinoline derivative F in a yield of 69%.

[0116] 3-Chlorobenzylamidine hydrochloride has a CAS number of 24095-60-1 and was purchased from Titan Technology Exploration Platform.

[0117] The synthetic route of this embodiment is specifically shown below:

[0118]

[0119] Aminoisoquinoline derivative F, white solid; 1 H NMR(DMSO-d6,500MHz)δ8.21(d,J=10.0Hz,1H),7.90(s,2H),7.76(d,J=10.0Hz,1H),7.49-7.46(m,1H),2.79(s,2H),2.47(s,2H),1.08(s,6H); 13 C NMR (DMSO-d6, 125 MHz) δ 193.7, 161.8, 159.5, 133.4, 132.8, 130.2, 125.9, 123.0, 119.1, 113.9, 52.4, 46.7, 32.6 (see Figure 12 and Figure 13 ).

[0120] Example 7: Synthesis of 6-amino-2H-pyran-[3,4-c]-isoquinolin-1(4H)-one

[0121] In a 25 mL reactor, add (triacetonitrile-pentamethylcyclopentadienyl)cobalt hexafluoroantimonate (0.0039 g, 0.005 mmol), benzamidine hydrochloride (0.2 mmol), cyclopentanedione iodide ylide (0.2 mmol), potassium dihydrogen phosphate (0.0544 g, 0.4 mmol), and trifluoroethanol (1 mL) as solvent, and stir at 100 ° C for 12 h.

[0122] Column chromatography (silica gel, 200-300 mesh; developing solvent, n-hexane:ethyl acetate) gave 0.026 g of 6-amino-2H-pyran-[3,4-c]-isoquinolin-1(4H)-one in a yield of 66%.

[0123] The CAS number of the cyclopentanedione iodide ylide in this embodiment is 1415261-29-8.

[0124] The structural formula of cyclopentanedione iodide ylide is shown in formula (2).

[0125] The synthetic route of this embodiment is specifically shown below:

[0126]

[0127] 6-amino-2H-pyran-[3,4-c]-isoquinolin-1(4H)-one, white solid; 1 H NMR(DMSO-d6,500MHz)δ8.64(d,J=10.0Hz,1H),8.24(d,J=10.0Hz,1H),8.00( s,2H),7.72-7.69(m,1H),7.48-7.45(m,1H),2.88-2.85(m,2H),2.45(s,2H); 13 C NMR (DMSO-d6, 125 MHz) δ 202.5, 176.4, 162.2, 133.0, 132.1, 125.9, 124.6, 122.3, 115.8, 113.6, 35.1 (see Figure 14 and Figure 15 ).

[0128] Example 8: Synthesis of 6,6-dimethyl-2-phenyl-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one

[0129] In a 25 mL reactor, cobalt acetate (0.0048 g, 0.01 mmol) and benzamidine hydrochloride (0.039 g, 0.2 mmol) were added.

[0130] 5,5-Dimethylcyclohexanedione iodide (0.069 g, 0.2 mmol), magnesium carbonate (0.0169 g, 0.2 mmol), and 1,2-dichloroethane (1 mL) were used as solvents and stirred at 80°C for 12 h.

[0131] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:ethyl acetate) gave 0.042 g of 6,6-dimethyl-2-phenyl-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in a yield of 86%.

[0132] The synthetic route of this embodiment is specifically shown below:

[0133]

[0134] 6,6-Dimethyl-2-phenyl-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one, white solid; 1 HNMR(DMSO-d6,500MHz)δ8.07(d,J=5.0Hz,2H),7.49-7.40(m,3H),2.73(s,2H),2.39-2.36(m,3H);1.07(s,6H),0.99(s,2H); 13 C{ 1 H} NMR (DMSO-d6, 125 MHz) δ 139.1, 129.4, 126.8, 125.9, 105.8, 51.7, 35.5, 31.5, 28.2, 27.6, 20.9 (see Figure 16 and Figure 17 ).

[0135] Example 9: Synthesis of 6,6-dimethyl-2-(4-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one

[0136] In a 25 mL reactor, cobalt acetate (0.0048 g, 0.01 mmol) and 4-methylbenzamidine hydrochloride (0.2 mmol) were added.

[0137] 5,5-Dimethylcyclohexanedione iodide (0.069 g, 0.2 mmol), magnesium carbonate (0.0169 g, 0.2 mmol), and 1,2-dichloroethane (1 mL) were used as solvents and stirred at 80°C for 12 h.

[0138] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:ethyl acetate) gave 0.045 g of 6,6-dimethyl-2-(4-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in a yield of 88%.

[0139] The synthetic route of this embodiment is specifically shown below:

[0140]

[0141] 6,6-Dimethyl-2-(4-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one, white solid; 1 H NMR (DMSO-d6, 500MHz) δ7.96 (d, J = 5.0 Hz, 2H), 7.28 (d, J = 5.0 Hz, 2H), 2.71 (s, 2H), 2.39 (s, 2H), 2.35-2.34 (m, 5H); 1.07 (s, 6H), 0.99 (s, 2H); 13 C{ 1 H} NMR (DMSO-d6, 125 MHz) δ 129.5, 129.4, 128.8, 125.9, 105.8, 51.8, 35.5, 31.5, 28.1, 27.6 (see Figure 18 and Figure 19 ).

[0142] Example 10: Synthesis of 6,6-dimethyl-2-(4-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one

[0143] In a 25 mL reactor, cobalt acetate (0.0048 g, 0.01 mmol) and 4-chlorobenzamidine hydrochloride (0.2 mmol) were added.

[0144] 5,5-Dimethylcyclohexanedione iodide (0.069 g, 0.2 mmol), magnesium carbonate (0.0169 g, 0.2 mmol), and 1,2-dichloroethane (1 mL) were used as solvents and stirred at 80°C for 12 h.

[0145] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:ethyl acetate) gave 0.043 g of 6,6-dimethyl-2-(4-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in a yield of 78%.

[0146] The synthetic route of this embodiment is specifically shown below:

[0147]

[0148] 6,6-Dimethyl-2-(4-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one, white solid; 1H NMR(DMSO-d6,500MHz)δ8.07(d,J=5.0Hz,2H),7.54(d,J=10.0Hz,2H),2.72(s,2H),2.39-2.36(m,3H),1.07(s,6H),0.99(s,2H); 13 C{ 1 H} NMR (DMSO-d6, 125 MHz) δ 134.0, 128.9, 128.4, 127.6, 105.9, 51.8, 35.5, 31.5, 28.1, 27.6 (see Figure 20 and Figure 21 ).

[0149] Example 11: Synthesis of 6,6-dimethyl-2-(4-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one

[0150] In a 25 mL reactor, cobalt acetate (0.0048 g, 0.01 mmol) and 4-bromobenzylamidine hydrochloride (0.2 mmol) were added.

[0151] 5,5-Dimethylcyclohexanedione iodide (0.069 g, 0.2 mmol), magnesium carbonate (0.0169 g, 0.2 mmol), and 1,2-dichloroethane (1 mL) were used as solvents and stirred at 80°C for 12 h.

[0152] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:ethyl acetate) gave 0.049 g of 6,6-dimethyl-2-(4-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in a yield of 76%.

[0153] The CAS number of 4-bromobenzamidine hydrochloride in this example is 55368-42-8, which was purchased from Titan Technology Exploration Platform.

[0154] The synthetic route of this embodiment is specifically shown below:

[0155]

[0156] 6,6-Dimethyl-2-(4-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one, white solid; 1 H NMR(DMSO-d6,500MHz)δ8.00(d,J=5.0Hz,2H),7.68(d,J=10.0Hz,2H),2.72(s,2H),2.39-2.36(m,3H),1.07(s,6H),1.00(s,2H); 13 C{1 H} NMR (DMSO-d6, 125 MHz) δ 131.8, 128.7, 127.9, 105.8, 51.8, 35.5, 31.5, 28.1, 27.6 (see Figure 22 and Figure 23 ).

[0157] Example 12: Synthesis of 6,6-dimethyl-2-(3-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one

[0158] In a 25 mL reactor, cobalt chloride (0.0030 g, 0.02 mmol), 3-methylbenzamidine hydrochloride (0.034 g, 0.2 mmol), 5,5-dimethylcyclohexanedione iodide (0.069 g, 0.2 mmol), calcium carbonate (0.020 g, 0.2 mmol), and tetrahydrofuran (2 mL) as solvent were added and stirred at 100 °C for 24 h.

[0159] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:dichloromethane) gave 0.039 g of 6,6-dimethyl-2-(3-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in a yield of 77%.

[0160] The CAS number of 3-methylbenzamidine hydrochloride in this example is 20680-59-5, which was purchased from Titan Technology Exploration Platform.

[0161] The synthetic route of this embodiment is specifically shown below:

[0162]

[0163] 6,6-Dimethyl-2-(3-methylphenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one, white solid; 1 H NMR(DMSO-d6,500MHz)δ7.93(s,1H),7.86(d,J=10.0Hz,1H),7.38-7.35(m,1H),7 .25(d,J=10.0Hz,1H),2.73(s,2H),2.40-2.36(m,6H),1.08(s,6H),0.99(s,2H); 13 C{ 1 H} NMR (DMSO-d6, 125 MHz) δ 187.9, 149.0, 138.0, 130.2, 128.9, 128.7, 126.7, 123.2, 51.7, 36.7, 35.5, 31.5, 28.1, 27.6, 20.9 (see Figure 24 and Figure 25 ).

[0164] Example 13: Synthesis of 6,6-dimethyl-2-(3-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one

[0165] In a 25 mL reactor, cobalt chloride (0.0030 g, 0.02 mmol) and 3-chlorobenzamidine hydrochloride (0.2 mmol) were added.

[0166] 5,5-Dimethylcyclohexanedione iodide ylide (0.069 g, 0.2 mmol), calcium carbonate (0.020 g, 0.2 mmol), tetrahydrofuran (2 mL) were used as solvent and stirred at 100°C for 24 h.

[0167] Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether:dichloromethane) gave 0.040 g of 6,6-dimethyl-2-(3-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one in a yield of 72%.

[0168] The synthetic route of this embodiment is specifically shown below:

[0169]

[0170] 6,6-Dimethyl-2-(3-chlorophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one, white solid; 1 H NMR(DMSO-d6,500MHz)δ8.12-8.01(m,2H),7.52-7.46(m,2H),2.73(s,2H),2.39-2.36(m,3H),1.07(s,6H),0.99(s,2H); 13 C{ 1 H} NMR (DMSO-d6, 125 MHz) δ 133.7, 131.5, 130.8, 129.0, 125.5, 124.4, 105.8, 51.8, 35.5, 31.5, 28.1, 27.6 (see Figure 26 and Figure 27 ).

[0171] Example 14: Synthesis of 6,6-dimethyl-2-(3-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one

[0172] In a 25 mL reactor, cobalt chloride (0.0030 g, 0.02 mmol) and 3-bromobenzamidine hydrochloride (0.2 mmol) were added.

[0173] 5,5-dimethylcyclohexanedione iodine ylide (0.069 g, 0.2 mmol), calcium carbonate (0.020 g, 0.2 mmol), tetrahydrofuran (2 mL) as solvent, 100 °C stirring for 24 h.

[0174] Column chromatography separation (silica gel, 200-300 mesh; developing agent, petroleum ether: dichloromethane) to obtain 6,6-dimethyl-2-(3-bromophenyl)-1,2,3,4,5,6,7- hexahydro-4H-benzo[d]imidazol-4-one 0.045 g, yield 70%.

[0175] The CAS number of 3-bromobenzamidine hydrochloride of the present example is 16796-52-4, which is purchased from Titan Scientific Exploration Platform.

[0176] The synthetic route of the present example is specifically as follows:

[0177]

[0178] 6,6-dimethyl-2-(3-bromophenyl)-1,2,3,4,5,6,7-hexahydro-4H-benzo[d]imidazol-4-one, white solid; 1 H NMR (DMSO-d6, 500 MHz) δ 8.27 (s, 1H), 8.06 (d, J = 10.0 Hz, 1H), 7.62-7.59 (m, 1H), 7.45-7.42 (m, 1H), 2.73 (s, 2H), 2.39-2.37 (m, 3H), 1.07 (s, 6H), 1.00 (s, 2H); 13 C{ 1 H} NMR (DMSO-d6, 125 MHz) δ 131.9, 131.7, 131.0, 128.4 124.8, 122.1, 105.9, 51.8, 35.5, 31.5, 28.1, 27.6 (see Figure 28 and Figure 29 ).

[0179] The above describes the present application and its embodiments, which is not restrictive, and the examples shown is only one of the embodiments of the present application, and the actual structure is not limited thereto. In general, if a person skilled in the art is inspired, without departing from the purpose of the present application, without creative design, similar structure and embodiments to the technical solution, should belong to the protection scope of the present application.

Claims

1. A method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by regulating cobalt catalysis using an alkali salt, characterized in that: Under heating conditions, benzamidine hydrochloride or substituted benzamidine hydrochloride and iodine ylide are used as starting materials, a cobalt catalyst is used to catalyze the C-H cyclization reaction, and aminoisoquinoline derivatives or aryl imidazole derivatives are selectively prepared by adjusting the type of base salt; selectively preparing an alkali salt of an aminoisoquinoline derivative selected from a phosphate or a dihydrogen phosphate; The base salt for selectively preparing the aryl imidazole derivative is selected from carbonates; The structural formula of the aminoisoquinoline derivative is shown in the following formula (I): The structural formula of the aryl imidazole derivative is shown in the following formula (II): R is selected from one of hydrogen, alkyl, halogen, ester or trifluoromethyl; The cobalt catalyst is selected from at least one of a II cobalt catalyst and a III cobalt catalyst.

2. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to claim 1, characterized in that: The phosphate is selected from potassium phosphate, and the dihydrogen phosphate is selected from potassium dihydrogen phosphate.

3. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to claim 1, characterized in that: The carbonate is selected from at least one of magnesium carbonate and calcium carbonate.

4. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to claim 1, characterized in that: The para or meta position of the phenyl ring of the substituted benzamidine hydrochloride is substituted by a substituent, and the substituent is selected from one of an alkyl group, a halogen group, an ester group or a trifluoromethyl group.

5. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to claim 1, characterized in that: The cobalt catalyst is selected from at least one of Cp*Co(CO)I2, [Cp*Co(CH3CN)3](SbF6)2, Co(OAc)2, and CoCl2.

6. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to claim 1, characterized in that: The structural formula of the iodine ylide is one of the following:

7. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to claim 6, characterized in that: The 1-aminoisoquinoline derivative of formula (I) is specifically any one of the following compounds:

8. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to claim 6, characterized in that: The 2-aryl imidazole derivative having the structural formula (II) is specifically any one of the following compounds:

9. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to any one of claims 1 to 8, characterized in that: It specifically includes the following steps: 1) adding benzamidine hydrochloride or substituted benzamidine hydrochloride, iodine ylide, cobalt catalyst and alkali salt into an organic solvent and dispersing; 2) Seal the tube and stir the reaction at a temperature of 80-100°C, and separate the reacted materials.

10. The method for selectively preparing aminoisoquinoline derivatives or aryl imidazole derivatives by alkali salt-regulated cobalt catalysis according to claim 9, characterized in that: The molar ratio of benzamidine hydrochloride or substituted benzamidine hydrochloride, iodine ylide and cobalt catalyst is 1: (0.01-1): 0.1; The molar ratio of the benzamidine hydrochloride or substituted benzamidine hydrochloride to the alkali salt is 1:(1-3).

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