CN110143962B - Novel method for synthesizing benzimidazole [1,2-a ] quinoline derivative - Google Patents

Novel method for synthesizing benzimidazole [1,2-a ] quinoline derivative Download PDF

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CN110143962B
CN110143962B CN201910607822.9A CN201910607822A CN110143962B CN 110143962 B CN110143962 B CN 110143962B CN 201910607822 A CN201910607822 A CN 201910607822A CN 110143962 B CN110143962 B CN 110143962B
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benzimidazole
dimer
benzisoxazole
phenyl
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CN110143962A (en
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吴勇
海俐
刘艳昭
聂瑞芳
胡瑶
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Sichuan University
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to a method for synthesizing benzimidazole [1,2-a ]]A novel process for quinoline derivatives. N-aryl amidines and benzisoxazole compounds are used as raw materials, N1,N3-disubstituted imidazole type ionic liquids as solvents, C-H activation/ring catalyzed by transition metalsThe synthesis of benzimidazole [1,2-a ] by the ring-merging reaction of C-C bond on aromatic ring]Quinoline derivatives. Compared with the traditional method, the method has the following advantages: (1) simple steps, easily obtained raw materials, wide application range of substrates and high reaction yield. (2) The catalytic system avoids the addition of silver salt and acid or alkali additives, has low cost, is safe and convenient, and has wide application prospect.

Description

Novel method for synthesizing benzimidazole [1,2-a ] quinoline derivative
Technical Field
The invention relates to a method based on N1,N3High-efficiency synthesis of benzimidazole [1,2-a ] by using-disubstituted imidazole ionic liquid as solvent and N-aryl amidines and benzisoxazole compounds as raw materials through transition metal catalysis C-H activation/cyclization reaction]A novel process for quinoline derivatives.
Background
Benzimidazoles, like purines, are the main backbone of many pharmaceutical chemical and biochemical agents, and therefore compounds with a benzimidazole as the core backbone have numerous activities, such as: anti-tumor, antiviral, antibacterial, antifungal, antihistaminic, and antispasmodic activities. And the benzimidazole [1,2-a ] formed by combining the quinoline ring]Quinoline derivatives have a stronger antitumor activity because they can easily interfere with the replication of DNA or RNA. Currently, benzimidazole [1,2-a ] is synthesized]Common methods for quinoline analogs include cyclization or photochemical dehydrocyclization, however, these methods generally have the disadvantages of requiring multiple reactions, low yield, high amount of by-products, environmental pollution, requirement of additional additives, limited substrate range, and difficulty in synthesis. Thus, the development of highly efficient synthesis of benzimidazole [1,2-a ]]The method of quinoline derivatives is of great significance. Based on the advantages of safety, stability, easiness in synthesis and the like of N-phenylamidine compounds and benzisoxazole compounds, the invention provides a method for synthesizing a compound which takes N-phenylamidine compounds as a substrate, benzisoxazole compounds as a coupling reagent and N1,N3The-disubstituted imidazole ionic liquid is used as a solvent, and C-N bond is simply, conveniently and efficiently formed on an aromatic ring of the N-phenylamidine compound to synthesize benzimidazole [1,2-a ] through cyclization under the catalysis of transition metal]A novel process for quinoline derivatives.
Disclosure of Invention
The invention realizes a novel method for synthesizing the benzimidazole [1,2-a ] quinoline derivative by taking N-aryl amidines and benzisoxazole compounds as raw materials and ionic liquid as a solvent through a C-H activation/cyclization reaction of aryl catalyzed by transition metal, and solves the problems of complicated reaction steps, difficult raw material obtaining, low atom utilization rate, toxic organic solvent use, high cost and the like in the traditional synthetic method. The invention provides a preparation method which is simpler, safer, more effective, lower in cost, good in substrate applicability and free of additives in a reaction system, and has a wide application prospect.
The chemical reaction formula of the invention is as follows:
Figure 36358DEST_PATH_IMAGE001
wherein:
ring A is phenyl, naphthyl, thienyl, furyl or pyridyl;
R1、R2is one or more of hydrogen, halogen, alkyl, phenyl, alkoxy, carbonyl and cyano;
R3、R4is one or more of hydrogen, halogen, alkyl, phenyl, alkoxy, carbonyl and amino.
The preparation steps are as follows:
(1) adding an N-aryl amidine compound serving as a substrate, a benzisoxazole compound, a catalyst and an ionic liquid into a clean reactor, replacing with argon, and stirring in an oil bath kettle at 140 ℃ for 24 hours;
(2) after the reaction is finished, the product is obtained by directly adopting silica gel column chromatography for separation and purification.
The catalyst in the step (1) is rhodium trichloride, rhodium acetate, acetylacetonatocarbonyltriphenylphosphine rhodium, a dimer of rhodium bicyclooctenylchloride, a dimer of dichloro (pentamethylcyclopentadienyl) rhodium (III), a dimer of bis (hexafluoroantimonic) triethylenenitrile (pentamethylcyclopentadienyl) rhodium (III), rhodium triphenylphosphine chloride, ruthenium trichloride, ruthenium triphenylphosphine chloride, bis (triphenylphosphinyl) ruthenium dichlorodicarbonyl, bis (2-methylallyl) (1, 5-cyclooctadiene) ruthenium (II), a dimer of p-cymene ruthenium dichloride, cobalt chloride, cobalt acetoacetato, cobaltocene octacarbonyl, a dimer of dichloro (pentamethylcyclopentadienyl) cobalt (III), cobalt pentamethylcyclopentadienylcarbonyldiiodide, cobalt (hexafluoroantimonic) triethylenenitrile (pentamethylcyclopentadienyl) cobalt (III), iridium trichloride, a dimer of dichloro (pentamethylcyclopentadienyl) iridium (III), rhodium (III), iridium trichloride, or a dimer of dichloro (pentamethylcyclopentadienylcyclopentadienyl) iridium (III), One or more of bis (1, 5-cyclooctadiene) iridium chloride (I) dimer and methoxyl (cyclooctadiene) iridium dimer.
The solvent in the step (1) is N1,N3-one of disubstituted imidazole ionic liquids.
In the step (1), the N-aryl amidine compound: benzisoxazole compounds: the molar ratio of the catalyst is 1 (1.1-3.0): (0.02-0.05).
In the step (1), the reaction concentration of the N-aryl amidine compound is 0.1-0.5 mol/L.
By nuclear magnetic resonance hydrogen spectroscopy (1H NMR), carbon spectrum (13C NMR) and high resolution mass spectrometry prove the structure of the benzothiazine derivative formed by C-C bond on aromatic heterocyclic ring and synthesized by ring, as shown in figure 1 and figure 2. Wherein the NMR chart is measured by a Varian INOVA-400 NMR spectrometer, Tetramethylsilane (TMS) is taken as an internal standard (delta 0 ppm), and deuterated chloroform is taken as a solvent; high resolution mass spectra were determined using an Agilent 1946B mass spectrometer.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of Compound 1 of the present invention;
FIG. 2 shows a nuclear magnetic carbon spectrum of Compound 1 of the present invention.
Detailed Description
The present invention will be further described with reference to specific embodiments to assist in understanding the invention. It is not intended that the scope of the invention be limited thereby, but rather that the invention be defined by the claims appended hereto.
Example 1 was carried out: synthesis of Compound 1
Figure 953498DEST_PATH_IMAGE002
(1) Sequentially adding N- (4-methylphenyl) acetamidine (29.6 mg, 0.20 mmol), 5-chloro-3-phenylbenzisoxazole (55.1 mg, 0.24 mmol), dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (6.2 mg, 0.01 mmol) and 1-butyl-3-methylimidazolium tetrafluoroborate (0.6 mL) into a clean reactor, replacing with argon, and stirring in an oil bath at 140 ℃ for 24 hours;
(2) after the reaction is finished, the product 57.6 mg, yellow solid and yield 84% are obtained by directly adopting silica gel column chromatography for separation and purification;1H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.63 - 7.47 (m, 5H), 7.39 (d, J = 8.4 Hz, 1H), 2.68 (s, 3H); 13C NMR (100 MHz, Chloroform-d) Delta 147.4, 143.3, 141.8, 137.6, 134.4, 133.2, 131.0, 129.6, 129.5, 129.5, 129.0, 128.8, 127.7, 126.5, 124.8, 120.3, 118.9, 116.9, 113.9, 22.5, HRMS (ESI) calculated C22H16ClN2 [M + H]+343.0997, found: 343.0996.
example 2 was carried out: synthesis of Compound 2
Figure 733236DEST_PATH_IMAGE003
(1) Sequentially adding N- (4-fluorophenyl) acetamidine (26.8 mg, 0.20 mmol), 5-chloro-3-phenylbenzisoxazole (55.1 mg, 0.24 mmol), dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (8.0 mg, 0.01 mmol) and 1-butyl-3-methylimidazolium tetrafluoroborate (0.6 mL) into a clean reactor, replacing with argon, and stirring in an oil bath at 140 ℃ for 24 hours;
(2) after the reaction is finished, the product 51.2 mg of light yellow solid is obtained by directly adopting silica gel column chromatography for separation and purification, and the yield is 78%;1H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.63 - 7.42 (m, 8H); 13C NMR (100 MHz, Chloroform-d) δ 147.7, 145.1, 142.4, 137.5, 134.4, 130.8, 129.8, 129.8, 129.5, 129.1, 128.9, 127.8, 124.9, 124.8, 123.2, 120.8, 118.8, 116.9, 114.0, HRMS (ESI) calculated C21H14ClN2 [M + H]+329.0840, found: 329.0842.
example 3 of implementation: synthesis of Compound 3
Figure 128445DEST_PATH_IMAGE004
(1) Sequentially adding N-phenyl acetamidine (30.4 mg, 0.20 mmol), 5-chloro-3-phenyl benzisoxazole (55.1 mg, 0.24 mmol), dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (6.2 mg, 0.01 mmol) and 1-butyl-3-methylimidazole trifluoromethanesulfonate (0.6 mL) into a clean reactor, replacing with argon, and stirring in an oil bath at 140 ℃ for 24 h;
(2) after the reaction is finished, the product of 62.2 mg is obtained by directly adopting silica gel column chromatography for separation and purification, and the yield is 81 percent;1H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.97 (dd, J = 8.8, 5.2 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 - 7.50 (m, 6H), 7.33 (td, J = 8.8, 2.4 Hz, 1H); 13C NMR (101 MHz, Chloroform-d) δ 160.6, 158.2, 148.3, 142.4, 141.5, 137.3, 134.1, 130.2, 129.9, 129.5, 129.1, 129.0, 128.0, 124.8, 121.4 (d, J = 10.0 Hz), 118.8, 116.6, 113.4 (d, J = 24.9 Hz), 101.0 (d, J= 29.3 Hz), calculated value C21H13ClFN2 [M + H]+347.0746, found: 347.0753.
example 4 of implementation: synthesis of Compound 4
Figure 942817DEST_PATH_IMAGE005
(1) Sequentially adding N- (4-methylphenyl) N-butylamidine (35.2 mg, 0.20 mmol), 5-chloro-3-phenylbenzoisoxazole (55.1 mg, 0.24 mmol), dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (6.2 mg, 0.01 mmol) and 1-butyl-3-methylimidazolium tetrafluoroborate (0.6 mL) into a clean reactor, replacing with argon, and stirring in an oil bath at 140 ℃ for 24 hours;
(2) after the reaction is finished, the product of 54.8 mg and yellow solid with the yield of 74 percent are obtained by directly adopting silica gel column chromatography for separation and purification;1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 - 7.52 (m, 3H), 7.39 (dd, J = 8.4, 1.2 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.26 (s, 1H), 2.91 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.25 (d, J = 7.6 Hz, 3H); 13C NMR (150 MHz, Chloroform-d) Delta 147.8, 137.9, 136.5, 133.1, 133.0, 132.1, 131.5, 129.8, 129.8, 129.3, 129.0, 128.8, 128.4, 127.8, 126.4, 126.3, 120.3, 116.3, 114.0, 23.2, 22.5, 14.4, HRMS (ESI) calculated as C24H20ClN2 [M + H]+371.1310, found: 371.1314.
example 5 was carried out: synthesis of Compound 5
Figure 207357DEST_PATH_IMAGE006
(1) Sequentially adding N- (4-methylphenyl) acetamidine (29.6 mg, 0.20 mmol), 5-chloro-3- (4-methoxyphenyl) benzisoxazole (62.4 mg, 0.24 mmol), dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (6.2 mg, 0.01 mmol), 1-butyl-3-methylimidazolium bistrifluoromethylsulfonyl imide salt (0.6 mL) into a clean reactor, replacing with argon, and stirring in an oil bath at 140 ℃ for 24 h;
(2) after the reaction is finished, the product of 62.5 mg and yellow solid with the yield of 72 percent is obtained by directly adopting silica gel column chromatography for separation and purification;1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 8.8, 2.4 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 3.92 (s, 3H), 2.67 (s, 3H); 13C NMR (100 MHz, Chloroform-d) Delta 160.1, 147.6, 143.3, 141.5, 134.5, 133.1, 131.0, 130.8, 129.8, 129.6, 129.5, 127.8, 126.5, 125.0, 120.2, 118.7, 116.9, 114.5, 113.9, 55.6, 22.5, HRMS (ESI) calcd C23H18ClN2O [M + H]+373.1102, found: 373.1105.

Claims (3)

1. synthesis of benzimidazole [1,2-a ]]The method for preparing quinoline derivatives is characterized in that N-aryl amidine compounds are used as substrates, benzisoxazole compounds are used as coupling reagents, transition metals are used as catalysts, and N is1,N3The disubstituted imidazole type ionic liquid is a solvent and has a chemical reaction formula:
Figure 544033DEST_PATH_IMAGE001
wherein:
ring A is phenyl, naphthyl, thienyl, furyl or pyridyl;
R1、R2is one or more of hydrogen, halogen, alkyl, phenyl, alkoxy and cyano;
R3、R4is one or more of hydrogen, halogen, alkyl, phenyl, alkoxy and amino;
the synthesis method of the derivative comprises the following preparation steps:
(1) adding an N-aryl amidine compound serving as a substrate, a benzisoxazole compound, a catalyst and an ionic liquid into a clean reactor, replacing with argon, and stirring in an oil bath kettle at 140 ℃ for 24 hours;
(2) after the reaction is finished, directly adopting silica gel column chromatography for separation and purification to obtain a product;
the catalyst in the step (1) is one or more of dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer and dichloro (pentamethylcyclopentadienyl) iridium (III) dimer;
the solvent in the step (1) is one or more than one of 1-butyl-3-methylimidazole tetrafluoroborate, 1-butyl-3-methylimidazole trifluoromethanesulfonate and 1-butyl-3-methylimidazole bistrifluoromethylsulfonyl imide ionic liquid.
2. The process according to claim 1, wherein in step (1) the N-arylamidine compound: benzisoxazole compounds: the mole of the catalyst is 1 (1.1-3.0): (0.02-0.05).
3. The preparation method according to claim 2, wherein the reaction concentration of the N-arylamidine compound in the step (1) is 0.1-0.8 mol/L.
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