1. A phosphine ligand with a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton is characterized in that the structural formula is shown as the following formula I:

wherein, R is¹、R²Each independently selected from alkyl or aryl, R³Selected from alkyl, said R⁴Selected from alkyl or aryl, said R⁵、R⁶、R⁷、R⁸Each independently selected from hydrogen, alkyl, alkoxy, aryl or fluoro.

2. The phosphine ligand with 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 1, wherein R is¹、R²Each independently selected from phenyl, ethyl, isopropyl, tert-butylOne of butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-di (trifluoromethyl) phenyl and 1-naphthyl; the R is³One selected from C1-10 alkyl, C3-10 cycloalkyl, 1-adamantyl and trifluoromethyl; the R is⁴One selected from C1-C10 alkyl, C3-10 cycloalkyl, oxygen heterocycle, epoxy alkyl, alkoxy alkyl, oxygen heterocycle and phenyl; the R is⁵、R⁶、R⁷、R⁸Each independently selected from one of hydrogen, C1-10 alkyl, C1-C10 alkoxy, phenyl, fluorine and trifluoromethyl.

3. A phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 2, wherein said alkyl groups of C1-C10 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and alkyl groups of C5-C10, said cycloalkyl groups of C3-10 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloalkyl groups of C7-C10, said oxirane ring includes tetrahydrofuran, said epoxyalkyl group includes epoxypropyl, said alkoxyalkyl group includes methoxymethyl, said oxacycloalkyl group includes tetrahydrofurylmethyl, and said alkoxy groups of C1-C10 include methoxy, ethoxy, n-propoxy, isopropoxy and alkoxy groups of C4-C10.

4. A preparation method of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand is characterized by comprising the following steps:

mixing alkyl methyl ketone and substituted phenylhydrazine, and adding polyphosphoric acid for reaction to prepare a 2-alkyl-1H-indole intermediate;

reacting the 2-alkyl-1H-indole intermediate with sodium hydride and dialkyl sulfate to prepare a 2-alkyl-1H-indole intermediate;

reacting the 2-alkyl-1H-indole intermediate with N-bromosuccinimide to prepare a 3-bromo-2-alkyl-1H-indole intermediate;

and reacting the 3-bromo-2-alkyl-1H-indole intermediate with n-butyllithium and disubstituted phosphine chloride to prepare the phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton.

5. The method for preparing a phosphine ligand having a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 4, wherein the specific steps for preparing the 2-alkyl-1H-indole intermediate comprise:

mixing and stirring alkyl methyl ketone and substituted phenylhydrazine, then adding polyphosphoric acid, and reacting to obtain a first mixed solution; heating the first mixed solution to 80-85 ℃ and keeping the temperature for 45 minutes, then heating to 110 ℃ and keeping the temperature for 60 minutes, and extracting with diethyl ether after the reaction is finished to obtain a first organic layer; drying and concentrating the first organic layer, loading the first organic layer on a short silica gel column for filtering, and eluting the first organic layer by using an ethyl acetate/hexane mixture to obtain a first eluent; then, concentrating and evaporating the first eluent to obtain a first solid product; further washing, filtering and vacuum drying the first solid product to obtain 2-alkyl-1H-indole;

wherein the molar ratio of the alkyl methyl ketone to the substituted phenylhydrazine is 1: 1.2.

6. The method for preparing a phosphine ligand with 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 4, wherein the specific steps for preparing the 2-alkyl-1H-indole intermediate comprise:

adding 2-alkyl-1H-indole into a dropping funnel, and then adding tetrahydrofuran to prepare a second mixed solution; dropwise adding the second mixed solution into a tetrahydrofuran solution containing sodium hydride at room temperature, and stirring for 1 hour to prepare a third mixed solution; adding dimethyl sulfate into the third mixed solution, stirring overnight, and obtaining a fourth mixed solution after the reaction is finished; slowly dripping ethanol into the fourth mixed solution for quenching reaction to obtain a fifth mixed solution; concentrating the fifth mixed solution under reduced pressure, and extracting with ethyl acetate to obtain a second organic layer; washing, drying and concentrating the second organic layer, loading the second organic layer on a short silica gel column for filtering, and eluting the second organic layer by using an ethyl acetate/hexane mixture to obtain a second eluent; then concentrating and evaporating the second eluent to obtain a 2-alkyl-1H-indole intermediate;

wherein the molar ratio of the 2-alkyl-1H-indole intermediate to the sodium hydride to the dialkyl sulfate is 1.0 (2.0-2.5) to 2.0-2.5.

7. The method for preparing a phosphine ligand with 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 4, wherein the specific steps for preparing the 3-bromo-2-alkyl-1H-indole intermediate comprise:

dissolving the 2-alkyl-1H-indole intermediate in anhydrous chloroform to prepare a sixth mixed solution; adding N-bromosuccinimide into the sixth mixed solution at the temperature of between 0 and 20 ℃ below zero, and preparing a seventh mixed solution after the reaction is finished; adding ethyl acetate and water into the seventh mixed solution, and layering to obtain a third organic layer; washing, drying and concentrating the third organic layer, loading the third organic layer on a short silica gel column for filtering, and eluting the third organic layer by using an ethyl acetate/hexane mixture to obtain a third eluent; then concentrating and evaporating the third eluent to obtain a 3-bromo-2-alkyl-1H-indole intermediate;

wherein the molar ratio of the 2-alkyl-1H-indole intermediate to the N-bromosuccinimide is 1.0 (1.0-1.05).

8. The method for preparing a phosphine ligand having a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 4, wherein the specific steps for preparing the phosphine ligand having a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton comprise:

dissolving the 3-bromo-2-alkyl-1H-indole intermediate in freshly distilled tetrahydrofuran in a nitrogen atmosphere to prepare an eighth mixed solution; cooling the eighth mixed solution to-75 ℃ to-80 ℃ in a dry ice/acetone bath, adding n-butyllithium, and stirring for 30 minutes at-78 ℃ to-80 ℃ to prepare a ninth mixed solution; then adding disubstituted phosphine chloride into the ninth mixed solution, heating to room temperature, stirring overnight, and preparing a tenth mixed solution after the reaction is finished; concentrating the tenth mixed solution under reduced pressure, washing, collecting a solid product, and drying in vacuum to obtain a phosphine ligand with a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton;

wherein the molar ratio of the 3-bromo-2-alkyl-1H-indole to the n-butyllithium to the disubstituted chlorophosphine is 1.0 (1.05-1.1) to (1.1-1.2).

9. Use of the phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to any one of claims 1 to 3, wherein the phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton is used as a synergist for transition metal catalysts in cross-coupling reactions.

10. Use of a phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 9, characterized in that said cross-coupling reaction comprises a chemoselective suzuki coupling reaction of polyhalo-triflic aryl esters.

11. The use of a phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 9, wherein in the cross-coupling reaction the reaction sequence is C-Br > C-Cl > C-OTf.

12. The use of the phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to claim 9, wherein the phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton is such that the molar amount of the transition metal catalyst used in the reaction system for the chemoselective suzuki coupling of polyhalo aryl triflates is 10 ppm.

Background

Transition metal catalyzed cross-coupling reactions, which build carbon-carbon and carbon-heteroatom bonds through the linkage between electrophilic and nucleophilic reagents, have become one of the most efficient tools in organic synthesis. In the medical and industrial fields, aryl bromides, aryl chlorides and aryl triflates are the most widely used electrophiles, and therefore the selective synthesis of a diversified aryl compound using these electrophiles is of considerable importance. In transition metal catalyzed cross-coupling reactions, the reaction sequence is mostly C-I > C-Br > C-OTf > C-Cl, but in practical chemoselective reactions, correct sequence prediction is very complicated. Changes in the catalyst, reaction conditions (e.g., different additives and solvents), position, size, steric hindrance, electrical properties, etc. of the substituents on the substrate can all affect the outcome of the selective reaction.

One strategy to manipulate the highly selective reaction is by changing the catalyst or ligand. Ligands play a considerable role in transition metal-catalyzed cross-coupling reactions. The ligand can effectively adjust the performance of the catalyst, and the coupling reaction is performed more perfectly. Currently, the ligands used in comparison are generally organophosphinic compounds. The researches on phosphine ligands in the past years show that the slight changes of the position, the size, the steric hindrance, the electrical property and the like of substituents on the phosphine ligand skeleton can generate important influence on the result of the coupling reaction. Among these, well-known phosphine ligands, such as those of Fu, Beller, Buchwald, Hartwig and other groups, all provide excellent catalytic performance in palladium-catalyzed cross-coupling reactions.

However, of these effective ligands, most use aryl groups as the ligand bottom ring, which is also a guaranteed structural feature. In contrast, phosphine ligands with alkyl groups as the base ring are less interesting and have not been developed. In addition, when multiple (pseudo) halides are present, how to effectively control the selectivity of the cross-coupling reaction remains a challenging problem, and few reports have been made. Therefore, the phosphine ligand which is easy to prepare, stable in structure and has both catalytic activity and selectivity is designed and synthesized, and the phosphine ligand has profound significance in catalytic cross-coupling reaction.

Disclosure of Invention

In view of the above-mentioned shortcomings of the prior art, the present invention aims to provide a phosphine ligand with 2-alkyl-indole skeleton, and a preparation method and application thereof, aiming to design and synthesize a phosphine ligand which is easy to prepare, stable in structure, and has both catalytic activity and selectivity by introducing an indole skeleton with an alkyl group at the 2-position.

The technical scheme of the invention is as follows:

in a first aspect, the present invention provides a phosphine ligand with a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton, having the structural formula shown in formula i below:wherein, R is¹、R²Each independently selected from alkyl or aryl, R³Selected from alkyl, said R⁴Selected from alkyl or aryl, said R⁵、R⁶、R⁷、R⁸Each independently selected from hydrogen, alkyl, alkoxy, aryl or fluoro.

The 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand is shown in the specification, wherein R is¹、R²Each independently selected from phenyl, ethyl, isopropyl, tert-butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-di (trifluoromethyl) phenyl and 1-naphthyl; the R is³One selected from C1-10 alkyl, C3-10 cycloalkyl, 1-adamantyl and trifluoromethyl; the R is⁴One selected from C1-C10 alkyl, C3-10 cycloalkyl, oxygen heterocycle, epoxy alkyl, alkoxy alkyl, oxygen heterocycle and phenyl; the R is⁵、R⁶、R⁷、R⁸Each independently selected from one of hydrogen, C1-10 alkyl, C1-C10 alkoxy, phenyl, fluorine and trifluoromethyl.

The 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand is characterized in that the alkyl groups of C1-C10 comprise methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and alkyl groups of C5-C10, the cycloalkyl groups of C3-C3810 comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloalkyl groups of C7-C10, the oxa-ring comprises tetrahydrofuran, the epoxyalkyl group comprises epoxypropyl, the alkoxyalkyl group comprises methoxymethyl, the oxa-cycloalkyl group comprises tetrahydrofuryl, and the alkoxy groups of C1-C10 comprise methoxy, ethoxy, n-propoxy, isopropoxy and alkoxy groups of C4-C10.

In a second aspect, the present invention provides a method for preparing a phosphine ligand having a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton, comprising the steps of:

mixing alkyl methyl ketone and substituted phenylhydrazine, and adding polyphosphoric acid for reaction to prepare a 2-alkyl-1H-indole intermediate;

reacting the 2-alkyl-1H-indole intermediate with sodium hydride and dialkyl sulfate to prepare a 2-alkyl-1H-indole intermediate;

reacting the 2-alkyl-1H-indole intermediate with N-bromosuccinimide to prepare a 3-bromo-2-alkyl-1H-indole intermediate;

and reacting the 3-bromo-2-alkyl-1H-indole intermediate with n-butyllithium and disubstituted phosphine chloride to prepare the phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton.

The preparation method of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand comprises the following specific steps of:

mixing and stirring alkyl methyl ketone and substituted phenylhydrazine, then adding polyphosphoric acid, and reacting to obtain a first mixed solution; heating the first mixed solution to 80-85 ℃ and keeping the temperature for 45 minutes, then heating to 110 ℃ and keeping the temperature for 60 minutes, and extracting with diethyl ether after the reaction is finished to obtain a first organic layer; drying and concentrating the first organic layer, loading the first organic layer on a short silica gel column for filtering, and eluting the first organic layer by using an ethyl acetate/hexane mixture to obtain a first eluent; then, concentrating and evaporating the first eluent to obtain a first solid product; further washing, filtering and vacuum drying the first solid product to obtain 2-alkyl-1H-indole; wherein the molar ratio of the alkyl methyl ketone to the substituted phenylhydrazine is 1: 1.2.

The preparation method of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand comprises the following specific steps of:

adding 2-alkyl-1H-indole into a dropping funnel, and then adding tetrahydrofuran to prepare a second mixed solution; dropwise adding the second mixed solution into a tetrahydrofuran solution containing sodium hydride at room temperature, and stirring for 1 hour to prepare a third mixed solution; adding dimethyl sulfate into the third mixed solution, stirring overnight, and obtaining a fourth mixed solution after the reaction is finished; slowly dripping ethanol into the fourth mixed solution for quenching reaction to obtain a fifth mixed solution; concentrating the fifth mixed solution under reduced pressure, and extracting with ethyl acetate to obtain a second organic layer; washing, drying and concentrating the second organic layer, loading the second organic layer on a short silica gel column for filtering, and eluting the second organic layer by using an ethyl acetate/hexane mixture to obtain a second eluent; then concentrating and evaporating the second eluent to obtain a 2-alkyl-1H-indole intermediate; wherein the molar ratio of the 2-alkyl-1H-indole intermediate to the sodium hydride to the dialkyl sulfate is 1.0 (2.0-2.5) to 2.0-2.5.

The preparation method of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand comprises the following specific steps of:

dissolving the 2-alkyl-1H-indole intermediate in anhydrous chloroform to prepare a sixth mixed solution, adding N-bromosuccinimide into the sixth mixed solution in batches at the temperature of between 0 and 20 ℃ below zero, and preparing a seventh mixed solution after the reaction is finished; adding ethyl acetate and water into the seventh mixed solution, and layering to obtain a third organic layer; washing, drying and concentrating the third organic layer, loading the third organic layer on a short silica gel column for filtering, and eluting the third organic layer by using an ethyl acetate/hexane mixture to obtain a third eluent; then concentrating and evaporating the third eluent to obtain a 3-bromo-2-alkyl-1H-indole intermediate; wherein the molar ratio of the 2-alkyl-1H-indole intermediate to the N-bromosuccinimide is 1.0 (1.0-1.05).

The preparation method of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand comprises the following specific steps of:

dissolving the 3-bromo-2-alkyl-1H-indole intermediate in freshly distilled tetrahydrofuran in a nitrogen atmosphere to prepare an eighth mixed solution; cooling the eighth mixed solution to-75 ℃ to-80 ℃ in a dry ice/acetone bath, dropwise adding n-butyllithium, and stirring for 20-30 minutes at-75 ℃ to-80 ℃ to prepare a ninth mixed solution; then adding disubstituted phosphine chloride into the ninth mixed solution, heating to room temperature, stirring overnight, and preparing a tenth mixed solution after the reaction is finished; concentrating the tenth mixed solution under reduced pressure, washing, collecting a solid product, and drying in vacuum to obtain a phosphine ligand with a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton; wherein the molar ratio of the 3-bromo-2-alkyl-1H-indole to the n-butyllithium to the disubstituted chlorophosphine is 1.0 (1.05-1.1) to (1.1-1.2).

In a third aspect, the invention provides an application of a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand, wherein the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand as described above is used as a synergist of a transition metal catalyst in a cross-coupling reaction.

The application of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand is characterized in that the cross-coupling reaction comprises the chemical selective Suzuki coupling reaction of polyhalogenated aryl trifluoromethanesulfonate.

The 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand is applied, wherein in the cross-coupling reaction, the reaction sequence is C-Br > C-Cl > C-OTf.

The application of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand is characterized in that the molar amount of the transition metal catalyst in a chemical selectivity Suzuki coupling reaction system of the polyhalogenated aryl trifluoromethanesulfonate is 10ppm by the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand.

Has the advantages that: the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand provided by 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, so that the catalytic activity and selectivity of the catalytic reaction of the transition metal such as palladium are improved, and particularly can be suitable for high-difficulty chemoselectivity reactions including Chemoselective Suzuki coupling reaction (polyhalogenated aryl trifluoromethanesulfonate), wherein the catalytic dosage of the transition metal catalyst such as palladium catalyst can be as low as 10ppm, the separation yield is up to 99%, the application range is wide, the selectivity is good, the reaction condition is mild, and functional groups such as ester, ketone, methoxy and the like can be compatible at the same time. Moreover, the 2-position indole skeleton with alkyl is introduced into the phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton provided by the invention, and the new reaction sequence of C-Br > C-Cl > C-OTf is discovered when the phosphine ligand is applied to the chemoselective Suzuki-Miyaura reaction. In addition, the phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton is simple and direct to synthesize, can be prepared in a large scale and is easy to store and treat; the structure and charge properties of the ligand are easy to adjust and modify; the ligand has wide application range, high catalytic activity, low dosage of the used catalyst, mild reaction conditions, easy amplification of reaction proportion and high practical value in synthesis.

Drawings

FIG. 1 is a schematic flow chart of a preparation method of a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand in the embodiment of the invention.

Detailed Description

The invention provides a phosphine ligand with a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton, a preparation method and application thereof, and the invention is further detailed below in order to make the purposes, technical schemes and effects of the invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

It should be noted that the term "comprises/comprising" when used in this specification and claims and in the above-described drawings is intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus; the terms "first", "second", "third", etc. are used only to distinguish different reaction substances, and do not set any limit on the number, concentration, volume, reaction sequence, etc. of the reaction substances; it should also be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict.

The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps or conditions described in the literature in the field. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. The compounds for which no synthetic process is mentioned in the examples are all starting products obtained commercially.

The embodiment of the invention provides a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand, which has a structural formula shown as the following formula I:wherein, R is¹、R²Each independently selected from alkyl or aryl, R³Selected from alkyl, said R⁴Selected from alkyl or aryl, said R⁵、R⁶、R⁷、R⁸Each independently selected from hydrogen, alkyl, alkoxy, aryl or fluoro.

In some embodiments, the R is¹、R²Each independently selected from phenyl, ethyl, isopropyl, tert-butyl, 1-adamantyl, cyclopentyl, cyclohexyl, o-tolyl, p-methoxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl, 3, 5-dimethylphenyl, 3, 5-di (trifluoromethyl) phenyl and 1-naphthyl; the R is³One selected from C1-10 alkyl, C3-10 cycloalkyl, 1-adamantyl and trifluoromethyl; the R is⁴One selected from C1-C10 alkyl, C3-10 cycloalkyl, oxygen heterocycle, epoxy alkyl, alkoxy alkyl, oxygen heterocycle and phenyl; the R is⁵、R⁶、R⁷、R⁸Each independently selected from hydrogen, C1-10 alkaneAnd one of C1-C10 alkoxy, phenyl, fluorine and trifluoromethyl.

In some specific embodiments, the C1-C10 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and C5-C10 alkyl groups, the C3-10 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C7-C10 cycloalkyl groups, the oxa rings include tetrahydrofuran, the epoxyalkyl groups include glycidyl, the alkoxyalkyl groups include methoxymethyl groups, the oxa cycloalkyl groups include tetrahydrofurylmethyl groups, and the C1-C10 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and C4-C10 alkoxy groups.

The phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton provided by the embodiment of the invention can form a complex with a stable structure with transition metal such as palladium, 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 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand and a transition metal such as palladium form a catalytic system, can be used for preparing a multi-element aryl compound, and has great application potential in the synthesis of natural products and drug intermediates.

Furthermore, the phosphine ligands of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole frameworks prepared in the examples of the present invention, in which the 2-position of the indole is an alkyl group, are reacted first with chlorine (-Cl) and then with chlorotrifluoromethanesulfonic acid chloride ester (-OTf) in a chemoselective Suzuki-Miyaura reaction, i.e., in the presence of a plurality of (pseudo) halides in the substrate, in the order C-Br > C-Cl > C-OTf.

In transition metal, such as palladium catalyzed cross-coupling reactions, various aryl bromides, aryl chlorides, and aryl triflates are the electrophiles that are currently most widely used in pharmaceutical, industrial, and conventional syntheses. For these commonly used electrophiles, the reactivity generally depends on the oxidative addition step it performs on the palladium catalyst (palladium/ligand). For most palladium catalysts currently used in cross-coupling reactions, the general order of reactivity is C-I > C-Br > C-OTf > C-Cl. However, a single reaction sequence has many limitations in practical synthetic routes, such as the introduction of halogen or hydroxyl groups on the aryl groups is generally limited by the electrophilic substitution positioning effect of the benzene ring, and the problems of the current commercial raw materials which are not consistent with the synthetic routes in many cases in order to cater for the single reaction sequence, such as the tedious synthetic routes, the low efficiency and the generation of many chemical wastes. In addition, in the case of a wide variety of poly (pseudo) haloaromatic substrates, the chemoselectivity is sometimes affected by various factors, such as steric hindrance and electric phase difference of the substrate itself, making practical synthesis difficult. The reactivity of palladium catalysts depends to a large extent on the nature of the ligands, so that it is very attractive to modify the reaction sequence by means of ligand design and innovation to fit the ideal synthesis route for practical applications.

Thus, the phosphine ligands of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole backbones of the examples of the present invention provide an aryl chloride which is preferentially less reactive than the conventional reaction sequence (C-Br > C-Cl > C-OTf). When the phosphine ligand (Phendole-Phos) with the 2-position benzene ring of the indole is applied to the chemoselective Suzuki-Miyaura reaction, the reaction sequence is C-Br > C-OTf > C-Cl, and the reaction sequence is consistent with the common reaction sequence. This is because the phosphine ligands of the embodiments of the present invention are those in which an alkyl group is introduced as a base ring of the phosphine ligand, which is different from other aryl-based phosphine ligands used for cross-coupling reactions. Although the aryl bottom ring of the phosphine ligand can effectively stabilize the unsaturated palladium metal center and promote the reaction to occur through the coordination of pi bonds of aryl and palladium metal in the catalytic reaction, the palladium metal center with phosphine atoms complexed with the pi bonds is generated, and the reaction sequence completely conforms to the conventional C-Br > C-OTf > C-Cl. Through mechanism research, the phosphine ligand with an alkyl bottom ring, hydrogen atoms on the alkyl substrate ring can grab hydrogen bonds with palladium metal centers in a form of stable unsaturated palladium metal centers, and under the coordination effect of alkyl, the palladium catalytic centers completely different from the aryl bottom ring phosphine ligand are provided, aryl chlorides with lower reaction activity can be preferentially subjected to oxidative addition reaction, and therefore another reaction sequence C-Br > C-Cl > C-OTf with high catalytic efficiency and high chemical selectivity is provided.

The embodiment of the invention also provides a preparation method of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand, which specifically comprises the following steps:

s10, mixing alkyl methyl ketone and substituted phenylhydrazine, and adding polyphosphoric acid for reaction to prepare a 2-alkyl-1H-indole intermediate;

s20, reacting the 2-alkyl-1H-indole intermediate with sodium hydride and dialkyl sulfate to prepare a 2-alkyl-1H-indole intermediate;

s30, reacting the 2-alkyl-1H-indole intermediate with N-bromosuccinimide to prepare a 3-bromo-2-alkyl-1H-indole intermediate;

s40, reacting the 3-bromo-2-alkyl-1H-indole intermediate with n-butyllithium and disubstituted phosphine chloride to prepare the phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton.

In some embodiments, after the alkyl methyl ketone and the substituted phenylhydrazine are mixed in step S10, a mixture of polyphosphoric acid and phosphonic acid may be added to react to prepare a 2-alkyl-1H-indole intermediate.

In some embodiments, in step S10, the specific steps for preparing the 2-alkyl-1H-indole intermediate comprise:

mixing and stirring alkyl methyl ketone and substituted phenylhydrazine, then adding polyphosphoric acid, and reacting to obtain a first mixed solution; heating the first mixed solution to 80-85 ℃ and keeping the temperature for 45 minutes, then heating to 110 ℃ and keeping the temperature for 60 minutes, and extracting with diethyl ether after the reaction is finished to obtain a first organic layer; drying and concentrating the first organic layer, loading the first organic layer on a short silica gel column for filtering, and eluting the first organic layer by using an ethyl acetate/hexane mixture to obtain a first eluent; then, concentrating and evaporating the first eluent to obtain a first solid product; and further washing, filtering and vacuum drying the first solid product to obtain the 2-alkyl-1H-indole.

Specifically, the reaction formula of the above steps is as follows:

in some embodiments, the molar ratio of the alkyl methyl ketone to the substituted phenylhydrazine is preferably 1:1.2 for better reaction effect.

In some embodiments, the stirring treatment is a room temperature stirring treatment.

In some embodiments, after the first mixed solution is heated and reacted, the mixed solution can be directly poured into ice water, and ether is added for extraction and separation; and combining the organic phases, concentrating, and filtering by a short silica gel column to obtain the high-purity 2-alkyl-1H-indole intermediate.

In some embodiments, after the first solid product is obtained, it may also be directly recrystallized from methanol/water and washed with a methanol/water mixture. And filtering the solid product, and then drying in vacuum to obtain the 2-alkyl-1H-indole intermediate.

In some specific embodiments, the detailed step of step S10 includes:

the alkyl methyl ketone and substituted phenylhydrazine were mixed and stirred, then polyphosphoric acid was added, and after the reaction exotherm occurred, the mixture was heated to 85 ℃ and held at that temperature for 45 minutes. The temperature was then raised to 110 ℃ and the mixture was held at this temperature for a further 1 hour. After completion of the reaction, the mixture was poured into ice water and stirred for 1 hour. Then extracted with ether. The combined organic layers were dried over anhydrous sodium sulfate. The dried organic layer was concentrated, loaded on a short silica gel column for filtration, and eluted with an ethyl acetate/hexane mixture. Concentrating and evaporating the eluent to obtain a solid product. The product was further washed with cold hexane. And filtering the solid product, and then drying in vacuum to obtain the 2-alkyl-1H-indole.

In some embodiments, in step S20, the specific steps for preparing the 2-alkyl-1H-indole intermediate comprise:

adding 2-alkyl-1H-indole into a dropping funnel, and then adding tetrahydrofuran to prepare a second mixed solution; dropwise adding the second mixed solution into a tetrahydrofuran solution containing sodium hydride at room temperature, and stirring for 1 hour to prepare a third mixed solution; adding dimethyl sulfate into the third mixed solution, stirring overnight, and obtaining a fourth mixed solution after the reaction is finished; slowly dripping ethanol into the fourth mixed solution for quenching reaction to obtain a fifth mixed solution; concentrating the fifth mixed solution under reduced pressure, and extracting with ethyl acetate to obtain a second organic layer; washing, drying and concentrating the second organic layer, loading the second organic layer on a short silica gel column for filtering, and eluting the second organic layer by using an ethyl acetate/hexane mixture to obtain a second eluent; and then concentrating and evaporating the second eluent to obtain the 2-alkyl-1H-indole intermediate.

Specifically, the reaction formula of the above steps is as follows:

in some embodiments, the molar ratio of the 2-alkyl-1H-indole intermediate, sodium hydride and dialkyl sulfate is preferably 1.0 (2.0-2.5) to (2.0-2.5) in order to obtain better reaction results.

In some embodiments, sodium hydride (60% dispersed in mineral oil) is washed with anhydrous hexane to remove mineral oil prior to use.

In some embodiments, the addition funnel may be rinsed with additional tetrahydrofuran and added to the third mixed liquor.

In some embodiments, after detecting the total consumption of the substrate by thin layer chromatography, water may be further added to the fourth mixture to stop the reaction, ethyl acetate is added to extract, separate, dry with sodium sulfate and concentrate the organic phase, and the 2-alkyl-1H-indole intermediate is obtained by column chromatography purification.

In some specific embodiments, the detailed step of step S20 includes:

adding 2-alkyl-1H-indole into a dropping funnel, adding tetrahydrofuran to prepare a solution, and then dropwise adding the solution into a tetrahydrofuran solution containing sodium hydride at room temperature. Sodium hydride (60% dispersed in mineral oil) was washed with anhydrous hexane to remove mineral oil prior to use. After the addition of the solution was completed, the dropping funnel was rinsed with additional tetrahydrofuran and added to the reaction mixture. After the reaction mixture was stirred at room temperature for 1 hour, dimethyl sulfate was added to the reaction mixture, and the reaction mixture was stirred overnight. After completion of the reaction, the reaction was quenched by slowly dropping ethanol into the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The concentrated mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was loaded onto a short silica gel column and eluted with an ethyl acetate/hexane mixture. Concentrating and evaporating the eluent to obtain the 2-alkyl-1H-indole intermediate.

In some embodiments, the specific steps for preparing the 3-bromo-2-alkyl-1H-indole intermediate in step S30 include:

dissolving the 2-alkyl-1H-indole intermediate in anhydrous chloroform to prepare a sixth mixed solution, adding N-bromosuccinimide into the sixth mixed solution in batches at the temperature of between 0 and 20 ℃ below zero, and preparing a seventh mixed solution after the reaction is finished; adding ethyl acetate and water into the seventh mixed solution, and layering to obtain a third organic layer; washing, drying and concentrating the third organic layer, loading the third organic layer on a short silica gel column for filtering, and eluting the third organic layer by using an ethyl acetate/hexane mixture to obtain a third eluent; and then concentrating and evaporating the third eluent to obtain the 3-bromo-2-alkyl-1H-indole intermediate.

Specifically, the reaction formula of the above steps is as follows:

in some embodiments, the molar ratio of the 2-alkyl-1H-indole intermediate to N-bromosuccinimide is 1.0 (1.0-1.05) for better reaction performance.

In some embodiments, after the N-bromosuccinimide is added in portions to the sixth mixture, the mixture is stirred at 0 ℃ to-20 ℃ for 1 to 2 hours.

It is noted that in other embodiments, the 3-bromo-2-alkyl-1H-indole intermediate is prepared in step S30, and the 2-alkyl-1H-indole intermediate may also be prepared by dissolving in anhydrous dimethylformamide, adding a solution of the combined N-bromosuccinimide and anhydrous dimethylformamide at a ratio of 1:1.05 at 0 ℃, and stirring at room temperature for 2 hours. After the reaction is finished, pouring the mixture into ice water, and 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 3-bromo-2-alkyl-1H-indole intermediate.

Specifically, the reaction formula of the above steps is as follows:

in some specific embodiments, the detailed step of step S30 includes:

the 2-alkyl-1H-indole intermediate is dissolved in anhydrous chloroform and N-bromosuccinimide is added to the solution in portions at 0 ℃ to-20 ℃. After confirming the completion of the reaction by GCMS analysis, ethyl acetate and water were added to the mixture. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated mixture was loaded onto a silica gel column and then eluted with ethyl acetate/hexane. Concentrating and evaporating the eluent to obtain the 3-bromo-2-alkyl-1H-indole intermediate.

In some embodiments, in step S40, the specific steps for preparing the phosphine ligand of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton include:

dissolving the 3-bromo-2-alkyl-1H-indole intermediate in freshly distilled Tetrahydrofuran (THF) in a nitrogen atmosphere to form an eighth mixed solution; cooling the eighth mixed solution to-75 ℃ to-80 ℃ in a dry ice/acetone bath, dropwise adding n-butyllithium, and stirring for 20-30 minutes at-75 ℃ to-80 ℃ to prepare a ninth mixed solution; then adding disubstituted phosphine chloride into the ninth mixed solution, heating to room temperature, stirring overnight, and preparing a tenth mixed solution after the reaction is finished; and (3) concentrating the tenth mixed solution under reduced pressure, washing, collecting a solid product, and drying in vacuum to obtain the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand.

Specifically, the reaction formula of the above steps is as follows:

in some embodiments, the molar ratio of 3-bromo-2-alkyl-1H-indole, n-butyllithium, and disubstituted chlorophosphine is preferably 1.0 (1.05-1.1) to (1.1-1.2) in order to obtain better reaction results.

In some preferred embodiments, the eighth mixed liquor is cooled to-78 ℃ in a dry ice/acetone bath.

In some preferred embodiments, the tenth mixture is concentrated under reduced pressure and then washed with a cold degassed methanol/water mixture followed by a cold degassed methanol.

In some specific embodiments, the detailed step of step S40 includes:

the 3-bromo-2-alkyl-1H-indole intermediate was dissolved in freshly distilled THF under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (concentration determined by titration) was added dropwise to the reaction mixture using a syringe. The reaction mixture was stirred at-78 ℃ to-80 ℃ for 30 minutes and then disubstituted phosphonium chloride was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with a cold degassed methanol/water mixture and cold degassed methanol in this order. The solid product is filtered, collected and dried in vacuum to obtain the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand.

The preparation method of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand provided by the embodiment of the invention has the advantages of simple and easily obtained raw materials, simple method, simple and direct synthesis, high total yield, capability of large-scale preparation and easiness in storage and treatment.

The embodiment of the invention also provides application of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand, wherein the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand is used as a synergist of a transition metal catalyst in cross-coupling reaction.

In some embodiments, the transition metal catalyst is a palladium catalyst.

The phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton provided by the embodiment of the invention can form a complex with a stable structure with palladium, so that the catalytic activity of palladium catalytic reaction is improved, and the phosphine ligand has the advantages of wide application range, good selectivity and mild reaction conditions.

In some embodiments, the cross-coupling reaction includes, but is not limited to, a chemoselective suzuki coupling reaction of a polyhalo-triflate aryl ester.

The phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton provided by the embodiment of the invention can be widely used for highly difficult transition metal catalyzed cross-coupling reactions, including Chemoselective Suzuki coupling reaction of polyhalogenated aryl trifluoromethanesulfonate (Chemoselective Suzuki reactions of polyhalogenated aryl triflates), but is not limited thereto.

In some embodiments, in the cross-coupling reaction, the reaction sequence is C-Br > C-Cl > C-OTf.

The 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand prepared in the embodiment of the invention, the 2-position of indole of which is alkyl, is firstly reacted with chlorine (-Cl) in a chemoselective Suzuki-Miyaura reaction, and then reacted with trifluoromethanesulfonic acid chloro ester (-OTf), namely when a plurality of (pseudo) halides exist in a substrate, the reaction sequence is C-Br > C-Cl > C-OTf. For most of the palladium catalysts currently used in cross-coupling reactions, the order of reactivity is usually C-I > C-Br > C-OTf > C-Cl. However, a single reaction sequence imposes many limitations on the actual synthetic route. Thus, the phosphine ligands of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole backbones of the examples of the present invention provide an aryl chloride which is less reactive than the conventional reaction sequence (C-Br > C-Cl > C-OTf) in preference. And when the phosphine ligand (Phendole-Phos) with the 2-position benzene ring of the indole is applied to the chemoselective Suzuki-Miyaura reaction, the reaction sequence is C-Br > C-OTf > C-Cl, which is consistent with the common reaction sequence. This is because the phosphine ligand of the present invention is a phosphine ligand in which an alkyl group is introduced as a base ring of the phosphine ligand, unlike other phosphine ligands in which an aryl group is commonly used as a base ring of a phosphine ligand in a cross-coupling reaction. Although the aryl bottom ring of the phosphine ligand can effectively stabilize the unsaturated palladium metal center and promote the reaction to occur through the coordination of the pi bond of the aryl and the palladium metal in the catalytic reaction, the palladium metal center with phosphine atoms complexed with the pi bond is generated, and the reaction sequence is completely in accordance with the conventional C-Br > C-OTf > C-Cl. However, through the mechanism research, the phosphine ligand with alkyl base ring, hydrogen atom on the alkyl base ring can form hydrogen-grasping bond with palladium metal center, and unsaturated palladium metal center is stabilized, under the coordination effect of alkyl, a palladium catalytic center completely different from aryl base ring phosphine ligand is provided, aryl chloride with lower preferential reaction activity is provided, and oxidation addition reaction is carried out, so that another reaction sequence with high catalytic efficiency, high chemoselectivity and difference from the conventional reaction sequence C-Br > C-Cl > C-OTf is provided.

In some embodiments, the phosphine ligand of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole backbone is such that the molar amount of transition metal catalyst used in the chemoselective suzuki coupling reaction system of polyhalo-triflic aryl esters is 10 ppm.

The phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-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, so that the catalytic activity chemistry of the transition metal such as palladium during the catalytic reaction is improved, and particularly, the phosphine ligand can be suitable for a difficult selective Suzuki-Argi coupling reaction of a polyhalogenated trifluoromethanesulfonic aryl ester, wherein the catalytic activity amount of the transition metal catalyst such as a palladium catalyst can be as low as 10ppm, the separation yield is as high as 99%, and the phosphine ligand has profound significance for the cross-coupling reaction.

In the above embodiments of the present invention, the room temperature refers to a room temperature of 10 ℃ to 30 ℃.

The phosphine ligands of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton according to the invention, their preparation and use are further illustrated by the following specific examples:

example 1: synthesis of 2-cyclohexyl-3- (diisopropylphosphino) -1-methyl-1H-indole

In a 100 ml round-bottom flask, 1-cyclohexylethane-1-one (11.58 g, 91.7 mmol) and phenylhydrazine (10.8 ml, 110 mmol) were mixed and stirred, then 100 g of polyphosphoric acid was added. After the reaction exotherm occurred, it was stirred at room temperature for a few minutes. The mixture was heated to 80 ℃ and held at this temperature for 45 minutes. The temperature was then raised to 110 ℃ and the mixture was held at this temperature for a further 1 hour. After completion of the reaction, the mixture was poured into ice water and stirred for 1 hour. The grey solid product was collected by filtration and recrystallized from methanol/water to yield a white solid. After washing the white solid with methanol/water (8:2), the white solid was filtered and dried under vacuum to give 2-cyclohexyl-1H-indole (12 g, 66%).¹H NMR(400MHz,CDCl₃)δ1.34-1.60(m,5H),1.76-1.79(m,1H),1.86-1.89(m,2H),2.08-2.11(m,2H),2.69-2.75(m,1H),6.25(s,1H),7.06-7.15(m,2H),7.31(d,J＝7.8Hz,1H),7.56(d,J＝7.6Hz,1H),7.90(s,1H)；¹³C NMR(100MHz,CDCl₃)δ26.1,26.3,33.0,37.4,97.5,110.4,119.6,119.9,120.9,128.7,135.5,145.1.

2-cyclohexyl-1H-indole (10.4 g, 52.5 mmol) was added to a dropping funnel, 250 ml of tetrahydrofuran was added to prepare a solution, and the solution was added dropwise to a tetrahydrofuran solution containing 2.5 equivalents of sodium hydride (5.25 g, 131 mmol, 60% dispersion in mineral oil) at room temperature. Sodium hydride (60% dispersed in mineral oil) was washed with anhydrous hexane (10 ml x3) to remove mineral oil before use. After the addition of the solution was completed, the dropping funnel was washed with an additional 10 ml of tetrahydrofuran and added to the reaction mixture. After the reaction mixture was stirred at room temperature for 1 hour, dimethyl sulfate (12.4 ml, 131 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight. After completion of the reaction, the reaction was quenched by slowly dropping 50 ml of ethanol into the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The concentrated mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to give a yellow solid. The yellow solid was washed with a methanol/water (9:1) mixture (60mL) and filtered to give 2-cyclohexyl-1-methyl-1H-indole (10.2 g, 91%).¹H NMR(400MHz,CDCl₃)δ1.44-1.56(m,5H),1.82-1.85(m,1H),1.91-1.94(m,2H),2.07-2.09(m,2H),2.70-2.75(m,1H),3.72(s,3H),6.29(s,1H),7.11(t,J＝7.5Hz,1H),7.20(t,J＝7.1Hz,1H),7.31(d,J＝8.1Hz,1H),7.59(d,J＝7.7Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ26.2,26.6,29.4,33.2,35.9,96.5,108.7,119.1,119.8,120.5,127.9,137.2,146.7.

2-cyclohexyl-1-methyl-1H-indole (10.0 g, 47.0 mmol) was dissolved in anhydrous chloroform (200 mL). N-bromosuccinimide (8.36 g, 47.0 mmol) was added portionwise to the solution at 0 ℃. After stirring for 30 minutes, the mixture was poured onto a short silica gel column, filtered off with suction and eluted with dichloromethane. After concentrating the eluate and evaporating, a methanol/water (9:1) mixture (90 ml) was added and stirred to give a white solid. The solid was filtered and dried in vacuo to give 3-bromo-2-cyclohexyl-1-methyl-1H-indole (12.1 g, 89%).¹H NMR(400MHz,CDCl₃)δ1.36-1.46(m,3H),1.79-1.88(m,3H),1.89-1.98(m,2H),2.07-2.16(m,2H),2.99-3.06(m,1H),3.77(s,3H),7.17-7.29(m,3H),7.52-7.55(m,1H)；¹³C NMR(100MHz,CDCl₃)δ25.9,27.0,30.6,30.7,37.0,88.0,109.0,118.5,120.0,121.9,127.4,136.1,140.8.

3-bromo-2-cyclohexyl-1-methyl-1H-indole (5.80 g, 20.0 mmol) was dissolved in freshly distilled THF (60mL) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (21.0 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes, chlorodiisopropylphosphine (3.34 ml, 21.0 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with 90% degassed methanol/water mixture (20 ml × 3) and cold degassed methanol (10 ml × 3). The solid product was collected by filtration and dried in vacuo to give 2-cyclohexyl-3- (diisopropylphosphino) -1-methyl-1H-indole cat1(5.19 g, 79%).¹H NMR(400MHz,C₆D₆)δ0.93-0.99(m,7H),1.16-1.49(m,10H),1.61-1.83(m,6H),2.54-2.63(m,2H),3.14(s,3H),7.03(d,J＝8.2Hz,1H),7.18-7.24(m,2H),7.85(s,1H)；¹³C NMR(100MHz,C₆D₆)δ21.0,21.1,21.8,22.1,24.1,26.0,27.1,30.6,31.2,37.2,37.4,103.2,103.3,109.3,119.6,120.9,121.2,130.2,130.3,138.5,153.1,153.5；³¹P NMR(162MHz,C₆D₆)δ-8.3.

Example 2: synthesis of 2-cyclohexyl-3- (dicyclohexylphosphino) -1-methyl-1H-indole

2-cyclohexyl-1H-indole, 2-cyclohexyl-1-methyl-1H-indole and 3-bromo-2-cyclohexyl-1-methyl-1H-indole were prepared as in example 1.

3-bromo-2-cyclohexyl-1-methyl-1H-indole (1.46 g, 5.0 mmol) was dissolved in freshly distilled THF (15 mL) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (5.25 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. The reaction mixture was stirred at-78 ℃ for 30 minutes and chlorobicyclohexyl was addedPhenylphosphine (1.16 ml, 5.25 mmol). After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with 90% degassed methanol/water mixture (5 ml × 3) and cold degassed methanol (10 ml × 3). The solid product was collected by filtration and dried in vacuo to give 2-cyclohexyl-3- (dicyclohexylphosphino) -1-methyl-1H-indole cat2(1.33 g, 65%).¹H NMR(400MHz,C₆D₆)δ1.07-2.11(m,31H),2.43-2.56(m,2H),3.17(s,3H),7.01-7.04(m,1H),7.19-7.24(m,2H),7.93-7.94(m,1H)；¹³C NMR(100MHz,C₆D₆)δ26.0,26.4,26.97,27.05,27.1,30.7,32.1,32.5,32.7,34.2,37.3,37.5,102.3,109.3,119.7,120.9,121.1,130.6,135.6,138.6,146.0,146.7,153.3,153.7；³¹P NMR(162MHz,C₆D₆)δ-19.8.

Example 3: synthesis of 2-cyclohexyl-3- (diphenylphosphino) -1-methyl-1H-indole

2-cyclohexyl-1H-indole, 2-cyclohexyl-1-methyl-1H-indole and 3-bromo-2-cyclohexyl-1-methyl-1H-indole were prepared as in example 1.

3-bromo-2-cyclohexyl-1-methyl-1H-indole (1.46 g, 5.0 mmol) was dissolved in freshly distilled THF (15 mL) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (5.25 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes, chlorodiphenylphosphine (0.940 ml, 5.25 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with 90% degassed methanol/water mixture (5 ml x3) and cold degassed methanol (5 ml x 3). The solid product was collected by filtration and dried in vacuo to give 2-cyclohexyl-3- (diphenylphosphino) -1-methyl-1H-indole cat3(1.71 g, 86%).¹H NMR(400MHz,C₆D₆)δ1.04-1.35(m,3H),1.49-1.92(m,5H),1.93-2.44(m,2H),3.12(s,3H),3.36-3.73(m,1H),6.87-7.30(m,10H),7.54-7.76(m,4H)；¹³C NMR(100MHz,C₆D₆)δ25.9,27.1,30.2,32.3,37.8,37.9,109.3,120.0,121.2,121.9,128.07,128.13,130.16,130.20,132.18,132.36,138.5,138.6,138.8,153.4,153.7；³¹P NMR(162MHz,C₆D₆)δ-30.7.

Example 4: synthesis of 2- (1-adamantyl) -3- (dicyclohexylphosphino) -1-methyl-1H-indole

1-adamantyl methyl ketone (3.6 g, 20 mmol) and phenylhydrazine (2.4 ml, 24 mmol) were mixed and stirred, then after addition of phosphoric acid (4 ml), 25 g of polyphosphoric acid was added. After the reaction exotherm occurred, it was stirred at room temperature for a few minutes. The mixture was heated to 85 ℃ and held at this temperature for 45 minutes. The temperature was then raised to 110 ℃ and the mixture was held at this temperature for a further 1 hour. After completion of the reaction, the mixture was poured into ice water and stirred for 1 hour. Then extracted with ether. The combined organic layers were dried over anhydrous sodium sulfate. The dried organic layer was concentrated, loaded on a short silica gel column for filtration, and eluted with an ethyl acetate/hexane (1:9) mixture. Concentrating and evaporating the eluent to obtain a solid product. The product was further washed with cold hexane. The solid product was filtered and dried in vacuo to give 2- (1-adamantyl) -1H-indole (3.68 g, 74%).¹H NMR(400MHz,CDCl₃)δ1.85-2.19(m,15H),6.33(s,1H),7.15-7.24(m,2H),7.39(d,J＝7.8Hz,1H),7.66(d,J＝7.5Hz,1H),8.05(s,1H)；¹³C NMR(100MHz,CDCl₃)δ28.4,33.6,36.7,42.5,96.2,110.4,119.4,119.9,120.9,128.4,135.4,149.2.

2- (1-adamantyl) -1H-indole (3.52 g, 14.0 mmol) was added to a dropping funnel, 42 ml of tetrahydrofuran was added to prepare a solution, and the solution was added dropwise to 42 ml of tetrahydrofuran solution containing 2.5 equivalents of sodium hydride (1.40 g, 35.0 mmol, 60% dispersion in mineral oil) at room temperature. Sodium hydride (60% dispersed in mineral oil) was washed with anhydrous hexane (10 ml x3) to remove mineral oil before use. After the addition of the solution was completed, the dropping funnel was washed with an additional 5 ml of tetrahydrofuran and added to the reaction mixture. The reaction mixture was refluxed for 15 minutes and then after stirring at room temperature for 15 minutes, dimethyl sulfate (3.30 ml, 35.0 mm)Molar) was added to the reaction mixture, and the reaction mixture was stirred for 2 hours. After completion of the reaction, 10 ml of ethanol was slowly added dropwise to the reaction mixture to quench the reaction, and then the reaction mixture was concentrated under reduced pressure. The concentrated mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was loaded on a silica gel column and then eluted with ethyl acetate/hexane (1: 50). Concentrating and evaporating the eluent to obtain a solid product. The solid was washed with a methanol/water (9:1) mixture (50 ml x1 and 25 ml x1) and filtered to give 2- (1-adamantyl) -1-methyl-1H-indole (3.59 g, 97%) as a white solid.¹H NMR(400MHz,CDCl₃)δ1.87-2.20(m,15H),3.97(s,3H),6.34(s,1H),7.11-7.33(m,3H),7.61(d,J＝7.4Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ28.6,32.8,34.7,36.8,41.4,98.2,108.5,119.2,119.9,120.8,127.2,138.6,149.3.

2- (1-adamantyl) -1-methyl-1H-indole (1.33 g, 5.0 mmol) was dissolved in anhydrous chloroform (15 mL). N-bromosuccinimide (0.89 g, 5.0 mmol) was added portionwise to the solution at 0 ℃. After stirring for 30 minutes, ethyl acetate and water were added to the mixture and the organic layer was separated. The organic layer was washed twice with water and then with brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was loaded on a silica gel column and then eluted with ethyl acetate/hexane (1: 50). The eluent was concentrated and evaporated to give 2- (1-adamantyl) -3-bromo-1-methyl-1H-indole (1.54 g, 90%) as a white solid.¹H NMR(400MHz,CDCl₃)δ1.84-2.47(m,15H),4.00(s,3H),7.21-7.30(m,3H),7.65(d,J＝7.8Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ28.6,34.6,36.6,37.5,41.5,88.2,108.7,119.3,120.0,122.4,128.1,137.3,141.3.

2- (1-adamantyl) -3-bromo-1-methyl-1H-indole (1.38 g, 4.0 mmol) was dissolved in freshly distilled THF (12 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (4.40 mmol) (concentration determined by titration) was added dropwise to the reaction mixture using a syringe. Inverse directionAfter the mixture was stirred at-78 ℃ for 30 minutes, chlorodicyclohexylphosphine (0.97 ml, 4.40 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 30 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with 95% degassed methanol/water mixture (10 ml) and cold degassed methanol (5 ml × 3). The solid product was collected by filtration and dried in vacuo to yield 2- (1-adamantyl) -3- (dicyclohexylphosphino) -1-methyl-1H-indole cat4(1.04 g, 57%).¹H NMR(400MHz,C₆D₆)δ1.01-1.41(m,8H),1.49-1.82(m,17H),2.08-2.15(m,5H),2.58-2.70(m,7H),3.40(s,3H),7.04-7.07(m,1H),7.22-7.24(m,2H),7.99-8.01(m,1H)；¹³C NMR(100MHz,C₆D₆)δ26.9,27.3,27.4,27.6,27.7,29.4,31.4,31.5,33.7,34.0,34.7,35.9,36.0,37.0,39.29,39.32,44.6,44.7,104.6,104.8,109.9,119.8,121.6,121.8,131.28,131.33,139.8,155.4,155.6；³¹P NMR(162MHz,C₆D₆)δ-15.9.

Example 5: synthesis of 2- (1-adamantyl) -3- (diisopropylphosphino) -1-methyl-1H-indole

The procedure for the preparation of 2- (1-adamantyl) -1H-indole, 2- (1-adamantyl) -1-methyl-1H-indole and 2- (1-adamantyl) -3-bromo-1-methyl-1H-indole is as in example 4.

2- (1-adamantyl) -3-bromo-1-methyl-1H-indole (1.03 g, 3.00 mmol) was dissolved in freshly distilled THF (9 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (3.30 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes, chlorodiisopropylphosphine (0.530 ml, 3.30 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with cold degassed methanol (5 ml × 3). The solid product was collected by filtration and dried in vacuo to yield 2- (1-adamantyl) -3- (diisopropylphosphino) -1-methyl-1H-indole cat5(0.940 g, 82%).¹H NMR(400MHz,C₆D₆)δ0.95-1.00(m,6H),1.28-1.34(m,6H),1.65-1.68(m,4H),1.77-1.80(m,3H),1.94-2.06(m,4H),2.52-2.56(m,4H),2.74-2.82(m,2H),3.39(s,3H),7.07(d,J＝7.7Hz,1H),7.20-7.28(m,2H),7.93(d,J＝7.4Hz,1H)；¹³C NMR(100MHz,C₆D₆)δ22.1,22.2,22.9,23.2,25.4,25.5,28.9,29.4,34.7,36.9,37.0,39.3,41.6,44.7,44.8,109.9,119.7,121.6,121.9,130.8,130.9,139.8,155.1；³¹P NMR(162MHz,C₆D₆)δ-3.5.

Example 6: synthesis of 2- (1-adamantyl) -3- (diphenylphosphino) -1-methyl-1H-indole

The procedure for the preparation of 2- (1-adamantyl) -1H-indole, 2- (1-adamantyl) -1-methyl-1H-indole and 2- (1-adamantyl) -3-bromo-1-methyl-1H-indole is as in example 4.

2- (1-adamantyl) -3-bromo-1-methyl-1H-indole (1.37 g, 4.00 mmol) was dissolved in freshly distilled THF (20 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (4.40 mmol) (concentration determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes, chlorodiphenylphosphine (0.810 ml, 4.40 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with cold degassed methanol (5 ml × 3). The solid product was collected by filtration and dried in vacuo to give 2- (1-adamantyl) -3- (diphenylphosphino) -1-methyl-1H-indole cat6(0.860 g, 48%).¹H NMR(400MHz,C₆D₆)δ1.60-1.63(m,3H),1.71-1.74(m,3H),1.94-1.99(m,3H),2.55-2.63(m,6H),3.42(s,3H),6.82(t,J＝7.2Hz,1H),6.96-7.10(m,8H),7.25(d,J＝8.0Hz,1H),7.65(t,J＝6.8Hz,4H)；¹³C NMR(100MHz,C₆D₆)δ29.3,34.6,36.7,39.5,39.6,43.8,43.9,102.3,102.4,109.7,120.1,121.7,123.3,127.5,128.4,128.5,132.1,132.3,138.9,139.1,140.1,156.1,156.4；³¹P NMR(162MHz,C₆D₆)δ-26.1.

Example 7: synthesis of 2- (tert-butyl) -3- (dicyclohexylphosphino) -1-methyl-1H-indole

2- (tert-butyl)) -1H-indole (0.800 g, 4.60 mmol) was added to a dropping funnel, 15 ml of tetrahydrofuran was added to prepare a solution, and the solution was added dropwise to 15 ml of tetrahydrofuran solution containing sodium hydride (9.20 mmol, 60% dispersion in mineral oil) at room temperature. Sodium hydride (60% dispersed in mineral oil) was washed with anhydrous hexane (10 ml x3) to remove mineral oil before use. After the addition of the solution was completed, the dropping funnel was washed with an additional 5 ml of tetrahydrofuran and added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The mixture was then cooled to 0 ℃, dimethyl sulfate (1.10 ml, 11.5 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight. After completion of the reaction, 10 ml of ethanol was slowly added dropwise to the reaction mixture to quench the reaction, and then the reaction mixture was concentrated under reduced pressure. The concentrated mixture was diluted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. The concentrated mixture was loaded onto a silica gel column and then eluted with ethyl acetate/hexane. The eluate was concentrated and evaporated to give 2- (tert-butyl) -1-methyl-1H-indole (0.80 g, 93%).¹H NMR(400MHz,CDCl₃)δ1.50(s,9H),3.90(s,3H),6.33(s,1H),7.09(t,J＝7.4Hz,1H),7.19(t,J＝8.2Hz,1H),7.28(d,J＝8.2Hz,1H),7.56(d,J＝7.8Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ30.2,32.3,98.0,108.6,119.3,119.9,120.8,127.2,138.6,149.1.

2- (tert-butyl) -1-methyl-1H-indole (1.44 g, 7.70 mmol) was dissolved in anhydrous chloroform (40 ml). N-bromosuccinimide (1.37 g, 7.70 mmol) was added portionwise to the solution at 0 ℃. After completion of the reaction, the mixture was quenched with water and then extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by flash column chromatography on silica gel to give 3-bromo-2- (tert-butyl) -1-methyl-1H-indole (2.03 g, 99%) as a pale yellow liquid.¹H NMR(400MHz,CDCl₃)δ1.70(s,9H),3.93(s,3H),7.20-7.24(m,1H),7.28-7.30(m,2H),7.63(d,J＝7.8Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ31.5,34.0,34.4,88.0,108.7,119.3,120.1,122.5,128.0,137.3,141.9.

3-bromo-2- (tert-butyl) -1-methyl-1H-indole (0.530 g, 2.00 mmol) was dissolved in freshly distilled THF (30 ml) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (2.20 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 20 minutes, dicyclohexylchlorophosphine (0.560 g, 2.40 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with cold degassed methanol (10 ml × 3). The white solid product was collected by filtration and dried in vacuo to yield 2- (tert-butyl) -3- (dicyclohexylphosphino) -1-methyl-1H-indole cat7(0.360 g, 47%).¹H NMR(400MHz,CDCl₃)δ0.95-1.11(m,4H),1.14-1.23(m,2H),1.30-1.37(m,6H),1.48-1.54(m,2H),1.59-1.62(m,2H),1.70(s,9H),1.77-1.80(m,2H),1.98-2.05(m,2H),2.41-2.48(m,2H),3.91(s,3H),7.07(t,J＝7.2Hz,1H),7.18(t,J＝8.0Hz,1H),7.28(d,J＝8.1Hz,1H),7.75(d,J＝8.0Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ26.4,27.0,27.1,27.2,27.3,30.8,30.9,33.2,33.4,34.0,34.1,34.4,35.1,35.2,35.62,35.64,103.4,103.6,109.1,119.1,121.0,121.5,130.7,139.1,155.5,155.8；³¹P NMR(162MHz,CDCl₃)δ-15.1.

Example 8: synthesis of 3- (dicyclohexylphosphine) -1, 2-dimethyl-1H-indole

1, 2-dimethyl-1H-indole (1.09 g, 7.50 mmol) was dissolved in anhydrous dimethylformamide (15 ml). To this solution was added a solution of N-bromosuccinimide (1.40 g, 7.88 mmol) in dimethylformamide (10 ml) at 0 ℃. After stirring for 2 hours, the mixture was poured onto crushed ice, and then dichloromethane and water were added. The organic layer was washed with copious amounts of water and then concentrated. The concentrate was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:20) as eluent to give 3-bromo-1, 2-dimethyl-1H-indole (0.84 g, 50%) as a white solid.¹H NMR(400MHz,CDCl₃)δ2.46(s,3H),3.72(s,3H),7.16-7.29(m,3H),7.52(d,J＝7.6Hz,1H)；¹³C NMR(100MHz,CDCl₃)δ11.1,30.2,89.1,108.9,118.4,119.9,121.7,126.8,134.1,136.1.

3-bromo-1, 2-dimethyl-1H-indole (0.670 g, 3.00 mmol) was dissolved in freshly distilled THF (6 mL) under a nitrogen atmosphere. The solution was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (3.30 mmol) (the concentration was determined by titration) was added dropwise to the reaction mixture using a syringe. After the reaction mixture was stirred at-78 ℃ for 30 minutes chlorodicyclohexylphosphine (0.730 ml, 3.30 mmol) was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated mixture was washed with cold degassed methanol (5 ml × 3). The white solid product was collected by filtration and dried in vacuo to yield 3- (dicyclohexylphosphine) -1, 2-dimethyl-1H-indole cat8(0.720 g, 70%).¹H NMR(400MHz,C₆D₆)δ1.02-1.44(m,10H),1.51-1.61(m,4H),1.72-1.88(m,4H),2.04-2.17(m,2H),2.41(s,3H)；2.43-2.52(m,2H),2.81(s,3H)；7.03(d,J＝7.0Hz,1H),7.20-7.26(m,2H),7.97(d,J＝6.8Hz,1H)；¹³C NMR(100MHz,C₆D₆)δ11.7,11.9,26.5,27.08,27.12,27.2,28.8,30.3,30.4,32.0,32.2,33.7,33.8,101.5,101.6,109.0,119.8,120.8,120.9,131.2,138.0；³¹P NMR(162MHz,C₆D₆)δ-18.0.

In examples 1 to 8, the following reaction formulae can be referred to:

preparation of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole product cat1-cat8, the results are shown in Table 1 below:

TABLE 1

Example 9: application of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand in palladium-catalyzed chemoselective coupling reaction

The phosphine ligand product cat1-8 with 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton, prepared in examples 1-8 of the present invention, has the following structure:

9.1 comparison of phosphine ligands of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton with other phosphine ligands in catalytic chemoselective cross-coupling reactions

Palladium acetate (0.0018 g, 0.008 mmol), phosphine ligand (palladium: phosphine ligand ratio 4.0 mol%: 4.0 mol%), o-tolylboronic acid (0.2 mmol), potassium fluoride (0.6 mmol), and a magnetic stir bar fitted with a polytetrafluoroethylene coating were placed in a 20 ml Schlenk tube. After purging nitrogen 3 times, 4-chlorophenyl trifluoromethanesulfonate (0.2 mmol) and freshly distilled tetrahydrofuran (0.6 ml) were added under nitrogen. The Schlenk tube was then left to react at room temperature for 1 hour. Ethyl acetate (4.0 ml), dodecane (45.2 μ l) and water (2.0 ml) were then added to the system, and the organic layer after extraction was subjected to gas chromatography analysis and examined to determine the yield of the coupled product. The reaction formula of the above reaction is as follows:

the phosphine ligands and the corresponding products and yield conditions of different catalysts used in the above catalytic selective cross-coupling reaction are shown in table 2 below.

TABLE 2^a

^aReaction conditions 4-chlorophenyl triflate (0.20 mmol), o-tolylboronic acid (0.20 mmol), palladium acetate (4 mol%), a phosphine ligand (4 mol%), potassium fluoride (0.60 mmol) and tetrahydrofuran (0.60 ml) were reacted at room temperature for 1 hour.^bCorrected GC yield using dodecane as internal standard.

Wherein, Nos. 1 to 8 are phosphine ligands prepared in examples 1 to 8 of the present application, Nos. 9 to 12 are phosphine ligands in which 2-position is benzene ring, and Nos. 13 to 25 are other common commercially available phosphine ligands. As can be seen from Table 2, the phosphine ligands of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton prepared in the examples of the present application can show very good chemoselectivity and catalytic performance in the above-mentioned chemoselective cross-coupling reaction of 4-chlorophenyl trifluoromethanesulfonate. The alkyl group at position 2 of the indolylphosphine ligand has special efficacy, and can bring out a new reaction sequence of C-Cl > C-OTf, thereby providing the ideal product 3a with high yield. While phosphine ligands with a phenyl ring in position 2 of the indolylphosphine ligand are amenable to most reaction sequences C-OTf > C-Cl to provide product 4 a. Other commercially available phosphine ligands are also amenable to most reaction sequences C-OTf > C-Cl to provide product 4a, or have no catalytic properties for this chemoselective cross-coupling reaction.

9.2 Selective Cross-coupling reactions catalyzed by phosphine ligands of 2, 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeletons in the Presence of different substrates

(1) Palladium acetate (0.0023 g, 0.010 mmol), phosphine ligand (palladium: phosphine ligand ratio 5.0 mol%: 10 mol%) and a magnetic stir bar equipped with a polytetrafluoroethylene coating were placed in a 50 ml Schlenk tube. After 3 nitrogen purges, freshly distilled tetrahydrofuran (25 ml) was added under nitrogen and stirred at room temperature for 1 min. The magnetic stir bar with teflon coating was placed in another 20 ml Schlenk tube and the system replaced with nitrogen blanket, then the corresponding palladium metal complex solution was added, then concentrated under reduced pressure, and then the aryl boronic acid (0.2-0.3 mmol), polyhalogenated aryl triflate (0.2 mmol if solid) and potassium fluoride (0.6 mmol) were added under nitrogen. After 3 nitrogen purges, the polyhalogenated aryl triflate (0.2 mmol if liquid) and freshly distilled tert-butanol or toluene (0.6 ml) were added under nitrogen. The Schlenk tube was then placed in an oil bath at room temperature or preheated to 60 ℃ or 110 ℃ for 1.5 to 18 hours, and the reaction formula is shown below. After completion of the reaction, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (4.0 ml) and water (2.0 ml) were added to the system, and then the organic layer after extraction was subjected to gas chromatography. After which about 10 ml of ethyl acetate are added three to four times each for extraction and the organic phases are combined. The organic phase is concentrated under reduced pressure and purified by column chromatography on silica gel to give the cross-coupled product. The reaction formula of the above reaction is as follows:

wherein the catalyst phosphine ligand is the phosphine ligand cat1 prepared in example 1.

The substrate, palladium amount, product and yield in the above catalytic selective cross-coupling reaction are shown in table 3 below:

TABLE 3^a

^aReaction conditions 1(0.20 mmol), Ar' B (OH)₂(0.20 mmol), Pd (OAc)₂Cat1 ═ 1:2, KF (0.60 mmol) and t-BuOH (0.60 ml) were stirred at 110 ℃ under nitrogen for 2 hours.^bUsing 1.2 times of Ar' B (OH)₂.^cUsing 1.1 times of Ar' B (OH)₂.^dUsing 1.5 times of Ar' B (OH)₂.^eToluene was used and the reaction time was 4 hours f toluene/t-butanol was 1:1( was 0.6 ml) and the reaction time was 4 hours.^gThe reaction time is 1 hour.^hUsing 1(0.3 mmol) and Ar' B (OH)₂(0.20 mmol).ⁱUsing 3.0 times of Ar' B (OH)₂And toluene, and the reaction time was 30 minutes.

As can be seen from Table 3, when the phosphine ligand cat1 prepared in example 1 of this application is used to catalyze selective cross-coupling reaction, Cl-Ar-OTf and Ar' B (OH) are present in the substrate₂When it catalyzes the reaction sequence of C-Cl>C-OTf。

The substrate, palladium amount, product and yield in the above-described catalytic selective cross-coupling reaction are shown in table 4 below:

TABLE 4^a

^aReaction conditions Br-Ar-OTf (0.20 mmol), Ar' B (OH)₂(0.30 mmol), Pd (OAc)₂Cat1 ═ 1:2, KF (0.60 mmol) and t-BuOH (0.60 ml) were stirred at 110 ℃ under nitrogen for 3 hours.^bToluene was used.^cThe temperature was 60 ℃.^dThe reaction time was 16 hours.

As can be seen from Table 4, the phosphine ligand cat1 prepared in example 1 of the present application was usedWhen Br-Ar-OTf and Ar' B (OH) are present in the substrate during the catalytic selective cross-coupling reaction₂When the reaction sequence is C-Br>C-OTf。

(2) Palladium acetate (0.0023 g, 0.010 mmol), phosphine ligand (palladium: phosphine ligand ratio 5.0 mol%: 10 mol%) and a magnetic stir bar equipped with a polytetrafluoroethylene coating were placed in a 50 ml Schlenk tube. After 3 nitrogen purges, freshly distilled tetrahydrofuran (25 ml) was added under nitrogen and stirred at room temperature for 1 min. The magnetic stir bar with teflon coating was placed in another 20 ml Schlenk tube and the system replaced with nitrogen blanket, then the corresponding palladium metal complex solution was added, then concentrated under reduced pressure, and then the aryl boronic acid (0.2 mmol), polyhalogenated aryl triflate (0.2 mmol if solid) and potassium fluoride (1.2 mmol) were added under nitrogen. After 3 nitrogen purges, polyhalogenated aryl triflate (0.2 mmol if liquid) and freshly distilled toluene (0.6 ml) were added under nitrogen. The Schlenk tube was then placed in an oil bath at room temperature or preheated 110 ℃ for reaction for 2 hours, then the reaction tube was cooled to room temperature, arylboronic acid (0.4 mmol) was added to the system, and then the Schlenk tube was placed in an oil bath at room temperature or preheated 110 ℃ for reaction for 2 to 16 hours. The reaction formula is shown below. When the reaction was completed, the reaction tube was cooled to room temperature, the reaction was stopped, ethyl acetate (4.0 ml) and water (2.0 ml) were added to the system, and then the organic layer after extraction was subjected to gas chromatography. After which about 10 ml of ethyl acetate are added three to four times each for extraction and the organic phases are combined. The organic phase is concentrated under reduced pressure and purified by column chromatography on silica gel to give the cross-coupled product. The chemical formula of the above reaction is as follows:

wherein the catalyst phosphine ligand is the phosphine ligand cat1 prepared in example 1.

The substrate, palladium amount, product and yield in the above-described catalytic selective cross-coupling reaction are shown in table 5 below:

TABLE 5

As can be seen from Table 5, when the phosphine ligand cat1 prepared in example 1 of the present application is used for catalyzing selective cross-coupling reaction, when Br, Cl and OTf exist in a substrate at the same time, the reaction sequence is C-Br > C-Cl > C-OTf.

From the above tables 3, 4 and 5, it can be seen that the phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton prepared in the examples of the present invention reacts with chlorine (-Cl) first and then with trifluoromethanesulfonic acid chloroester (-OTf) in the chemoselective Suzuki-Miyaura reaction, i.e., when a plurality of (pseudo) halides are present in the substrate, the reaction sequence is C-Br > C-Cl > C-OTf.

9.3 reactivity of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand in catalyzing selective cross-coupling reaction

The specific reaction steps and reaction formula are as described in 9.2 (1). Wherein the catalyst phosphine ligand is the phosphine ligand cat1 prepared in example 1.

The substrate, palladium amount, product and yield in the above-described catalytic selective cross-coupling reaction are shown in table 6 below:

TABLE 6^a

^aReaction conditions 1(0.20 mmol), Ar' B (OH)₂(0.20 mmol), Pd (OAc)₂Cat1 ═ 1:2, KF (0.60 mmol) and t-BuOH (0.60 ml) were stirred at 110 ℃ under nitrogen for 2 hours.^bThe reaction time was 18 hours.^cUsing 1.5 times of Ar' B (OH)₂.

As can be seen from table 6 above, when the phosphine ligand of 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton of the present invention is used for the first palladium-catalyzed chemoselective reaction, the palladium usage (mol%) can be greatly reduced to 10ppm, the separation yield can reach 99%, and even the reaction can be performed at room temperature, while the separation yield is ensured.

In conclusion, the invention provides a phosphine ligand with a 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton, which can form a complex with a stable structure with a transition metal such as palladium, 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 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand and a transition metal such as palladium form a catalytic system, can be used for preparing a multi-element aryl compound, and has great application potential in the synthesis of natural products and drug intermediates. The phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton provided by the invention can be widely used for high-difficulty transition metal-catalyzed cross-coupling reactions, including selective Suzuki coupling reaction (Chemoselective Suzuki reactions of polyhalogenated aryl triflates). The catalytic activity of a transition metal catalyst such as a palladium catalyst is as low as 10ppm, the separation yield is as high as 99 percent, and the method has profound significance for cross coupling reaction; and simultaneously compatible with functional groups such as ester, ketone, methoxyl and the like. Furthermore, the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand provided by the invention has an alkyl group at the 2-position of indole, and is firstly reacted with chlorine (-Cl) and then reacted with trifluoromethanesulfonic acid chlorine ester (-OTf) in a chemoselective Suzuki-Miyaura reaction, namely, when a plurality of (pseudo) halides exist in a substrate, the reaction sequence is C-Br > C-Cl > C-OTf. When the phosphine ligand (Phendole-Phos) with the 2-position benzene ring of the indole is applied to the chemoselective Suzuki-Miyaura reaction, the reaction sequence is C-Br > C-OTf > C-Cl, and the reaction sequence is consistent with the common reaction sequence. In addition, the phosphine ligand with the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton is simple and direct to synthesize, can be prepared in a large scale and is easy to store and treat; the structure and charge properties of the ligand are easy to adjust and modify; the ligand has wide application range, high catalytic activity, low dosage of the used catalyst, mild reaction conditions, easy amplification of reaction proportion and high practical value in synthesis.

The preparation method of the 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand provided by the invention has the advantages of simple and easily obtained raw materials, simple method and high total yield.

The 2-alkyl-3- (disubstituted phosphino) -1-alkyl-1H-indole skeleton phosphine ligand provided by 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, so that the catalytic activity and selectivity of the catalytic reaction of the transition metal such as palladium are improved, and the phosphine ligand is particularly suitable for a high-difficulty chemical selectivity reaction, wherein the catalytic activity of the transition metal catalyst such as a palladium catalyst can be as low as 10ppm, and the separation yield is as high as 99%.

It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.