CN107445989B - Phosphine ligand with indole skeleton and preparation method and application thereof - Google Patents

Phosphine ligand with indole skeleton and preparation method and application thereof Download PDF

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CN107445989B
CN107445989B CN201610387558.9A CN201610387558A CN107445989B CN 107445989 B CN107445989 B CN 107445989B CN 201610387558 A CN201610387558 A CN 201610387558A CN 107445989 B CN107445989 B CN 107445989B
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bromophenyl
indole
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disubstituted phosphino
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邝福儿
苏秋铭
周永健
原安莹
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Shenzhen Research Institute HKPU
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    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
    • B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
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Abstract

The invention provides a phosphine ligand with a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton, and a preparation method and application thereof. The phosphine ligand of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton has the structure shown in the following formula I:
Figure DDA0001006702650000011
wherein R is hydrogen group, alkyl group, substituted amino group, alkoxy group, alkylene group, aryl group or fluorine, and R is1Is alkyl, substituted alkyl, alkyl ether, oxyalkyl, alkoxy or aryl, said R2Is alkyl, substituted alkyl, alkoxy or fluorine, said R3Is alkyl, substituted alkyl or aryl.

Description

Phosphine ligand with indole skeleton and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic compounds and synthesis, relates to a phosphine ligand with an indole skeleton, and a preparation method and application thereof, and particularly relates to a phosphine ligand with a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton, and a preparation method and application thereof.
Background
In the field of carbon-carbon bond formation, the cross-coupling reaction of Suzuki (Suzuki), hinoki (Hiyama), radicle (Negishi), panda (Kumada), Stille (Stille), and α -monoarylation of carbonyl compounds (α -aromatization of carbon compounds), etc. is a common method for preparing biaryls and/or related compounds.
At present, the commonly used ligand is generally an organic phosphine compound, and the researches on phosphine ligands for years show that the slight changes of the position, the size, the steric hindrance, the electrical property and the like of a substituent group on a phosphine ligand skeleton can generate important influence on the result of the coupling reaction. Among the well-known phosphine ligands, for example: tri-tert-butylphosphine of Fu research group, phosphine ligand of Beller research group, biaryl phosphine ligand of Buchwald research group, phosphine ligand of Hartwig research group and indole phosphine ligand of Kwong research group (the structures are respectively shown in the following formulas) all provide excellent catalytic performance in palladium-catalyzed cross-linking reaction.
Figure BDA0001006702640000021
Fu research team Beller research team Hartwig research team Kwong research team
Different cross-coupling reactions require different catalytic systems, and suitable catalytic systems, especially effective phosphine ligands, are important keys to breaking through the limitations of coupling reactions. Although many phosphine ligands have been widely used in cross-coupling reactions catalyzed by transition metals, designing phosphine ligands with high catalytic activity, stable structure and simple synthesis has great significance in cross-coupling reactions.
Disclosure of Invention
The invention aims to provide a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand, and aims to solve the problem of poor catalytic activity when the existing phosphine ligand is used as a synergist of a transition metal catalyst in cross-coupling reaction.
The invention also aims to provide a preparation method of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand.
The invention aims at providing the application of 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand.
The invention is realized by the following steps that the phosphine ligand of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton has the structure shown as the following formula I:
Figure BDA0001006702640000022
wherein R is hydrogen group, alkyl group, substituted alkyl group, alkoxy group, substituted amino group, alkylene group, aryl group or fluorine, and R is1Is alkyl, alkyl ether, oxyalkyl, alkoxy, substituted alkyl or aryl, said R2Is alkyl, substituted alkyl, alkoxy or fluorine, said R3Is alkyl, substituted alkyl or aryl.
And two methods for preparing phosphine ligands with 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton, wherein,
a method for preparing a phosphine ligand of a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton, which comprises the following steps:
mixing 2 '-bromoacetophenone and N-alkyl phenylhydrazine, adding phosphoric acid as a catalyst, stirring, adding polyphosphoric acid, and carrying out a heating reaction to obtain a 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate, wherein the heating temperature of the heating reaction is 80-120 ℃, and the reaction time is 1-2 hours;
dissolving the 2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate and N-bromosuccinimide in dimethylformamide, and stirring at room temperature to obtain a 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate;
dissolving the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate in tetrahydrofuran, adding n-butyllithium at-75 to-80 ℃, uniformly stirring for 0.5 to 1 hour, then adding disubstituted phosphine chloride, and reacting at room temperature for 12 to 24 hours to obtain the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-1H-indolphosphine ligand.
A method for preparing a phosphine ligand of a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton, which comprises the following steps:
mixing 2 '-bromoacetophenone and phenylhydrazine, adding phosphoric acid as a catalyst, stirring, adding polyphosphoric acid, and carrying out heating reaction to obtain a 2- (2' -bromophenyl) -1H-indole intermediate, wherein the heating temperature of the heating reaction is 80-120 ℃, and the reaction time is 1-2 hours;
mixing the 2- (2 '-bromophenyl) -1H-indole intermediate with sodium hydride and dialkyl sulfate according to the molar ratio of 1 (1.1-2.0) to 1.05-1.5 to form a tetrahydrofuran mixed solution, and stirring at room temperature for 1-2 hours to obtain a 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate;
dissolving the 2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate and N-bromosuccinimide in dimethylformamide, and stirring at room temperature to obtain a 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate;
dissolving the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate in tetrahydrofuran, adding n-butyllithium at-75 to-80 ℃, uniformly stirring for 0.5 to 1 hour, then adding disubstituted phosphine chloride, and reacting at room temperature for 12 to 24 hours to obtain the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-1H-indolphosphine ligand.
And the application of the phosphine ligand of 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton as the synergist of transition metal catalyst in cross-coupling reaction.
The phosphine ligand with the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton provided by the invention can form a complex with a stable structure with transition metal such as palladium metal, so that the catalytic activity of the catalytic reaction of the transition metal such as palladium is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions. The catalytic system formed by the phosphine ligand of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton and transition metal such as palladium metal can be used for preparing various synthetic products such as sulfur-containing compounds, and has great application potential in the synthesis of natural products and pharmaceutical intermediates. Particularly, the catalytic system formed by the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand and palladium metal provided by the invention can be suitable for the reaction of forming carbon-sulfur bonds in aryl bromides, the catalytic activity of a transition metal catalyst such as a palladium catalyst can be as low as 0.5 mol%, the yield is as high as 90%, and the catalytic system has profound significance for cross-coupling reaction. In addition, the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand has stability to air and moisture and is easy to store; and the space structure and the electric property of the ligand can be adjusted by changing the substituent group on the indole, so that the coordination performance of the ligand is changed.
The preparation method of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand provided by the invention has the advantages of simple and easily-obtained raw materials, simple method, high total yield and capability of being prepared in large scale only by a Fischer indole synthesis method, alkylation, bromination and phosphorylation reactions.
The 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand provided by the invention can be widely used as a synergist of a transition metal catalyst, is used for cross-coupling reaction, and forms a complex with a stable structure with a transition metal such as palladium metal, so that the catalytic activity of the transition metal such as palladium during catalytic reaction is improved, and particularly can be suitable for the reaction of forming carbon-sulfur bonds in aryl bromides, the catalytic activity of the transition metal catalyst such as the palladium catalyst can be as low as 0.5 mol%, and the yield is as high as 90%.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand, which has the following structure shown in the formula I:
Figure BDA0001006702640000051
wherein R is hydrogen group, alkyl group, substituted alkyl group, alkoxy group, substituted amino group, alkylene group, aryl group or fluorine, and R is1Is alkyl, substituted alkyl, alkyl ether, alkoxy, oxyalkyl or aryl, said R2Is alkyl, alkoxy, substituted alkyl or fluorine, said R3Is alkyl, substituted alkyl or aryl.
In the structural formula I, particularly preferably, R is one of hydrogen, alkyl of C1-10, alkoxy of C1-C10, cycloalkoxy of C3-C10, dimethylamino, 1, 3-butylene, phenyl, benzyloxy, fluorine and trifluoromethyl; the R is1Is one of C1-C10 alkyl, C3-C10 cycloalkyl, cycloalkyl ether, alkylene oxide alkyl, alkyl alkoxy, alkyl cycloalkyl ether and phenyl; the R is2Is one of C1-C10 alkyl, methoxy, fluorine and trifluoromethyl; the aryl is one of phenyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, o-tolyl, p-tolyl and p-methoxyphenyl.
Still further, in the R, the C1-10 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and C5-10 alkyl groups, the C1-C10 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and C4-C10 alkoxy groups, the C3-C10 cycloalkoxy groups include cyclopropyloxy, cyclobutoxy and C5-C10 cycloalkoxy groups;
the R is1Wherein the C1-C10 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C5-C10 alkyl, the C3-10 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C7-C10 cycloalkyl, the cycloalkyl ether includes tetrahydrofuran, the epoxyalkyl group includes epoxypropyl, the alkylalkoxy group includes methylmethoxy, and the alkylcycloalkyl ether includes methyltetrahydrofuran;
the R is2The C1-C10 alkyl group includes methyl, ethyl and C3-C10 alkyl groups.
The phosphine ligand of the above preferred 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton can be combined with a transition metal such as palladium metal to obtain a catalytic system with better catalytic effect, and various synthetic products such as sulfur-containing compounds can be prepared.
The phosphine ligand with the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton provided by the embodiment of the invention can form a complex with a stable structure with transition metal such as palladium metal, so that the catalytic activity of the catalytic reaction of the transition metal such as palladium is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions. The catalytic system formed by the phosphine ligand of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton and transition metal such as palladium metal can be used for preparing various synthetic products such as sulfur-containing compounds, and has great application potential in the synthesis of natural products and pharmaceutical intermediates. In particular, the catalytic system formed by the phosphine ligand of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton and palladium metal provided by the embodiment of the invention can be suitable for the reaction for forming carbon-sulfur bonds of aryl bromides, the catalytic activity of a transition metal catalyst such as a palladium catalyst can be as low as 0.5 mol%, the yield is as high as 90%, and the catalytic system has profound significance for cross-coupling reaction. In addition, the phosphine ligand with the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton disclosed in the embodiment of the invention has stability to air and moisture and is easy to store; and the space structure and the electric property of the ligand can be adjusted by changing the substituent group on the indole, so that the coordination performance of the ligand is changed.
The phosphine ligands of 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeletons described in the examples of the present invention can be prepared by several methods as described below.
As an example, there is provided a method for preparing a phosphine ligand of a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton, comprising the steps of:
s01, mixing 2 '-bromoacetophenone and N-alkyl phenylhydrazine, adding phosphoric acid as a catalyst, stirring, adding polyphosphoric acid, and carrying out a heating reaction to obtain a 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate, wherein the heating temperature of the heating reaction is 80-120 ℃, and the reaction time is 1-2 hours;
s02, dissolving the 2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate and N-bromosuccinimide in dimethylformamide, and stirring at room temperature to obtain a 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate;
s03, dissolving the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate in tetrahydrofuran, adding n-butyllithium at-75 to-80 ℃, uniformly stirring for 0.5 to 1 hour, then adding disubstituted phosphine chloride, and reacting at room temperature for 12 to 24 hours to obtain the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-1H-indolphosphine ligand.
Specifically, in step S01 above, the reaction scheme for preparing the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate is as follows:
Figure BDA0001006702640000071
in order to obtain better reaction effect, the molar ratio of the 2' -bromoacetophenone to the N-alkyl phenylhydrazine is preferably 1 (1.1-1.2), the stirring treatment is room-temperature stirring treatment, and the stirring time is preferably 0.5-1 hour, more preferably 0.5 hour.
Further preferably, after the reaction is completed, the mixture is poured into ice water, and extracted and separated by adding ether. And combining the organic phases, concentrating, and purifying by column chromatography to obtain the high-purity 2- (2' -bromophenyl) -1-alkyl-1H-indole.
It is noted that the preparation of the embodiment of the present invention can also be prepared by mixing the 2 '-bromoacetophenone and the N-alkyl phenylhydrazine in a molar ratio of 1 (1.1-1.2), adding acetic acid and ethanol, reacting at 70-80 ℃, preferably 80 ℃ for 0.5-1.5 hours, then pumping off all solvents under reduced pressure, adding polyphosphoric acid, and reacting at 80-120 ℃ for 1-2 hours to prepare the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate, wherein the reaction formula is shown as follows:
Figure BDA0001006702640000081
in the step of preparing the 3-bromo-2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate in step S02, as a preferred example, the molar ratio of the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the N-bromosuccinimide is 1 (1.05 to 1.2), and the stirring time is 1 to 2 hours. As a specific example, the 2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate and N-bromosuccinimide in a molar ratio of 1 (1.05-1.2) were dissolved in dimethylformamide and stirred at room temperature for 1-2 hours to give a 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate of the formula:
Figure BDA0001006702640000082
preferably, after the reaction is finished, pouring the product into ice water, adding dichloromethane for extraction and separation; then adding a large amount of water into the organic phase for washing, combining the organic phases, concentrating, and purifying by column chromatography to obtain the high-purity 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate.
In the above step S03, as a preferred example, in the step of preparing the 3- (disubstituted phosphino) -1-alkyl-2-substituted phenyl-indolylphosphine ligand, the molar ratio of the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the n-butyllithium is 1 (1.1 to 1.2); the molar ratio of the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the disubstituted phosphine chloride is 1 (1.1-1.2). As a specific example, the 3-bromo-2- (2 ' -bromophenyl) -1-alkyl-1H-indole intermediate is dissolved in tetrahydrofuran, and n-butyllithium is added, with stirring homogeneously for 0.5 to 1 hour, followed by addition of a disubstituted phosphine chloride, at a temperature of-75 to-80 ℃, more preferably-78 ℃, in a molar ratio of the 3-bromo-2- (2 ' -bromophenyl) -1-alkyl-1H-indole intermediate to the n-butyllithium of 1 (1.1 to 1.2), the 3-bromo-2- (2 ' -bromophenyl) -1-alkyl-1H-indole intermediate to the disubstituted phosphine chloride of 1 (1.1 to 1.2), reacting at room temperature for 12-24 hours to obtain 3- (disubstituted phosphino) -1-alkyl-2-substituted phenyl-indolphosphine ligand, wherein the reaction formula is shown as follows:
Figure BDA0001006702640000091
more preferably, after the reaction is completed, all the solvent is removed under reduced pressure, and the reaction mixture is washed three times with cold methanol to obtain a white powder of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indolphosphine ligand.
The embodiment of the invention also provides a preparation method of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand, which comprises the following steps:
D01. mixing 2 '-bromoacetophenone and phenylhydrazine, adding phosphoric acid as a catalyst, stirring, adding polyphosphoric acid, and carrying out heating reaction to obtain a 2- (2' -bromophenyl) -1H-indole intermediate, wherein the heating temperature of the heating reaction is 80-120 ℃, and the reaction time is 1-2 hours;
D02. mixing the 2- (2' -bromophenyl) -1H-indole intermediate, sodium hydride and dialkyl sulfate according to a molar ratio of 1: (1.1-2.0): (1.05-1.5) to form a tetrahydrofuran mixture, and stirring the tetrahydrofuran mixture at room temperature for 1-2 hours to obtain the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate.
D03. Dissolving the 2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate and N-bromosuccinimide in dimethylformamide, and stirring at room temperature to obtain a 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate;
D04. dissolving the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate in tetrahydrofuran, adding n-butyllithium at-75 to-80 ℃, uniformly stirring for 0.5 to 1 hour, then adding disubstituted phosphine chloride, and reacting at room temperature for 12 to 24 hours to obtain the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-1H-indolphosphine ligand.
Specifically, in step D01 above, the reaction scheme for preparing the 2- (2-bromophenyl) -1H-indole intermediate is as follows:
Figure BDA0001006702640000092
for better reaction effect, the molar ratio of the 2' -bromoacetophenone to the phenylhydrazine is preferably 1: (1.1-1.2), the stirring treatment is room-temperature stirring treatment, and the stirring time is preferably 0.5-1 hour, more preferably 0.5 hour.
Further preferably, after the reaction is completed, the mixture is poured into ice water, and extracted and separated by adding ether. And combining the organic phases, concentrating, and purifying by column chromatography to obtain the high-purity 2- (2' -bromophenyl) -1H-indole.
It is noteworthy that the preparation of the embodiment of the invention can also be realized by mixing the 2' -bromoacetophenone and the phenylhydrazine in a molar ratio of 1: (1.1-1.2), adding acetic acid and ethanol, reacting at 70-80 ℃, preferably 80 ℃ for 0.5-1.5 hours, then decompressing, pumping all solvents away, adding polyphosphoric acid, and reacting at 80-120 ℃ for 1-2 hours to prepare a 2- (2' -bromophenyl) -1H-indole intermediate, wherein the reaction formulas are respectively shown as follows:
Figure BDA0001006702640000101
the reaction scheme for the preparation of the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate in step D02 above is shown below:
Figure BDA0001006702640000102
preferably, the sodium hydride is uniformly stirred in tetrahydrofuran, and then a solution of the mixed 2- (2' -bromophenyl) -1H-indole intermediate and tetrahydrofuran is added and stirred at room temperature for 0.25-0.5 hours; then adding dialkyl sulfate and reacting for 1-2 hours at room temperature.
Further preferably, when the reaction is completed, ethanol is added to stop the reaction; then, all solvents are pumped out under reduced pressure, and ethyl acetate and water are added for extraction and separation; and combining the organic phases, concentrating, and purifying by column chromatography to obtain the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate.
In the above step D03, as a preferred example, in the step of preparing the 3-bromo-2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate, the molar ratio of the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the N-bromosuccinimide is 1 (1.05-1.2), and the stirring time is 1-2 hours. As a specific example, the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate and N-bromosuccinimide are mixed in a molar ratio of 1: (1.05-1.2) in dimethylformamide and treated with stirring at room temperature for 1-2 hours to give the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate of the formula:
Figure BDA0001006702640000111
preferably, after the reaction is finished, pouring the product into ice water, adding dichloromethane for extraction and separation; then adding a large amount of water into the organic phase for washing, combining the organic phases, concentrating, and purifying by column chromatography to obtain the high-purity 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate.
In the above step D04, as a preferred example, in the step of preparing the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indolylphosphine ligand, the molar ratio of the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the n-butyllithium is 1 (1.1 to 1.2); the molar ratio of the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the disubstituted phosphine chloride is 1 (1.1-1.2). As a specific example, the 3-bromo-2- (2 ' -bromophenyl) -1-alkyl-1H-indole intermediate is dissolved in tetrahydrofuran, and n-butyllithium is added, with stirring homogeneously for 0.5 to 1 hour, followed by addition of a disubstituted phosphine chloride, at a temperature of-75 to-80 ℃, more preferably-78 ℃, in a molar ratio of the 3-bromo-2- (2 ' -bromophenyl) -1-alkyl-1H-indole intermediate to the n-butyllithium of 1 (1.1 to 1.2), the 3-bromo-2- (2 ' -bromophenyl) -1-alkyl-1H-indole intermediate to the disubstituted phosphine chloride of 1 (1.1 to 1.2), reacting at room temperature for 12-24 hours to obtain 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indolphosphine ligand, wherein the reaction formula is shown as follows:
Figure BDA0001006702640000112
more preferably, after the reaction is completed, all the solvent is removed under reduced pressure, and the reaction mixture is washed three times with cold methanol to obtain a white powder of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indolphosphine ligand.
The preparation method of the phosphine ligand with the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton provided by the embodiment of the invention has the advantages of simple and easily obtained raw materials, simple method, high total yield and capability of being prepared in a large scale only by a Fischer indole synthesis method, alkylation, bromination and phosphonation reactions.
The embodiment of the invention also provides application of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand as a synergist of a transition metal catalyst in cross-coupling reaction.
Further, as a preferred example, the use of the phosphine ligand of 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton as a synergist of a palladium catalyst in a carbon-sulfur bond formation reaction of an aryl bromide, and the phosphine ligand of 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton makes the molar amount of the catalyst in the carbon-sulfur bond formation reaction system of an aryl bromide be 0.5 to 1.0%.
The phosphine ligand of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton provided by the embodiment of the invention can be widely used as a synergist of a transition metal catalyst, is used for a cross-coupling reaction, and forms a complex with a stable structure with a transition metal such as palladium metal, so that the catalytic activity of the transition metal such as palladium during a catalytic reaction is improved, and particularly can be suitable for a reaction of forming a carbon-sulfur bond in an aryl bromide, the catalytic activity of the transition metal catalyst such as the palladium catalyst can be as low as 0.5 mol%, and the yield is as high as 90%.
In the embodiment of the invention, the room temperature refers to the room temperature of 10-30 ℃, the N-alkyl phenylhydrazine includes but is not limited to N-methyl phenylhydrazine, and the dialkyl sulfate includes but is not limited to dimethyl sulfate.
The following description is made with reference to specific embodiments.
Example 1: synthesis of 3- (dicyclohexylphosphino) -2- (2- (dicyclohexylphosphino) phenyl) -1-methyl-1H-indole
In a 100 ml round-bottom flask, 1.31 ml of 2' -bromoacetophenone (10mmol) and 1.30 ml of N-methylphenylhydrazine (11mmol) were added, followed by slow addition of 5 ml of phosphoric acid and stirring at room temperature for 0.5 hour. Then 30 grams of polyphosphoric acid was added slowly. As the reaction proceeded, the system exothermed significantly. The mixture was then slowly heated to 120 ℃ and kept at 120 ℃ for 1 hour of reaction. The reaction was terminated by pouring the mixture into ice water, 150 ml of diethyl ether was added to the system three times, extraction was carried out, the organic phases were combined, and dried over anhydrous sodium sulfate. After all the solution was removed under reduced pressure, the concentrated reaction mixture was purified by column chromatography to give a pale yellow powder. Then 5 ml of n-hexane are added for cleaning and filtering for three times, thus obtaining a light yellow powder pure product 2- (2-bromophenyl) -1-methyl-1H-indole intermediate 2.13 g with 75 percent of yield. 1H NMR (400MHz, CDCl)3)δ3.61(s,3H),6.56(s,1H),7.20-7.45(m,6H),7.70-7.75(m,2H)。
In a 100 ml round bottom flask, 2.85 g of 2- (2-bromophenyl) -1-methyl-1H-indole (10mmol) was added, followed by 20ml of anhydrous dimethylformamide and uniform stirring. Then, a mixed solution of 1.95 g of N-bromosuccinimide (11mmol) and 10 ml of anhydrous dimethylformamide was added thereto, and the reaction was carried out at room temperature for two hours. When the reaction was completed, the reaction mixture was poured into ice water, and then 100 ml of dichloromethane and 50 ml of water were added. The organic phase is then washed five times by adding 100 ml of water each, and the organic phases are combined. After removing all the solution under reduced pressureThe concentrated reaction mixture was purified by column chromatography to give the pure product 3-bromo-2- (2-bromophenyl) -1-methyl-1H-indole intermediate 2.8 g as a white powder in 77% yield. 1HNMR (400MHz, CDCl)3)δ3.61(s,3H),7.28-7.31(m,1H),7.35-7.52(m,5H),7.67-7.69(m,1H),7.78-7.81(m,1H)。
In a 50 ml two-necked flask, 1.81 g of 3-bromo-2- (2-bromophenyl) -1-methyl-1H-indole (5.0mmol) were weighed in. After 3 cycles of exchange of vacuum nitrogen, 15 ml of freshly distilled tetrahydrofuran were added with nitrogen and stirred homogeneously. After the mixture was cooled to-78 deg.C, n-butyllithium (11mmol) was then slowly added and reacted for 0.5 hour. Then, 2.64 ml of dicyclohexyl phosphine chloride (12mmol) which had been mixed and 5 ml of a freshly distilled tetrahydrofuran solution were slowly added. The reaction was allowed to proceed at room temperature for 18-24 hours. After all the solution was pumped under reduced pressure and washed three times with cold methanol, the pure product 3- (dicyclohexylphosphino) -2- (2- (dicyclohexylphosphino) phenyl) -1-methyl-1H-indole was obtained as a white powder in 5.12 g, 71% yield. 1H NMR (400MHz, CDCl)3)δ1.16-1.28(m,22H),1.63-1.94(m,23H),2.10-2.19(m,2H),2.50-2.52(m,1H),3.44(s,3H),7.17(d,J＝7.2Hz,1H),7.25-7.28(m,2H),7.37(d,J＝8.0Hz,1H)；7.41-7.50(m,2H),7.67(d,J＝7.6Hz,1H),7.83(d,J＝7.2Hz,1H)。
Further, 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkylindole skeleton phosphorus ligands shown in the following Table 1 can be prepared by referring to the methods shown in the following reaction formulae.
Figure BDA0001006702640000141
TABLE 1
Figure BDA0001006702640000142
Example 2: use of a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indolylphosphine ligand in a reaction in which palladium catalyzes the formation of a carbon-sulphur bond in an aryl bromide.
EXAMPLE 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indolphosphines
Several catalysts of ligands, the structure of which is shown as cat1-3 below, catalyze the reaction of forming carbon-sulfur bonds:
Figure BDA0001006702640000143
tris (dibenzylideneacetone) dipalladium (0.0023 g, 0.0025mmol), phosphine ligand (palladium: phosphine ligand ratio 0.5 mol%: 1 mol%), sodium tert-butoxide (3.0mmol) and a magnetic stir bar fitted with a polytetrafluoroethylene coating were placed in a 20ml Schlenk tube and the system replaced with nitrogen blanket. 4-bromoanisole (1.0mmol) was then added under nitrogen, followed by 3mL of freshly distilled dioxane and stirring continued at room temperature for 1 min. Then thiophenol or 3-methylphenylthiol or 2-naphthalenethiol (1.05mmol) was added and stirring was continued at room temperature for 1 minute. The Schlenk tube was then placed in a preheated 110 ℃ oil bath for 2-18 hours, the reaction scheme is shown below. After the reaction was completed, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (6.0mL) and water (2.0mL) were added to the system, and then the organic layer was subjected to gas chromatography analysis and examined to determine the yield of the coupled product.
Figure BDA0001006702640000151
In the above reaction for catalyzing the formation of carbon-sulfur bonds, the phosphine ligands and the yield of the catalyst are shown in table 2 below.
TABLE 2
Figure BDA0001006702640000152
As can be seen from Table 2, each of the above-mentioned 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indolphosphine ligands can exhibit a good catalytic performance in the above-mentioned reaction for forming a carbon-sulfur bond.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (7)

1. The phosphine ligand of 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton has the following structures of cat1, cat 2 and cat 3:
Figure FDA0002275235480000011
and the phosphine ligand of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton and the transition metal form a complex with stable structure.
2. A method for preparing a phosphine ligand of a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton, which comprises the following steps:
mixing 2 '-bromoacetophenone and N-alkyl phenylhydrazine, adding phosphoric acid as a catalyst, stirring, adding polyphosphoric acid, heating to react to obtain a 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate, or mixing the 2 '-bromoacetophenone and N-alkyl phenylhydrazine, adding acetic acid and ethanol, reacting at 70-80 ℃ for 0.5-1.5 hours, then pumping out all solvents under reduced pressure, adding polyphosphoric acid, heating to react to prepare the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate, wherein the heating temperature of the heating reaction is 80-120 ℃, and the reaction time is 1-2 hours;
dissolving the 2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate and N-bromosuccinimide in dimethylformamide, and stirring at room temperature to obtain a 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate;
dissolving the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate in tetrahydrofuran, adding n-butyllithium at-75 to-80 ℃, uniformly stirring for 0.5 to 1 hour, then adding disubstituted phosphine chloride, and reacting at room temperature for 12 to 24 hours to obtain the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-1H-indolphosphine ligand.
3. The method for preparing a phosphine ligand with a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton according to claim 2, wherein in the step of preparing the 3-bromo-2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate, the molar ratio of the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the N-bromosuccinimide is 1 (1.05-1.2), and the stirring time is 1-2 hours;
and/or
In the step of preparing the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-1H-indolylphosphine ligand, the molar ratio of the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the n-butyllithium is 1 (1.1-1.2); the molar ratio of the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the disubstituted phosphine chloride is 1 (1.1-1.2).
4. A method for preparing a phosphine ligand of a 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton, which comprises the following steps:
mixing 2 '-bromoacetophenone and phenylhydrazine, adding phosphoric acid as a catalyst, stirring, adding polyphosphoric acid, heating to react to prepare a 2- (2' -bromophenyl) -1H-indole intermediate, or mixing the 2 '-bromoacetophenone and phenylhydrazine, adding acetic acid and ethanol, reacting at 70-80 ℃ for 0.5-1.5 hours, then decompressing, pumping away all solvents, adding polyphosphoric acid, heating to react to prepare the 2- (2' -bromophenyl) -1H-indole intermediate, wherein the heating temperature of the heating reaction is 80-120 ℃, and the reaction time is 1-2 hours;
mixing the 2- (2 '-bromophenyl) -1H-indole intermediate with sodium hydride and dialkyl sulfate according to the molar ratio of 1 (1.1-2.0) to 1.05-1.5 to form a tetrahydrofuran mixed solution, and stirring at room temperature for 1-2 hours to obtain a 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate;
dissolving the 2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate and N-bromosuccinimide in dimethylformamide, and stirring at room temperature to obtain a 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate;
dissolving the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate in tetrahydrofuran, adding n-butyllithium at-75 to-80 ℃, uniformly stirring for 0.5 to 1 hour, then adding disubstituted phosphine chloride, and reacting at room temperature for 12 to 24 hours to obtain the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-1H-indolphosphine ligand.
5. The method for preparing a phosphine ligand with 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton according to claim 4, wherein in the step of preparing the 3-bromo-2- (2 '-bromophenyl) -1-alkyl-1H-indole intermediate, the molar ratio of the 2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the N-bromosuccinimide is 1 (1.05-1.2), and the stirring time is 1-2 hours;
and/or
In the step of preparing the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-1H-indolylphosphine ligand, the molar ratio of the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the n-butyllithium is 1 (1.1-1.2); the molar ratio of the 3-bromo-2- (2' -bromophenyl) -1-alkyl-1H-indole intermediate to the disubstituted phosphine chloride is 1 (1.1-1.2).
6. The use of the phosphine ligand of 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton according to claim 1 as a synergist for transition metal catalysts in cross-coupling reactions.
7. The use of the phosphine ligand of 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton according to claim 6, characterized in that the phosphine ligand of the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton is used as a synergist of a palladium catalyst in the reaction of forming a carbon-sulfur bond in aryl bromide, and the 3- (disubstituted phosphino) -2- (2- (disubstituted phosphino) substituted phenyl) -1-alkyl-indole skeleton phosphine ligand enables the molar use amount of the catalyst in a reaction system for forming a carbon-sulfur bond of an aryl bromide to be 0.5-1.0%.
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