CN114591344B - Synthesis method of chiral spiro tetrahydrofuran-pyrazolone compound - Google Patents

Synthesis method of chiral spiro tetrahydrofuran-pyrazolone compound Download PDF

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CN114591344B
CN114591344B CN202210252565.3A CN202210252565A CN114591344B CN 114591344 B CN114591344 B CN 114591344B CN 202210252565 A CN202210252565 A CN 202210252565A CN 114591344 B CN114591344 B CN 114591344B
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pyrazolone
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tetrahydrofuran
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spiro
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CN114591344A (en
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王兴旺
吕昊朋
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Suzhou University
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10Spiro-condensed systems
    • C07D491/107Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07Optical isomers

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Abstract

The invention discloses a synthesis method of chiral spiro-tetrahydrofuran pyrazolone compound, which specifically comprises the steps of using vinyl cyclic carbonate andα,βunsaturated pyrazolones as reactants, in Pd (PPh 3 ) 4 The chiral phosphorus ligand is a chiral ligand, and the chiral spiro-tetrahydrofuran pyrazolone compound is obtained by reacting the chiral phosphorus ligand in an organic solvent. The method disclosed by the invention has the advantages of simple and easily obtained raw materials, mild reaction conditions, simple and convenient post-treatment, wide applicable substrate range, high yield and high enantioselectivity; the product thus synthesized can be used for synthesizing intermediates of medicaments.

Description

Synthesis method of chiral spiro tetrahydrofuran-pyrazolone compound
Technical Field
The invention relates to synthesis of spiro pyrazolone compounds, in particular to a catalytic synthesis method of chiral spiro pyrazolone tetrahydrofuran compounds.
Background
Pyrazolone compounds are valued by chemists based on self-diazo lactam structures, and have great application value in the field of biological medicine. And spiro pyrazolone compounds have great application value. The prior common knowledge shows that the active molecules containing the spiro pyrazolone skeleton have the functions of resisting bacteria, diminishing inflammation, relieving pain, antagonizing, resisting tumor and the like. Therefore, there is great interest in developing synthetic methods for highly efficient synthesis of spiro pyrazolone structural compounds.
In the prior art, the Rios group reports 4-site unsubstituted pyrazolone and pyrazolone with diphenyl proline derivatives as catalystsα,βTandem michael addition-aldol condensation of unsaturated aldehydes, capable of yielding spiro pyrazolone compounds (Alba, a. -n.r.; zea, a.; valero, g.; calset, t.; font-bardi, m.; mazzanti, a.; monoyano, a.; rios, r. Hi.) with a maximum of 99% enantioselectivity and a diastereoselectivity of greater than 25:1ghly Stereoselective Synthesis of Spiropyrazolones [J]. Eur. J. Org. Chem. 2011, 20111318-1325); biju problem reports [3+3 ] of azacyclocarbene catalyzed vinylogous pyrazolones]Cycloaddition, which gives spiro pyrazolone compounds (Yetra, s.r.; mondal, s.; mukherjee, s.; gonnede, r.g.; biju, A.T. Enantioselective Synthesis of Spirocyclohexadienones by NHC-Catalyzed Formal [3+3 ]) with 99% enantioselectivity in yields of up to 84%] Annulation Reaction of Enals [J]. Angew. Chem. Int. Ed. 2016, 55268-272); buddhadeb Mondeal discloses the following reaction, requiring a reaction time of 5 days.
The use of catalytic amounts of catalyst to promote multiple new species formation is one of the most efficient and economical methods of synthesizing organic compounds. In the field of organic synthesis research, a catalyst for complexing metal and chiral ligands can be applied to synthesis of a plurality of organic matters; however, the efficient synthesis of chiral spiro-tetrahydrofuran pyrazolone structural compounds by metal palladium complex catalysis is not reported in the literature.
Disclosure of Invention
The invention aims to provide a chiral spiro-tetrahydrofuran pyrazolone compound and a catalytic synthesis method thereof.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
a synthesis method of chiral spiro-tetrahydrofuran pyrazolone compound comprises the following steps: with vinyl cyclic carbonatesα,βAnd (3) reacting unsaturated pyrazolone serving as a reactant in the presence of a palladium catalyst and a chiral phosphorus ligand to prepare the chiral spiro-tetrahydrofuran pyrazolone compound.
The invention uses vinyl cyclic carbonateα,βUnsaturated pyrazolone is used as a reactant, and chiral spiro-tetrahydrofuran pyrazolone compounds are prepared by reacting in an organic solvent in the presence of a palladium catalyst and chiral phosphorus ligands; in particular, a chamberMixing palladium catalyst, chiral phosphorus ligand and organic solvent at a temperature, then adding vinyl cyclic carbonate andα,β-unsaturated pyrazolone, then reacting at 0-room temperature, preferably 0-10 ℃ for 15-30 hours to obtain the chiral spiro-tetrahydrofuran pyrazolone compound; as common knowledge, after the reaction is finished, the reaction liquid is subjected to column chromatography to obtain the chiral spiro-tetrahydrofuran pyrazolone compound.
In the invention, the chemical structural formula of the vinyl carbonate is as follows:
the saidα,βThe chemical formula of the unsaturated pyrazolone is as follows:
the structural formula of the chiral spiro-tetrahydrofuran pyrazolone compound is as follows:
in the structural formula, ar 1 One or more selected from phenyl, substituted phenyl, thienyl and naphthyl, wherein the substituent in the substituted phenyl is one or more selected from alkyl, halogen and alkyl halogen, such as one or more selected from methyl, halogen and trifluoromethyl; ar (Ar) 2 One or more selected from phenyl, substituted phenyl, thienyl and naphthyl, wherein the substituent in the substituted phenyl is one or more selected from alkyl, halogen, alkoxy and cyano, such as one or more selected from methyl, halogen, methoxy and cyano; ar (Ar) 3 Is phenyl or substituted phenyl, wherein the substituent is alkyl or halogen, such as methyl or halogen.
In the technical scheme, the palladium catalyst is an organic phosphine palladium compound, and the chiral phosphorus ligand has one of the following chemical structural formulas:
r is a C1-C6 alkyl group such as methyl or ethyl.
In the technical scheme, the palladium catalyst is used in the following amount by molα,β3% -6% of unsaturated pyrazolone; the chiral phosphorus ligand is used in an amount ofα,β8% -12% of unsaturated pyrazolone; the amount of vinyl carbonate isα,β1.4 to 1.6 times of unsaturated pyrazolone. In a preferred embodiment, the palladium catalyst is used in an amount ofα,β5% of unsaturated pyrazolone, chiral phosphorus ligand in an amount ofα,β10% of unsaturated pyrazolones.
According to the report of the prior art, the active molecules containing the spiro pyrazolone skeleton have the effects of resisting bacteria, diminishing inflammation, relieving pain, antagonizing, resisting tumors and the like, so that the invention discloses the application of the chiral spiro pyrazolone compound as a medicament or an intermediate.
As an example, the present invention is a process comprising reacting a vinyl cyclic carbonate withα,βUnsaturated pyrazolones as reactants, in Pd (PPh 3 ) 4 The chiral phosphorus ligand is a chiral ligand, and the chiral spiro-tetrahydrofuran pyrazolone compound is obtained by reacting the chiral phosphorus ligand with an organic solvent at 10 ℃.
In the technical scheme, the organic solvent is an ether solvent or a benzene solvent; such as methylene chloride, tetrahydrofuran, toluene, 1, 2-dichloroethane, p-xylene, m-xylene, methyl t-butyl ether.
In the technical scheme, palladium catalyst is preferably tetraphenylphosphine palladium, and chiral phosphorus ligand is preferably chiral biphosphinamide.
The invention sequentially adds palladium metal catalyst, chiral diphosphorous amide and solvent into a reactor at room temperature, stirs for 1 hour, then vinyl carbonate,α,βAdding unsaturated pyrazolone, carrying out conventional stirring reaction for 20-25 hours at the temperature of 10 ℃, and carrying out column chromatography (the eluent is preferably ethyl acetate: petroleum ether=100:1) on the reaction solution to obtain the chiral spiro-tetrahydrofuran pyrazolone compound of the target product; the compounds are analogues of a plurality of antibacterial drugs, anti-tumor, anti-human immunodeficiency virus, antiviral agents and enzyme inhibitors, and have practical application values.
In the invention, the reaction system uses m-xylene as a solvent and tetraphenylphosphine palladium as metal, and chiral biphosphinamide as a chiral ligand, so that the reaction yield is improved, and the highest yield can reach 95% and the highest enantioselectivity can reach 99%.
The reaction process is as follows:
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the invention uses the tetraphenylphosphine palladium and the chiral phosphorus ligand as the catalysts to catalyze the vinyl cyclic carbonate and the chiral phosphorus ligand for the first timeα,β-asymmetric [3+2 ] of unsaturated pyrazolones]A series of chiral spiro-tetrahydrofuran pyrazolone compounds are synthesized by cycloaddition reaction with excellent enantioselectivity and high yield. The compound combines the efficacies of spiro pyrazolone and tetrahydrofuran structures with biological activity and pharmacological action, and provides more choices for the development of organic synthesis and biological medicine.
2. The synthesis method for the chiral spiro-tetrahydrofuran pyrazolone compound disclosed by the invention has the advantages of high reaction catalysis efficiency, low catalyst consumption, simple post-treatment, no byproduct generation in a system, and the reaction belongs to cycloaddition reaction.
3. The method for synthesizing the chiral spiro-tetrahydrofuran pyrazolone compound disclosed by the invention has the advantages that the application substrate range is wide, the raw materials are all industrial, cheap and easily available products, and no pollution is caused; the operation is simple and convenient, the yield is high, and the chemical selectivity is good; the reaction condition is mild, heating or cooling condition is not needed, the functional group compatibility is high, the enantioselectivity is excellent, and the yield is high.
Detailed Description
The raw materials of the invention are all existing products, and the specific preparation operation and test are all conventional technologies. The chemical structural formula of the metal catalyst tetra-triphenylphosphine palladium is as follows:
the chemical structural formula of the chiral biphosphite is as follows:
according to the report of the prior art, the active molecules containing the spiro pyrazolone skeleton have the effects of resisting bacteria, diminishing inflammation, relieving pain, antagonizing, resisting tumors and the like, so that the chiral spiro pyrazolone compound disclosed by the invention can be used as a medicament or an intermediate, and further, the chiral spiro pyrazolone compound contains a reactive group such as a double bond as shown by the structure of the chiral spiro pyrazolone compound, thereby expanding the application of the compound in the field of materials and being used as a material modifier.
The invention is further described below with reference to the examples, all reactions being carried out in air:
example 1
To the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol) and 2a (26.2 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the desired product 3a (yield 35.9, mg, 88%), a brown solid, 99% enantioselectivity, and >20:1 diastereoselectivity.
Product 3a was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 3H), 7.28 (m, 8H), 6.92 (d, J = 8.0 Hz, 1H), 6.78 (dd, J = 17.2, 10.8 Hz, 1H), 5.82 (s, 1H), 5.37 (d, J = 10.4 Hz, 1H), 5.01 (d, J = 8.8 Hz, 1H), 4.92 (d, J = 4.4 Hz, 1H), 4.89 (d, J = 4.0 Hz, 1H), 1.63 (s, 3H) ; 13 C NMR (101 MHz, CDCl 3 ) δ170.6, 159.5, 140.7, 139.7, 137.8, 136.2, 129.0, 128.9, 128.5, 128.3, 127.6, 126.2, 125.5, 124.4, 119.5, 87.2, 76.0, 70.1, 60.8, 17.7; IR (KBr) ν max : 3030, 2921, 1703, 1595, 1497, 1362, 1317, 1128, 1069, 726, 690, 642, 504 cm -1 ; HRMS (ESI): m/z = 431.1730 (calcd for C 27 H 24 N 2 O 2 +Na + = 431.1730) the above data demonstrate successful synthesis of the target product.
Extended embodiment
Pd is added into the reaction bottle in sequence 2 (dba) 3 (0.005 mmol) and L9 (0.01 mmol), 1.1 mL m-xylene was added, and the mixture was stirred at room temperature for 1 hour, then 1a (0.1 mmol), 2a (0.1 mmol) and reacted at 30℃for 12 hours. The reaction system can obtain the target product 3a (separation yield 85%) through simple column chromatography (eluent is ethyl acetate: petroleum ether=100:1), the enantioselectivity is 93%, the diastereoselectivity is>19:1。
Pd is added into the reaction bottle in sequence 2 (dba) 3 (0.005 mmol) and L10 (0.01 mmol), 1.1 mL m-xylene was added, and the mixture was stirred at room temperature for 1 hour, then 1a (0.1 mmol), 2a (0.1 mmol) and reacted at 30℃for 12 hours. The reaction system is communicatedThe target product 3a (separation yield 78%) can be obtained by simple column chromatography (eluent is ethyl acetate: petroleum ether=100:1), the enantioselectivity is 36%, the diastereoselectivity is>3:1。
The ligand L is as follows:
referring to the cell experiments prior to the subject group (e.g., the literature published in 2017 on org. Lett.) compound 3a had some toxicity to MCF-7 cells, and after 48 hours incubation, cell viability was reduced compared to conventional culture as a control; the product prepared by the method disclosed by the invention has the property of spiro pyrazolone skeleton, and provides a basis for further drug development.
Example two
To the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1b (30.6 mg, 0.15 mmol) and 2a (26.2 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the target product 3b (yield 33.7, mg, 80%, respectively), as a white solid, with an enantioselectivity of 94% and a diastereoselectivity of >20:1.
Product 3b was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.34–7.23 (m, 6H), 7.10 (d, J = 7.6 Hz, 2H), 6.81 (d, J = 7.6 Hz, 2H), 6.76 (dd, J = 17.2, 10.8 Hz, 1H ), 5.82 (s, 1H), 5.36 (d, J = 10.6 Hz, 1H), 5.00 (d, J = 8.8 Hz, 1H), 4.91 (m, 2H), 2.31 (s, 3H), 1.65 (s, 3H) ; 13 C NMR (101 MHz, CDCl 3 ) δ170.6, 159.6, 140.9, 137.9, 137.3, 136.6, 136.3, 129.7, 128.9, 128.4, 128.2, 126.0, 125.5, 124.4, 119.5, 114.7, 87.1, 76.1, 70.2, 60.5, 21.0, 17.8; IR (KBr) ν max : 3019, 2924, 1704, 1597, 1500, 1366, 1321, 1259, 1094, 927, 667, 539 cm -1 ; HRMS (ESI): m/z = 445.1859 (calcd for C 28 H 26 N 2 O 2 +Na + = 445.1886) the above data demonstrate successful synthesis of the target product.
Example III
To the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1d (40.2 mg, 0.15 mmol), 2a (26.2 mg, 0.1 mmol) and 10℃were added and the mixture was reacted for 24 hours. The reaction system is subjected to simple column chromatography (the eluent is ethyl acetate: petroleum ether=100:1) to obtain a target product 3d (the yields are 40.8 mg and 84 percent respectively), a white solid, the enantioselectivity is 95 percent, and the diastereoselectivity is >20:1.
Product 3d was analyzed and the results were as follows: 1H NMR (400 MHz, CDCl 3)δ 7.81 (d, J = 8.0 Hz, 2H), 7.44 – 7.37 (m, 4H), 7.23 (m, 6H), 6.76 (d, J = 8.8 Hz, 2H), 6.72 (dd, J = 17.6, 10.8 Hz, 1H), 5.78 (s, 1H), 5.34 (d, J = 10.4 Hz, 1H), 4.92 (d, J = 8.8 Hz, 1H), 4.88–4.79 (m, 2H), 1.60 (s, 3H); 13C NMR (101 MHz, CDCl3) δ170.3, 159.2, 140.2, 138.6, 136.0, 132.2, 129.0, 128.5, 128.3, 128.0, 125.7, 124.3, 121.7, 119.5, 115.3, 87.1, 76.0, 69.9, 60.4, 17.8; IR (KBr) ν max : 3015, 2923, 1703, 1595, 1498, 1364, 1259, 1073, 1010, 908, 666, 506 cm -1 HRMS (ESI): m/z= 509.0812 (calculated for C27H23brn2o2+na+ = 509.0835.) the above data demonstrate successful synthesis of the target product.
Example IV
To the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1g (40.2 mg, 0.15 mmol) and 2a (26.2 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system is subjected to simple column chromatography (eluent is ethyl acetate: petroleum ether=100:1) to obtain 3g of target product (yield is 38.9 mg, 85 percent respectively), white solid, enantioselectivity is 78 percent, diastereoselectivity is >20:1.
Product 3g was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 8.0 Hz, 2H), 7.44 (m, 2H), 7.27 (m, 7H), 7.22–7.08 (m, 1H), 6.97–6.77 (m, 2H), 6.73 (dd, J = 17.2, 10.8 Hz, 1H), 5.81 (s, 1H), 5.39 (d, J = 10.8 Hz, 1H), 5.02–4.77 (m, 3H), 1.65 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ170.3, 159.1, 141.6, 140.0, 137.6, 135.9, 134.9, 130.4, 129.0, 128.5, 128.4, 127.9, 126.6, 124.8, 124.3, 119.7, 115.5, 87.0, 75.8, 69.8, 60.4, 17.8; IR (KBr) ν max : 3016, 2924, 1072, 1595, 1498, 1362, 1318, 1258, 1208, 1071, 693, 643, 506 cm -1 ; HRMS (ESI): m/z = 509.0837 (calcd for C 27 H 23 BrN 2 O 2 +Na + = 509.0835) the above data demonstrate successful synthesis of the target product.
Fifth embodiment:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1k (36.0 mg, 0.15 mmol) and 2a (26.2 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system is subjected to simple column chromatography (the eluent is ethyl acetate: petroleum ether=100:1) to obtain a target product 3k (the yields are 40.3 mg and 88 percent respectively), a white solid, the enantioselectivity is 96 percent and the diastereoselectivity is 19:1.
Product 3k was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (d, J = 8.0 Hz, 2H), 7.84–7.80 (m, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.74–7.71 (m, 1H), 7.53–7.48 (m, 4H), 7.43 (s, 1H), 7.38–7.26 (m, 6H), 7.04 (dd, J = 8.4, 1.6 Hz, 1H), 6.91 (dd, J = 17.2, 10.8 Hz, 1H), 5.92 (s, 1H), 5.40 (d, J = 10.8 Hz, 1H), 5.19 (d, J = 9.2 Hz, 1H), 5.02 (d, J = 8.4 Hz, 1H), 4.93 (d, J = 16.8 Hz, 1H), 1.62 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ170.7, 159.5, 140.6, 137.9, 137.0, 136.3, 133.1, 132.4, 129.0, 129.0, 128.5, 128.3, 128.0, 127.6, 126.6, 126.5, 125.7, 125.1, 124.4, 124.3, 119.6, 115.3, 87.1, 76.3, 70.2, 61.0, 17.9; IR (KBr) ν max : 2955, 2920, 1072, 1595, 1498, 1363, 1317, 1070, 1029, 707, 726, 643, 505 cm -1 ; HRMS (ESI): m/z = 481.1882 (calcd for C 31 H 26 N 2 O 2 +Na + = 481.1886) the above data demonstrate successful synthesis of the target product.
Example six:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol) and 2b (29.2 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the desired product 4a (yield: 39.9, mg, 90%, respectively), as a yellow solid, with an enantioselectivity of 96% and a diastereoselectivity of 9:1.
Product 4a was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.35–7.25 (m, 4H), 7.22 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 6.8 Hz, 2H), 6.83–6.70 (m, 3H), 5.78 (s, 1H), 5.36 (d, J = 10.4 Hz, 1H), 5.00 (d, J = 9.2 Hz, 1H), 4.92–4.83 (m, 2H), 3.75 (s, 3H), 1.65 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ170.6, 159.7, 159.4, 140.8, 139.8, 137.8, 129.0, 128.9, 128.0, 127.6, 126.2, 125.6, 125.5, 119.5, 114.8, 113.8, 87.2, 75.9, 70.2, 60.7, 55.2, 17.8; IR (KBr) ν max : 2956, 2920, 1702, 1595, 1498, 1393, 1361, 1247, 1030, 753, 690, 641, 507 cm -1 ; HRMS (ESI): m/z = 461.1836 (calcd for C 28 H 26 N 2 O 3 +Na + = 461.1836) the above data demonstrate successful synthesis of the target product.
Embodiment seven:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol) and 2c (34.0 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the desired product 4b (yield: 41.8, mg, 86%, respectively), as a white solid, with an enantioselectivity of 96% and a diastereoselectivity of 19:1.
Product 4b was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.34–7.25 (m, 4H), 7.18 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 7.6 Hz, 2H), 6.74 (dd, J = 17.2, 10.8 Hz, 1H), 5.75 (s, 1H), 5.37 (d, J = 10.8 Hz, 1H), 4.99 (d, J = 9.2 Hz, 1H), 4.91 (m, 2H), 1.63 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ170.3, 159.2, 140.5, 139.5, 137.7, 135.4, 131.6, 129.1, 129.0, 127.7, 126.1, 126.1, 125.7, 122.2, 119.4, 115.0, 86.5, 76.0, 69.9, 60.8, 17.8; IR (KBr) ν max : 2921, 1702, 1595, 1498, 1362, 1257, 1128, 1082, 1031, 959, 757, 691, 505 cm -1 ; HRMS (ESI): m/z = 509.0835 (calcd for C 27 H 23 BrN 2 O 2 +Na + = 509.0835) the above data demonstrate successful synthesis of the target product.
Amplification experiment
The scale of the reaction was scaled up. Expanding the amount of substrate 1.194a from 0.15 mmol to 1.2 mmol and the amount of substrate 3.5c from 0.1mmol to 0.8 mmol, the reaction product 3.44b was finally obtained in 96% ee, 19:1 dr and 80% yield. The results of the amplification experiments show that when the substrate dosage is amplified, the yield and the stereoselectivity of the reaction can be well maintained. According to the prior common knowledge, the product of the invention can be judged to have a general spiro pyrazolone skeleton, can be used as a medicament or a medicament intermediate, further, the product of the invention contains double bonds of a reactive group, can be used as a material modifier in the field of materials, for example, can be beneficial to improving the flame retardant property by halogen and is beneficial to improving the thermal property by a rigid structure.
Example eight:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol) and 2e (27.6 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours under stirring at room temperature for 1 hour. The reaction system is subjected to simple column chromatography (the eluent is ethyl acetate: petroleum ether=100:1) to obtain a target product 4d (the yields are 38.9 mg and 92 percent respectively) as a pale yellow solid, the enantioselectivity is 94 percent, and the diastereoselectivity is >20:1.
Product 4d was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ7.88 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.35–7.24 (m, 4H), 7.12 (m, 4H), 6.94 (d, J = 8.0 Hz, 2H), 6.80 (dd, J = 17.2, 10.4 Hz, 1H), 5.81 (s, 1H), 5.38 (d, J = 10.4 Hz, 1H), 5.02 (d, J = 8.8 Hz, 1H), 4.92 (m, 2H), 2.22 (s, 3H), 1.64 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ170.7, 159.6, 140.8, 139.8, 138.1, 137.8, 136.1, 129.0, 129.0, 128.9, 128.3, 127.6, 126.2, 125.6, 125.0, 121.4, 119.6, 114.8, 87.3, 76.1, 70.1, 60.6, 21.4, 17.8; IR (KBr) ν max : 3015, 2922, 1702, 1596, 1498,1363, 1318, 1216, 1162, 699, 643, 666, 507 cm -1 ; HRMS (ESI): m/z = 445.1855 (calcd for C 28 H 26 N 2 O 2 +Na + = 445.1886) the above data demonstrate successful synthesis of the target product.
Example nine:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol) and 2f (34.0 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the desired product 4e (yield: 40.8, mg, 84%, respectively), as a yellow solid, 95% enantioselectivity, 19:1 diastereoselectivity.
Product 4e was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (d, J = 8.0 Hz, 2H), 7.45 (s, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.29 – 7.24 (m, 1H), 7.17 (m, 4H), 6.98 (m, 2H), 6.79 (d, J = 7.2 Hz, 2H), 6.62 (dd, J = 17.2, 10.8 Hz, 1H), 5.63 (s, 1H), 5.25 (d, J = 10.8 Hz, 1H), 4.87 (d, J = 9.2 Hz, 1H), 4.79 (m, 2H), 1.51 (s, 3H).; 13 C NMR (101 MHz, CDCl 3 ) δ170.3, 159.2, 140.5, 139.5, 138.7, 137.6, 131.4, 130.1, 129.1, 129.0, 127.7, 127.6, 126.1, 125.8, 123.0, 122.8, 119.7, 115.1, 86.3, 76.1, 69.9, 60.7, 17.8; IR (KBr) ν max : 2962, 1702, 1595, 1497, 1258, 1070, 963, 921, 794, 689, 641, 505 cm -1 ; HRMS (ESI): m/z = 509.0845 (calcd for C 27 H 23 BrN 2 O 2 +Na + = 509.0835) the above data demonstrate successful synthesis of the target product.
Example ten:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol), 2g (30.7 mg, 0.1 mmol), and reacted at 10℃for 24 hours, were added and stirred at room temperature for 1 hour. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the desired product 4f (yield: 39.9, mg, 90%, respectively), as a yellow solid, with an enantioselectivity of 96% and a diastereoselectivity of 13:1.
Product 4f was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ8.04 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 7.32–7.20 (m, 5H), 7.05–6.96 (m, 3H), 6.91 (dd, J = 17.2, 10.8 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.96 (s, 1H), 5.31 (d, J = 10.4 Hz, 1H), 4.95 (d, J = 8.4 Hz, 1H), 4.72 (m, 2H), 3.36 (s, 3H), 1.25 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ172.1, 159.3, 156.0, 141.0, 138.6, 138.6, 129.0, 128.9, 128.7, 127.7, 126.7, 126.6, 126.1, 124.6, 120.1, 118.3, 115.3, 109.6, 83.8, 76.8, 69.3, 62.3, 54.8, 17.6; IR (KBr) ν max : 2921, 1702, 1595, 1498, 1363, 1317, 1257, 1070, 1029, 757, 689, 643, 503 cm -1 ; HRMS (ESI): m/z = 461.1836 (calcd for C 28 H 26 N 2 O 3 +Na + = 461.1836) the above data demonstrate successful synthesis of the target product.
Example eleven:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol) and 2h (29.6 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give 4g of the target product (yield: 37.7. 37.7 mg, 85%, respectively), a white solid, an enantioselectivity of 94%, and a diastereoselectivity of 12:1.
Product 4g was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ7.92 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.31 (m, 4H), 7.22 (m, 3H), 7.04 (d, J = 7.6 Hz, 2H), 6.88 (dd, J = 17.2, 10.8 Hz, 1H), 6.05 (s, 1H), 5.31 (d, J = 10.8 Hz, 1H), 4.98 (d, J = 8.4 Hz, 1H), 4.74 (m, 2H), 1.19 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ171.8, 158.7, 140.4, 138.7, 138.7, 136.1, 131.6, 130.0, 129.4, 128.9, 128.8, 127.8, 127.7, 126.9, 126.5, 125.2, 119.2, 115.7, 84.9, 76.9, 69.6, 62.8, 17.7; IR (KBr) ν max : 2920, 1704, 1595, 1498, 1363, 1317, 1129, 1070, 1029, 757, 706, 643, 505 cm -1 ; HRMS (ESI): m/z = 465.1340 (calcd for C 27 H 23 ClN 2 O 2 +Na + = 465.1340) the above data demonstrate successful synthesis of the target product.
Embodiment twelve:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol), 2i (31.2 mg, 0.1 mmol) and 10℃were added and the mixture was stirred at room temperature for 1 hour, followed by reaction for 24 hours. The reaction system is subjected to simple column chromatography (the eluent is ethyl acetate: petroleum ether=100:1) to obtain the target product for 4h (the yields are 38.5 mg and 95 percent respectively), the light yellow solid is a light yellow solid, the enantioselectivity is 95 percent, and the diastereoselectivity is >20:1.
Product 4h was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ7.99–7.87 (m, 3H), 7.79 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.48 (m, 4H), 7.31 (m, 5H), 6.98 (d, J = 7.2 Hz, 2H), 6.87 (dd, J = 17.8, 10.4 Hz, 1H), 6.03 (s, 1H), 5.44 (d, J = 10.4 Hz, 1H), 5.11 (d, J = 8.8 Hz, 1H), 5.04–4.89 (m, 2H), 1.65 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ170.7, 159.6, 140.8, 139.6, 137.9, 133.9, 133.2, 133.1, 129.1, 129.0, 128.4, 128.1, 127.8, 127.7, 126.3, 126.2, 126.2, 125.6, 123.5, 122.2, 119.6, 115.0, 87.3, 76.2, 70.1, 60.9, 17.8; IR (KBr) ν max : 2921, 1700, 1558, 1498, 1362, 1314, 1124, 1093, 755, 690, 645, 481 cm -1 ; HRMS (ESI): m/z = 481.1886 (calcd for C 31 H 26 N 2 O 2 +Na + = 481.1886) the above data demonstrate successful synthesis of the target product.
Embodiment thirteen:
to the reaction flask were successively added tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol) and 2j (26.8 mg, 0.1 mmol) were added and reacted at 10℃for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the desired product 4i (yield: 36.1, mg, 87%, respectively), as a yellow solid, with an enantioselectivity of 94% and a diastereoselectivity of 9:1.
Product 4i was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ7.92 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.30 (m, 4H), 7.20 (d, J = 4.8 Hz, 1H), 6.95–6.88 (m, 3H), 6.85 (d, J = 3.6 Hz, 1H), 6.69 (dd, J = 17.2, 10.8 Hz, 1H), 5.98 (s, 1H), 5.37 (d, J = 10.8 Hz, 1H), 4.99 (m, 2H), 4.90 (d, J = 8.8 Hz, 1H), 1.78 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ169.8, 159.3, 140.4, 139.8, 138.5, 137.8, 129.1, 129.0, 127.7, 127.1, 126.0, 125.5, 124.8, 123.3, 119.4, 114.9, 84.8, 75.7, 69.9, 60.6, 17.9; IR (KBr) ν max : 2920, 1701, 1558, 1498, 1490, 1362, 1316, 1128, 1066, 757, 690, 642, 506 cm -1 ; HRMS (ESI): m/z = 437.1302 (calcd for C 25 H 22 N 2 SO 2 +Na + = 437.1294) the above data demonstrate successful synthesis of the target product.
Fourteen examples:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol), 2k (27.6 mg, 0.1 mmol) and 10℃were added and the mixture was stirred at room temperature for 1 hour, followed by reaction for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the target product 4j (yield: 39.7, mg, 94%, respectively), as a white solid, with a enantioselectivity of 57% and a diastereoselectivity of >20:1.
Product 4j was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ7.76 (d, J = 8.4 Hz, 2H), 7.29 (m, 10H), 7.05–6.88 (d, J = 8.0 Hz, 2H), 6.79 (dd, J = 17.2, 10.8 Hz, 1H), 5.83 (s, 1H), 5.38 (d, J = 10.8 Hz, 1H), 5.02 (d, J = 8.8 Hz, 1H), 4.97–4.86 (m, 2H), 2.41 (s, 3H), 1.63 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ170.4, 159.3, 140.8, 139.7, 136.3, 135.4, 135.3, 129.5, 129.0, 128.4, 128.2, 127.6, 126.2, 124.4, 119.5, 114.8, 87.1, 76.0, 70.0, 60.7, 21.1, 17.7; IR (KBr) ν max : 1700, 1541, 1558, 1508, 1362, 1361, 1318,1258, 1072, 819, 701, 500, 420 cm -1 ; HRMS (ESI): m/z = 445.1863 (calcd for C 28 H 26 N 2 O 2 +Na + = 445.1886) the above data demonstrate successful synthesis of the target product.
Example fifteen:
to the reaction flask was added, in order, tetrakis triphenylphosphine palladium (5.7 mg,0.005 mmol), chiral bis-phosphoramidite (7.6 mg,0.01 mmol), 2 mL m-xylene, and then 1a (28.5 mg, 0.15 mmol), 2l (29.6 mg, 0.1 mmol) and 2l were added and reacted at 10℃for 24 hours. The reaction system was subjected to simple column chromatography (eluent: ethyl acetate: petroleum ether=100:1) to give the objective product 4k (yield: 39.8 mg, 90%, respectively), yellow solid, enantioselectivity 87%, diastereoselectivity 19:1.
Product 4k was analyzed and the results were as follows: 1 H NMR (400 MHz, CDCl 3 ) δ7.86 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.35–7.21 (m, 9H), 6.89 (d, J = 6.4 Hz, 2H), 6.76 (dd, J = 16.8, 10.4 Hz, 1H), 5.81 (s, 1H), 5.37 (d, J = 10.4 Hz, 1H), 5.01 (d, J = 8.8 Hz, 1H), 4.90 (m, 2H), 1.63 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ170.6, 159.9, 140.6, 139.6, 136.4, 136.1, 130.6, 129.1, 129.0, 128.5, 128.4, 127.7, 126.2, 124.3, 120.4, 115.1, 87.2, 76.1, 70.2, 60.8, 17.7; IR (KBr) ν max : 2962, 1702, 1490, 1361, 1318, 1259, 1207, 1128, 1090, 1027, 799, 698, 499 cm -1 ; HRMS (ESI): m/z = 465.1322 (calcd for C 27 H 23 ClN 2 O 2 +Na + = 465.1340) the above data demonstrate successful synthesis of the target product.

Claims (3)

1. The synthesis method of the chiral spiro-tetrahydrofuran pyrazolone compound is characterized by comprising the following steps of: with vinyl cyclic carbonatesα,βUnsaturated pyrazolone is used as a reactant, and chiral spiro-tetrahydrofuran pyrazolone compounds are prepared by reacting in the presence of a palladium catalyst and chiral phosphorus ligand in the presence of an organic solvent;
the chemical structural formula of the vinyl carbonate is as follows:
the saidα,βThe chemical formula of the unsaturated pyrazolone is as follows:
the structural formula of the chiral spiro-tetrahydrofuran pyrazolone compound is as follows:
the method comprises the steps of carrying out a first treatment on the surface of the Wherein Ar is 1 One selected from phenyl, substituted phenyl, thienyl and naphthyl; ar (Ar) 2 One selected from phenyl, substituted phenyl, thienyl and naphthyl; ar (Ar) 3 Is phenyl or substituted phenyl; ar (Ar) 1 In the substituted phenyl of (2), the substituent is one or more of alkyl, halogen and alkyl halogen;Ar 2 in the substituted phenyl of (2), the substituent is one or more of alkyl, halogen, alkoxy and cyano; ar (Ar) 3 In the substituted phenyl of (2), the substituent is alkyl or halogen; the palladium catalyst is Pd (PPh) 3 ) 4 The chemical structural formula of the chiral phosphorus ligand is as follows:
the palladium catalyst is used in an amount ofα,β3% -6% of unsaturated pyrazolone; the chiral phosphorus ligand is used in an amount ofα,β8% -12% of unsaturated pyrazolone; the amount of vinyl carbonate isα,β-1.4 to 1.6 times of unsaturated pyrazolone; the temperature of the reaction is 0-room temperature.
2. The method for synthesizing chiral spiro-tetrahydrofuran pyrazolone compound according to claim 1, wherein: mixing palladium catalyst, chiral phosphorus ligand and organic solvent at room temperature, and then adding vinyl cyclic carbonate andα,βunsaturated pyrazolone and then reacting for 15-30 hours at 0-10 ℃ to obtain the chiral spiro-tetrahydrofuran pyrazolone compound.
3. The method for synthesizing chiral spiro-tetrahydrofuran pyrazolone compound according to claim 2, wherein: and after the reaction is finished, the reaction liquid is subjected to column chromatography to obtain the chiral spiro-tetrahydrofuran pyrazolone compound.
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Buddhadeb Mondal等.Highly Diastereo- and Enantioselective Synthesis of Spiro-tetrahydrofuran-pyrazolones via Organocatalytic Cascade Reaction between γ-Hydroxyenones and Unsaturated Pyrazolones.《Journal of Organic Chemistry》.2018,第83卷(第15期),8645-8654. *
Highly Diastereo- and Enantioselective Synthesis of Spiro-tetrahydrofuran-pyrazolones via Organocatalytic Cascade Reaction between γ-Hydroxyenones and Unsaturated Pyrazolones;Buddhadeb Mondal等;《Journal of Organic Chemistry》;20180529;第83卷(第15期);8645-8654 *
Palladium-Catalyzed Asymmetric [4+2] Cycloaddition of 2-Methylidenetrimethylene Carbonate with Alkenes: Access to Chiral Tetrahydropyran-Fused Spirocyclic Scaffolds;Biming Mao等;《Angewandte Chemie International Edition》;20200416;第59卷(第28期);11316-11320&supporting information *

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