CN117209522A

CN117209522A - Preparation method of multi-substituted aromatic compound containing alkyne and amine functional groups

Info

Publication number: CN117209522A
Application number: CN202311035075.9A
Authority: CN
Inventors: 李先纬; 陈小健; 陈迁; 霍延平
Original assignee: Guangdong University of Technology
Current assignee: Guangdong University of Technology
Priority date: 2023-08-16
Filing date: 2023-08-16
Publication date: 2023-12-12

Abstract

The present application provides a process for the preparation of polysubstituted aromatic compounds containing alkyne and amine functions. Specifically, under the condition of inert solvent, the C (sp) of the triflyl aryl propylamine is promoted by divalent palladium catalysis and amino acid ligand ² ) The activation of the H bond, via a 7-membered cyclic metal intermediate, followed by coupling with an alkynylating reagent, rapidly constructs a variety of alkyne and amine functional polysubstituted aromatic compounds. The easily-converted trifluoro methanesulfonamide guiding group and alkyne functional group can be further modified and applied, so that a molecular library of the polysubstituted aromatic hydrocarbon compound can be quickly constructed.

Description

Preparation method of multi-substituted aromatic compound containing alkyne and amine functional groups

Technical Field

The present application relates to the field of organic compound synthesis technology, and more specifically, to a method for preparing a polysubstituted aromatic compound containing alkyne and amine functional groups.

Background

Amine, as a multifunctional block and ubiquitous structural backbone, is widely found in pharmaceutical, materials and life sciences. In addition to amino acids, benzylamine, phenethylamine and amphetamine derivatives are also important precursors for drugs such as ampicillin (broad spectrum β -lactam antibiotics against a variety of gram positive and gram negative bacteria), formoterol (for the treatment of chronic obstructive pulmonary disease), neupro (for the treatment of parkinson's disease), duloxetine (for the treatment of generalized anxiety disorder), cinacalcet (for cardiovascular disease research), tolterodine (an effective muscarinic receptor antagonist, selective for the bladder in vivo).

In addition, alkynes are one of the most valuable functional groups in synthetic chemistry and material chemistry, are extremely important synthons, can be widely converted into various functional groups or molecular core skeletons, and have wide application in the fields of medicines, natural products and materials. Numerous human-name reactions, such as Sonogashira coupling, larock indole synthesis, click reaction, double decomposition reaction of eneyne and alkyne, etc., represent the conversion and application potential of alkyne functional groups. Therefore, it is of great theoretical and practical value to selectively introduce alkynyl groups to molecular sites.

In recent years, oxidative coupling functionalization of derivatives of transition metal-catalyzed amines directly through C-H bonds with alkynyl halides, hypervalent iodinated reagents, or terminal alkynes has become a rapidly evolving field in synthetic chemistry. In order to regulate the reactivity of metal catalysts and the regioselectivity of amine substrates, synthetic chemists have made great efforts in the design of catalytic systems, directing groups and ligands. However, rigid strongly coordinated bidentate directing groups such as pyridine, quinoline, oxazole, triazole derived amine or amide directing groups will be difficult to remove or further convert; although the polyfluoroanilide guide group developed by the Yu Jinquan subject group solves the problem that the guide group is difficult to remove, the strategy has certain practical limitations because polyfluoroanilines are expensive and not readily available. Thus, the development of readily available and easily convertible amine derivatives for direct site-selective hydrocarbon bond functionalization has great synthetic utility.

Furthermore, the basis for promoting site-selective hydrocarbon bond activation reactions achieved under the targeting strategy, which mainly utilizes in-situ cyclometallation, whereas classical cyclometallation tends to be kinetically and thermodynamically favored for in-situ generation of 5-membered and 6-membered ring metal species, which is kinetically and thermodynamically unfavorable. This also makes site-selective hydrocarbon bond activation for remote-directed control very challenging to date.

In summary, although significant progress has been made in aromatic ring ortho alkynylation of benzamide, benzyl amine and phenethylamine derivatives, a more remote C (sp) of gamma-arylpropylamine derivatives was achieved ² ) H bond activation alkynyl has been reported.

Content of the patent application

To overcome at least one of the problems of the prior art, the present application provides a process for the preparation of polysubstituted aromatic compounds containing alkyne and amine functionalities. The preparation method is assisted by bivalent palladium catalysis and amino acid ligand, uses simple and easily available trifluoro methanesulfonyl aryl propylamine and alkyne halogen reagent as reaction substrates, and rapidly constructs various polysubstituted aromatic compounds containing alkyne and amine functional groups with good yield and site selectivity.

The application provides a method for preparing and converting a weakly coordinated trifluoro methanesulfonamide-oriented remote aromatic ring hydrocarbon bond alkynyl, and a related compound, wherein a trifluoro methanesulfonamide guiding group and an alkyne functional group which are easy to convert can be further modified and applied, so that a molecular library of a polysubstituted aromatic hydrocarbon compound can be quickly constructed.

In the preparation method of the patent application, a possible reaction mechanism flow chart is as follows:

the specific mechanism is as follows: the trifluoro methanesulfonyl aryl propylamine compound II is reacted with bivalent palladium catalyst, N-tert-butyloxycarbonyl-L-leucine (MPAA) and alkali to obtain intermediate A, which has C (sp) ² ) The activation of the H-bond, forming a 7-membered cyclic metal intermediate B, may then undergo the following two pathways: 1) Alkyne bromine testOxidizing and adding the intermediate B by the agent III to generate a tetravalent palladium species C, and reducing and eliminating to obtain a required alkyne compound I; 2) Alkyne bromine reagent III migrates and intercalates into intermediate B to form the 9-membered ring palladium species C', trans β -bromine elimination liberates the desired alkyne compound I. And finally, regenerating the catalyst under the action of a halogen ion capturing agent to complete the catalytic cycle.

In order to solve the technical problems, the technical scheme adopted by the patent application is as follows:

a process for the preparation of a polysubstituted aromatic compound containing alkyne and amine functions, comprising the steps of: in an inert solvent, under the catalysis of a divalent palladium catalyst and the promotion of a single-protection amino acid ligand, a trifluoro methanesulfonyl aryl propylamine compound (formula II) and an alkynyl bromine compound (formula III) are reacted to obtain a multi-substituted aromatic compound (formula I) containing alkyne and amine functional groups, wherein the reaction equation is as follows:

wherein Ar is an ortho-, meta-, para-, or polysubstituted aromatic, condensed or heterocyclic compound; r is R ¹ Is H, alkyl, ester group, X is C or O atom; r is R ² Is a triisopropyl silicon group, tert-butyl dimethyl silicon group protected alkyl alcohol or aryl alcohol substituent.

Compared with the prior art, the beneficial effect of this patent application is:

the preparation method of the polysubstituted aromatic compound containing alkyne and amine functional groups has the characteristics of easily obtained and converted guide groups, good atom step economy, and capability of overcoming the difficulty in activation and functionalization of remote carbon-hydrogen bonds of amine, and simultaneously introduces alkyne functional groups which are easy to modify and convert in later period into molecules through the synthesis strategy, so as to quickly construct a molecular library of the polysubstituted aromatic compound.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound 1a prepared in example 1 of the present patent application;

FIG. 2 is a nuclear magnetic resonance carbon spectrum of compound 1a prepared in example 1 of the present patent application;

FIG. 3 is a nuclear magnetic resonance fluorine spectrum of compound 1a prepared in example 1 of the present patent application;

FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of compound 1b prepared in example 2 of the present patent application;

FIG. 5 is a nuclear magnetic resonance carbon spectrum of compound 1b prepared in example 2 of the present patent application;

FIG. 6 is a nuclear magnetic resonance fluorine spectrum of compound 1b prepared in example 2 of the present patent application;

FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of compound 1c prepared in example 3 of the present patent application

FIG. 8 is a nuclear magnetic resonance carbon spectrum of compound 1c prepared in example 3 of the present patent application;

FIG. 9 is a nuclear magnetic resonance fluorine spectrum of compound 1c prepared in example 3 of the present patent application;

FIG. 10 is a nuclear magnetic resonance hydrogen spectrum of compound 1d prepared in example 4 of the present patent application;

FIG. 11 is a nuclear magnetic resonance carbon spectrum of compound 1d prepared in example 4 of the present patent application;

FIG. 12 is a nuclear magnetic resonance fluorine spectrum of compound 1d prepared in example 4 of the present patent application;

FIG. 13 is a nuclear magnetic resonance hydrogen spectrum of compound 1e prepared in example 5 of the present patent application;

FIG. 14 is a nuclear magnetic resonance carbon spectrum of compound 1e prepared in example 5 of the present patent application;

FIG. 15 is a nuclear magnetic resonance fluorine spectrum of compound 1e prepared in example 5 of the present patent application;

FIG. 16 is a nuclear magnetic resonance hydrogen spectrum of compound 1f prepared in example 6 of the present patent application;

FIG. 17 is a nuclear magnetic resonance carbon spectrum of compound 1f prepared in example 6 of the present patent application;

FIG. 18 is a nuclear magnetic resonance fluorine spectrum of compound 1f prepared in example 6 of the present patent application;

FIG. 19 is a hydrogen nuclear magnetic resonance spectrum of 1g of the compound prepared in example 7 of the present patent application;

FIG. 20 is a nuclear magnetic resonance carbon spectrum of 1g of the compound prepared in example 7 of the present patent application;

FIG. 21 is a nuclear magnetic resonance fluorine spectrum of 1g of the compound prepared in example 7 of the present patent application;

FIG. 22 is a nuclear magnetic resonance hydrogen spectrum of compound 3h prepared in example 7 of the present patent application;

FIG. 23 is a nuclear magnetic resonance carbon spectrum of compound 3h prepared in example 7 of the present patent application;

FIG. 24 is a nuclear magnetic resonance fluorine spectrum of compound 3h prepared in example 7 of the present patent application.

Detailed Description

Embodiments of the present application will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustration of the present application and should not be construed as limiting the scope of the present application. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

It should be noted that:

in this patent application, all the embodiments mentioned herein and the preferred methods of implementation can be combined with each other to form new solutions, if not specifically stated.

In this application, unless otherwise indicated, the various reactions or steps may be performed sequentially or sequentially. Preferably, the reaction processes herein are performed sequentially.

Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any method or material similar or equivalent to those described may be used in the present application.

Aiming at the technical problems in the prior art, the application provides a method for preparing a remote aromatic ring hydrocarbon bond alkynyl guided by a weak coordination trifluoromethanesulfonamide and preparation and conversion of related compounds. Under the condition of an inert solvent, the application uses a simple and easily available trifluoromethanesulfonyl aryl propylamine and alkyne halogen reagent as reaction substrates with the assistance of divalent palladium catalysis and amino acid ligand, and various polysubstituted aromatic compounds containing alkyne and amine functional groups are quickly constructed with good yield and site selectivity. The easily-converted trifluoro methanesulfonamide guiding group and alkyne functional group can be further modified and applied to quickly construct a molecular library of the polysubstituted aromatic hydrocarbon compound.

The present application provides a process for the preparation of polysubstituted aromatic compounds containing alkyne and amine functions. The preparation method comprises the following steps: in an inert solvent, under the catalysis of a divalent palladium catalyst and the promotion of a single-protection amino acid ligand, a trifluoro methanesulfonyl aryl propylamine compound (formula II) and an alkynyl bromine compound (formula III) are reacted to obtain a multi-substituted aromatic compound (formula I) containing alkyne and amine functional groups, wherein the reaction equation is as follows:

The application discloses a method for alkynyl remote aromatic ring hydrocarbon bond guided by weakly coordinated trifluoromethanesulfonamide and preparation and conversion of related compounds.

In the application, "weak coordination" refers to that the coordination capability of hetero atoms such as N or O of a guiding group on a metal catalyst is weak, and the coordination and dissociation of the guiding group and the catalyst are easier to realize compared with the coordination capability of strongly coordinated pyridine, quinoline, oxazole and triazole derived amine or amide guiding groups, so that the remote activation and subsequent functionalization are facilitated; "directing" refers to directing a directing group as an internal ligand to direct a metal catalyst near a particular C-H bond, thereby effecting site-selective hydrocarbon bond activation functionalization; in addition, "remote" in this patent application means that the directing group is relatively far from the desired activated C-H bond, classical cyclometallation tends to be kinetically and thermodynamically favored for in situ formation of 5-membered and 6-membered ring metal species where formation of 7-membered ring metal species, which are both kinetically and thermodynamically unfavorable, is very challenging.

In the preparation method of the patent application, a possible specific reaction mechanism flow is as follows:

under the condition of inert solvent, the intermediate A is obtained by bivalent palladium catalysis, single-protection amino acid ligand assistance and acid radical ion synergistic metallization deprotonation, so that C (sp ² ) The activation of the H-bond, forming a 7-membered cyclic metal intermediate B, may then undergo the following two pathways: 1) Oxidizing and adding the alkyne bromine reagent to the intermediate B to generate a tetravalent palladium species C, and reducing and eliminating to obtain a required alkyne compound; 2) The alkyne bromine reagent migrates and intercalates into intermediate B to form the 9-membered ring palladium species C', trans β -bromine elimination liberates the desired alkyne compound. And finally, regenerating the catalyst under the action of a halogen ion capturing agent to complete the catalytic cycle. The method has the characteristics of easily obtained guiding group, easy conversion, good economy of atomic steps and difficult activation and functionalization of the remote carbon-hydrogen bond of the amine, and can rapidly construct various multi-substituted aromatic compounds containing alkyne and amine functional groups; the specific reaction mechanism flow chart is as follows:

in some embodiments, the inert solvent is any one or more of 1, 2-dichloroethane, 1, 2-dimethoxyethane, t-butanol, 2-methyl-2-butanol, toluene, 1, 4-dioxane, tetrahydrofuran, N' -dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile.

In some preferred embodiments, the divalent palladium catalyst is: any one or combination of palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride and diacetonitrile palladium dichloride.

In some preferred embodiments, the mono-protected amino acid ligand is any one of, or a combination of, N-t-butoxycarbonyl-L-leucine, N-t-butoxycarbonyl-L-alanine, N-t-butoxycarbonyl-L-phenylalanine, N-acetyl-L-valine, N-acetyl-L-phenylalanine, N-acetyl-L-t-leucine.

In some preferred embodiments, the additive is any one or more of sodium acetate, potassium acetate, sodium trifluoroacetate, sodium pivalate, sodium propionate, sodium glycinate, sodium 1-adamantanecarboxylate, sodium 2,4, 6-trimethylbenzoate.

In some preferred embodiments, the halide ion scavenger is any one or more of silver acetate, silver carbonate, silver oxide, and silver trifluoroacetate.

In some preferred embodiments, the base is any one or more of potassium carbonate, potassium bicarbonate, cesium carbonate, sodium bicarbonate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.

In some preferred embodiments, the reaction molar ratio of the trifluoromethanesulfonyl aryl propylamine compound (formula II) to the alkynyl bromo compound (formula III) is from 1:1.1 to 1:1.5. In the application, for the trifluoro methanesulfonyl aryl propylamine compound without substituent at the ortho position, in order to reduce the generation of the ortho-position double alkynyl byproducts, the reaction molar ratio can be set to be 1:1.1-1:1.2; for the trifluoromethyl sulfonyl aryl propylamine compound with substituent at the ortho-position or meta-position, the yield can be improved by properly increasing the equivalent weight of the alkynyl bromine reagent, and the reaction molar ratio can be set to be 1:1.2-1:1.5.

In some preferred embodiments, the divalent palladium catalyst is used in an amount of 2 to 10 mole% of the amount of the triflylarylamine compound (formula II). The divalent palladium catalyst is generally 5mol% of the trifluoro methanesulfonyl aryl propylamine compound, the reaction time is longer (for example, about 24 hours is needed for 2 mol%) when the catalyst is reduced, and the reaction time is shortened (for example, about 6 hours is needed for 10 mol%) when the catalyst is increased

In some preferred embodiments, the reaction is carried out at 80 to 120 ℃; the reaction is carried out for 6 to 24 hours.

In some more preferred embodiments, the process for preparing the alkyne and amine functional polysubstituted aromatic compounds in this application comprises the following specific steps:

s1: 1.7mg of palladium acetate, 10.4mg of N-t-butoxycarbonyl-L-leucine, 3.7mg of sodium acetate, 30.0mg of silver acetate, 24.9mg of potassium carbonate, 1.5mL of 1, 2-dichloroethane, 51.7mg of trifluoromethanesulfonyl (3- (2-bromophenyl)) propylamine and 46.8mg of triisopropylsilylacetyl bromide were sequentially added to the reactor in air;

s2: reacting the reaction solution at 100 ℃ for 12 hours;

s3: separating the mixture by thin layer chromatography separation technology after the reaction is finished to obtain the target compound, namely the polysubstituted aromatic compound containing alkyne and amine functional groups.

Next, a method for preparing the multi-substituted aromatic compound having alkyne and amine functional groups of the present application will be described in detail with specific examples.

1. Preparation example

Example 1 preparation of trifluoromethanesulfonyl (2- (2- ((triisopropylsilyl) ethynyl) phenoxy)) ethylamine (1 a)

Into a 15mL Schlenk reaction tube was successively charged trifluoromethanesulfonyl (2-phenoxy) ethylamine 2a (40.4 mg,0.15 mmol) under an atmospheric air atmosphere, and a divalent palladium catalyst PdCl ₂ (1.3 mg,0.0075 mmol), amino acid ligand N-Boc-L-Leu-OH (10.4 mg,0.045 mmol), sodium acetate (3.7 mg,0.045 mmol), silver acetate (30.0 mg,0.18 mmol), potassium carbonate (24.9 mg,0.18 mmol), 1, 2-dichloroethane (DCE, 1.5 mL), triisopropylsilylacetylene bromide 3a (46.8 mg,0.18 mmol) was reacted at 100℃for 12 hours. The crude product was chromatographed on a prepared silica gel plate with a volume ratio of petroleum ether to ethyl acetate of 45:1 selected as the developing solvent or eluent to give the product trifluoromethanesulfonyl (2- (2- ((triisopropylsilyl) ethynyl) phenoxy)) ethylamine (1 a,31.7 mg) in 47% yield. The chemical reaction equation corresponding to this example is as follows:

the nuclear magnetic hydrogen spectrum, the carbon spectrum and the fluorine spectrum of the compound prepared in the example 1 are shown in figures 1,2 and 3. As can be seen from fig. 1: ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.47 (dd, j=7.6, 1.6hz, 1H), 7.31-7.27 (m, 1H), 6.97 (td, j=7.6, 1.2hz, 1H), 6.83 (dd, j=8.4, 1.2hz, 1H), 5.57 (s, 1H), 4.18 (t, j= 4.8,2H), 3.70 (q, j=5.2 hz, 2H), 1.14 (s, 21H); as can be seen from fig. 2 ¹³ C NMR(100MHz,CDCl ₃ ) Delta 158.7,134.4,130.1,121.8,113.5,112.3,102.8,95.8,67.9,44.0,18.8,11.4; as can be seen from fig. 3 ¹⁹ F NMR(376MHz,CDCl ₃ ) Delta-77.57. Molecular nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum wave peaks can be in one-to-one correspondence with target products, and the quantity is reasonable. From the above data, it is seen that the product prepared in example 1 is trifluoromethanesulfonyl (2- (2- ((triisopropylsilyl) ethynyl) phenoxy)) ethylamine (1 a).

In the embodiment, the simple and easily available trifluoro methanesulfonyl (2-phenoxy) ethylamine 2a and the alkyne halogen reagent triisopropyl silicon-based acetylene bromide 3a are used as reaction substrates, and the divalent palladium catalyst PdCl is used ₂ Under the promotion action of catalytic and single-protection amino acid ligand N-Boc-L-Leu-OH, remote aromatic ring hydrocarbon bond alkynyl reaction occurs, and multi-substituted aromatic compound trifluoro methanesulfonyl (2- (2- ((triisopropyl silicon base) ethynyl) phenoxy)) ethylamine (1 a) containing alkyne and amine functional groups is constructed in a site-selective and rapid mode. The reaction in this example was carried out at 100℃for 12 hours under an atmospheric air atmosphere and then a simple subsequent treatment was carried out to give the final target product trifluoromethanesulfonyl (2- (2- ((triisopropylsilyl) ethynyl) phenoxy)) ethylamine (1 a) in good yield.

Therefore, the preparation method of the polysubstituted aromatic compound containing alkyne and amine functional groups in the embodiment is a simple and easy method, easily available raw materials and safe operation. And the aromatic ring alkynyl modification of the trifluoromethanesulfonyl (2-phenoxy) ethylamine containing the flexible chain can be realized, the synthesis method of the phenol ether compound containing alkynyl is enriched, and the application value is potential.

Example 2 preparation of trifluoromethanesulfonyl (3- (2-bromo-6- ((triisopropylsilyl) ethynyl) phenyl)) propanamine (1 b)

To a 15mL Schlenk reaction tube was successively added trifluoromethanesulfonyl (3- (2-bromophenyl)) propylamine 2b (51.7 mg,0.15 mmol) under an atmospheric air atmosphere, and a divalent palladium catalyst Pd(OAc) ₂ (1.7 mg,0.0075 mmol), amino acid ligand N-Boc-L-Leu-OH (10.4 mg,0.045 mmol), sodium acetate (3.7 mg,0.045 mmol), silver acetate (30.0 mg,0.18 mmol), potassium carbonate (24.9 mg,0.18 mmol), 1, 2-dichloroethane (DCE, 1.5 mL), triisopropylsilylacetylene bromide 3a (46.8 mg,0.18 mmol) was reacted at 100℃for 12 hours. The crude product was chromatographed on a prepared silica gel plate with a volume ratio of petroleum ether to ethyl acetate of 40:1 selected as the developing agent or eluent to give the product trifluoromethanesulfonyl (3- (2-bromo-6- ((triisopropylsilyl) ethynyl) phenyl)) propylamine (1 b,66.9 mg) in 85% yield. The chemical reaction equation corresponding to this example is as follows:

the nuclear magnetic hydrogen spectrum, the carbon spectrum and the fluorine spectrum of the compound prepared in example 2 are shown in fig. 4, 5 and 6. As can be seen from fig. 4: ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.51 (dd, j=8.0, 1.2hz, 1H), 7.45 (dd, j=7.6, 1.2hz, 1H), 7.03 (t, j=7.6 hz, 1H), 5.08-5.05 (m, 1H), 3.37 (q, j=6.8 hz, 2H), 3.10 (t, j= 7.6,2H), 1.97 (p, j=7.2 hz, 2H), 1.14 (d, j=3.2 hz, 21H); as can be seen from fig. 5 ¹³ C NMR(100MHz,CDCl ₃ )δ140.2,134.3,132.0,130.1,127.5,125.3,119.8(q,J _C-F = 319.4 Hz), 104.6,96.2,44.1,29.6,29.1,18.8,11.4; as can be seen from fig. 6 ¹⁹ F NMR(376MHz,CDCl ₃ ) Delta-77.28. Molecular nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum wave peaks can be in one-to-one correspondence with target products, and the quantity is reasonable. In combination with the above data, the product from example 2 was trifluoromethanesulfonyl (3- (2-bromo-6- ((triisopropylsilyl) ethynyl) phenyl)) propylamine (1 b).

In this example, a simple and readily available trifluoromethanesulfonyl (3- (2-bromophenyl)) propylamine 2b and the alkyne halogen reagent triisopropylsilylacetylene bromide 3a were used as substrates over a divalent palladium catalyst Pd (OAc) ₂ Under the promotion of catalytic and single-protection amino acid ligand N-Boc-L-Leu-OH, naOAc is used as an additive for synergistic metallization deprotonation, agOAc is used as a halide ion capturing agent, and K ₂ CO ₃ DCE as a base and as a solvent was reacted at 100℃for 12 hoursIn the process, a remote Cheng Fanghuan hydrocarbon bond alkynyl reaction occurs, and the polysubstituted aromatic compound trifluoro methanesulfonyl (3- (2-bromo-6- ((triisopropyl silicon-based) ethynyl) phenyl)) propylamine (1 b) containing alkyne and amine functional groups is efficiently and selectively and rapidly built.

The atomic steps of the embodiment have good economy, can be compatible with bromine functional groups, are convenient for subsequent modification and conversion, construct complex molecules such as Suzuki coupling, buchwald-Hartwig coupling, sonogashira coupling and the like, and have potential practical values.

Example 3 preparation of trifluoromethanesulfonyl (3- (2, 4-dichloro-6- ((triisopropylsilyl) ethynyl) phenyl)) propanamine (1 c)

To a 15mL Schlenk reaction tube was successively charged, under an atmospheric air atmosphere, trifluoromethanesulfonyl (3- (2, 4-dichlorophenyl)) propylamine 2c (50.2 mg,0.15 mmol) as a divalent palladium catalyst Pd (OAc) ₂ (1.7 mg,0.0075 mmol), amino acid ligand N-Boc-L-Phe-OH (11.9 mg,0.045 mmol), sodium acetate (3.7 mg,0.045 mmol), silver acetate (30.0 mg,0.18 mmol), potassium carbonate (24.9 mg,0.18 mmol), 1, 2-dichloroethane (DCE, 1.5 mL), triisopropylsilylacetylene bromide 3a (46.8 mg,0.18 mmol) was reacted at 100℃for 12 hours. The crude product was chromatographed on a prepared silica gel plate with a volume ratio of petroleum ether to ethyl acetate of 40:1 selected as the developing agent or eluent to give the product trifluoromethanesulfonyl (3- (2, 4-dichloro-6- ((triisopropylsilyl) ethynyl) phenyl)) propylamine (1 c,66.4 mg) in 86% yield. The chemical reaction equation corresponding to this example is as follows:

the nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum of the compound prepared in example 3 are shown in fig. 7, 8 and 9. As can be seen from fig. 7: ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.38 (d, j=2.4 hz,1 h), 7.34 (d, j=2.0 hz,1 h), 5.00 (t, j=6.0 hz,1 h), 3.35 (q, j=6.4 hz,2 h), 3.02 (t, j=7.6 hz,2 h), 1.93 (p, j=7.6 hz,2 h), 1.13 (d, j=3.6 hz,21 h); as can be seen from fig. 8 ¹³ C NMR(100MHz,CDCl ₃ )δ138.8,135.0,132.6,131.7,129.8,126.3,119.8(q,J _C-F = 319.2 Hz), 103.2,97.8,44.1,29.5,28.7,18.8,11.4; as can be seen from fig. 9 ¹⁹ F NMR(376MHz,CDCl ₃ ) Delta-77.28. Molecular nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum wave peaks can be in one-to-one correspondence with target products, and the quantity is reasonable. In combination with the above data, the product obtained in example 3 was trifluoromethanesulfonyl (3- (2, 4-dichloro-6- ((triisopropylsilyl) ethynyl) phenyl)) propylamine (1 c).

In this example, a simple and readily available trifluoromethanesulfonyl (3- (2, 4-dichlorophenyl)) propylamine 2c and the alkyne halogen reagent triisopropylsilylacetylene bromide 3a were used as substrates over a divalent palladium catalyst Pd (OAc) ₂ The catalytic, single-protected amino acid ligand N-Boc-L-Phe-OH is promoted to generate remote aromatic hydrocarbon bond alkynyl reaction, so that the polysubstituted aromatic compound trifluoro methanesulfonyl (3- (2, 4-dichloro-6- ((triisopropyl silicon-based) ethynyl) phenyl)) propylamine (1 c) containing alkyne and amine functional groups is quickly constructed with very high yield (86%) and site selectivity.

The conversion steps in the embodiment are few, and the method can be compatible with chlorine functional groups widely applied to the fields of materials and medicines, and aryl chlorine groups have good chemical activity, such as Ullmann coupling reaction catalyzed by palladium. According to the method, the trifluoro methanesulfonamide which is weakly coordinated and easily converted is used as a guiding group for remote carbon-hydrogen bond activation, so that subsequent removal and conversion are facilitated, a platform can be provided for construction of more complex molecules, and the method has potential application value.

Example 4 preparation of trifluoromethanesulfonyl (3- (3- ((triisopropylsilyl) ethynyl) naphthalen-2-yl)) propanamine (1 d)

To a 15mL Schlenk reaction tube was added, in order, trifluoromethanesulfonyl (3- (naphthalen-2-yl)) propylamine 2d (47.6 mg,0.15 mmol) under an atmospheric air atmosphere, a divalent palladium catalyst Pd (OAc) ₂ (1.7 mg,0.0075 mmol), the amino acid ligand N-Boc-L-Leu-OH (10.4 mg,0.045 mmol), sodium pivalate (6.5 mg,0.045 mmol), silver acetate (30.0 mg,0.18 mmol), potassium carbonate (24.9 mg,0.18 mmol), 1, 2-dichloroethane (DCE, 1.5 mL), triisopropylsilylacethylene bromide 3a (46.8 mg,0.18 mmol) was reacted at 100℃for 12 hours. Chromatographic separation of the crude product with silica gel plate, wherein the selected developing agent or eluent is petroleum ether and ethyl acetateThe product trifluoromethanesulfonyl (3- (3- ((triisopropylsilyl) ethynyl) naphthalen-2-yl)) propylamine (1 d,51.5 mg) was obtained in 69% yield. The chemical reaction equation corresponding to this example is as follows:

the nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum of the compound prepared in example 4 are shown in fig. 10, 11 and 12. As can be seen from fig. 10: ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.04 (s, 1H), 7.78-7.74 (m, 2H), 7.62 (s, 1H), 7.50-7.43 (m, 2H), 5.02 (t, j=6.8 hz, 1H), 3.36 (q, j=6.8 hz, 2H), 3.04 (t, j=7.6 hz, 2H), 2.09 (p, j=7.2 hz, 2H), 1.18 (d, j=2.8 hz, 21H); as can be seen from fig. 11 ¹³ C NMR(100MHz,CDCl ₃ )δ138.6,133.6,133.2,131.9,127.5,127.4,127.4,127.2,126.3,121.3,119.8(q,J _C-F = 319.2 Hz), 105.7,95.0,44.1,31.6,31.2,18.9,11.5; as can be seen from fig. 12 ¹⁹ F NMR(376MHz,CDCl ₃ ) Delta-77.22. Molecular nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum wave peaks can be in one-to-one correspondence with target products, and the quantity is reasonable. From the above data, it is seen that the product prepared in example 4 is trifluoromethanesulfonyl (3- (3- ((triisopropylsilyl) ethynyl) naphthalen-2-yl)) propylamine (1 d).

In this example, a simple and readily available trifluoromethanesulfonyl (3- (naphthalen-2-yl)) propylamine 2d and the alkyne halogen reagent triisopropylsilylacetylene bromide 3a are used as reaction substrates over a divalent palladium catalyst Pd (OAc) ₂ Under the promotion effect of catalytic and single-protection amino acid ligand N-Boc-L-Leu-OH, naOPiv is used as an additive for synergic metallization deprotonation to generate remote aromatic hydrocarbon bond alkynyl reaction, and the polysubstituted aromatic compound trifluoro methanesulfonyl (3- (3- ((triisopropyl silicon-based) ethynyl) naphthalene-2-yl)) propylamine (1 d) containing alkyne and amine functional groups is selectively and rapidly constructed with high yield (69%).

The embodiment can realize site-selective modification of condensed rings, introduce alkynyl functional groups at the C-3 position of naphthalene rings, and has good step economy and atom economy. In addition, the chemical conversion in this embodiment can provide synthetic building blocks for fused ring type functional materials, and thus has potential practical value.

Example 5 preparation of methyl (2S) -2-trifluoromethanesulfonamide-3- (1- (triisopropylsilyl) -4- ((triisopropylsilyl) ethynyl) -1H-indol-3-yl) propionate (1 e)

To a 15mL Schlenk reaction tube was added, in order, methyl (2S) -2-trifluoromethanesulfonyl-3- (1- (triisopropylsilyl) -1H-indol-3-yl) propionate 2e (75.9 mg,0.15 mmol) as a divalent palladium catalyst Pd (OAc) under an atmospheric air atmosphere ₂ (1.7 mg,0.0075 mmol), amino acid ligand N-Boc-L-Leu-OH (10.4 mg,0.045 mmol), sodium acetate (3.7 mg,0.045 mmol), silver acetate (30.0 mg,0.18 mmol), cesium carbonate (58.6 mg,0.18 mmol), 1, 2-dichloroethane (DCE, 1.5 mL), triisopropylsilylacetylene bromide 3a (46.8 mg,0.18 mmol) was reacted at 100℃for 12 hours. The crude product was chromatographed on a prepared silica gel plate with a volume ratio of petroleum ether to ethyl acetate of 20:1 as the selected developing solvent or eluent to give the product methyl (1 e,61.8 mg) of (2S) -2-trifluoromethylsulfonamido-3- (1- (triisopropylsilyl) -4- ((triisopropylsilyl) -ethynyl) -1H-indol-3-yl) propanoate in 60% yield. The chemical reaction equation corresponding to this example is as follows:

the nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum of the compound prepared in example 5 are shown in fig. 13, 14 and 15. As can be seen from fig. 13: ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.50 (d, j=8.4 hz, 1H), 7.36 (d, j=7.2 hz, 1H), 7.27 (s, 1H), 7.10 (dd, j=8.4, 7.6hz, 1H), 6.38 (d, j=8.8 hz, 1H), 4.43 (td, j=9.6, 3.6hz, 1H), 3.87 (dd, j=15.2, 10.8hz, 1H), 3.79 (s, 3H), 3.64 (dd, j=15.2, 4.4hz, 1H), 1.70 (hept, j=7.25 hz, 3H), 1.22-1.18 (m, 21H), 1.15 (dd, j=7.6, 1.2hz, 18H); as can be seen from fig. 14 ¹³ C NMR(100MHz,CDCl ₃ )δ171.1,141.4,131.4,129.8,127.5,121.5,119.3(q,J _C-F =319.1 Hz), 115.3,113.5,112.8,108.4,95.7,59.7,52.9,28.4,18.8,18.1 (d, j=3.0 Hz), 12.9,11.6; as can be seen from fig. 15 ¹⁹ F NMR(376MHz,CDCl ₃ ) Delta-78.04. Molecular nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrumThe graph peaks can be in one-to-one correspondence with target products, and the number is reasonable. From the above data, the product obtained in example 5 was methyl (2S) -2-trifluoromethanesulfonamide-3- (1- (triisopropylsilyl) -4- ((triisopropylsilyl) -ethynyl) -1H-indol-3-yl) propionate (1 e).

In this example, the tryptophan derivative (2S) -2-trifluoromethanesulfonamide-3- (1- (triisopropylsilyl) -1H-indol-3-yl) propionic acid methyl ester 2e and the alkyne halogen reagent triisopropylsilyl acetylene bromide 3a are used as reaction substrates over the divalent palladium catalyst Pd (OAc) ₂ Cs under promotion of catalytic and single-protection amino acid ligand N-Boc-L-Leu-OH ₂ CO ₃ As a base, the alkynylation reaction of the remote Cheng Fanghuan hydrocarbon bond occurs to rapidly construct methyl (1 e) of the multi-substituted aromatic compound (2S) -2-trifluoromethanesulfonamide-3- (1- (triisopropylsilyl) -4- ((triisopropylsilyl) ethynyl) -1H-indol-3-yl) propanoate containing alkyne and amine functional groups in good yield and site selectivity.

In the embodiment, N-H of the indole is protected by using the tri-isopropyl silicon base with large steric hindrance, C-4-position trans-cyclic hydrocarbon bond activation alkynyl of the indole is realized, and a new strategy is provided for selective modification of a bioactive tryptophan molecular site. Through the synthetic strategy, a molecular library of tryptophan analogues can be quickly constructed, and a new strategy is provided for the development of related new drugs.

Example 6 preparation of trifluoromethanesulfonyl (3- (2-methyl-6- ((1- (tert-butyldimethylsilyloxy) cyclohexyl) ethynyl) phenyl)) propanamine (1 f)

To a 15mL Schlenk reaction tube was successively charged trifluoromethanesulfonyl (3- (2-methylphenyl)) propylamine 2f (42.2 mg,0.15 mmol) under an atmospheric air atmosphere, and a divalent palladium catalyst Pd (OAc) ₂ (1.7 mg,0.0075 mmol), the amino acid ligand N-Boc-L-Leu-OH (10.4 mg,0.045 mmol), sodium acetate (3.7 mg,0.045 mmol), silver oxide (41.7 mg,0.18 mmol), potassium carbonate (24.9 mg,0.18 mmol), 1, 2-dichloroethane (DCE, 1.5 mL), 2- ((1-t-butyldimethylsilyloxy) cyclohexyl) acetylene bromide 3b (56.9 mg,0.18 mmol) was reacted at 100℃for 12 hours. The crude product is subjected to chromatographic separation by using a prepared silica gel plate, and the volume ratio of the selected developing agent or eluent to the ethyl acetate is 60:1, so as to obtain the product trifluoromethanesulfonyl (3- (2-)Methyl-6- (2- ((1-t-butyldimethylsilyloxy) cyclohexyl) ethynyl) phenyl) propanamine (1 f,32.6 mg) in 42% yield. The chemical reaction equation corresponding to this example is as follows:

the nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum of the compound prepared in example 6 are shown in fig. 16, 17 and 18. As can be seen from fig. 16: ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.29 (dd, j=7.6, 2.0hz, 1H), 7.13 (dd, j=7.6, 1.6hz, 1H), 7.09 (t, j=7.2 hz, 1H), 4.94 (t, j=6.8 hz, 1H), 3.37 (q, j=6.8 hz, 2H), 2.91 (t, j=7.6 hz, 2H), 2.32 (s, 3H), 1.93-1.85 (m, 4H), 1.76-1.69 (m, 4H), 1.57-1.52 (m, 2H), 1.46-1.42 (m, 1H), 1.40-1.35 (m, 1H), 0.90 (s, 9H), 0.20 (s, 6H); as can be seen from fig. 17 ¹³ C NMR(100MHz,CDCl ₃ )δ140.5,136.2,130.8,130.6,126.4,123.2,119.8(q,J _C-F =319.3 Hz), 97.8,83.7,69.9,44.5,41.4,30.2,28.4,26.0,25.4,23.0,19.7,18.3, -2.6; as can be seen from fig. 18 ¹⁹ F NMR(376MHz,CDCl ₃ ) Delta-77.27. Molecular nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum wave peaks can be in one-to-one correspondence with target products, and the quantity is reasonable. In combination with the above data, the product obtained in example 6 was trifluoromethanesulfonyl (3- (2-methyl-6- (2- ((1-t-butyldimethylsilyloxy) cyclohexyl) ethynyl) phenyl)) propylamine (1 f).

In this example, a simple and readily available triflyl (3- (2-methylphenyl)) propylamine 2f and an alkyne-halogen reagent 2- ((1-tert-butyldimethylsilyloxy) cyclohexyl) ethyne bromide 3b were used as substrates over a divalent palladium catalyst Pd (OAc) ₂ Under the promotion effect of catalysis and single-protection amino acid ligand N-Boc-L-Leu-OH, ag ₂ O is taken as a halide ion capturing agent to generate remote hydrocarbon bond alkynyl reaction of an aromatic ring, and a multi-substituted aromatic compound trifluoro methanesulfonyl (3- (2-methyl-6- (2- ((1-tert-butyldimethylsilyloxy) cyclohexyl) ethynyl) phenyl)) propylamine (1 f) containing alkyne and amine functional groups is quickly constructed in good yield and site selectivity.

The remote carbon-hydrogen bond alkynyl reaction of the embodiment can be compatible with the site selective coupling of dialkyl tertiary alcohol alkynyl reagents, provides a new idea for the simple construction of asymmetric internal alkynes containing aryl and alkyl alcohol, and has potential application value.

EXAMPLE 7 preparation of trifluoromethanesulfonyl (3- (2- (3, 3-diphenyl-3- (t-butyldimethylsilyloxy) propargyl) -6-chlorophenyl)) propylamine (1 g)

To a 15mL Schlenk reaction tube was successively charged 2g (45.2 mg,0.15 mmol) of trifluoromethanesulfonyl (3- (2-chlorophenyl)) propylamine (Pd) as a divalent palladium catalyst (OAc) under an atmospheric air atmosphere ₂ (1.7 mg,0.0075 mmol), amino acid ligand N-Boc-L-Leu-OH (10.4 mg,0.045 mmol), sodium acetate (3.7 mg,0.045 mmol), silver acetate (30.0 mg,0.18 mmol), potassium carbonate (24.9 mg,0.18 mmol), 1, 2-dimethoxyethane (DME, 1.5 mL), 3-diphenyl-3- (tert-butyldimethylsilyloxy) propynyl bromide 3c (72.0 mg,0.18 mmol) was reacted at 90℃for 24 hours. The crude product was chromatographed on a prepared silica gel plate with a 50:1 volume ratio of petroleum ether to ethyl acetate as the selected developing or eluting solvent to give the product trifluoromethanesulfonyl (3- (2- (3, 3-diphenyl-3- (t-butyldimethylsilyloxy) propargyl) -6-chlorophenyl)) propylamine (1 g,50.3 mg) in 45% yield. The chemical reaction equation corresponding to this example is as follows:

the nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum of the compound prepared in example 7 are shown in fig. 19, 20 and 21. As can be seen from fig. 19: ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.57-7.55 (m, 4H), 7.43 (dd, j=7.6, 1.2hz, 1H), 7.35-7.29 (m, 5H), 7.26-7.22 (m, 2H), 7.14 (t, j=7.6 hz, 1H), 4.24 (t, j=6.0 hz, 1H), 2.97 (q, j=6.8 hz, 2H), 2.84-2.80 (m, 2H), 1.65-1.57 (m, 2H), 0.95 (s, 9H), -0.01 (s, 6H); as can be seen from fig. 20 ¹³ C NMR(100MHz,CDCl ₃ )δ146.7,140.9,134.5,131.1,130.4,128.3,127.6,127.6,126.4,124.2,119.8(q,J _C-F =319.3 Hz), 96.6,86.7,76.1,44.2,29.5,29.0,26.1,18.6, -3.1; as can be seen from fig. 21 ¹⁹ F NMR(376MHz,CDCl ₃ ) Delta-77.26. Molecular nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum peak energy are in one-to-one correspondence with target productsThe number is reasonable. As can be seen from the above data, the product obtained in example 7 was trifluoromethanesulfonyl (3- (2- (3, 3-diphenyl-3- (t-butyldimethylsilyloxy) propargyl) -6-chlorophenyl)) propylamine (1 g).

In this example, 2g of trifluoromethanesulfonyl (3- (2-chlorophenyl)) propylamine was reacted with 3, 3-diphenyl-3- (t-butyldimethylsilyloxy) propynyl bromide 3c as a reagent over a divalent palladium catalyst Pd (OAc) ₂ Under the promotion of catalytic and single-protection amino acid ligand N-Boc-L-Leu-OH, DME is used as a solvent to generate remote aromatic hydrocarbon bond alkynyl reaction, and a multi-substituted aromatic compound trifluoro methanesulfonyl (3- (2- (3, 3-diphenyl-3- (tert-butyldimethylsilyloxy) propargyl) -6-chlorophenyl)) propylamine (1 g) containing alkyne and amine functional groups is quickly constructed with good yield and site selectivity under relatively mild conditions.

The remote carbon-hydrogen bond alkynylation reaction of the embodiment can be compatible with the site-selective coupling of diaryl tertiary alcohol alkynylation reagents. It is worth noting that the compound is not easy to prepare by adopting a conventional method, and the strategy provides a new thought for rapidly constructing the multi-aromatic ring asymmetric internal alkyne, thereby having potential application value.

Example 8 preparation of N-methyl-trifluoromethanesulfonyl (3- (2- ((3, 5-dichlorophenyl) ethynyl) -6-chlorophenyl)) propanamine (3 h)

Sodium hydride (NaH, 8.0mg,0.20 mmol) with 60% of mineral oil protection mass fraction, trifluoromethanesulfonyl (3- (2-chloro-6- ((triisopropylsilyl) ethynyl) phenyl)) propylamine (48.1 mg,0.10 mmol), tetrahydrofuran (THF, 1.0 mL) were sequentially added to a 15mL Schlenk reaction tube under an atmospheric nitrogen atmosphere, the mixture was subjected to a hydrogen-extracting reaction at 0℃for 20min, and methyl iodide (CH) was further added ₃ I,17.0mg,0.12 mmol) was reacted at 25℃for 3 hours. After the reaction is finished, 3mL quenching is carried out by using saturated ammonium chloride aqueous solution, 2mL multiplied by 3 extraction is carried out by using ethyl acetate, anhydrous sodium sulfate is dried, a spin-dried solvent is used, chromatographic separation is carried out on a crude product by using a prepared silica gel plate, the volume ratio of petroleum ether to ethyl acetate is 50:1, and the product N-methyl-trifluoromethanesulfonyl (3- (2-chloro-6- ((triisopropylsilyl) ethynyl) phenyl)) propylamine (2 h,47.5 mg) is obtained, and the yield is 96%. Nitrogen at one atmosphereTo a 15mL Schlenk reaction tube was successively added under an atmosphere bis triphenylphosphine palladium dichloride (Pd (PPh) ₃ ) ₂ Cl ₂ 2.0mg,0.003 mmol), cuprous iodide (CuI, 1.0mg,0.005 mmol), N-methyl-trifluoromethanesulfonyl (3- (2-chloro-6- ((triisopropylsilyl) ethynyl) phenyl)) propylamine 2h (47.5 mg,0.1 mmol), 3, 5-dichloroiodobenzene 3d (32.6 mg,0.12 mmol), triethylamine (Et ₃ N,202.4mg,2.0 mmol), tetrabutylammonium fluoride (TBAF, 52.3mg,0.2 mmol), tetrahydrofuran (THF, 2.0 mL), and reacted at 60℃for 12 hours. After the reaction, 3mL of saturated ammonium chloride aqueous solution is used for quenching, 2mL multiplied by 3 of ethyl acetate is used for extraction, anhydrous sodium sulfate is used for drying, a solvent is dried by a spin-on method, a prepared silica gel plate is used for chromatographic separation of crude products, the volume ratio of petroleum ether to ethyl acetate is 30:1, and the product N-methyl-trifluoro methanesulfonyl (3- (2- ((3, 5-dichlorophenyl) ethynyl) -6-chlorophenyl)) propylamine (3 h,43.5 mg) is obtained, the yield is 90%, and the reaction equation is as follows:

the nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum of the compound prepared in example 8 are shown in fig. 22, 23 and 24. As can be seen from fig. 22: ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.44-7.35 (m, 5H), 7.17 (t, j=8.0 hz, 1H), 3.50 (br, 2H), 3.07-3.04 (m, 5H), 1.98 (dt, j=16.0, 7.2hz, 2H); as can be seen from fig. 23 ¹³ C NMR(100MHz,CDCl ₃ )δ140.6,135.3,134.5,131.4,130.6,129.8,129.2,127.6,125.5,123.9,120.4(q,J _C-F = 322.0 Hz), 91.0,89.3,50.9,35.0,29.3,26.9; as can be seen from fig. 24 ¹⁹ F NMR(376MHz,CDCl ₃ ) Delta-74.93. Molecular nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum wave peaks can be in one-to-one correspondence with target products, and the quantity is reasonable. From the above data, the product obtained in example 8 was N-methyl-trifluoromethanesulfonyl (3- (2- ((3, 5-dichlorophenyl) ethynyl) -6-chlorophenyl)) propylamine (3 h).

The conversion example realizes the nitrogen methylation of the trifluoromethanesulfonamide, and then desilication Sonogashira coupling is carried out to construct asymmetric internal alkyne, so that the total yield of the two steps is high, and the synthesis potential of amine and alkyne functional groups contained in the product molecule is reflected. The modification and transformation of diversity provide a new idea for the rapid construction of complex molecules, and have potential application value.

In summary, the present application provides a process for the preparation of polysubstituted aromatic compounds containing alkyne and amine functionalities. The preparation method comprises the following steps: in an inert solvent, under the catalysis of a divalent palladium catalyst and the promotion of a single-protection amino acid ligand, a trifluoro methanesulfonyl aryl propylamine compound (formula II) and an alkynyl bromine compound (formula III) are reacted to obtain a multi-substituted aromatic compound (formula I) containing alkyne and amine functional groups, wherein the reaction equation is as follows:

The application uses simple and easily available trifluoro methanesulfonyl aryl propylamine and alkyne halogen reagent as reaction substrates under the condition of inert solvent and with the help of bivalent palladium catalysis and amino acid ligand, and rapidly constructs the polysubstituted aromatic compound containing alkyne and amine functional groups with good yield and site selectivity.

The application discloses a preparation method of a polysubstituted aromatic compound containing alkyne and amine functional groups. The method has the characteristics of easily obtained and easily converted guide groups, good atom step economy and capability of overcoming the difficulty in activating and functionalizing amine remote carbon-hydrogen bonds, and simultaneously introduces alkyne functional groups which are easy to modify and convert in later stages into molecules through the synthesis strategy, so as to quickly construct a molecular library of the polysubstituted aromatic hydrocarbon compounds.

In the description of the present specification, reference to the terms "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present patent application. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

While several embodiments of the present patent application have been shown and described, it will be understood by those of ordinary skill in the art that: many changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the application, the scope of which is defined by the claims and their equivalents.

Claims

1. A process for the preparation of a polysubstituted aromatic compound containing alkyne and amine functions, characterized in that: in an inert solvent, under the catalysis of a divalent palladium catalyst and the promotion of a single-protection amino acid ligand, a trifluoro methanesulfonyl aryl propylamine compound (formula II) and an alkynyl bromine compound (formula III) are reacted to obtain a multi-substituted aromatic compound (formula I) containing alkyne and amine functional groups, wherein the reaction equation is as follows:

2. The method for producing a polysubstituted aromatic compound containing alkyne and amine functional groups according to claim 1, wherein: the reaction molar ratio of the trifluoro methanesulfonyl aryl propylamine compound (formula II) to the alkynyl bromine compound (formula III) is 1:1.1-1:1.5.

3. The method for producing a polysubstituted aromatic compound containing alkyne and amine functional groups according to claim 1, wherein: the amount of the divalent palladium catalyst is 2 to 10mol% based on the amount of the trifluoromethanesulfonyl aryl propylamine compound (formula II).

4. The method for producing a polysubstituted aromatic compound containing alkyne and amine functional groups according to claim 1, wherein: the single-protection amino acid ligand is any one or combination of N-tert-butoxycarbonyl-L-leucine, N-tert-butoxycarbonyl-L-alanine, N-tert-butoxycarbonyl-L-phenylalanine, N-acetyl-L-valine, N-acetyl-L-phenylalanine and N-acetyl-L-tert-leucine.

5. The method for producing a polysubstituted aromatic compound containing alkyne and amine functional groups according to claim 1, wherein: the additive is any one or more of sodium acetate, potassium acetate, sodium trifluoroacetate, sodium pivalate, sodium propionate, sodium glycinate, sodium 1-adamantane formate and sodium 2,4, 6-trimethyl benzoate.

6. The method for producing a polysubstituted aromatic compound containing alkyne and amine functional groups according to claim 1, wherein: the halide ion capturing agent is any one or more of silver acetate, silver carbonate, silver oxide and silver trifluoroacetate, and/or;

the alkali is any one or more of potassium carbonate, potassium bicarbonate, cesium carbonate, sodium bicarbonate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate.

7. The method for producing a polysubstituted aromatic compound containing alkyne and amine functional groups according to claim 1, wherein: the inert solvent is any one or more of 1, 2-dichloroethane, 1, 2-dimethoxyethane, tertiary butanol, 2-methyl-2-butanol, toluene, 1, 4-dioxane, tetrahydrofuran, N' -dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and acetonitrile.

8. A process for the preparation of polysubstituted aromatic compounds containing alkyne and amine functionalities according to claim 3, characterized in that the divalent palladium catalyst is: any one or combination of palladium acetate, palladium chloride, bis (triphenylphosphine) palladium dichloride and diacetonitrile palladium dichloride.

9. The method for producing a polysubstituted aromatic compound containing alkyne and amine functional groups according to claim 8, wherein: the reaction is carried out at 80-120 ℃; the reaction is carried out for 6 to 24 hours.

10. The method for producing a polysubstituted aromatic compound containing alkyne and amine functional groups according to claim 1, wherein: the method comprises the following specific steps:

s1: 1.7mg of palladium acetate, 10.4mg of N-t-butoxycarbonyl-L-leucine, 3.7mg of sodium acetate, 30.0mg of silver acetate, 24.9mg of potassium carbonate, 1.5mL of 1, 2-dichloroethane, 51.7mg of trifluoromethanesulfonyl (3- (2-bromophenyl)) propylamine and 46.8mg of triisopropylsilylacetyl bromide were sequentially added to the reactor in the air;

s2: reacting the reaction solution at 100 ℃ for 12 hours;

s3: and after the reaction is finished, separating the mixture by using a thin layer chromatography separation technology to obtain the target compound, namely the polysubstituted aromatic compound containing alkyne and amine functional groups.