Preparation method of 9-benzylmethylfluorene compound
阅读说明：本技术 一种9-苄亚甲基芴类化合物的制备方法 (Preparation method of 9-benzylmethylfluorene compound ) 是由 周云兵 麻洋通 王建龙 蒋丹娜 赵亚恒 李国兴 刘妙昌 吴华悦 于 2021-09-08 设计创作，主要内容包括：本发明公开了一种9-苄亚甲基芴类化合物的合成新策略,利用原位生成的五元环钯中间体与烯基溴类化合物进行氧化加成生成Pd(IV)配合物,然后还原消除和Heck偶联生成9-苄亚甲基芴类化合物,该合成策略具有反应操作简单、目标产物收率高,原子经济性高的优点。(The invention discloses a new synthesis strategy of 9-benzylidene fluorene compounds, which is characterized in that a five-membered ring palladium intermediate generated in situ and an alkenyl bromine compound are subjected to oxidation addition to generate a Pd (IV) complex, and then the Pd (IV) complex is subjected to reduction elimination and Heck coupling to generate the 9-benzylidene fluorene compounds.)
1. The preparation method of the 9-benzylidene fluorene compound is characterized by comprising the following steps:
adding a 2-iodobiphenyl compound shown in formula 1, an alkenyl bromine compound shown in formula 2, a palladium catalyst, an organic phosphine ligand, alkali and an organic solvent into a reactor, heating and stirring the mixture to react under an inert atmosphere, and after the reaction is finished, carrying out post-treatment to obtain a 9-benzylidene fluorene compound shown in formula 3; the reaction formula is as follows:
in the above reaction formula, m is 1,2,3 or 4; n is 1,2,3 or 4; each R is1And/or R2The substituents are independently of one another selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Acyl radical, C6-20Aryl radical, C3-20Heteroaryl group, C7-20Arylalkyl, -CN, -NO2、-OH、C1-6Alkoxy radicalCarbonyl radical, C1-6An acyloxy group; and/or two adjacent R1And/or R2Are connected with each other to form a 3-8 membered ring structure containing or not containing heteroatoms selected from O, N, S and P;
R3,R4independently of one another, from hydrogen, C1-6Alkyl, substituted or unsubstituted C6-20Aryl, substituted or unsubstituted C3-20A heteroaryl group; wherein R is3,R4Not hydrogen at the same time; and said substituted substituents referred to are selected from halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Acyl radical, C6-20Aryl, -CN, -NO2、-OH、C1-6Alkoxycarbonyl group, C1-6An acyloxy group;
wherein the palladium catalyst is selected from Pd (OAc)2、PdCl2、Pd(PPh3)Cl2、Pd(dppf)Cl2、Pd(CH3CN)2Cl2、Pd(PPh3)4、Pd2(dba)3、Pd(dba)2Any one of the above;
the organic phosphine ligand is selected from P (o-tol)3、PPh3、PCy3Any one of DPPB, BINAP;
the alkali is selected from any one or a mixture of more of potassium carbonate, potassium acetate, potassium phosphate, sodium carbonate and cesium carbonate;
the organic solvent is selected from any one or a mixture of DMF, DMSO and NMP.
2. The method of claim 1, wherein m is 1, n is 1; r1,R2Independently of one another, from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, acetyl, phenyl, -CN, -NO2-OH, thienyl, furyl, pyridyl;
R3,R4independently of one another, from hydrogen, methyl, ethyl, tert-butyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substitutedOr unsubstituted furyl, substituted or unsubstituted pyridyl; wherein R is3,R4Not hydrogen at the same time; and said substituted designated substituents are selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, acetyl, phenyl, -CN, -NO2。
3. The process according to claim 1 or 2, wherein the palladium catalyst is selected from Pd (OAc)2(ii) a The organic phosphine ligand is selected from P (o-tol)3(ii) a The alkali is selected from potassium carbonate; the organic solvent is selected from DMSO.
4. The method according to claim 1 or 2, wherein the inert gas atmosphere is selected from a nitrogen or argon atmosphere.
5. The production method according to claim 1 or 2, wherein the reaction temperature of the heating stirring reaction is 80 to 140 ℃; the reaction time is 4-48 hours.
6. The method according to claim 5, wherein the reaction temperature of the heating and stirring reaction is 120 ℃ and the reaction time is 24 hours.
7. The method according to claim 1 or 2, wherein the molar ratio of the 2-iodobiphenyl compound represented by formula 1 to the alkenyl bromide compound represented by formula 2 to the palladium catalyst to the organophosphine ligand to the base is 1 (1-3): 0.001-0.05): 0.002-0.10): 2-5.
8. The method according to claim 7, wherein the 2-iodobiphenyl compound represented by formula 1, the alkenyl bromide compound represented by formula 2, the palladium catalyst, the organophosphine ligand and the base are fed in a molar ratio of 1:2:0.02:0.04: 4.
9. The method according to claim 1 or 2, characterized in that the post-treatment operation is as follows: after the reaction is finished, the reaction mixture is diluted by deionized water, extracted by an organic solvent, then concentrated under reduced pressure, and the residue is purified by silica gel chromatography to obtain the 9-benzylmethylfluorene compound shown in the formula 3.
Technical Field
The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a 9-benzylmethylfluorene compound.
Background
Fluorene compounds are an important class of Polycyclic Aromatic Hydrocarbons (PAHs) that exhibit many unique optoelectronic properties and biological activities due to their specific rigid planar biphenyl structures, some relevant examples include antiarrhythmic drugs (indefinides, a) and plant growth regulators. Recently, a fluorene-based photocatalyst was designed and applied to decarboxylated arylation. Among them, 9- (diorganomethylene) fluorene has attracted considerable attention as a cross-conjugated compound in pharmaceutical chemistry and material chemistry. For example, flunomide is a low-toxicity antimalarial drug, has a remarkable killing effect on animal plasmodium falciparum and human plasmodium falciparum, has a high killing effect on chloroquine-resistant plasmodium falciparum, and can be used for preventing or treating potential multidrug-resistant malaria (for the application of fluorene compounds, see the following documents: mater.technol.,2013,28, 71; polymer.chem., 2011,2, 1919; org.process res.dev.,2007,11, 341; j.med.chem.,2003,46, 4552; biochem.pharmacol, 2000,60, 817; org.lett.,2016,18, 5192; Shi, sci.rep.,2016,6, 33131; org.lett.,2016,18, 2.). Therefore, it is important to develop a novel and easy-to-operate method for synthesizing fluorene compounds with high atom economy.
Disclosure of Invention
The invention aims to provide a new synthesis strategy of 9-benzylidene fluorene compounds, which is characterized in that a five-membered ring palladium intermediate generated in situ and an alkenyl bromine compound are subjected to oxidation addition to generate a Pd (IV) complex, and then the Pd (IV) complex is subjected to reduction elimination and Heck coupling to generate the 9-benzylidene fluorene compounds.
The preparation method of the 9-benzylidene fluorene compound provided by the invention comprises the following steps:
adding a 2-iodobiphenyl compound shown in formula 1, an alkenyl bromine compound shown in formula 2, a palladium catalyst, an organic phosphine ligand, alkali and an organic solvent into a reactor, heating and stirring the mixture to react under an inert atmosphere, and after the reaction is finished, carrying out post-treatment to obtain a 9-benzylidene fluorene compound shown in formula 3; the reaction formula is as follows:
in the above reaction formula, m is 1,2,3 or 4; n is 1,2,3 or 4; each R is1And/or R2The substituents are independently of one another selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Acyl radical, C6-20Aryl radical, C3-20Heteroaryl group, C7-20Arylalkyl, -CN, -NO2、-OH、C1-6Alkoxycarbonyl group, C1-6An acyloxy group; and/or two adjacent R1And/or R2Are connected with each other to form a 3-8 membered ring structure containing or not containing heteroatoms selected from O, N, S and P.
R3,R4Independently of one another, from hydrogen, C1-6Alkyl, substituted or unsubstituted C6-20Aryl, substituted or unsubstituted C3-20A heteroaryl group; wherein R is3,R4Not hydrogen at the same time; and said substituted substituents referred to are selected from halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Acyl radical, C6-20Aryl, -CN, -NO2、-OH、C1-6Alkoxycarbonyl group, C1-6And (4) acyloxy.
Preferably, m is 1, n is 1; r1,R2Independently of one another, from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, acetyl, phenyl, -CN, -NO2OH, -thienyl, furyl and pyridyl.
R3,R4Independently of one another, from hydrogen, methyl, ethyl, tert-butyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyridyl; wherein R is3,R4Not hydrogen at the same time; and said substituted designated substituents are selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, acetyl, phenyl, -CN, -NO2。
The preparation method according to the invention is characterized in that the palladium catalyst is selected from Pd (OAc)2、PdCl2、Pd(PPh3)Cl2、Pd(dppf)Cl2、Pd(CH3CN)2Cl2、Pd(PPh3)4、Pd2(dba)3、Pd(dba)2Etc., preferably Pd (OAc)2。
According to the aforementioned preparation process of the present invention, the organophosphine ligand is selected from P (o-tol)3、PPh3、PCy3Any one of DPPB and BINAP, preferably P (o-tol)3。
According to the preparation method, the alkali is selected from any one or a mixture of more of potassium carbonate, potassium acetate, potassium phosphate, sodium carbonate and cesium carbonate, and potassium carbonate is preferred.
According to the preparation method, the organic solvent is selected from one or a mixture of several of DMF, DMSO and NMP, and DMSO is preferred.
According to the foregoing preparation method of the present invention, the inert atmosphere is selected from a nitrogen or argon atmosphere, and preferably a nitrogen atmosphere.
According to the preparation method of the invention, the reaction temperature of the heating and stirring reaction is 80-140 ℃, preferably 100-120 ℃, and more preferably 120 ℃; the reaction time is 4 to 48 hours, preferably 12 to 24 hours, and more preferably 24 hours.
According to the preparation method, the feeding molar ratio of the 2-iodobiphenyl compound shown in the formula 1, the alkenyl bromine compound shown in the formula 2, the palladium catalyst, the organic phosphine ligand and the alkali is 1 (1-3): 0.001-0.05): 0.002-0.10): 2-5; preferably, the feeding molar ratio of the 2-iodobiphenyl compound shown in the formula 1, the alkenyl bromine compound shown in the formula 2, the palladium catalyst, the organic phosphine ligand and the alkali is 1:2:0.02:0.04: 4.
According to the preparation method of the gelatin, the post-treatment operation is as follows: after the reaction is finished, the reaction mixture is diluted by deionized water, extracted by an organic solvent, then concentrated under reduced pressure, and the residue is purified by silica gel chromatography to obtain the 9-benzylmethylfluorene compound shown in the formula 3.
The method of the invention has the following beneficial effects:
the invention reports a synthesis strategy for preparing 9-benzylidene fluorene compounds by taking 2-iodobiphenyl compounds shown in formula 1 and alkenyl bromine compounds shown in formula 2 as raw materials under the condition of palladium catalysis for the first time, and enriches the ways for preparing 9-benzylidene fluorene compounds in the prior art. The method utilizes the five-membered ring palladium intermediate generated in situ to carry out oxidation addition with the alkenyl bromine compound to generate the Pd (IV) complex, and then carries out reduction elimination and Heck coupling to generate the 9-benzylidene fluorene compound.
Detailed Description
The present invention will be described in more detail with reference to specific examples. In the following, unless otherwise specified, all methods used are conventional in the art, and the reagents involved are commercially available and/or prepared by known synthetic means in the art.
Examples 1-17 optimization of reaction conditions
The 2-iodobiphenyl shown in formula 1 and the bromostyrene shown in formula 2 are used as template substrates, the influence of different catalytic reaction conditions on the synthesis of the 9-benzylidene fluorene shown in formula 3 is researched, and the results are shown in table 1, and the reaction formulas are as follows:
table 1:
taking example 9 as an example, a typical reaction run is as follows:
a10 mL pressure tube equipped with a stirring magneton was charged with 2-iodobiphenyl (0.2mmol) represented by formula 1, bromostyrene (0.4mmol) represented by formula 2, Pd (OAc)2(2mol％),P(o-tol)3(4mol％),K2CO3(4equiv), DMSO (2mL), under nitrogen at 120 ℃ for 24 h. After the reaction was complete, the reaction mixture was diluted with 10mL of deionized water, extracted with ethyl acetate (3X 10mL), and then concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel using petroleum ether as an eluting solvent to give 9-benzylmethylenofluorene of formula 3 (white solid, 50mg, yield 97%).1H NMR(500MHz,CDCl3)δ7.81(d,J＝7.5Hz,1H),7.76–7.70(m,3H),7.65–7.50(m,3H),7.51–7.45(m,2H),7.44–7.37(m,2H),7.37–7.30(m,2H),7.07(t,J＝7.6Hz,1H)；13C NMR(125MHz,CDCl3)δ141.3,139.5,139.2,137.0,136.6,136.6,129.3,128.5,128.2,128.0,127.2,127.0,126.7,124.4,120.2,119.7,119.6。
On the basis of optimizing the reaction conditions (example 9), the inventors further expanded the substrate range, found that the reaction substrates were very tolerant, and most of the substrates had higher yields, with the results as follows:
structural characterization of the product:
a white solid;1H NMR(500MHz,CDCl3)δ7.74(d,J＝7.6Hz,1H),7.71–7.67(m,2H),7.57(s,1H),7.50(dd,J＝8.0,4.9Hz,3H),7.44–7.42(m,2H),7.41–7.36(m,1H),7.33–7.28(m,2H),7.11–7.06(m,1H)；13C NMR(125MHz,CDCl3)δ141.4,139.3,139.3,137.1,136.3,135.4,133.9,130.7,128.8,128.4,127.1,126.8,125.6,124.34,120.3,119.8,119.6。
a white solid;1H NMR(500MHz,CDCl3)δ7.75(d,J＝7.5Hz,1H),7.70(d,J＝7.5Hz,2H),7.60(s,1H),7.53(dd,J＝8.3,5.5Hz,2H),7.49(d,J＝7.8Hz,1H),7.40(t,J＝7.4Hz,1H),7.37–7.31(m,2H),7.13(t,J＝8.6Hz,2H),7.06(t,J＝7.6Hz,1H)；13C NMR(125MHz,CDCl3)δ162.5(d,J＝248.0Hz),141.4,139.4,139.2,136.8,136.4,132.9,131.1,131.0,128.7,128.3,127.0,126.7,126.0,124.2,120.2,119.8,115.7；19F NMR(470MHz,CDCl3)δ-113.21。
a white solid;1H NMR(500MHz,CDCl3)δ7.77(d,J＝7.5Hz,1H),7.71(d,J＝7.6Hz,2H),7.67–7.62(m,2H),7.48(d,J＝7.6Hz,2H),7.36(t,J＝7.4Hz,1H),7.31(q,J＝7.6Hz,2H),7.27–7.22(m,2H),7.06(t,J＝7.6Hz,1H),2.43(s,3H)；13C NMR(125MHz,CDCl3)δ141.2,139.7,139.1,138.0,136.7,136.1,133.9,129.3,129.2,128.4,128.0,127.5,126.9,126.6,124.4,120.2,119.6,119.5,21.4。
a white solid;1H NMR(500MHz,CDCl3)δ7.80–7.75(m,1H),7.73–7.69(m,3H),7.66(s,1H),7.56–7.52(m,2H),7.49–7.44(m,2H),7.38–7.34(m,1H),7.33–7.28(m,2H),7.11–7.06(m,1H),1.39(s,9H)；13CNMR(125MHz,CDCl3)δ151.3,141.2,139.7,139.1,136.7,136.0,133.8,129.2,128.4,128.01,127.5,126.9,126.6,125.4,124.4,120.2,119.7,119.5,34.8,31.4。
a white solid;1H NMR(500MHz,CDCl3)δ7.65(d,J＝7.6Hz,1H),7.58(d,J＝7.6Hz,1H),7.45–7.36(m,10H),7.22(t,J＝7.5Hz,1H),7.06(d,J＝7.7Hz,1H),6.90(t,J＝7.7Hz,1H),6.62(d,J＝7.9Hz,1H),6.38(s,1H),2.11(s,3H)；13C NMR(125MHz,CDCl3)δ145.1,143.1,143.0,140.7,139.0,138.7,138.1,135.9,134.3,129.7,128.8,128.7,128.5,128.1,128.1,127.6,125.9,125.7,124.9,118.9,118.9,21.7。
a white solid;1H NMR(500MHz,CDCl3)δ7.76–7.69(m,2H),7.53–7.49(m,1H),7.46–7.41(m,9H),7.34–7.22(m,7H),6.94(t,J＝7.6Hz,1H),6.86(s,1H),6.68(d,J＝7.9Hz,1H)；13C NMR(125MHz,CDCl3)δ145.7,143.1,142.7,141.2,140.3,139.6,139.3,139.0,138.9,134.3,129.7,129.6,128.9,128.8,128.8,128.5,128.3,128.2,127.8,126.9,126.7,126.4,124.9,123.9,119.5,119.4,77.3,77.0,76.8.HRMS:(ESI)calculated for C32H22[M+H]+407.1794,found 407.1802。
a yellow solid;1H NMR(500MHz,CDCl3)δ7.84–7.79(m,1H),7.60–7.55(m,2H),7.45–7.37(m,9H),7.20(t,J＝7.5Hz,1H),6.88–6.83(m,1H),6.82–6.79(m,1H),6.61(d,J＝7.9Hz,1H),6.15(d,J＝2.5Hz,1H),3.43(s,3H)；13C NMR(125MHz,CDCl3)δ158.6,145.4,142.9,142.7,140.7,140.2,138.4,134.3,133.8,132.4,130.0,129.5,128.9,128.8,128.2,127.7,125.3,124.8,119.9,118.5,115.0,109.7,54.9。
a white solid;1H NMR(500MHz,CDCl3)δ8.33–8.28(m,1H),7.80(d,J＝7.5Hz,1H),7.56–7.52(m,1H),7.47–7.42(m,6H),7.42–7.35(m,4H),7.29(t,J＝7.4Hz,1H),6.99(t,J＝7.6Hz,1H),6.73–6.66(m,2H),2.61(s,3H)；13C NMR(125MHz,CDCl3)δ197.8,148.3,143.1,142.6,142.5,140.8,139.6,139.0,136.1,133.7,129.8,129.7,128.9,128.9,128.7,128.6,127.9,127.0,126.8,124.8,124.7,119.7,118.9,26.7.HRMS:(ESI)calculated for C28H20O[M+H]+373.1587,found 373.1588。
the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
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