CN112961138B - Polysubstituted chromone derivative and synthetic method thereof - Google Patents
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Abstract
The invention discloses a polysubstituted chromone derivative and a synthetic method thereof. The method comprises the steps of taking dimethylamino ethyl acetophenone and a diazo compound as raw materials, and carrying out intermolecular cross-coupling cyclization reaction on the dimethylamino ethyl acetophenone and the diazo compound under the conditions of transition metal catalysis, auxiliary agent promotion and alkaline additives to construct the polysubstituted chromone derivative in one step. The method has the advantages of easily obtained and stable raw materials, wide substrate adaptability, simple preparation method, simple and convenient operation, easy realization of reaction conditions, safety, environmental protection, one-step construction of the chromone ring, less side reaction and high yield of target products. The functional groups of the polysubstituted chromone derivative have diversity and can be widely applied to the field of medicine.
Description
Technical Field
The invention relates to a polysubstituted chromone derivative and a synthesis method thereof, belonging to the field of medicine synthesis.
Background
Polysubstituted chromones are the basic backbone for many active natural products and pharmaceutically active molecules; the research finds that the natural products and the drug active molecules with the skeleton are up to hundreds of kinds, and have wide biological activity (mol.Divers.2020, doi:10.1007/s11030-020-10123-0; in addition, some of the compounds also show the activities of resisting platelet aggregation, easing pain, reducing blood fat, destroying blood vessels, resisting estrogen coagulation and relieving spasm, breaking DNA, causing mutagenicity and the like. It was found that MX58151 (2-amino-7-dimethylamino-4- (3-bromo-4,5-dimethoxyphenyl) -4H-3-chromone carbonitrile) has a significant inhibitory effect on the growth of human uterine sarcoma (j.med.chem.2004, 47,6299.); SP-6-27 (2-amino-7-dimethylamino-4- (4- (1-dimethylaminonaphthyl)) -4H-3-chromone carbonitrile) has inhibitory activity against melanoma and prostate cancer cell lines (bioorg.med.chem.lett.2012, 22,4458.); daedalin a is an active species with tyrosinase inhibitory effect extracted from daedalaiadickingsii mycelium culture broth (biosci.biotechnol.biochem.2007, 71,70266-1.); dalen is a flavanone extracted from Dayeqing, and has significant inhibiting effect on tyrosinase-diene alcoholizing enzyme activity, and the inhibiting effect is equivalent to that of kojic acid. Therefore, the polysubstituted chromone has wide application in the biological science and the pharmaceutical chemistry, and the synthesis of the compound has important significance.
At present, the synthesis of the polysubstituted chromone compound is mainly realized by performing derivatization or multistep condensation reaction on the existing chromone skeleton, and the initial raw materials need to be pre-functionalized or toxic and unstable raw materials need to be used, and the reaction conditions are harsh, so that the process is complicated, and the total yield is reduced due to side reactions easily caused. Therefore, a simple and easily obtained reaction substrate is designed, the polysubstituted chromone derivative is constructed in one step, the diversity of functional groups is enriched, and a new way which is more green, concise, easy to realize, high-efficiency and high-yield is provided for synthesizing novel polysubstituted chromone molecules with potential biological activity and pharmaceutical activity, so that the problem to be solved urgently is formed. The invention is therefore proposed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a polysubstituted chromone derivative and a synthetic method thereof. The method has the advantages of easily obtained and stable raw materials, simple preparation method, simple and convenient operation, easily realized reaction conditions, safety, environmental protection, one-step construction of chromone rings, less side reactions and high yield of target products.
Description of terms:
a compound of formula II: dimethylamino vinyl acetophenone;
a compound of formula III: a diazo compound;
a compound of formula I: a polysubstituted chromone derivative.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a polysubstituted chromone derivative has the structure shown in the following general formula I:
in the general formula I:
R 1 is methyl, ethyl, propyl, butyl, isopropyl, tert-butyl or benzyl;
R 2 is methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, trifluoromethyl, phenyl or substituted aryl; the substituent of the substituted aryl is one or more than two of fluorine, chlorine, bromine, iodine, methyl or methoxy, and the number of the substituents is 1,2, 3, 4 or 5;
R 3 hydrogen, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, carbonyl, ester group, alkyl with 1-18 carbon atoms, benzyl or substituted aryl; the substituent of the substituted aryl is one or more than two of fluorine, chlorine, bromine, iodine, methyl or methoxy, and the number of the substituents is 1,2, 3, 4 or 5.
Preferred according to the invention are those of the formula I:
R 1 is methyl, ethyl or tert-butyl;
R 2 is methyl, ethyl, propyl, butyl, cyclopropyl or phenyl;
R 3 is hydrogen, methoxy, fluorine, chlorine, bromine or iodine.
Preferably, in formula I:
R 1 is methyl or ethyl;
R 2 is methyl or ethyl;
R 3 is hydrogen, methoxy or chlorine.
The synthesis method of the polysubstituted chromone derivative comprises the following steps:
in a solvent, under the conditions of transition metal catalyst catalysis, auxiliary agent promotion and alkalinity, a compound of a formula II and a compound of a formula III generate cross coupling reaction to obtain a polysubstituted chromone derivative I;
wherein, in the structural formula of the compound of the formula II, a substituent R 3 And the substitution position and R in the general formula I 3 The same; in the structural formula of the compound of the formula III, a substituent R 1 、R 2 Are respectively connected with R in the general formula I 1 、R 2 The same is true.
According to a preferred embodiment of the invention, the solvent is dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), hexamethylphosphoramide (HMPA), toluene, 1,4-dioxane, acetic anhydride (Ac) 2 O), 1,2-Dichloroethane (DCE), dichloromethane (DCM), ethanol or water; preferably, the solvent is DCM or DCE; the volume ratio of the total amount of the compound of the formula II and the compound of the formula III to the solvent is 0.01-1.0mol/L; preferably, the volume ratio of the total amount of the compound of the formula II and the compound of the formula III to the solvent is 0.1 to 0.5mol/L.
According to the invention, the compounds of the formula II can be prepared according to the prior art.
Preferably according to the invention, the molar ratio of the compound of formula II to the compound of formula III is 1:1-5; preferably, the molar ratio of the compound of formula II to the compound of formula III is 1:2-4, most preferably 1:3.
According to a preferred embodiment of the invention, the transition metal catalyst is trivalent rhodium [ Cp + RhCl ] 2 ] 2 、[Cp*Rh(MeCN) 3 ](SbF 6 ) 2 Or Cp Rh (OAc) 2 (ii) a Preferably, the transition metal catalyst is [ Cp × RhCl 2 ] 2 (ii) a The molar ratio of the transition metal catalyst to the compound of formula II is 0.01 to 0.1; preferably, the molar ratio of the transition metal catalyst to the compound of formula II is from 0.03 to 0.08.
According to the invention, the auxiliary agent is AgSbF 6 、AgBF 4 、AgPF 6 、AgOAc、Cu(OAc) 2 Or a mixture of two or more of NaOAc;preferably, the auxiliary agent is AgSbF 6 And AgOAc; the molar ratio of the auxiliary agent to the compound of the formula II is 0.1-0.5; preferably, the molar ratio of the auxiliary agent to the compound of formula II is 0.2 to 0.4. The present invention converts a catalyst precursor to an active catalyst species by adding a promoter.
Preferably, according to the invention, the base is Cs 2 CO 3 、LiOAc、NaOAc、KOAc、Na 2 CO 3 Or Li 2 CO 3 One or a mixture of two or more of them; preferably, the base is Li 2 CO 3 (ii) a The molar ratio of the base to the compound of formula II is 1-5:1; preferably, the molar ratio of the base to the compound of formula II is from 1 to 3:1, most preferably 2:1. The invention controls the alkaline environment by adding alkali and accepts hydrogen lost in the reaction process of reactants.
According to the present invention, the reaction atmosphere of the cross-coupling reaction is preferably one or a combination of two or more of air, oxygen, nitrogen or argon.
Preferably, according to the invention, the reaction temperature of the cross-coupling reaction is between 0 and 150 ℃; preferably, the reaction temperature of the cross-coupling reaction is 80 to 120 ℃ and more preferably 100 to 120 ℃. The reaction time of the cross-coupling reaction is 1-48 hours; preferably, the reaction time for the cross-coupling reaction is 22 to 26 hours, most preferably 24 hours.
According to the invention, after the compound of formula II and the compound of formula III are subjected to cross-coupling reaction, the product can be separated and characterized according to a conventional separation and purification method. Preferably, the post-treatment step of the reaction solution obtained after the cross-coupling reaction between the compound of formula II and the compound of formula III is as follows: separating the reaction solution by silica gel column chromatography to obtain polysubstituted chromone derivative I, wherein the eluent is mixed solution of petroleum ether (boiling point of 60-90 ℃) and ethyl acetate; more preferably, in the petroleum ether/ethyl acetate mixture, the volume ratio of petroleum ether to ethyl acetate is 10.
The synthetic route of the invention is as follows:
wherein, in formula I:
R 1 is methyl, ethyl, propyl, butyl, isopropyl, tert-butyl or benzyl;
R 2 is methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, trifluoromethyl, phenyl or substituted aryl; the substituent of the substituted aryl is one or more than two of fluorine, chlorine, bromine, iodine, methyl or methoxy, and the number of the substituents is 1,2, 3, 4 or 5;
R 3 hydrogen, methoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, carbonyl, ester group, alkyl with 1-18 carbon atoms, benzyl or substituted aryl; the substituent of the substituted aryl is one or more than two of fluorine, chlorine, bromine, iodine, methyl or methoxy, and the number of the substituents is 1,2, 3, 4 or 5.
In the structural formula of the compound of formula II, a substituent R 3 And the substitution position and R in the general formula I 3 The same; in the structural formula of the compound of the formula III, a substituent R 1 、R 2 Are respectively connected with R in the general formula I 1 、R 2 The same is true.
The invention has the technical characteristics and beneficial effects that:
1. in the invention, under the catalysis of transition metal and the promotion of auxiliary agent, dimethylamino ethyl acetophenone II and diazo compound III are subjected to cross coupling cyclization reaction to synthesize the polysubstituted chromone derivative I. The reaction directly prepares the polysubstituted chromone derivative I by site-selective multiple C-H bond activation, carbene insertion, cyclization coupling and other processes through a one-pot method, avoids the separation of intermediates, and has simple preparation steps. The steps and conditions of the invention are taken as a whole, and the smooth preparation of the target product of the invention is realized under the combined action; and excellent effects are achieved by optimizing the preparation conditions and the like.
2. Compared with the existing synthesis method of the polysubstituted chromone derivative, the method has the advantages of easily available and stable raw materials, capability of preparing the polysubstituted chromone derivative in one step, concise and efficient preparation method, simple and convenient operation, easy realization of reaction conditions, safety, environmental protection, less side reactions, high yield of target products and high yield of more than 80 percent. The polysubstituted chromone derivative prepared by the invention has good functional group diversity and potential pharmaceutical activity. The method provides a new idea for the synthesis of novel chromone medicines.
Detailed Description
The present invention is further illustrated by the following specific examples, but the present invention is not limited thereto.
The methods described in the examples are conventional methods unless otherwise specified; the reagents used are commercially available or can be prepared according to the prior art, unless otherwise specified.
The yields in the examples are mass yields.
The synthesis method of the raw material dimethylamino vinyl acetophenone II can be found in the documents of org.Lett.2018,20,3975.
Example 1
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the preparation method comprises the following specific steps: a25 mL reaction tube was charged with dimethylaminovinylacetophenone IIa (35mg, 0.2mmol), diazo compound IIIa (93.7mg, 0.6mmol) and [ Cp + RhCl ] 2 ] 2 (5.1mg,0.008mmol)，AgSbF 6 (11mg,0.032mmol)，AgOAc(6.7mg,0.04mmol)，Li 2 CO 3 (30mg,0.4mmol)；N 2 Dichloromethane (2 mL) was added under protection and the reaction was carried out at 100 ℃ for 24 hours. Then, the residue was subjected to silica gel column chromatography (eluent: petroleum ether (boiling point 60 to 90 ℃ C.)/ethyl acetate =10:1,v/v) to obtain yellow liquid Ia (58 mg, yield 78%), and the target product was confirmed by NMR spectroscopy and high-resolution mass spectrometry.
Characterization data for the polysubstituted chromone derivative Ia:
a polysubstituted chromanone derivative Ia, a red solid;
1 H NMR(400MHz,CDCl 3 )δ8.40(d,J＝8.3Hz,1H),7.76–7.66(m,2H),7.61(m,1H),4.54(q,J＝7.1Hz,2H),4.43(q,J＝7.1Hz,2H),2.88(s,3H),2.58(s,3H),1.43(m,6H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ176.0,169.3,165.1,163.7,154.7,132.8,131.7,130.9,130.2,126.9,124.6,122.5,122.4,121.0,118.2,62.0,61.9,19.7,18.9,14.4,14.3.HRMS Calcd for C 21 H 20 O 6 [M+H] + :369.1333；Found:369.1341.
example 2
A polysubstituted chromone derivative has a structure shown in a formula Ib as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the structural formula of the reaction substrate is shown as IIb (41mg, 0.2mmol); the other steps and conditions were identical to those of example 1.
This example gives 64mg of the polysubstituted chromone derivative Ib in 80% yield.
Characterization data for the polysubstituted chromone derivative Ib:
polysubstituted chromone derivative Ib, red solid.
1 H NMR(400MHz,CDCl 3 )δ8.55(d,J＝3.1Hz,1H),7.75(d,J＝15.0Hz,1H),7.08(dd,J＝15.0,3.1Hz,1H),4.34(q,J＝11.7Hz,2H),4.19(q,J＝11.8Hz,2H),3.81(s,3H),2.54(s,3H),2.09(s,3H),1.28(m,6H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ184.9,171.3,166.5,163.3,162.8,151.3,143.0,138.2,125.3,123.2,120.0,117.7,115.7,111.8,107.8,61.4,61.22(s),56.0,19.3,17.1,14.6.HRMS Calcd for C 12 H 22 O 7 [M+H] + :399.1438；Found:399.1440.
Example 3
A polysubstituted chromone derivative has a structure shown as the following formula Ic, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the structural formula of the reaction substrate is shown as IIc (42mg, 0.2mmol); the other steps and conditions were identical to those of example 1.
This example gave 61mg of the polysubstituted chromone derivative Ic in 75% yield.
Characterization data for the polysubstituted chromone derivative Ic:
polysubstituted chromone derivative Ic, red solid.
1 H NMR(400MHz,CDCl 3 )δ8.00(d,J＝15.0Hz,1H),7.78(d,J＝3.1Hz,1H),7.53(dd,J＝15.0,2.9Hz,1H),4.34(q,J＝11.7Hz,2H),4.19(q,J＝11.8Hz,2H),2.54(s,3H),2.09(s,3H),1.28(m,6H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ184.9,171.3,166.5,163.3,149.7,143.2,140.7,137.0,129.1,128.3,126.2,125.1,123.1,113.9,111.8,61.44,61.2,19.3,17.1,14.6.HRMS Calcd for C 21 H 19 O 6 Cl[M+H] + :403.0943；Found:403.0950.
Example 4
A polysubstituted chromone derivative has the structure shown as the following formula Id, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the structural formula of the reaction substrate is shown as IIIb (85.3mg, 0.6mmol); the other steps and conditions were identical to those of example 1.
This example gives 54mg of the polysubstituted chromone derivative Id in 79% yield.
Characterization data for the polysubstituted chromone derivative Id:
polysubstituted chromone derivative Id, red liquid.
1 H NMR(400MHz,CDCl 3 )δ8.95(dd,J＝6.8,2.1Hz,1H),8.24(dd,J＝6.9,2.0Hz,1H),7.88–7.52(m,2H),3.90(s,3H),3.71(s,3H),2.54(s,3H),2.09(s,3H).. 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ184.9,171.2,167.1,162.8,151.0,141.9,137.3,130.3,127.1,126.7,126.6,124.4,122.3,118.3,111.3,52.1,52.0,19.3,17.1.HRMS Calcd for C 19 H 16 O 6 [M+H] + :341.1020；Found:341.1025.
Example 5
A polysubstituted chromone derivative has a structure shown as the following formula Ie, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the structural formula of the reaction substrate is shown as IIIc (102.1mg, 0.6 mmol); the other steps and conditions were identical to those of example 1.
This example gives 65mg of the polysubstituted chromone derivative Ie in 82% yield.
Characterization data for the polysubstituted chromone derivative Ie:
polysubstituted chromone derivative Ie, red solid.
1 H NMR(400MHz,CDCl 3 )δ9.00–8.87(m,1H),8.33–8.19(m,1H),7.81–7.64(m,1H),4.34(q,J＝11.7Hz,1H),4.19(q,J＝11.8Hz,1H),2.82(q,J＝13.2Hz,1H),2.65(q,J＝13.4Hz,1H),1.41–1.15(m,3H),1.01(t,J＝13.4Hz,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 )δ181.2,170.6,165.6,164.1,148.8,141.7,136.7,134.1,130.2,127.0,126.7,126.2,124.4,122.6,116.3,61.4,61.2,26.5,24.6,14.6,13.8,9.7.HRMS Calcd for C 23 H 24 O 6 [M+H] + :397.1646；Found:397.1650.
Example 6
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the reaction catalyst is [ CpRh (MeCN) 3 ](SbF 6 ) 2 (13.3mg, 0.016mmol); the other steps and conditions were identical to those of example 1.
This example gives 48mg of the polysubstituted chromaone derivative Ia in a yield of 65%.
Example 7
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the reaction catalyst is CpRh (OAc) 2 (5.8mg, 0.016mmol); the other steps and conditions were identical to those of example 1.
This example gives 40mg of the polysubstituted chromone derivative Ia in 54% yield.
Example 8
A polysubstituted chromone derivative has a structure shown as formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the reaction auxiliary agent is AgBF 4 (2mg, 0.032mmol), agOAc (6.7mg, 0.04mmol); the other steps and conditions were identical to those of example 1.
This example gives 40mg of the polysubstituted chromone derivative Ia in 54% yield.
Example 9
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the reaction auxiliary agent is AgSbF 6 (11mg,0.032mmol)、Cu(OAc) 2 (7.3mg, 0.04mmol); the other steps and conditions were identical to those of example 1.
This example gives 19.5mg of the polysubstituted chromone derivative Ia in a yield of 26%.
Example 10
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the reaction auxiliary agent is AgSbF 6 (111mg, 0.032mmol), naOAc (3.3mg, 0.04mmol); the other steps and conditions were identical to those of example 1.
This example gives 37mg of the polysubstituted chromone derivative Ia in 50% yield.
Example 11
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the base used for the reaction was LiOAc (26.4mg, 0.4mmol); the other steps and conditions were identical to those of example 1.
This example gives 24mg of the polysubstituted chromone derivative Ia in a yield of 32%.
Example 12
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the base used in the reaction is Na 2 CO 3 (42.4mg, 0.4mmol); the other steps and conditions were identical to those of example 1.
This example gives 9mg of the polysubstituted chromone derivative Ia in a yield of 12%.
Example 13
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the solvent used in the reaction is toluene; the other steps and conditions were identical to those of example 1.
This example gives 15mg of the polysubstituted chromone derivative Ia in 20% yield.
Example 14
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and the differences from the example 1 are as follows: the solvent used in the reaction is 1,2-Dichloroethane (DCE); the other steps and conditions were identical to those of example 1.
This example gives 52mg of the polysubstituted chromone derivative Ia in a yield of 70%.
Example 15
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the reaction temperature is 80 ℃; the other steps and conditions were identical to those of example 1.
This example gives 30mg of the polysubstituted chromone derivative Ia in 41% yield.
Example 16
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and the differences from the example 1 are as follows: the reaction temperature is 120 ℃; the other steps and conditions were identical to those of example 1.
This example gives 52mg of the polysubstituted chromone derivative Ia in a yield of 70%.
Example 17
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: reaction catalyst [ Cp RhCl 2 ] 2 The amount of (2.5mg, 0.004mmol); the other steps and conditions were identical to those of example 1.
This example gives 32mg of the polysubstituted chromone derivative Ia in 42% yield.
Example 18
A polysubstituted chromone derivative has a structure shown as formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the amount of the reaction substrate IIIa was (62.5mg, 0.4 mmol); the other steps and conditions were identical to those of example 1.
This example gives 24mg of the polysubstituted chromone derivative Ia in a yield of 32%.
Comparative example 1
A polysubstituted chromone derivative has a structure shown as formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: no auxiliary AgSbF is added in the reaction 6 (ii) a The other steps and conditions were identical to those of example 1.
The present comparative example did not give the polysubstituted chromone derivative Ia in a 0% yield. From this comparative example, it is understood that the reaction assistant plays an important role in smoothly proceeding the reaction.
Comparative example 2
A polysubstituted chromone derivative has a structure shown as the following formula Ia, and the reaction route is as follows:
the specific preparation steps are the same as those of the example 1, and are different from the example 1 in that: the solvent used in the reaction is N, N-Dimethylformamide (DMF); the other steps and conditions were identical to those of example 1.
The present comparative example did not give the polysubstituted chromone derivative Ia in a 0% yield. As is clear from this comparative example, the selection of the type of solvent also plays an important role in the smooth progress of the reaction.
Claims (10)
1. A method for synthesizing a polysubstituted chromone derivative is characterized in that the polysubstituted chromone derivative has a structure shown in a general formula I:
in formula I: r 1 Is methyl or ethyl; r 2 Is methyl or ethyl; r 3 Is hydrogen, methoxy or chlorine;
the preparation method of the polysubstituted chromone derivative comprises the following steps:
in a solvent, under the conditions of transition metal catalyst catalysis, auxiliary agent promotion and alkalinity, a compound of a formula II and a compound of a formula III generate cross coupling reaction to obtain a polysubstituted chromone derivative I;
wherein, in the structural formula of the compound of the formula II, a substituent R 3 And the substitution position and R in the general formula I 3 The same; in the structural formula of the compound of the formula III, a substituent R 1 、R 2 Are respectively connected with R in the general formula I 1 、R 2 The same;
the solvent is 1,2-dichloroethane or dichloromethane; the reaction temperature of the cross-coupling reaction is 100-120 ℃; the transition metal catalyst is [ Cp + RhCl 2 ] 2 (ii) a The auxiliary agent is AgSbF 6 And AgOAc; the base is Li 2 CO 3 。
2. The method for synthesizing polysubstituted chromone derivative according to claim 1, wherein the ratio of the total amount of the compound of formula II and the compound of formula III to the volume of the solvent is 0.01-1.0 mol/L.
3. The method for synthesizing polysubstituted chromone derivative according to claim 2, wherein the ratio of the total amount of the compound of formula II and the compound of formula III to the volume of the solvent is 0.1-0.5mol/L.
4. The method for synthesizing polysubstituted chromone derivative according to claim 1, wherein the molar ratio of the compound of formula II to the compound of formula III is 1:3-4.
5. The method of claim 4, wherein the molar ratio of the compound of formula II to the compound of formula III is 1:3.
6. A method of synthesising a polysubstituted benzotriazol derivative according to claim 1, comprising one or more of the following conditions:
i. the molar ratio of the transition metal catalyst to the compound of formula II is 0.03-0.08;
ii. The molar ratio of the auxiliary agent to the compound of the formula II is 0.1-0.5;
iii, the molar ratio of the base to the compound of formula II is 1-5:1.
7. The method of synthesizing polysubstituted chromone derivatives according to claim 6, comprising one or more of the following conditions:
i. the molar ratio of the transition metal catalyst to the compound of formula II is 0.04;
ii. The molar ratio of the auxiliary agent to the compound of the formula II is 0.2-0.4;
iii, the molar ratio of the base to the compound of formula II is 1-3:1.
8. The method for synthesizing polysubstituted chromone derivative according to claim 1, wherein the reaction atmosphere of the cross-coupling reaction is one or a combination of two or more of air, oxygen, nitrogen or argon.
9. The method for synthesizing polysubstituted chromone derivative according to claim 1, wherein the post-treatment step of the reaction solution obtained after the cross-coupling reaction between the compound of formula II and the compound of formula III is as follows: and (3) carrying out chromatographic separation on the reaction liquid by using a silica gel column to obtain a polysubstituted chromone derivative I, wherein the eluent is petroleum ether/ethyl acetate mixed liquid.
10. The method of synthesizing a polysubstituted chromone derivative according to claim 9, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether/ethyl acetate mixture is 10.
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| "Controllable Rh(III)-Catalyzed Annulation between Salicylaldehydes and Diazo Compounds: Divergent Synthesis of Chromones and Benzofurans";Sun, Peng等;《Organic Letters》;20161201;第18卷(第24期);6464-6467 * |
| "Enaminones as Synthons for a Directed C-H Functionalization: RhIII-Catalyzed Synthesis of Naphthalenes";Zhou, Shuguang等;《Angewandte Chemie, International Edition》;20160615;第55卷(第32期);9384-9388 * |
| "Synthesis of 2-aminofurans and 2-unsubstituted furans via carbenoid-mediated [3 + 2] cycloaddition";Jiang, Yaojia等;《Chemical Communications》;20120209;第48卷(第25期);1359-7345 * |
| Sun, Peng等."Controllable Rh(III)-Catalyzed Annulation between Salicylaldehydes and Diazo Compounds: Divergent Synthesis of Chromones and Benzofurans".《Organic Letters》.2016,第18卷(第24期), * |
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