CN113149976A - N- (3-thienyl) -2-oxazole amine and preparation method thereof - Google Patents

N- (3-thienyl) -2-oxazole amine and preparation method thereof Download PDF

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CN113149976A
CN113149976A CN202110352940.7A CN202110352940A CN113149976A CN 113149976 A CN113149976 A CN 113149976A CN 202110352940 A CN202110352940 A CN 202110352940A CN 113149976 A CN113149976 A CN 113149976A
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palladium
alkyl
chloride
independently selected
aryl
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施继成
周发斌
张力学
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Guangdong University of Petrochemical Technology
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Guangdong University of Petrochemical Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Plural Heterocyclic Compounds (AREA)
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Abstract

Heterocyclic amines are often physiologically active and are an important fine chemical. The invention provides N- (3-thienyl) -2-aminooxazole and a preparation method thereof.

Description

N- (3-thienyl) -2-oxazole amine and preparation method thereof
Technical Field
The invention relates to preparation of N- (3-thienyl) -2-aminooxazole by using palladium-catalyzed Buchwald-Hartwig coupling amination reaction, belonging to the field of organic synthesis.
Background
Heterocyclic amines are often physiologically active and are important fine chemicals, in particular thiophenes, oxazoles are frequently found in drug structures, but N- (3-thienyl) -2-aminooxazoles are not known in the literature. Palladium-catalyzed C-N coupling reactions, designed for 5-membered ring heteroarenes, are a challenging class of reactions. Buchwald et al, 2017, reported the coupling of several halogenated aromatic hydrocarbons with 2-aminooxazoles (Esben P.K, Angew. chem. int. Ed., 2017, 56, 10569-containing 10572), but with catalyst levels as high as 6 mol%. The invention provides double 5-membered heterocyclic secondary aromatic amine N- (3-thienyl) -2-amino oxazole and a preparation method thereof.
Disclosure of Invention
The invention provides N- (3-thienyl) -2-aminooxazoles having the general formula I,
Figure 516014DEST_PATH_IMAGE001
wherein
R1、R2、R3、R4And R5Each independently selected from H, F, Cl, CN, NO2C1-10 alkyl, C3-10 cycloalkyl, C6-10 aryl, C4-10 heteroaryl and CO2R6Wherein the C1-10 alkyl and C3-10 cycloalkyl groups may carry O, S, N and F atoms, the heteroatom in the C4-10 heteroaryl group is O, S and N and CO2R6In the radical R6Is C1-10 alkyl.
The invention provides a method for preparing N- (3-thienyl) -2-aminooxazole by using a palladium catalyst to realize the coupling reaction between 3- (pseudo) halothiophene and 2-aminooxazole under the promotion of alkali, the reaction equation is as follows,
Figure 195257DEST_PATH_IMAGE002
wherein
R1、R2、R3、R4And R5Is as defined in claim 1.
X1Is Cl, Br, I atom, OSO2R7Or O2CCF3Where R is7Is methyl, phenyl or p-tolyl.
The palladium catalyst consists of a supporting ligand and a palladium source in a ratio of 5:1 to 1:1, with or without additional addition of the supporting ligand to the palladium source already bearing the palladium complex of the supporting ligand.
The base is potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, triethylamine, diisopropylethylamine, or DBU.
The solvent is one or two of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, formic acid, acetic acid and water.
The reaction temperature is 50 to 130 degrees celsius.
The supporting ligands of the palladium catalysts of the present invention have the tertiaryarylmonophosphine ligands of the general formulae IIa and IIb or mixtures thereof,
Figure 282161DEST_PATH_IMAGE003
wherein Ar is selected from (C6-C20) aryl, which may have 1 to 3 substituents independently selected from (C1-C6) alkyl, -O (C1-C6) alkoxy, -N (C1-C6)2Dialkylamino or (C6-C10) aryl which may have 1 to 3 substituents independently selected from (C1-C6) alkyl, -O (C1-C6) alkoxy or-N (C1-C6)2A substituent of a dialkylamino group;
R8selected from H, (C1-C6) alkyl, -O (C1-C6) alkoxy or-N (C1-C6)2A dialkylamino group;
R9and R10Each independently selected from (C1-C10) alkyl, (C3-C10) cycloalkyl, (5-11 membered) heterocycloalkyl, (C6-C20) aryl, (C4-C20) heteroaryl or-CH2(C6-C10) arylmethylene, here (C3-C10) cycloalkyl, (5-11 membered) heterocycloalkyl, (C6-C20) aryl, (C4-C20) heteroaryl and-CH2(C6-C10) the arylmethylene group may have 1 to 3 groups independently selected from (C1-C6) alkyl or-O (C1-C6) alkoxy-N (C1-C6)2A substituent of dialkylamino, where the heteroatom in heteroaryl is selected from O, N or an S atom.
The palladium source of the palladium catalyst used in the present invention includes palladium acetate, palladium chloride, palladium acetylacetonate, palladium diphenylmethyleneacetonate, tetrakis (triphenylphosphine) palladium, palladium diacetonitrile chloride, palladium diphenylnitrile chloride, allylpalladium chloride dimer, crotyl palladium chloride dimer, phenylpropenylpalladium chloride dimer, 2-aminobiphenyl-2-palladium chloride, 1, 5-cyclooctadiene palladium chloride or 1, 5-cyclooctadiene bis (trimethylsilylmethyl) palladium; or palladium compounds having the structure of formulae III, IV and V, wherein R11、R12、R13And R14Each independently selected from hydrogen, methyl and phenyl, X2Selected from chlorine, bromine, iodine, methanesulfonate, benzenesulfonate or p-toluenesulfonate; even palladium complexes VI, VII, VIII, IX, X, XI and XII which have been coordinated by supporting ligands, where L is as defined in claim 3 and R is11、R12、R13、R14And X2Is as defined above, X3Selected from chlorine, bromine and iodine.
Figure RE-882728DEST_PATH_IMAGE002
The terphenylphosphine used in the present invention includes a terphenylphosphine of the following structure,
Figure RE-439611DEST_PATH_IMAGE003
Figure RE-175486DEST_PATH_IMAGE004
in the present invention, the ratio of thiophene (pseudo) halide to 2-aminooxazole is from 1.2:1 to 1: 1.2; the amount of palladium is 0.05 mol% to 5 mol% (based on the least amount of substrate); the amount of base used is 1 to 2 equivalents based on the least amount of substrate used; the reaction time is in the range of 0.5 to 48 hours.
The present invention can be illustrated in further detail by the following examples, but it is not intended that the present invention be limited to these examples.
Example 1N- (3-thienyl) -2-aminooxazole
Figure 132995DEST_PATH_IMAGE007
In a glove box, 3-bromothiophene (0.1630 g, 1.0 mmol), 2-aminooxazole (0.1009 g, 1.2 mmol), base (1.3 mmol), catalyst, ligand, 0.13 mL dodecane (GC internal standard), and 4 mL tetrahydrofuran were placed in a pressure resistant tube. The tube was sealed and suspended in an oil bath at 110 ℃ and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered through celite (dichloromethane), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a black oil in the yield shown in the following table.
1H NMR (400 MHz, Chloroform-d) δ:9.39 (s, 1H), 7.31 (d, J = 1.1 Hz, 1H), 7.25 (dd, J = 5.1, 3.2 Hz, 1H), 7.17 (dd, J = 3.2, 1.5 Hz, 1H), 6.98 (dd, J = 5.1, 1.5 Hz, 1H), 6.94 (d, J = 1.1 Hz, 1H)。
13C NMR (101 MHz, Chloroform-d) δ: 158.2, 136.8, 132.3, 126.1, 125.1, 120.6, 105.3。
Figure 980865DEST_PATH_IMAGE008
Figure 906096DEST_PATH_IMAGE009
Example 2N- (2-methyl-4-thienyl) -2-aminooxazole
Figure 927141DEST_PATH_IMAGE010
In a glove box, 2-methyl-4-bromothiophene (0.1759 g, 1.0 mmol), 2-aminooxazole (0.1009 g, 1.2 mmol), a base (1.3 mmol), a palladium complex, (2, 6-bis (2,4, 6-triisopropylphenyl) phenyl) -dicyclohexylphosphine, 0.13 mL of dodecane (GC internal standard), and 4 mL of tetrahydrofuran were placed in a pressure-resistant tube. The tube was sealed and suspended in an oil bath at 110 ℃ and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered through celite (dichloromethane), the filtrate was concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1), and the yields are shown in the following table.
Figure 723059DEST_PATH_IMAGE011
Figure 1
Example 3N- (3-methyl-4-thienyl) -2-aminooxazole
Figure 216674DEST_PATH_IMAGE013
In a glove box, 3-methyl-4-bromothiophene (0.177 g, 1.0 mmol), 2-aminooxazole (0.1009 g, 1.2 mmol), a base (1.3 mmol), a palladium complex, (2, 6-bis (2,4, 6-triisopropylphenyl) phenyl) -dicyclohexylphosphine, 0.13 mL of dodecane (GC internal standard), and 4 mL of tetrahydrofuran were placed in a pressure resistant tube. The tube was sealed and suspended in an oil bath at 110 ℃ and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered through celite (dichloromethane), the filtrate was concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1), and the yields are shown in the following table.
Figure 979094DEST_PATH_IMAGE014
Figure 160676DEST_PATH_IMAGE015
Example 4N- (3-thienyl) -4-ethoxyformyl-2-aminooxazole
Figure 897819DEST_PATH_IMAGE016
In a glove box, 3-bromothiophene (0.163 g, 1.0 mmol), 4-carbothoxy-2-aminooxazole (0.187 g, 1.2 mmol), a base (1.3 mmol), a palladium complex, (2, 6-bis (2,4, 6-triisopropylphenyl) phenyl) -dicyclohexylphosphine, 0.13 mL of dodecane (GC internal standard), and 4 mL of tetrahydrofuran were placed in a pressure-resistant tube. The tube was sealed and suspended in an oil bath at 110 ℃ and reacted for 12 hours. After cooling to room temperature, the reaction mixture was filtered through celite (dichloromethane), the filtrate was concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1), and the yields are shown in the following table.
Figure 532063DEST_PATH_IMAGE017
Figure 98174DEST_PATH_IMAGE018

Claims (6)

1. The invention provides N- (3-thienyl) -2-aminooxazoles having the general formula I,
Figure 995037DEST_PATH_IMAGE001
wherein
R1、R2、R3、R4And R5Each independently selected from H, F, Cl, CN, NO2C1-10 alkyl, C3-10 cycloalkyl, C6-10 aryl, C4-10 heteroaryl and CO2R6Wherein the C1-10 alkyl and C3-10 cycloalkyl groups may carry O, S, N and F atoms, the heteroatom in the C4-10 heteroaryl group is O, S and N and CO2R6In the radical R6Is C1-10 alkyl.
2. The invention provides a method for preparing N- (3-thienyl) -2-aminooxazole by using a palladium catalyst to realize the coupling reaction between 3- (pseudo) halothiophene and 2-aminooxazole under the promotion of alkali, the reaction equation is as follows,
Figure 443336DEST_PATH_IMAGE002
wherein
R1、R2、R3、R4And R5Is as defined in claim 1; x1Is Cl, Br, I atom, OSO2R7Or O2CCF3Where R is7Is methyl, phenyl or p-tolyl; the palladium catalyst consists of a supporting ligand and a palladium source in a ratio of 5:1 to 1:1, and the supporting ligand can be additionally added or not added for the palladium source of the palladium complex with the supporting ligand; the base is potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, triethylamine, diisopropylethylamine, or DBU; the solvent is one or two of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, dioxane, toluene, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, formic acid, acetic acid and water; the reaction temperature is 50 to 130 degrees celsius.
3. According to the preceding claim, the supporting ligands in the palladium catalyst have the tertiaryarylmonophosphine ligands of the general formulae IIa and IIb or mixtures thereof,
Figure 223073DEST_PATH_IMAGE003
wherein Ar is selected from (C6-C20) aryl, which may have 1 to 3 substituents independently selected from (C1-C6) alkyl, -O (C1-C6) alkoxy, -N (C1-C6)2Dialkylamino or (C6-C10) aryl which may have 1 to 3 substituents independently selected from (C1-C6) alkyl, -O (C1-C6) alkoxy or-N (C1-C6)2A substituent of a dialkylamino group;
R8selected from H, (C1-C6) alkyl, -O (C1-C6) alkoxy or-N (C1-C6)2A dialkylamino group;
R9and R10Each independently selected from (C1-C10) alkyl, (C3-C10) cycloalkyl, (5-11 membered) heterocycloalkyl, (C6-C20) aryl, (C4-C20) heteroaryl or-CH2(C6-C10) arylmethylene, here (C3-C10) cycloalkyl, (5-11 membered) heterocycloalkyl, (C6-C20) aryl, (C4-C20) heteroaryl and-CH2(C6-C10) the arylmethylene group may have 1 to 3 groups independently selected from (C1-C6) alkyl or-O (C1-C6) alkoxy-N (C1-C6)2A substituent of dialkylamino, where the heteroatom in heteroaryl is selected from O, N or an S atom.
4. The palladium sources of the palladium catalysts used according to the invention include palladium acetate, palladium chloride, palladium acetylacetonate, palladium diphenylmethylidene acetonate, tetrakis (triphenylphosphine) palladium, palladium diacetonitrile chloride, palladium diphenylnitrile chloride, allylpalladium chloride dimer, crotyl palladium chloride dimer, phenylpropenylpalladium chloride dimer, 2-aminobiphenyl-2-palladium chloride, 1, 5-cyclooctadienepalladium chloride or 1, 5-cyclooctadienebis (trimethylsilylmethyl) palladium; or palladium compounds having the structure of formulae III, IV and V, wherein R11、R12、R13And R14Each independently selected from hydrogen, methyl and phenyl, X2Selected from chlorine, bromine, iodine, methanesulfonate, benzenesulfonate or p-toluenesulfonate; even palladium complexes VI, VII, VIII, IX, X, XI and XII which have been coordinated by supporting ligands, where L is as defined in claim 3 and R is11、R12、 R13、R14And X2Is as defined above, X3Selected from chlorine, bromine and iodine:
Figure RE-172482DEST_PATH_IMAGE002
。
5. the invention according to the above claims uses a tris-biaryl phosphine comprising a tris-biaryl phosphine of the structure:
Figure 714546DEST_PATH_IMAGE005
Figure 333746DEST_PATH_IMAGE006
。
6. according to claim 2, the ratio of thiophene (pseudo) halide to 2-aminooxazole is from 1.2:1 to 1: 1.2; the amount of palladium is 0.05 mol% to 5 mol% (based on the least amount of substrate); the amount of base used is 1 to 2 equivalents based on the least amount of substrate used; the reaction time is in the range of 0.5 to 48 hours.
CN202110352940.7A 2021-03-31 2021-03-31 N- (3-thienyl) -2-oxazole amine and preparation method thereof Pending CN113149976A (en)

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