CN114478388A - Multifunctional pyrazolone compound and preparation method thereof - Google Patents

Multifunctional pyrazolone compound and preparation method thereof Download PDF

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CN114478388A
CN114478388A CN202210058957.6A CN202210058957A CN114478388A CN 114478388 A CN114478388 A CN 114478388A CN 202210058957 A CN202210058957 A CN 202210058957A CN 114478388 A CN114478388 A CN 114478388A
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pyrazolone
aryl
ewg
compound
ligand
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赵洪武
张恒
蔡璐羽
王阔
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Beijing University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/824—Palladium

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Abstract

A polyfunctionalized pyrazolone compound and a preparation method thereof belong to the technical field of compound preparation. The method specifically comprises the steps of taking pyrazolone exocyclic olefin, aryl allyl carbonate and active methylene compounds as reactants, adding a transition metal catalyst and a phosphorus-containing ligand, and reacting in an organic solvent with the polarity of 2-6 at normal temperature to obtain a product, namely a polyfunctionalized pyrazolone compound; the preparation method has the advantages of mild reaction conditions, simple operation, high chemical yield, wide applicable substrate range, good chemical selectivity and regioselectivity of the reaction, and realization of efficient and simple construction of the high-functionalization drug-like molecular skeleton pyrazolone ring outer chain derivative. The method is a brand-new method for efficiently synthesizing the multifunctional pyrazolone compound with potential medicinal value.

Description

Multifunctional pyrazolone compound and preparation method thereof
Technical Field
The invention relates to a polyfunctionalized pyrazolone compound and a preparation method thereof, belonging to the technical field of compound preparation.
Background
The pyrazolone five-membered heterocyclic compound contains a unique cyclic hydrazide structural unit, is an advantageous drug-like molecular skeleton structure, has wide physiological activity and important medicinal development value, and the multi-functionalized spiro, fused ring and chain derivatives thereof are mostly used for the research and development of various lead structures and candidate drugs aiming at different biological targets and have the biological activities of resisting tumors, bacteria, viruses, inflammation, analgesia and the like. At present, the method adopts cyclization reaction and cycloaddition reaction based on different reaction mechanisms, and can be used for efficiently and simply constructing spiro and fused ring derivatives of pyrazolone with complex and various chemical structures and spatial structures. In contrast, no research is reported at present on constructing a multifunctional pyrazolone chain derivative with a complex structure by using pyrazolone exocyclic olefin as a synthesis block and through a cross decarboxylation coupling reaction with allyl carbonate under the synergistic catalytic action of a palladium catalyst and a phosphine ligand. More particularly, the method utilizes the chemical regulation and control effect of an additionally added nucleophilic reagent to construct a three-component decarboxylation cross-coupling reaction based on participation of pyrazolone exocyclic olefin and allyl carbonate, and is more beneficial to regulating and controlling the complexity and diversity of a chemical structure and a spatial structure of a pyrazolone chain derivative; obviously, the research work in this aspect is more challenging and original innovative, and no relevant literature reports are reported at present. Therefore, by utilizing a catalytic system consisting of metal palladium and chiral phosphine ligands, pyrazolone exocyclic alkene and allyl carbonate are selected as synthesis building blocks, and a novel efficient three-component decarboxylation cross-coupling reaction is designed and constructed under the efficient regulation and control action of an additional active methylene nucleophilic reagent, so that the research on an organic synthesis methodology of decarboxylation cross-coupling reaction based on allyl carbonate can be greatly enriched and expanded, and the research and development of candidate pyrazolone drugs with different structural types can be effectively promoted and promoted.
The allyl carbonate and the analogues thereof can generate coupling reactions with different reaction paths and mechanisms through efficient decarboxylation under the catalysis of a palladium catalyst and a phosphine ligand, and the coupling reactions can be used for efficient and simple construction of organic synthetic building blocks with various drug-like molecular frameworks and advantages. In general, a catalytic system constructed with a palladium catalyst and a phosphine ligand can efficiently decarboxylate allyl carbonate and analogs thereof to simultaneously generate synthons with electrophilic and nucleophilic properties in situ. These synthons, generated in situ, can be recombined by means of direct intramolecular coupling to produce novel chemical entities with unique chemical structures. Moreover, they can be captured simultaneously by unsaturated reaction substrates with different structural types, and intermolecular cross-coupling reaction can occur. At present, the study examples of cross-coupling reactions based on allyl carbonate and various unsaturated reaction substrates are relatively rare; meanwhile, it should be noted that, under the control and participation of an additional nucleophilic reagent, no literature report exists at all for the research example of constructing the intermolecular cross-coupling reaction of multiple components based on allyl carbonate and various conjugated heterocyclic compounds. The invention adopts aryl allyl carbonate, pyrazolone exocyclic olefin and nucleophilic active methylene compound as reaction substrates for the first time, and realizes the efficient and simple construction of the highly functionalized drug-like molecular skeleton pyrazolone exocyclic chain derivative by constructing a novel efficient intermolecular decarboxylation cross-coupling reaction of three components under the catalytic action of a palladium catalyst and a phosphine ligand. The reaction has the characteristics of good chemical selectivity and regioselectivity, mild reaction conditions, simple operation, high chemical yield and the like.
Disclosure of Invention
The invention aims to provide a preparation method of a multifunctional pyrazolone compound.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a preparation method of a multifunctional pyrazolone compound comprises the following steps: taking pyrazolone exocyclic olefin, aryl allyl carbonate and nucleophilic active methylene compounds as reactants, adding a metal catalyst and a phosphorus-containing ligand, and reacting in an organic solvent with the polarity of 2-6 at normal temperature to obtain a product of a polyfunctional pyrazolone compound; preferably, the molar ratio of the pyrazolone exocyclic olefin to the arylallyl carbonate to the nucleophilic active methylene compound is 1:1.5: 2;
the structural formula of the multifunctional pyrazolone compound is as follows:
Figure BDA0003474566460000021
wherein R is1Aryl, aromatic heterocyclic group, chain alkyl and cyclic alkyl; r2Aryl, chain alkyl and cyclic alkyl; r3Is a hydrogen atom,An alkyl, aryl or heterocyclic group; r4Is a hydrogen atom, an alkyl group, an aryl group or a heterocyclic group; EWG1And EWG2Are various Electron Withdrawing Groups (EWG)1＝EWG2Or EWG1≠EWG2)。
The aryl group is naphthyl, phenyl or phenyl having 1 to 3 substituents. For example: mono-substituted phenyl, di-substituted phenyl, tri-substituted phenyl.
The substituents on the above phenyl groups are selected from: methyl, methoxy, nitro, fluoro, chloro, bromo or trifluoromethyl.
The aromatic heterocyclic group is an unsubstituted five-or six-membered heterocyclic group containing 1 to 4 heteroatoms selected from N, S, O, for example: pyridyl, furyl, piperidyl, pyrimidyl, thiazolyl, thienyl.
The chain alkyl group is selected from: methyl and ethyl.
The cyclic alkyl group is selected from: cyclohexyl and cyclopentyl.
In the technical scheme, the organic solvent is 1, 4-ethylene oxide, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, ethyl acetate, acetonitrile, chloroform, methanol, ethanol, pyridine, N-dimethylformamide, hexafluoroisopropanol, cyclohexane, acetone and the like.
In the technical scheme, the metal catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium or tris (dibenzylideneacetone) dipalladium-chloroform adduct, fac-tris (2-phenylpyridine) iridium, (triphenylphosphine) gold chloride, rhodium octoate polymer, gold chloride and ruthenium acetate.
In the above technical scheme, the phosphorus-containing ligand is triphenylphosphine (PPh)3) Tricyclohexylphosphine (PCy)3) 1, 3-bis (diphenylphosphino) propane (dpp), 1, 4-bis (diphenylphosphino) butane (dpppb), 1' -bis (diphenylphosphino) ferrocene (Dppf); chiral phosphate ligands or chiral binaphthyl-type bisphosphate ligands (BINAP) based on Binaphthol (BINOL) as a backbone, for example: s- (-) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, R- (+) -1,1' -binaphthyl-2, 2' -bisdiphenylphosphine, (S, S, S) - (3, 5-dioxa-4-phosphocyclohepta [2,1-a:3,4-a ']Dinaphthalen-4-yl) bis (1-phenylethyl) amine, (R, S, S) - (3, 5-dioxa-4-phosphocyclohepta [2,1-a:3,4-a']Dinaphthalen-4-yl) bis (1-phenylethyl) amine, and the like; trost ligands, for example: (1R,2R) - (+) -1, 2-diaminocyclohexyl-N, N '-bis (2' -diphenylphosphinylbenzoyl), (1S,2S) - (-) -N, N '-bis (2-diphenylphosphino-1-naphthoyl) -1, 2-cyclohexanediamine, (-) -N, N' - (1R,2R) -1, 2-diaminocyclohexanediylbis (2-pyridinecarboxamide), and the like; pybox ligands, for example: 2, 6-bis [ (4S) -4-phenyl-2-oxazolinyl]Pyridine, (S, S) - (-) -2,2' -isopropylidenebis (4-tert-butyl-2-oxazoline), (S, S) -2, 6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine, and the like; phox ligands, for example: (S) - (+) -2- [2- (diphenylphosphino) phenyl]-4-phenyl-2-oxazoline, (S) - (-) -2- [ 2-diphenylphosphine]Phenyl radical]-4-isopropyl-2-oxazoline and the like.
In the technical scheme, the reaction time is 1-48 hours.
In the technical scheme, the dosage of the metal catalyst is 2.5-10% of the molar weight of the aryl allyl carbonate compound.
In the technical scheme, the dosage of the ligand is 10-20% of the molar weight of the aryl allyl carbonate compound.
In the technical scheme, the reaction process comprises the steps of adding pyrazolone exocyclic olefin, aryl allyl carbonate, an active methylene compound, a transition metal catalyst and a ligand into a reaction bottle, adding an organic solvent for reaction at room temperature, detecting the reaction process by TLC (thin layer chromatography), and after the reaction is finished, carrying out simple column chromatography on the crude product (eluent is selected from ethyl acetate/petroleum ether mixed solution with the volume ratio of 1: 3-1: 5) to obtain the target product.
The preparation method of the phosphorus-containing ligand belongs to the prior art, and one of the structural formulas is shown as follows:
Figure BDA0003474566460000041
the preparation method of pyrazolone exocyclic olefin belongs to the prior art, and the structural formula is as follows:
Figure BDA0003474566460000042
R1aryl, aromatic heterocyclic group, chain alkyl and cyclic alkyl; r2Aryl, chain alkyl, cyclic alkyl.
The preparation method of the aryl allyl carbonate compound belongs to the prior art, and the structural formula is as follows:
Figure BDA0003474566460000043
Ar1is phenyl or an aromatic heterocyclic group; r3Is a hydrogen atom, an alkyl group, an aryl group or a heterocyclic group; r4Is hydrogen atom, alkyl, aryl or heterocyclic radical.
In the invention, the preparation of the active methylene compound belongs to the prior art, and the structural formula is as follows:
Figure BDA0003474566460000044
EWG1and EWG2Are various Electron Withdrawing Groups (EWG)1＝EWG2Or EWG1≠EWG2)。
The reaction process disclosed by the invention is as follows:
Figure BDA0003474566460000045
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the invention provides a method for preparing a multifunctional pyrazolone compound by taking pyrazolone exocyclic alkene, aryl allyl carbonate and an active methylene compound as reactants and adding a transition metal catalyst and a phosphorus-containing ligand for the first time; the method has the advantages of simple operation, mild reaction conditions and short reaction time.
2. The preparation method disclosed by the invention designs and constructs a novel high-efficiency three-component decarboxylation cross-coupling reaction by selecting pyrazolone exocyclic alkene and aryl allyl carbonate as synthetic building blocks under the high-efficiency regulation and control action of an externally added active methylene nucleophilic reagent, greatly enriches and develops the research of an organic synthesis methodology of decarboxylation cross-coupling reaction based on allyl carbonate,
2. the preparation method disclosed by the invention has the advantages of low consumption of the transition metal catalyst and the ligand and simple post-treatment.
3. The method disclosed by the invention has wide applicable substrate range.
4. The raw materials involved in the invention are convenient and easy to obtain, and the byproduct is carbon dioxide, thus having no pollution to the environment.
5. The multifunctional pyrazolone has a unique structure, rich and various functional groups, remarkable drug-like structure characteristics and potential biological activity and medicinal value.
Detailed Description
The present invention will be further described with reference to the following examples, but the present invention is not limited to the following examples.
Example 1:
Figure BDA0003474566460000051
1a (26.2mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3a (32.0mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) are weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 2 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4aaa (45.7mg), with the yield of 99%.
Characterization and analysis of the target: white solid, melting point 113.5-113.7 ℃;1H NMR(400MHz,CDCl3):δ7.63-7.61(m,2H),7.45-7.41(m,2H),7.36-7.34(m,2H),7.28.-7.24(m,3H),7.20-7.17(m,1H),5.46-5.37(m,1H),5.12(d,J＝12Hz,1H),5.06(dd,J＝10.8Hz,0.8Hz,1H),4.94(dd,J＝17.2Hz,0.8Hz,1H),4.17-4.11(m,2H),4.06-4.04(m,2H),3.91(q,J＝7.2Hz,2H),2.33(s,3H),1.22(t,J＝7.2Hz,3H),0.93(t,J＝8Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ168.6,168.5,165.0,152.8,140.5,134.91,129.9,129.1,128.6,128.4,126.9,126.5,124.1,119.4,110.9,61.3,61.1,53.7,50.0,42.1,14.1,13.7,10.9ppm；HRMS(ESI)m/z：C27H30N2O5[M+H]+theoretical calculation 463.2233, found 463.2233.
Example 2:
Figure BDA0003474566460000061
1a (26.2mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3b (26.0mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) are weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 2 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4aab (36.7mg), and the yield is 85%.
Characterization and analysis of the target: white solid, dr 2:1 melting point 116.3-116.6 deg.C;1H NMR(400MHz,CDCl3):δ7.62-7.55(m,2H),7.46-7.42(m,2H),7.37-6.33(m,2H),7.28-7.17(m,4H),5.45-5.34(m,2H),5.09-4.88(m,2H),4.47-4.42(m,1H),4.14-3.90(m,4H),2.33-2.28(m,5H),2.02(s,1H),1.23-0.98(m,3H)ppm；13C NMR(100MHz,CDCl3):δ203.6,202.6,168.3,168.1,167.8,165.3,165.2,152.9,152.8,141.3,140.7,134.8,132.3,131.0,130.0,129.8,129.1,129.0,128.9,128.7,128.47,128.41,128.37,126.9,126.8,126.6,126.5,124.3,124.2,119.54,119.46,111.1,110.8,65.6,61.3,61.22,61.16,60.1,50.0,49.9,41.7,41.1,32.1,30.58,30.55,29.7,19.2,14.0,13.8,13.8,11.0,10.9ppm；HRMS(ESI)m/z：C26H28N2O4[M+H]+theoretical calculation 433.2122, found 433.2115.
Example 3:
Figure BDA0003474566460000071
1a (26.2mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3c (13.2mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) were weighed and dissolved in 1.5mL of tetrahydrofuran, stirred at room temperature for 4 hours (detection reaction by TLC), after completion of the reaction, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4aac (26.9mg), with a yield of 73%.
Characterization and analysis of the target: white solid, melting point 148.4-148.7 ℃;1H NMR(400MHz,CDCl3):δ7.63-7.61(m,2H),7.52-7.48(m,2H),7.41-7.36(m,6H),5.78(d,J＝11.2Hz,1H),5.56-5.46(m,1H),5.16(d,J＝10.4Hz,1H),4.20(d,J＝16.8Hz,1H),4.26(d,J＝11.2Hz,1H),4.15(d,J＝5.6Hz,1H),2.27(s,3H)ppm；13C NMR(100MHz,CDCl3):δ165.8,165.7,164.82,164.75,152.7,152.5,139.0,138.9,134.5,129.7,129.3,129.0,128.8,128.2,128.1,127.9,127.8,127.2,127.1,124.8,124.5,119.7,116.6,116.3,108.7,108.6,62.6,62.4,49.8,44.0,42.6,40.4,39.8,13.9,13.6,10.9,10.8ppm；HRMS(ESI)m/z：C23H20N4O[M+H]+theoretical calculation 369.17099, found 369.17172.
Example 4:
Figure BDA0003474566460000072
1a (26.2mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3d (22.6mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) are weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 4 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4aad (24.0mg), and the yield is 58%.
Characterization and analysis of the target: semi-solid, dr 1: 1;1H NMR(400MHz,CDCl3):δ7.64-7.54(m,2H),7.49-7.45(m,2H),7.40-7.25(m,6H),5.57-5.38(m,1H),5.30-5.21(m,1H),5.16-4.93(m,2H),4.39-4.29(m,1H),4.24.-3.97(m,4H),2.32-2.18(s,3H),1.76-1.43(m,2H),1.27-0.98(m,3H)ppm；13C NMR(100MHz,CDCl3):δ165.8,165.7,164.82,164.75,152.7,152.5,139.0,138.9,134.5,129.7,129.3,129.0,128.8,128.2,128.1,127.9,127.8,127.2,127.1,124.8,124.5,119.7,116.6,116.3,108.7,108.6,62.6,62.4,49.8,44.0,42.6,40.4,39.8,13.9,13.6,10.9,10.8ppm；HRMS(ESI)m/z：C25H25N3O3[M+H]+theoretical calculation 416.1969, found 416.1965.
Example 5:
Figure BDA0003474566460000081
1a (26.2mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3e (44.8mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) were weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 2 hours (detection reaction by TLC), after completion of the reaction, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4aae (39.5mg), with a yield of 75%.
Characterization and analysis of the target: the semi-solid is a solid, and the solid is,1H NMR(400MHz,CDCl3):δ8.12(d,J＝7.2Hz,2H),7.93(d,J＝7.6Hz,2H),7.65(d,J＝7.6Hz,2H),7.49-7.47(m,2H),7.41-7.31(m,6H),7.27-7.24(m,3H),7.11(t,J＝7.2Hz,2H),7.03-6.99(m,1H),5.17-5.07(m,1H),4.97(d,J＝10.8Hz,1H),4.83(d,J＝10.4Hz,1H),4.77(d,J＝17.2Hz,1H),4.02-3.91(m,2H),2.35(s,3H)ppm；13C NMR(100MHz,CDCl3):δ195.2,195.0,165.7,152.8,140.6,137.0,136.9,134.7,133.2,133.1,129.6,129.1,129.0,128.9,128.6,128.4,128.2,126.7,126.6,124.4,119.4,111.2,56.6,50.0,43.4,10.9ppm；HRMS(ESI)m/z：C35H30N2O3[M+H]+theoretical calculation 527.2329, found 527.2335.
Example 6:
Figure BDA0003474566460000091
1a (26.2mg, 0.1mmol), 2b (38.1mg, 0.15mmol), 3a (32.0mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) were weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 12 hours (detection reaction by TLC), after completion of the reaction, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4aba (29.5mg), with a yield of 62%.
Characterization and analysis of the target: white solid, melting point 118.0-118.4 ℃;1H NMR(400MHz,CDCl3):δ7.61(d,J＝7.2Hz,2H),7.47-7.39(m,4H),7.30-7.17(m,9H),6.20(d,J＝15.6Hz,1H),5.08(dd,J＝10.8Hz,0.8Hz,1H),4.94(dd,J＝17.2Hz,0.8Hz,1H),4.44(d,J＝12Hz,1H),4.26-4.14(m,2H),4.05-3.90(m,4H),2.40(s,3H),1.08(t,J＝6.8Hz,3H),0.94(t,J＝7.2Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ168.7,168.6,164.6,156.4,151.7,140.8,139.4,134.7,129.4,129.1,128.5,128.4,126.9,126.8,125.0,119.9,115.5,113.7,108.2,61.3,61.1,53.6,52.3,42.1,20.1,14.0,13.7,10.9ppm；HRMS(ESI)m/z：C33H34N2O5[M+H]+theoretical calculation 477.2384, found 477.23868.
Example 7:
Figure BDA0003474566460000092
1a (26.2mg, 0.1mmol), 2c (28.8mg, 0.15mmol), 3a (32.0mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) were weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 12 hours (detection reaction by TLC), after completion of the reaction, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4aca (30.0mg), with a yield of 63%.
Characterization and analysis of the target: the semi-solid is a solid, which is,1H NMR(400MHz,CDCl3):δ7.62-7.61(m,2H),7.44-7.40(m,2H),7.32-7.18(m,6H),5.17(d,J＝12Hz,1H),4.74(s,1H),4.44-4.41(m,2H),4.04(s,2H),3.90(q,J＝7.2Hz,2H),2.34(s,3H),1.44(s,3H),1.22(t,J＝7.2Hz,3H),0.93(t,J＝7.2Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ168.58,168.55,165.1,153.2,140.5,135.9,135.0,134.5,129.1,128.5,128.4,128.1,126.9,126.5,126.4,124.0,120.9,111.9,61.2,61.1,53.6,49.9,42.1,13.9,13.7,11.2ppm；HRMS(ESI)m/z：C28H32N2O5[M+H]+theoretical calculation 539.2541, found 539.2541.
Example 8:
Figure BDA0003474566460000101
1a (26.2mg, 0.1mmol), 2d (33.0mg, 0.15mmol), 3a (32.0mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) are weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 6 hours (detection reaction by TLC), after the reaction is completed, the crude product is subjected to column chromatography (eluent is ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4ada (28.7mg), and the yield is 57%.
Characterization and analysis of the target: the semi-solid is a solid, and the solid is,1H NMR(400MHz,CDCl3):δ1H NMR(400MHz,CDCl3):δ7.61(d,J＝7.2Hz,2H),7.45-7.41(m,2H),7.37-7.35(m,2H),7.26(t,J＝7.2Hz,3H),7.20-7.16(m,1H),5.34-5.27(m,1H),5.21(d,J＝12Hz,1H),5.04-4.97(m,1H),4.42(d,J＝11.6Hz,1H),4.18-4.08(m,2H),3.99-3.97(m,2H),3.91(q,J＝7.2Hz,2H),2.33(s,3H),1.82(q,J＝7.2Hz,2H),1.24-1.19(m,5H),0.93(t,J＝7.2Hz,3H),0.77(t,J＝7.2Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ168.64,168.59,165.1,153.0,140.6,136.6,135.0,129.0,128.5,128.3,126.9,126.3,124.0,121.2,111.1,61.2,61.1,53.5,49.8,42.1,34.2,22.0,14.1,13.7,13.5,11.1ppm；HRMS(ESI)m/z：C30H36N2O5[M+H]+theoretical calculation 505.2697, found 505.2696.
Example 9:
Figure BDA0003474566460000111
1b (34.0mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3a (32.0mg, 0.2mmol) palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) were weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 2 hours (detection reaction by TLC), after completion of the reaction, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4baa (53.0mg), with a yield of 98%.
Characterization and analysis of the target: white solid, melting point 93.2-93.4 ℃;1H NMR(400MHz,CDCl3):δ7.53-7.50(m,2H),7.46-7.33(m,6H),7.30-7.26(m,1H),5.46.-5.36(m,1H),5.09-5.05(m,2H),4.94(d,J＝17.2Hz,1H),4.38(d,J＝11.6Hz,1H),4.16-4.10(m,2H),4.07-4.05(m,2H),3.95(q,J＝6.8Hz,2H),2.33(s,3H),1.22(t,J＝7.2Hz,3H),0.99(t,J＝7.2Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ168.4,168.3,164.9,152.7,139.6,134.8,131.4,130.3,129.9,129.1,126.7,124.2,120.9,119.5,110.2,61.4,61.3,53.5,49.9,41.5,14.1,13.8,10.9ppm；HRMS(ESI)m/z：C27H29BrN2O5[M+H]+theoretical calculation 541.1333, found 541.1340.
Example 10:
Figure BDA0003474566460000112
1c (30.6mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3a (32.0mg, 0.2mmol) palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) were weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 2 hours (detection reaction by TLC), after completion of the reaction, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4caa (43.2mg), with an yield of 85%.
Characterization and analysis of the target: white solid, melting point 101.6-101.9 ℃;1H NMR(400MHz,CDCl3):δ8.13(d,J＝8.8Hz 2H),7.82(d,J＝8.8Hz 2H),7.46-7.42(m,2H),7.33-7.27(m,3H),5.46-5.36(m,1H),5.12-5.07(m,2H),4.96-4.91(m,1H),4.54(d,J＝12Hz,1H),4.18-4.12(m,2H),4.10-4.07(m,2H),4.01-3.92(m,2H),2.37(s,3H),1.23(t,J＝7.2Hz,3H),1.01(t,J＝7.2Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ168.1,167.9,164.2,152.8,148.0,147.0,134.5,129.7,129.4,129.2,126.9,124.4,123.7,119.6,108.9,61.6,61.5,53.1,49.9,41.7,14.1,13.8,10.9ppm；HRMS(ESI)m/z：C27H29N3O7[M+H]+theoretical calculation 508.2078, found 508.2086.
Example 11:
Figure BDA0003474566460000121
1d (31.2mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3a (32.0mg, 0.2mmol) palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) were weighed and dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 2 hours (detection reaction by TLC), and after completion of the reaction, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4daa (49.8mg), with a yield of 97%.
Characterization and analysis of the target: the semi-solid is a solid, and the solid is,1H NMR(400MHz,CDCl3):δ7.95(s,1H),7.88-7.75(m,4H),7.45-7.35(m,6H),7.29-7.25(m,1H),5.46-5.36(m,1H),5.26(d,J＝12Hz,1H),5.05(d,J＝10.4Hz,1H),4.96.-4.92(m,1H),4.62(d,J＝11.6Hz,1H),4.21-4.13(m,2H),4.06-4.04(m,2H),3.90-3.81(m,2H),2.37(s,3H),1.24(t,J＝7.2Hz,3H),0.84(t,J＝7.2Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ168.6,168.5,165.1,152.9,138.1,135.0,133.3,132.5,129.9,129.1,128.2,128.0,127.5,127.0,126.8,126.5,125.8,125.5,124.2,119.5,110.8,61.3,61.1,53.6,50.0,42.2,14.1,13.6,11.0ppm；HRMS(ESI)m/z：C31H32N2O5[M+H]+theoretical calculation 513.2384, found 513.2390.
Example 12:
Figure BDA0003474566460000131
1e (29.6mg, 0.1mmol), 2a (26.7mg, 0.15mmol), 3a (32.0mg, 0.2mmol), palladium catalyst (5.2mg, 0.005mmol) and Ligand (8.0mg, 0.02mmol) were dissolved in 1.5mL tetrahydrofuran, stirred at room temperature for 2 hours (reaction detected by TLC), and after completion of the reaction, the crude product was subjected to column chromatography (eluent ethyl acetate/petroleum ether: 1/4-1/3) to obtain the target product 4eaa (44.2mg), with an yield of 89%.
Characterization and analysis of the target: the semi-solid is a solid, and the solid is,1H NMR(400MHz,CDCl3):δ8.13(d,J＝8.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.46-7.42(m,2H),7.33-7.27(m,3H),5.46-5.36(m,1H),5.12-5.07(m,2H),4.96.-4.91(m,1H),4.54(d,J＝12Hz,1H),4.18-4.12(m,2H),4.10-4.07(m,2H),4.01-3.92(m,2H),2.37(s,3H),1.23(t,J＝7.2Hz,3H),1.01(t,J＝7.2Hz,3H)ppm；13C NMR(100MHz,CDCl3):δ168.1,168.0,164.6,152.8,148.0,146.9,134.5,129.7,129.4,129.2,126.9,124.4,123.7,119.6,108.9,61.6,61.5,53.1,49.9,41.7,14.1,13.8,10.9,ppm；HRMS(ESI)m/z：C27H29ClN2O5[M+H]+theoretical calculation 497.1838, found 497.1841.
The results show that the preparation method disclosed by the invention has the advantages of mild reaction conditions, simple operation, high reaction speed, simple post-treatment and higher yield of most of synthesized target substances.

Claims (10)

1. A multifunctional pyrazolone compound is characterized in that the structural formula is as follows:
Figure FDA0003474566450000011
wherein R is1Is aryl, aromatic heterocyclic radical, chain alkyl, cyclic alkyl; r2Aryl, chain alkyl and cyclic alkyl; r3Is a hydrogen atom, an alkyl group, an aryl group or a heterocyclic group; r4Is a hydrogen atom, an alkyl group, an aryl group or a heterocyclic group; EWG1And EWG2Being various electron withdrawing groups, EWG1＝EWG2Or EWG1≠EWG2。
2. A polyfunctional pyrazolone compound according to claim 1,
the aryl group is naphthyl, phenyl or phenyl with 1-3 substituents;
the substituents on the above phenyl groups are selected from: methyl, methoxy, nitro, fluoro, chloro, bromo, or trifluoromethyl;
the aromatic heterocyclic group refers to an unsubstituted five-membered ring or six-membered heterocyclic group containing 1 to 4 heteroatoms, wherein the heteroatoms are selected from N, S, O;
the chain alkyl group is selected from: methyl, ethyl;
the cyclic alkyl group is selected from: cyclohexyl and cyclopentyl.
3. The method for preparing the multifunctional pyrazolone compound according to claim 1, wherein pyrazolone exocyclic olefin, aryl allyl carbonate and nucleophilic active methylene compound are used as reactants, a metal catalyst and a phosphorus-containing ligand are added, and the reaction is carried out in an organic solvent with polarity of 2-6 at normal temperature to obtain the multifunctional pyrazolone compound.
4. The method according to claim 3, wherein the molar ratio of pyrazolone exocyclic olefin, aryl allyl carbonate and active methylene compound is 1:1.5: 2.
5. The process according to claim 3, wherein the organic solvent is 1, 4-ethylene oxide, methylene chloride, tetrahydrofuran, 1, 2-dichloroethane, toluene, ethyl acetate, acetonitrile, chloroform, methanol, ethanol, pyridine, N-dimethylformamide, hexafluoroisopropanol, cyclohexane, acetone;
the metal catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, tris (dibenzylideneacetone) dipalladium or tris (dibenzylideneacetone) dipalladium-chloroform adduct, fac-tris (2-phenylpyridine) iridium, (triphenylphosphine) gold chloride, rhodium octoate polymer, gold chloride and ruthenium acetate;
the ligand is selected from the following: benzene, toluene and xylenePhenylphosphine (PPh)3) Tricyclohexylphosphine (PCy)3) 1, 3-bis (diphenylphosphino) propane (dpp), 1, 4-bis (diphenylphosphino) butane (dpppb), 1' -bis (diphenylphosphino) ferrocene (Dppf), a chiral phosphate ligand based on Binaphthol (BINOL) as a skeleton or a chiral binaphthyl-type bisphosphine ligand (BINAP), a Trost ligand, a Pybox ligand, a Phox ligand.
6. The method of claim 3, wherein the metal catalyst is used in an amount of 2.5 to 10% by mole based on the aryl allyl carbonate compound; the dosage of the ligand is 10 to 20 percent of the molar weight of the aryl allyl carbonate compound; the reaction time is 1-48 hours.
7. A process according to claim 3, wherein the ligand is prepared according to methods known in the art, one of which is represented by the formula:
Figure FDA0003474566450000021
8. the method according to claim 3, wherein the pyrazolone exocyclic olefin has the formula:
Figure FDA0003474566450000022
R1aryl, aromatic heterocyclic group, chain alkyl and cyclic alkyl; r2Aryl, chain alkyl, cyclic alkyl.
9. The method of claim 3, wherein the aryl allyl carbonate compound is prepared by a process known in the art and has the formula:
Figure FDA0003474566450000023
Ar1is phenyl or an aromatic heterocyclic group; r3Is a hydrogen atom, an alkyl group, an aryl group or a heterocyclic group; r4Is hydrogen atom, alkyl, aryl or heterocyclic radical.
10. The process of claim 3, wherein the active methylene compound is prepared according to the prior art and has the following formula:
Figure FDA0003474566450000024
EWG1and EWG2Being various electron withdrawing groups, EWG1＝EWG2Or EWG1≠EWG2,。
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* Cited by examiner, † Cited by third party
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CN114907266A (en) * 2022-05-17 2022-08-16 扬州大学 Preparation method of dihydropyrazole compound
CN114907266B (en) * 2022-05-17 2024-02-20 扬州大学 Preparation method of dihydropyrazole compound

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