CN111423405B - Method for synthesizing benzopyran 3 alcohol derivative compound - Google Patents
Method for synthesizing benzopyran 3 alcohol derivative compound Download PDFInfo
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Abstract
The invention relates to the technical field of compound preparation, and discloses a method for synthesizing benzopyran 3 alcohol derivative compounds, which comprises the following steps: (1) mixing the compound I with a palladium catalyst, an oxidant and a solvent, and carrying out closed stirring reaction for 1-24 h at the temperature of 70-130 ℃; carrying out post-treatment on the mixed solution obtained in the step (1) to obtain an intermediate product II; mixing the intermediate product II with a catalyst, acetonitrile and water, replacing air with nitrogen, and carrying out closed stirring reaction at 85-95 ℃ for 1-24 h; and (4) carrying out post-treatment on the mixed solution obtained in the step (3) to obtain a final product III benzopyran 3 alcohol derivative compound. The invention directly carries out intramolecular C (sp) through cross dehydrogenation coupling3) the-H arylation is carried out to synthesize the benzopyran 3 alcohol derivative compound, the route is simple, the yield is high, the universality is good, the reaction condition is mild, and the selectivity is high.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a method for synthesizing benzopyran-3-alcohol derivative compounds.
Background
C(sp3)-C(sp2) Bond is the basic chemical bond in organic chemistry, building C (sp)3)-C(sp2) Have long been receiving extensive attention and research. Construction of C (sp) in the prior art3)-C(sp2) The key method mainly comprises the following steps: 1. Friedel-Crafts reaction, but the method has relatively poor regioselectivity and narrow substrate application range, so the method limits the application of the method in the later functionalization of aromatic hydrocarbon (especially mono-substituted aromatic hydrocarbon) to some extent. 2. Construction of C (sp) by transition metal catalyzed cross-coupling reaction3)-C(sp2) Keys, for example: although these methods are widely used, they usually require two cross-coupled moieties for pre-functionalization, by Suzuki-Miyama coupling, Negishi arylation, Kumada reaction and Hiyama reaction, among others. And direct cross-coupling reaction to construct C (sp)3)-C(sp2) The manner of the keys has not been widely adopted at presentAnd (5) researching.
Benzopyran-3-ol derivatives have various biological activities such as analgesic, anticancer, antibacterial, antioxidant, etc., and are widely present in various bioactive compounds, for example: antioxidant and antibacterial catechin (Epicatechin) and chromancalin (Cromakalim) for treating hypertension, angina pectoris and asthma contain benzopyran-3-ol derivative skeleton structure. The methods for synthesizing benzopyran-3-ol derivatives reported in the prior art, such as CN105219815A and CN 1214675 disclosed in Chinese patent literature, generally adopt the above-mentioned method for constructing C (sp) in benzopyran-3-ol derivatives3)-C(sp2) The bond method has the defects of difficult obtainment of reaction raw materials, low yield of key intermediates, harsh reaction conditions and the like. Therefore, a method for synthesizing benzopyran-3-alcohol derivative compounds with simple route, higher yield and good universality is needed to be found.
Disclosure of Invention
The invention aims to solve the problems of difficult obtainment of reaction raw materials, low yield of key intermediates and harsh reaction conditions of a synthetic method of a benzopyran-3-alcohol derivative compound in the prior art, and provides a method for synthesizing the benzopyran-3-alcohol derivative compound, which directly carries out intramolecular C (sp) through cross dehydrogenation coupling3) The benzopyran-3-alcohol derivative compound is synthesized by-H arylation, and has the advantages of simple route, higher yield, good universality, mild reaction conditions and high selectivity.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) mixing a compound I with a palladium catalyst, an oxidant and a solvent, and carrying out closed stirring reaction for 1-24 hours at the temperature of 70-130 ℃, wherein the structural formula of the compound I is as follows:
wherein R is1、R2、R3、R4、R5、R6、R7、R8、R9Respectively selecting one from hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, C1-C6 alkoxy, halogen and C6-C10 aryl, wherein the halogen is selected from one from F, Cl, Br and I;
(2) carrying out post-treatment on the mixed solution obtained in the step (1) to obtain an intermediate product II;
(3) mixing the intermediate product II with a catalyst, acetonitrile and water, replacing air with nitrogen, and carrying out closed stirring reaction at 85-95 ℃ for 1-24 h;
(4) and (4) carrying out post-treatment on the mixed solution obtained in the step (3) to obtain a final product III benzopyran-3-alcohol derivative compound.
The invention firstly adopts the mode of cross dehydrogenation coupling to directly carry out intramolecular C (sp) on the compound I through the steps (1) and (2)3) -H arylation to give intermediate II of formula:
then, the guiding group in the intermediate product II is replaced by hydrogen through the steps (3) and (4), and finally, a final product III with the structural formula as follows is obtained:
the structural formula shows that the final product III is the benzopyran-3-alcohol derivative compound. The benzopyran-3-alcohol derivative compound is prepared by directly arylating in a cross dehydrogenation coupling mode, and the method has the advantages of simple route, higher yield, good universality, mild reaction conditions and high selectivity.
Preferably, R in the compound I1Is one of hydrogen and C1-C6 straight chain or branched chain fatty alkyl; r2Is selected from hydrogen, halogen, linear or branched aliphatic alkyl of C1-C6, aryl of C6-C10 and aromatic acylOne kind of the material is selected; r3Is one of hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, C1-C6 alkoxy and halogen; r4Is one of hydrogen and halogen; r5Is one of hydrogen, halogen, C1-C6 straight chain or branched chain aliphatic alkyl or R5And R6To form a pyridine ring; r6Is one of hydrogen, halogen and trifluoromethyl or R5And R6To form a pyridine ring; r7Is one of hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, halogen and trifluoromethyl; r8Is one of hydrogen, halogen and trifluoromethyl; r9Is one of hydrogen, halogen and C1-C6 straight chain or branched chain fatty alkyl.
Most preferably, R1Is hydrogen or methyl; r2Is one of hydrogen, methyl, fluorine, chlorine, bromine, phenyl and benzoyl; r3Is one of hydrogen, methyl and chlorine; r4Is hydrogen or bromine; r5Is one of hydrogen, fluorine and methyl or R5And R6To form a pyridine ring; r6Is one of hydrogen, fluorine and trifluoromethyl or R5And R6To form a pyridine ring; r7Is one of hydrogen, methyl, fluorine and trifluoromethyl; r8Is one of hydrogen, fluorine and trifluoromethyl; r9Is one of hydrogen, fluorine and methyl.
Preferably, in step (1), the palladium catalyst is selected from one of palladium acetate, palladium dichloride, palladium trifluoroacetate, bis (benzonitrile) palladium dichloride, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium dichloride, and the ratio of the amount of compound I to the amount of palladium catalyst material is 1: (0.05-0.15).
More preferably, in the step (1), the palladium catalyst is palladium acetate, and the ratio of the amount of the compound I to the amount of the palladium catalyst substance is 1 (0.05-0.1).
Preferably, in the step (1), the oxidizing agent is selected from one of iodobenzene acetate, potassium persulfate, tert-butyl hydroperoxide, N-fluoro-bis-benzenesulfonamide and Selectfluor, and the ratio of the amount of the compound I to the oxidizing agent is 1: (1.0-3.0).
More preferably, the oxidizing agent in step (1) is N-fluorobisbenzenesulfonamide, and the ratio of the amount of the substance of compound I to the oxidizing agent is 1: (1.0-2.0).
Preferably, in the step (1), the solvent is one selected from toluene, trifluorotoluene, chlorobenzene, xylene, nitromethane, acetic acid, ethyl acetate, 1, 2-dichloroethane, acetonitrile, chloroform, tetrahydrofuran, 1, 4-dioxane, N-hexane and N, N-dimethylformamide, and the volume of the solvent is 0.5 to 5mL/mmol based on the substance of the compound I.
More preferably, the solvent in the step (1) is 1, 2-dichloroethane, and the volume usage of the solvent is 0.75-2 mL/mmol.
Preferably, the reaction temperature in the step (1) is 75 to 90 ℃.
Preferably, the reaction time in the step (1) is 4-24 h, and more preferably 6-24 h.
Preferably, the post-treatment method in step (2) is: adding ethyl acetate into the mixed solution obtained in the step (1) for dilution, filtering, distilling the filtrate under reduced pressure to remove the solvent, separating the residue by column chromatography, taking the mixed solution of petroleum ether and ethyl acetate as an eluent, collecting the eluent containing the product, and distilling the eluent to remove the solvent to obtain an intermediate product II.
Preferably, the catalyst in the step (3) is molybdenum hexacarbonyl, and the mass ratio of the intermediate product II to the catalyst is 1 (1.0-5.0).
More preferably, the ratio of the amount of the intermediate product II to the amount of the catalyst substance in the step (3) is 1 (1.0 to 2.0).
Preferably, in the step (3), the volume usage of acetonitrile is 1-5 mL/mmol and the volume usage of water is 1-10 rops/mmol based on the substance of the intermediate product II.
More preferably, in the step (3), the volume usage of acetonitrile is 1-3 mL/mmol and the volume usage of water is 2-8 rops/mmol based on the mass of the intermediate product II.
Preferably, the reaction time in the step (3) is 12-24 h.
Preferably, the post-treatment method in step (4) is: and (3) distilling the mixed solution obtained in the step (3) under reduced pressure to remove the solvent, adding water, extracting with ethyl acetate, drying the organic phase, distilling under reduced pressure to remove the solvent, separating the residue by column chromatography, collecting the eluent containing the product by taking the mixed solution of petroleum ether and ethyl acetate as an eluent, and evaporating the eluent to remove the solvent to obtain the final product III.
Therefore, the beneficial effects of the invention are as follows: the benzopyran-3-alcohol derivative compound is prepared by adopting the following technical route, and has the advantages of simple route, higher yield, good universality, mild reaction conditions and high selectivity:
drawings
FIG. 1 is a drawing of intermediate II of example 11HNMR spectrogram;
FIG. 2 is a drawing of intermediate II of example 113CNMR spectrogram;
FIG. 3 is the intermediate II of example 21HNMR spectrogram;
FIG. 4 is the intermediate II of example 213CNMR spectrogram;
FIG. 5 is a drawing of intermediate II of example 31HNMR spectrogram;
FIG. 6 is intermediate II of example 313CNMR spectrogram;
FIG. 7 is the intermediate II of example 41HNMR spectrogram;
FIG. 8 is the intermediate product II of example 413CNMR spectrogram;
FIG. 9 is a drawing of intermediate II of example 51HNMR spectrogram;
FIG. 10 is the intermediate product II of example 513CNMR spectrogram;
FIG. 11 is intermediate II of example 61HNMR spectrogram;
FIG. 12 is intermediate II of example 613CNMR spectrogram;
FIG. 13 is intermediate II of example 71HNMR spectrogram;
FIG. 14 is a drawing of intermediate II of example 713CNMR spectrogram;
FIG. 15 is of intermediate II of example 81HNMR spectrogram;
FIG. 16 is the intermediate product II of example 813CNMR spectrogram;
FIG. 17 is intermediate II of example 91HNMR spectrogram;
FIG. 18 is intermediate II of example 913CNMR spectrogram.
Detailed Description
The invention is further described with reference to the following detailed description and accompanying drawings. The structural formula of the compound I in each embodiment of the invention is as follows:
wherein R is5、R7、R9Is hydrogen, R6And R8Is trifluoromethyl to form a guide group DG of the formulaAl：
That is, the structural formula of compound I in the examples of the present invention is:
example 1:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (134.4mg, 0.3mmol), palladium acetate (3.4mg, 0.015mmol), N-fluorobis (benzenesulfonamide) (0.142g, 0.45mmol), 1, 2-dichloroethane (3mL) were charged into a closed reaction vessel, and the reaction was stirred at 90 ℃ for 24 hours while sealing, wherein R in compound I1、R2、R3、R4Are all hydrogen;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 85.6mg of an intermediate product II (yield is 64%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
White solid；1H NMR(500MHz,CDCl3)δ＝8.61(s,1H),8.04(s,2H),7.62(s,1H),7.21-7.11(m,2H),6.96(td,J1＝7.4Hz,J2＝1.2Hz,1H),6.89(dd,J1＝8.2Hz,J2＝1.2Hz,1H),4.88-4.84(m,1H),4.39(ddd,J1＝11.6Hz,J2＝4.8Hz,J3＝1.9Hz,1H),4.30(d,J＝11.7Hz,1H),3.34-3.25(m,1H),3.15-3.07(m,1H),2.11(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝161.0,154.2,151.4,138.7,132.4(q,J＝33.5Hz,2C),129.8,127.7,123.1(q,J＝273.3Hz,2C),121.2,119.4(s,2C),119.4,117.5(dt,J1＝7.7Hz,J2＝3.9Hz),116.6,75.3,67.1,29.8,9.7ppm；HRMS(ESI-TOF):calcd.[M+Na]+469.0957；found:469.0955.
from the above data and FIGS. 1 and 2, it can be seen that intermediate II has the following structure:
(3) adding the intermediate product II (44.6mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, solvent is evaporated from the eluent to obtain 10.7mg of final product III (yield is 71%), and the final product III is the benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
Example 2:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (138.6mg, 0.3mmol), palladium chloride (5.4mg, 0.03mmol), N-fluorobis-benzenesulfonamide (0.142g, 0.45mmol), 1, 2-dichloroethane (3mL) were charged into a closed reaction vessel, and the reaction was stirred at 90 ℃ for 24 hours while sealing, wherein R in compound I1、R3、R4Are each hydrogen, R2Is methyl;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 114.5mg of an intermediate product II (yield is 83%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
1H NMR(500MHz,CDCl3)δ＝8.64(s,1H),8.05(s,2H),7.63(s,1H),6.99-6.92(m,2H),6.79(d,J＝8.2Hz,1H),4.85-4.82(m,1H),4.35(ddd,J1＝11.5Hz,J2＝4.9Hz,J3＝1.9Hz,1H),4.27(d,J＝11.6Hz,1H),3.25(dd,J1＝17.1Hz,J2＝5.6Hz,1H),3.06(dd,J1＝16.8Hz,J2＝3.6Hz,1H),2.29(s,3H),2.11(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝161.0,152.0,151.4,138.8,132.4(q,J＝33.5Hz,2C),130.5,130.2,128.3,123.1(q,J＝273.3Hz,2C),119.4(d,J＝3.7Hz,2C),119.0,118.1-117.0(m),116.3,75.5,67.1,29.8,20.5,9.7ppm；HRMS(ESI-TOF):calcd.[M+Na]+483.1114；found:483.1113.
from the above data and FIGS. 3 and 4, it can be seen that intermediate II has the following structure:
(3) adding the intermediate product II (46.0mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, the solvent is evaporated from the eluent to obtain 12.1mg of a final product III (yield is 74%), and the final product III is a benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
Example 3:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (157.2mg, 0.3mmol), palladium acetate (6.8mg, 0.03mmol), selectfluor (0.159g, 0.45mmol), 1, 2-dichloroethane (3mL) were charged into a closed reaction vessel, and the reaction was stirred at 90 ℃ for 24h with closed stirring, R in compound I1、R3、R4Are each hydrogen, R2Is phenyl;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 134.7mg of an intermediate product II (yield is 86%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
1H NMR(500MHz,CDCl3)δ＝8.75(s,1H),8.11(s,2H),7.64(s,1H),7.56(d,J＝7.0Hz,2H),7.47-7.39(m,3H),7.36(d,J＝2.3Hz,1H),7.33(t,J＝7.4Hz,1H),6.97(d,J＝8.4Hz,1H),4.91-4.87(m,1H),4.43(ddd,J1＝11.5Hz,J2＝5.0Hz,J3＝1.7Hz,1H),4.35(d,J＝11.2Hz,1H),3.35(dd,J1＝16.9Hz,J2＝5.3Hz,1H),3.17(dd,J1＝17.0Hz,J2＝4.7Hz,1H),2.13(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝160.9,153.6,151.7,140.6,138.7,134.4,132.5(q,J＝33.6Hz,2C),128.8(s,2C),128.5,126.8,126.7(s,2C),126.5,123.1(q,J＝273.4Hz,2C),119.4(d,J＝3.8Hz,2C),119.2,117.6(t,J＝3.9Hz),117.0,75.4,67.0,29.9,9.8ppm；HRMS(ESI-TOF):calcd.[M+Na]+545.1270；found:545.1270.
from the above data and FIGS. 5 and 6, it can be seen that intermediate II has the following structure:
(3) adding the intermediate product II (52.2mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, solvent is evaporated from the eluent to obtain 18.5mg of final product III (yield is 82%), and the final product III is the benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
Example 4:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (139.8mg, 0.3mmol), palladium acetate (6.8mg, 0.03mmol), N-fluorobis-benzenesulfonamide (0.142g, 0.45mmol), 1, 2-dichloroethane (3mL) were charged into a closed reaction vessel, and the reaction was stirred at 90 ℃ for 24 hours while sealing, wherein R in compound I1、R3、R4Are each hydrogen, R2Is fluorine;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 114.1mg of an intermediate product II (yield is 82%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
1H NMR(500MHz,CDCl3)δ＝8.69(s,1H),8.08(s,2H),7.63(s,1H),6.88-6.81(m,3H),4.85-4.82(m,1H),4.38(ddd,J1＝11.6Hz,J2＝4.8Hz,J3＝1.9Hz,1H),4.26(d,J＝11.6Hz,1H),3.26(dd,J1＝17.0Hz,J2＝5.4Hz,1H),3.08(dd,J1＝17.1Hz,J2＝4.2Hz,1H),2.10(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝160.9,157.2(d,J＝239.2Hz),151.8,150.1(d,J＝2.2Hz),138.7,132.5(q,J＝33.5Hz,2C),123.1(q,J＝273.3Hz,2C),120.3(d,J＝7.6Hz),119.4(d,J＝4.0Hz,2C),117.7-117.5(m),117.5,115.7(d,J＝23.0Hz),114.5(d,J＝23.2Hz),75.0,66.9,29.9,9.8ppm；HRMS(ESI-TOF):calcd.[M+Na]+487.0863；found:487.0863.
from the above data and FIGS. 7 and 8, it can be seen that intermediate II has the following structure:
(3) adding the intermediate product II (46.4mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, solvent is evaporated from the eluent to obtain 13.9mg of final product III (yield is 83%), and the final product III is the benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
Example 5:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (165.6mg, 0.3mmol), palladium acetate (6.8mg, 0.03mmol), N-fluorobisbenzenesulfonamide (0.142g, 0.45mmol), 1, 2-dichloroethane (3mL) was charged in a closed reaction vessel and sealed at 75 deg.CThe stirring is stopped for reaction for 24 hours, and R in the compound I1、R3、R4Are each hydrogen, R2Is benzoyl;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 140.2mg of an intermediate product II (yield is 85%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
1H NMR(500MHz,CDCl3)δ＝8.84(s,1H),8.12(s,2H),7.76(d,J＝7.0Hz,2H),7.69(d,J＝2.0Hz,1H),7.64(d,J＝8.3Hz,2H),7.58(t,J＝7.5Hz,1H),7.48(t,J＝7.6Hz,2H),6.92(d,J＝8.5Hz,1H),4.88(dd,J1＝4.7Hz,J2＝2.2Hz,1H),4.50(ddd,J1＝11.7Hz,J2＝4.7,J3＝2.0Hz,1H),4.35(d,J＝11.7Hz,1H),3.29(dd,J1＝17.0Hz,J2＝5.0Hz,1H),3.15(dd,J1＝17.1Hz,J2＝3.1Hz,1H),2.09(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝195.6,160.8,157.9,152.0,138.7,138.1,132.8,132.4(q,J＝33.6Hz,2C),132.0,130.7,130.6,129.7(s,2C),128.2(s,2C),123.0(q,J＝273.3Hz,2C),119.4(d,J＝3.7Hz,2C),118.9,118.0-117.4(m),116.3,74.7,67.1,29.6,9.9ppm；HRMS(ESI-TOF):calcd.[M+Na]+573.1219；found:573.1221.
from the above data and FIGS. 9 and 10, it can be seen that intermediate II has the following structure:
(3) adding the intermediate product II (55.0mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, solvent is evaporated from the eluent to obtain 20.6mg of final product III (yield 81%), and the final product III is the benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
Example 6:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (144.6mg, 0.3mmol), palladium acetate (6.8mg, 0.03mmol), N-fluorobis-benzenesulfonamide (0.142g, 0.45mmol), and toluene (3mL) were added to a closed reaction vessel, and the reaction was stirred at 90 ℃ for 24 hours while sealing, wherein R in compound I is1、R2、R4Are each hydrogen, R3Is chlorine;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 118.1mg of an intermediate product II (yield is 82%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
1H NMR(500MHz,CDCl3)δ＝8.65(s,1H),8.07(s,2H),7.63(s,1H),7.12(t,J＝8.1Hz,1H),7.04(d,J＝8.0Hz,1H),6.83(d,J＝8.3Hz,1H),4.93-4.86(m,1H),4.40(ddd,J1＝11.7Hz,J2＝4.7Hz,J3＝1.8Hz,1H),4.25(d,J＝11.7Hz,1H),3.22(dd,J1＝17.9Hz,J2＝5.7Hz,1H),3.14(dd,J1＝17.8Hz,J2＝2.6Hz,1H),2.12(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝160.8,155.3,151.8,138.7,134.7,132.5(q,J＝33.6Hz,2C),127.9,123.1(q,J＝273.2Hz,2C),121.8,119.4(d,J＝4.1Hz,2C),118.3,118.0-117.1(m),115.3,74.9,66.7,28.3,9.8ppm；HRMS(ESI-TOF):calcd.[M+Na]+503.0568；found:503.0568.
from the above data and FIGS. 11 and 12, it can be seen that intermediate II has the following structure:
(3) adding the intermediate product II (48.0mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, solvent is evaporated from the eluent to obtain 14.7mg of final product III (yield is 80%), and the final product III is the benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
Example 7:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (157.8mg, 0.3mmol), palladium acetate (6.8mg, 0.03mmol), N-fluorobis-benzenesulfonamide (0.142g, 0.45mmol), 1, 2-dichloroethane (4.5mL) were charged into a closed reaction vessel, and the reaction was stirred at 90 ℃ for 24 hours while sealing, whereby R in compound I was1、R2、R3Are each hydrogen, R4Is bromine;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 127.3mg of an intermediate product II (yield is 81%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
1H NMR(500MHz,CDCl3)δ＝8.64(s,1H),8.07(s,2H),7.63(s,1H),7.42(d,J＝8.0Hz,1H),7.07(d,J＝7.6Hz,1H),6.82(t,J＝7.7Hz,1H),4.88-4.85(m,1H),4.52(ddd,J1＝11.7Hz,J2＝4.8Hz,J3＝1.9Hz,1H),4.39(d,J＝11.2Hz,1H),3.30(dd,J1＝17.3Hz,J2＝4.6Hz,1H),3.12(dd,J1＝17.0Hz,J2＝3.3Hz,1H),2.10(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝160.8,151.8,150.7,138.7,132.5(q,J＝33.5Hz,2C),131.5,129.0,123.1(q,J＝273.4Hz,2C),121.9,120.9,119.4(d,J＝3.8Hz,2C),117.8-117.3(m),110.7,74.9,67.7,30.0,9.8ppm；HRMS(ESI-TOF):calcd.[M+Na]+547.0062；found:547.0059.
from the above data and fig. 13 and 14, it can be seen that the structure of intermediate II is:
(3) adding the intermediate product II (52.4mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, solvent is evaporated from the eluent to obtain 17.5mg of final product III (yield 77%), and the final product III is the benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
Example 8:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (153.0mg, 0.3mmol), palladium acetate (6.8mg, 0.03mmol), N-fluorobisphenylsulfonamide (0.190g, 0.6mmol), 1, 2-dichloroethane (3mL) were charged into a closed reaction vessel, and the reaction was stirred at 90 ℃ for 24 hours while sealing, wherein R in compound I1And R3Is methyl, R2Is chlorine, R4Is hydrogen;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 129.5mg of an intermediate product II (yield is 85%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
1H NMR(500MHz,CDCl3)δ＝8.75(s,1H),8.11(s,2H),7.64(s,1H),6.68(s,1H),4.88-4.85(m,1H),4.30(ddd,J1＝11.3Hz,J2＝5.3Hz,J3＝1.6Hz,1H),4.22(dd,J1＝11.3Hz,J2＝1.4Hz,1H),3.12(dd,J1＝17.1Hz,J2＝5.8Hz,1H),2.94(dd,J1＝17.1Hz,J2＝4.8Hz,1H),2.34(d,J＝6.1Hz,6H),2.12(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝160.9,152.2,151.8,138.7,135.4,135.2,132.5(q,J＝33.6Hz,2C),127.1,123.1(q,J＝273.3Hz,2C),119.4(d,J＝4.1Hz,2C),118.4-117.4(m),116.7,116.4,75.6,66.2,28.8,20.8,16.3,9.9ppm；HRMS(ESI-TOF):calcd.[M+Na]+531.0881；found:531.0875.
from the above data and FIGS. 15 and 16, it can be seen that intermediate II has the following structure:
(3) adding the intermediate product II (50.8mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, solvent is evaporated from the eluent to obtain 16.7mg of final product III (yield is 79%), and the final product III is the benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
Example 9:
a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:
(1) compound I (144.6mg, 0.3mmol), palladium acetate (6.8mg, 0.03mmol), N-fluorobis-benzenesulfonamide (0.142g, 0.45mmol), 1, 2-dichloroethane (3mL) were charged into a closed reaction vessel, and the reaction was stirred at 90 ℃ for 24 hours while sealing, wherein R in compound I1、R3、R4Are each hydrogen, R2Is chlorine;
(2) diluting the mixed solution obtained in the step (1) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and performing column chromatography on the residue [ GF254 silica gel; 100-200 mesh; separating and purifying the developing solvent V (petroleum ether)/V (ethyl acetate) ═ 50/1], collecting eluent containing the product, and evaporating the solvent from the eluent to obtain 121.0mg of an intermediate product II (yield is 84%);
the intermediate product II obtained was subjected to structural analysis, and the results were as follows:
1H NMR(500MHz,CDCl3)δ＝8.69(s,1H),8.09(s,2H),7.64(s,1H),7.11(dd,J1＝10.2Hz,J2＝1.7Hz,2H),6.81(d,J＝8.4Hz,1H),4.85-4.82(m,1H),4.40(ddd,J1＝11.7Hz,J2＝4.7Hz,J3＝2.0Hz,1H),4.27(d,J＝11.5Hz,1H),3.24(dd,J1＝17.7Hz,J2＝4.8Hz,1H),3.07(dd,J1＝17.3Hz,J2＝2.8Hz,1H),2.10(s,3H)ppm；13C NMR(126MHz,CDCl3)δ＝160.8,152.7,151.9,138.8,132.5(q,J＝33.6Hz,2C),129.4,127.8,125.9,123.1(q,J＝273.4Hz,2C),120.6,119.4(d,J＝4.1Hz,2C),117.9,117.8-117.2(m),74.8,66.9,29.6,9.8ppm；HRMS(ESI-TOF):calcd.[M+Na]+503.0568；found:503.0565.
from the above data and FIGS. 17 and 18, it can be seen that intermediate II has the following structure:
(3) adding the intermediate product II (48.0mg, 0.1mmol), molybdenum hexacarbonyl (33mg, 0.1mmol), acetonitrile (3mL) and water (4drops) into a 25mL closed reaction vessel, and reacting the mixture at 90 ℃ for 12h under the protection of nitrogen in a closed manner and with stirring;
(4) diluting the mixture obtained in step (3) with ethyl acetate (10mL), filtering, removing the solvent under reduced pressure, and subjecting the residue to column chromatography [ GF254 silica gel; 100-200 mesh; the developing solvent is V (petroleum ether)/V (ethyl acetate) ═ 3/1], separation and purification are carried out, eluent containing the product is collected, solvent is evaporated from the eluent to obtain 14.1mg of final product III (yield 76%), and the final product III is the benzopyran-3-alcohol derivative compound according to the structure of the intermediate product II.
As can be seen from the above examples, the benzopyran-3-alcohol derivative compound can be directly prepared by arylation in a cross dehydrogenation coupling mode by using the method of the invention, and the method has the advantages of simple route, high yield, good universality, mild reaction conditions and high selectivity.
Claims (8)
1. A method for synthesizing benzopyran 3 alcohol derivative compounds is characterized by comprising the following steps:
(1) mixing a compound I with a palladium catalyst, an oxidant and a solvent, and carrying out closed stirring reaction for 1-24 hours at the temperature of 70-130 ℃, wherein the structural formula of the compound I is as follows:
wherein R is1Is hydrogen or methyl; r2Is one of hydrogen, methyl, fluorine, chlorine, bromine, phenyl and benzoyl; r3Is one of hydrogen, methyl and chlorine; r4Is hydrogen or bromine; r5Is one of hydrogen, fluorine and methyl or R5And R6To form a pyridine ring; r6Is one of hydrogen, fluorine and trifluoromethyl or R5And R6To form a pyridine ring; r7Is one of hydrogen, methyl, fluorine and trifluoromethyl; r8Is one of hydrogen, fluorine and trifluoromethyl; r9Is one of hydrogen, fluorine and methyl;
the palladium catalyst is palladium acetate or palladium chloride; the oxidant is N-fluoro-diphenyl sulfonamide or Selectfluor; the solvent is 1, 2-dichloroethane or toluene;
(2) carrying out post-treatment on the mixed solution obtained in the step (1) to obtain an intermediate product II; the structural formula of the intermediate product II is as follows:
(3) mixing the intermediate product II with a catalyst, acetonitrile and water, replacing air with nitrogen, and carrying out closed stirring reaction for 1-24 h at 70-130 ℃, wherein the catalyst is molybdenum hexacarbonyl;
(4) carrying out post-treatment on the mixed solution obtained in the step (3) to obtain a final product III benzopyran 3 alcohol derivative compound; the structural formula of the final product III is as follows:
2. the method as claimed in claim 1, wherein the ratio of the amount of the compound I to the amount of the palladium catalyst material in the step (1) is 1: (0.05-0.15).
3. The method for synthesizing benzopyran 3 alcohol derivatives according to claim 1, wherein the ratio of the amount of the compound I to the amount of the oxidant in step (1) is 1: (1.0-3.0).
4. The method for synthesizing benzopyran 3 alcohol derivatives according to claim 1, wherein the volume of the solvent used in step (1) is 0.5 to 5 mL/mmol.
5. The method for synthesizing benzopyran 3 alcohol derivatives as claimed in claim 1, wherein the post-treatment method in step (2) is: adding ethyl acetate into the mixed solution obtained in the step (1) for dilution, filtering, distilling the filtrate under reduced pressure to remove the solvent, separating the residue by column chromatography, taking the mixed solution of petroleum ether and ethyl acetate as an eluent, collecting the eluent containing the product, and distilling the eluent to remove the solvent to obtain an intermediate product II.
6. The method for synthesizing benzopyran 3 alcohol derivatives as claimed in claim 1, wherein the ratio of the amount of intermediate II to the amount of catalyst substance in step (3) is 1 (1.0-5.0).
7. The method for synthesizing benzopyran 3 alcohol derivatives as claimed in claim 1 or 6, wherein in step (3), the volume of acetonitrile is 1-5 mL/mmol and the volume of water is 1-10 drops/mmol based on the substance of intermediate product II.
8. The method for synthesizing benzopyran 3 alcohol derivatives as claimed in claim 1, wherein the post-treatment method in step (4) is: and (3) distilling the mixed solution obtained in the step (3) under reduced pressure to remove the solvent, adding water, extracting with ethyl acetate, drying the organic phase, distilling under reduced pressure to remove the solvent, separating the residue by column chromatography, collecting the eluent containing the product by taking the mixed solution of petroleum ether and ethyl acetate as an eluent, and evaporating the eluent to remove the solvent to obtain the final product III.
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