CN108947906B - Method for preparing 1,3,4, 5-tetraaryl substituted pyrazole - Google Patents
Method for preparing 1,3,4, 5-tetraaryl substituted pyrazole Download PDFInfo
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- CN108947906B CN108947906B CN201810922123.9A CN201810922123A CN108947906B CN 108947906 B CN108947906 B CN 108947906B CN 201810922123 A CN201810922123 A CN 201810922123A CN 108947906 B CN108947906 B CN 108947906B
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
The invention discloses a method for preparing 1,3,4, 5-tetraaryl substituted pyrazole. The method comprises the steps of carrying out addition reaction on benzosultam and N-aryl arylhydrazinecarbonyl chloride under the action of an alkaline catalyst, and removing SO by using dipolar cycloaddition in series2Preparing 1,3,4, 5-tetraaryl substituted pyrazole by one-step reaction. The method has short reaction steps and mild reaction conditions; the feed ratio of the reaction substrate is low, and a large amount of waste cannot be generated; the reaction area selectivity is high, other byproducts are not generated, the reaction yield is high, and the 5-position aromatic ring in the product structure is connected with methylamino, so that more types of pyrazole derivatives can be prepared.
Description
Technical Field
The invention relates to a method for preparing 1,3,4, 5-tetraaryl substituted pyrazole.
Background
Polyaryl substituted pyrazole is an important nitrogenous five-membered heterocyclic compound, and has been successfully applied to the field of medicine, agricultural chemicals, transition metal catalyst ligands and good fluorescent material development potential; however, few reports on the synthesis methods of the polyaryl substituted pyrazole compounds so far exist, and the defects of low product yield, small substrate application range, difficult substrate synthesis and the like exist generally, so that the molecular diversity of the compounds is greatly limited.
At present, the conventional method for synthesizing polyaryl substituted pyrazoles mainly utilizes a condensation reaction between a hydrazine compound and a 1, 3-dicarbonyl compound or an α, β -unsaturated carbonyl compound (Murray, W.V.; Wachter, M.P.J.heterocyclic. chem.1989,26,1389), and the reaction formula is shown as follows:
this method has a small substrate applicability and a poor regioselectivity of the reaction, and usually a mixture of N1 and N2 substitutions will be present.
In 2015, pyrazole compounds having four different aryl substitutions were synthesized in a four-step reaction using 3-iodo-1H-pyrazole as a substrate by SNAr reaction, coupling reaction and C-H arylation reaction (t. morita, d.kobayashi, k.matsumura, k.jolmoto, h.uekusa, s.fuse, t.takahashi, chem.asian j.2015,10,1626), the reaction formula is shown below:
however, the method needs a noble metal palladium catalyst, so that the reaction economy is influenced, and meanwhile, the method has a long route and causes low product yield.
In conclusion, the preparation method of the 1,3,4, 5-tetraaryl substituted pyrazole, which has the advantages of mild reaction conditions, high regioselectivity, high product yield and simple synthetic route, is provided, and has important significance.
Disclosure of Invention
The invention provides a method for solving the problems that the preparation method of 1,3,4, 5-tetraaryl substituted pyrazole in the prior art needs heating, has low regioselectivity and product yield and has a complex synthetic route.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for preparing 1,3,4, 5-tetraaryl substituted pyrazole comprises the steps of carrying out addition reaction on benzosultam with a structure shown in a formula (I) and N-aryl arylmethyl hydrazine acyl chloride with a structure shown in a formula (II) under the action of an alkaline catalyst to generate 1,3,4, 5-tetraaryl substituted pyrazole with a structure shown in a formula (III); the specific reaction scheme is as follows:
wherein Ar is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, phenyl or C1-C4 alkyl substituted phenyl, fluorine substituted phenyl, chlorine substituted phenyl, bromine substituted phenyl or methoxy substituted phenyl; r1 is hydrogen, C1-C4 alkyl, fluoro, chloro, bromo, methoxy, nitro or cyano; r2 is hydrogen, C1-C4 alkyl, fluoro, chloro, bromo, methoxy, nitro or cyano.
Preferably, the basic catalyst is selected from one or more of trimethylamine, triethylamine, diisopropylmethylamine, diisopropylethylamine, pyridine, triethylenediamine or diazabicyclo.
Preferably, the addition reaction is carried out in an aprotic organic solvent selected from one or more of benzene, toluene, o-xylene, m-xylene, p-xylene, dichloromethane, 1, 2-dichloroethane or tetrahydrofuran.
Preferably, the molar ratio of the benzosultam to the N-aryl arylhydrazinecarbonyl chloride to the basic catalyst is 1:1: 1-1: 1.5: 5.
Preferably, the reaction conditions of the addition reaction are such that the reaction temperature is from trans 0 to 40 ℃ and the reaction time is from 1.0 to 12.0.
The invention also provides a 1,3,4, 5-tetraaryl substituted pyrazole compound prepared by the method.
Compared with the method for preparing 1,3,4, 5-tetraaryl substituted pyrazole in the prior art, the method has the following advantages: (one) the reaction step is short, and SO is removed by dipolar cycloaddition in series2Preparing a tetraaryl substituted pyrazole compound by one-step reaction; the reaction condition is mild, the reaction can be finished in a short time at room temperature without heating, the feeding ratio of the two substrates in the reaction is low, and a large amount of waste is not generated; (III) the substrate has strong stability, the self reaction can not occur in the reaction process, and meanwhile, the reaction area selectivity is high, and other byproducts can not be generated, so the reaction yield is high, the generated product is specific, and the product is convenient to separate; the product structure has methylamino radical connected to the 5-position aromatic ring, and may be used in preparing various kinds of pyrazole derivatives.
Detailed Description
The invention discloses a method for preparing 1,3,4, 5-tetraaryl substituted pyrazole, which can be realized by appropriately improving process parameters by the technical personnel in the field with reference to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The preparation method provided by the invention further comprises a step of purifying the product. Specifically, the method comprises the steps of separating, washing or drying the product.
The invention is further illustrated by the following examples:
example 1
0.25 mmol of benzosultam, 0.25 mmol of N-aryl arylhydrazinecarbonyl chloride and 1 ml of dichloromethane are put into a reaction bottle, stirred for five minutes at 10 ℃, then 0.25 mmol of benzene 1, 2-dichloroethane solution of triethylamine is dripped into the reaction solution within 1 hour, after the dripping is finished, the reaction is carried out for 6.5 hours at 25 ℃, and after the solvent is removed, the pure product 1,3,4, 5-tetraaryl substituted pyrazole is obtained by direct column chromatography separation.
Example 2
1 mmol of benzosultam, 1.5 mmol of N-arylarylarylmethyl hydrazine acyl chloride and 1 ml of o-xylene and m-xylene are put into a reaction bottle, stirred for five minutes at 10 ℃, then 5 mmol of dichloromethane solution of triethylamine is dripped into the reaction solution within 1 hour, after the dripping is finished, the reaction solution reacts for 1 hour at 40 ℃, saturated ammonium chloride solution is added into the reaction solution, phase separation is carried out, the organic phase is washed by saturated sodium chloride solution, anhydrous sodium sulfate is dried, and column chromatography is carried out to obtain the pure product 1,3,4, 5-tetraaryl substituted pyrazole.
Example 3
1 mmol of benzosultam, 1.25 mmol of N-aryl arylmethyl hydrazine acyl chloride and 1 ml of tetrahydrofuran are put into a reaction bottle, stirred for five minutes at 10 ℃, then 3 mmol of methylene chloride solution of diisopropylmethylamine is dripped into the reaction liquid within 1 hour, after the dripping is finished, the reaction liquid reacts for 12 hours at 10 ℃, saturated ammonium chloride solution is added into the reaction liquid, phase separation is carried out, the organic phase is washed by saturated sodium chloride solution, anhydrous sodium sulfate is dried, and column chromatography is carried out to obtain the pure product 1,3,4, 5-tetraaryl substituted pyrazole.
Example 4
1 mmol of benzosultam, 1.5 mmol of N-aryl arylhydrazinecarbonyl chloride and 1 ml of dichloromethane are put into a reaction bottle, stirred for five minutes at 10 ℃,5 mmol of diisopropylethylamine and pyridine dichloromethane solution are dropwise added into the reaction solution within 1 hour, after dropwise addition, the reaction solution reacts for 1 hour at 40 ℃, saturated ammonium chloride solution is added into the reaction solution, phase separation is carried out, the organic phase is washed by saturated sodium chloride solution, anhydrous sodium sulfate is dried, and column chromatography is carried out to obtain the pure product 1,3,4, 5-tetraaryl substituted pyrazole. The 1,3,4, 5-tetraaryl substituted pyrazoles having in part the structure of formula (III) and their respective corresponding yields are shown in Table 1:
TABLE 1 Structure of part 1,3,4, 5-tetraaryl-substituted pyrazole compounds and yield thereof
| Serial number | Ar of 1 | R of 21 | R of 22 | Yield (%) |
| 1 | 4-pyridyl group | Hydrogen | Hydrogen | 74 |
| 2 | 2-furyl radical | Hydrogen | Hydrogen | 72 |
| 3 | 4-fluorophenyl group | Hydrogen | Hydrogen | 82 |
| 4 | 4-chlorophenyl group | Hydrogen | Hydrogen | 85 |
| 5 | 4-bromophenyl radical | Hydrogen | Hydrogen | 90 |
| 6 | 4-methylphenyl radical | Hydrogen | Hydrogen | 82 |
| 7 | 4-methoxyphenyl radical | Hydrogen | Hydrogen | 81 |
| 8 | 2-methylphenyl radical | Hydrogen | Hydrogen | 76 |
| 9 | 3-methylphenyl radical | Hydrogen | Hydrogen | 79 |
| 10 | Phenyl radical | Hydrogen | 4-chloro group | 71 |
| 11 | Phenyl radical | 4-methyl group | 4-chloro group | 85 |
| 12 | Phenyl radical | Hydrogen | 4-Nitro radical | 74 |
| 13 | Phenyl radical | 4-methyl group | 4-Nitro radical | 88 |
| 14 | Phenyl radical | 2-fluoro | Hydrogen | 80 |
| 15 | Phenyl radical | 2-fluoro | 4-chloro group | 86 |
| 16 | Phenyl radical | 2-methyl radical | Hydrogen | 83 |
| 17 | Phenyl radical | 2-methyl radical | 4-chloro group | 87 |
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (3)
1. A method for preparing 1,3,4, 5-tetraaryl substituted pyrazole is characterized in that benzosultam with a structure shown in a formula (I) and N-aryl arylmethyl hydrazine acyl chloride with a structure shown in a formula (II) are subjected to addition reaction under the action of an alkaline catalyst to generate 1,3,4, 5-tetraaryl substituted pyrazole with a structure shown in a formula (III); the reaction temperature is 0-40 ℃, and the reaction time is 1.0-12.0 h;
wherein Ar is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, phenyl or C1-C4 alkyl substituted phenyl, fluorine substituted phenyl, chlorine substituted phenyl, bromine substituted phenyl or methoxy substituted phenyl; r1Is hydrogen, C1-C4 alkyl, fluoro, chloro, bromo, methoxy, nitro or cyano; r2Is hydrogen, C1-C4 alkyl, fluoro, chloro, bromo, methoxy, nitro or cyano; the basic catalyst is selected from one or more of trimethylamine, triethylamine, diisopropylmethylamine, diisopropylethylamine, triethylenediamine or diazabicyclo.
2. The process according to claim 1, wherein the addition reaction is carried out in an aprotic organic solvent selected from one or more of benzene, toluene, o-xylene, m-xylene, p-xylene, dichloromethane, 1, 2-dichloroethane or tetrahydrofuran.
3. The method of claim 1, wherein the molar ratio of the benzosultam, the N-arylarylarylarylhydrazinecarbonyl chloride, and the basic catalyst is from 1:1:1 to 1:1.5: 5.
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| A New Synthesis of Oxadiazole, Thiazolidinone, N-Phthalimidoamino Carbonyl and Arylidene Derivatives with Potential Antimicrobial Activity;H. M. Hassaneen et al.;《Arch. Pharm. Pharm. Med. Chem.》;20021231;第335卷(第6期);第251-261页 * |
| Synthesis and reactions of 3-alkylsulfanyl-1,3-dihydro-2,1-benzisothiazole 2,2-dioxides;Helena Modrzejewska et al.;《Tetrahedron》;20050726;第61卷(第37期);第8848-8854页 * |
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