CN113845550B - Flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, preparation method and application thereof - Google Patents

Flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, preparation method and application thereof Download PDF

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CN113845550B
CN113845550B CN202111137193.1A CN202111137193A CN113845550B CN 113845550 B CN113845550 B CN 113845550B CN 202111137193 A CN202111137193 A CN 202111137193A CN 113845550 B CN113845550 B CN 113845550B
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heterocyclic carbene
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benzene ring
palladium complex
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CN113845550A (en
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刘丰收
郑棣中
郭玉曼
张宇
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Guangdong Pharmaceutical University
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Abstract

The invention relates to a flexible large-steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene rings. The complex is characterized in that: (1) The acenaphthene base is used as a framework structure, and the excellent electron donating property and the rigid steric hindrance of the acenaphthene base are utilized to stabilize a metal center, so that the catalyst is ensured to maintain high stability in the presence of air and water vapor; (2) Introducing flexible large steric hindrance into an aromatic amine part of the N-heterocyclic carbene, so that a metal center has certain openness, and the structure of the active center can be changed under different reaction conditions by the metal center, so that different active species can be generated in situ, and the selective turnover of different carbon (quasi) halogen bonds can be realized only by adding one catalyst; (3) The catalyst has wide substrate adaptability range, has high activity on heterocyclic poly (pseudo) halogenated aromatic hydrocarbon, does not need to isolate air and water vapor in the reaction based on the catalyst, and can realize high reaction activity under mild reaction conditions.

Description

Flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, preparation method and application thereof
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a flexible large-steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene rings, a preparation method and application thereof.
Background
In the past few decades, compounds containing multiple C Ar-CAr and C Ar -X bonds have been widely used in the fields of medicine, pesticides, functional materials, etc., and development of chemoselective synthetic reactions has become an important research effort. To date, palladium-catalyzed Suzuki-Miyaura coupling reactions have become an effective method for constructing C Ar-CAr bonds and C Ar -heteroatom bonds due to the good tolerance of functional groups, low toxicity and the like. However, the Suzuki-Miyaura reaction often faces the defects of poor chemical selectivity, poor substrate adaptability, harsh reaction conditions and the like when catalyzing multi (quasi) halogenated compounds (such as C-I, C-Br, C-Cl and C-OTf bonds), so that the development of a catalytic system with high efficiency of chemical selectivity is an important work.
There are two strategies currently in achieving chemoselective cross-coupling reactions: the use of catalysts of different structures to effect the selective reaction (J.Am.Chem Soc.2010,132,2496–2497;Nat.Chem.2016,8,610-617;J.Org.Chem.2019,84,11474-11481;J.Org.Chem.2019,84,11799-11812;J.Am.Chem.Soc.2020,142,15454-15463;). by their difference in activity towards the substrate is one of the most costly strategies that limit the widespread use of such strategies due to the need to design catalysts of different structures. Yet another strategy is to design a single catalyst that allows for selective reaction upsets by simply changing the reaction conditions such as reaction solvent, reaction temperature or additives. (Angew.chem.int.ed.2011, 50,8192-8195; J.am.chem.Soc.2012,134, 606-612). The latter has significant advantages because it requires only a single catalyst to be able to construct complex functional molecules with high efficiency. However, to date, only a few catalytic systems such as Pd 2(dba)3/P(tBu)3 and monovalent palladium dimers [ (P tBu3)PdBr]2) have achieved "selective inversion" of C-Cl bonds and C-OTf bonds using only a single catalyst (Angew. Chem. Int. Ed.2011,50,8192-8195; J. Am. Chem. Soc.2012,134, 606-612.) although the above phosphine ligand-containing palladium catalysts exhibit good chemical selectivity, they are both sensitive to air and water vapor, unstable in solution, and have low reactivity with heterocyclic aromatic boronic acids for nitrogen-containing heterocyclic haloaromatic hydrocarbons, thus greatly limiting the use of the above catalysts.
Disclosure of Invention
Aiming at the defects of the catalytic system, the invention designs and synthesizes the flexible large-steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, which has the advantages of convenient synthesis, mild reaction condition and wide substrate applicability, and can realize selective coupling reaction turnover by changing specific reaction conditions. Therefore, the invention meets the economic demands of organic chemistry, medicaments and material synthesis, and the non-phosphine palladium catalyst developed on the basis of the economic demands provides a new thought for the design of the catalyst.
The invention discloses a flexible large-steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene rings, which is characterized in that: (1) The nucleophilicity of the metal center is regulated by utilizing the electronic effect of halogen atoms, so that the metal center can meet the electronic effect requirement of the metal center on the selectivity of electrophiles under the reaction condition, and the reaction has excellent selectivity; (2) The acenaphthene base or the derivative thereof is used as a framework structure, and the excellent electron donating property and the rigid steric hindrance of the acenaphthene base or the derivative thereof are utilized to stabilize the metal center, so that the catalyst is ensured to keep high stability in the presence of air and water vapor; (3) Introducing flexible large steric hindrance into an aromatic amine part of the N-heterocyclic carbene, so that a metal center has certain openness, and the structure of the active center can be changed under different reaction conditions by the metal center, so that different active species can be generated in situ, and the selective turnover of different carbon (quasi) halogen bonds can be realized only by adding one catalyst; (4) The catalyst has wide substrate adaptability range, has high activity on heterocyclic poly (pseudo) halogenated aromatic hydrocarbon, does not need to isolate air and water vapor in the reaction based on the catalyst, and can realize high reaction activity under mild reaction conditions.
In the present invention, the term "Suzuki-Miyaura coupling inversion reaction" means that in the Suzuki-Miyaura coupling reaction, when two (pseudo) halogen electrophilic substituent groups (X 1 and X 2) with different activities exist in the same electrophile to react with aryl boric acid (ester), one (pseudo) halogen electrophilic substituent group X 1 can be caused to react with high selectivity under certain conditions, while the other substituent group X 2 does not participate in the reaction. When the reaction conditions are changed, the selectivity of the coupling reaction is reversed, and the (quasi) halogen electrophilic substituent X 2 is coupled with aryl boric acid (ester), while the substituent X 1 does not participate in the reaction.
An object of the present invention is to provide a flexible, highly hindered N-heterocyclic carbene palladium complex containing a halogenated benzene ring, which is represented by the following structural formula:
wherein,
R 1-R3 is independently selected from a hydrogen atom, a halogen, a C1-C22 alkyl group, or a C1-C22 alkoxy group;
R 4-R6 is independently selected from C1-C22, aryl or aryl derivatives;
Y is selected from halogen or carboxyl;
X 1-X2 is selected from halogen;
X 3 is selected from a hydrogen atom or a halogen.
Further, X 1-X2 is a fluorine atom.
Further, the R 4-R6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, aryl, or aryl derivatives.
Further, the R 6 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
Further, R 1-R3 is a hydrogen atom.
Further, the flexible, highly hindered N-heterocyclic carbene palladium complex containing a halogenated benzene ring is selected from the following structures:
another object of the present invention is to provide a method for preparing the above flexible large steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, comprising the steps of:
the acenaphthoquinone or its derivative and halogenated aromatic amine are dissolved in solvent and heated to react under the action of catalyst to obtain precursor containing halogenated benzene ring.
Under the condition of inert gas, acenaphthoquinone or its derivative and halogenated aromatic amine are dissolved in solvent in the presence of catalyst system, then heated and refluxed for reaction for a given period of time, the obtained intermediate product is washed by means of solution, reduced pressure distilled to remove solvent, finally high-purity precursor containing halogenated benzene ring is obtained by means of recrystallization, so that the product alpha-diimine compound can be obtained.
Further, the acenaphthoquinone or the derivative thereof has the structure that:
further, the catalyst is a transition metal halide, preferably anhydrous zinc chloride.
The invention also aims to provide the application of the flexible large-steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring in a Suzuki-Miyaura coupling and overturning reaction.
Further, the reaction conditions of the Suzuki-Miyaura coupling inversion reaction are as follows:
Reaction condition a: the solvent is a mixed solvent of THF and DMAc;
Or (b)
Reaction condition B: the solvent is a mixed solvent of THF and toluene.
The invention has the following beneficial effects:
(1) The flexible large-steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring is used as a catalyst, is applied to selective Suzuki-Miyaura coupling turnover reaction, and utilizes the electronic effect of halogen atoms to adjust the nucleophilicity of a metal center, so that the complex can meet the electronic effect requirement of the metal center on the selectivity of different electrophiles under different reaction conditions, and the reaction has excellent selectivity.
(2) The catalyst introduces large flexible steric hindrance into the aromatic amine part of the N-heterocyclic carbene, so that the metal center has good openness, and the structure of the active center can be changed under different reaction conditions by the metal center, so that distinct active species can be generated in situ. Such as in polar coordination solvents, solvent molecules can be allowed to participate in coordination of the metal center due to the large steric hindrance of the metal center, so that the nucleophilicity of the metal center is increased, and carbon-pseudohalogen bonds (such as C-OTf bonds) can be selectively reacted; in the case of nonpolar solvents, however, the electron effect of the metal center is relatively weak, and it is only possible to react carbon-halogen bonds (e.g. C-Cl bonds) selectively. Thus enabling a highly selective turnover of the C-Cl bond with the arylboronic acid or the C-OTf bond with the arylboronic acid, by the addition of only a single catalyst.
(3) The Suzuki-Miyaura coupling turnover reaction has mild reaction conditions, can be performed under the conditions of air, water and the like, has higher reaction yield, can be used for preparing synthesized polyaryl substituted bioactive molecules and functional materials, and has wide commercialized prospect.
Drawings
FIG. 1 (a) shows a nuclear magnetic resonance hydrogen spectrum of Compound 7; fig. 1 (b) shows a nuclear magnetic carbon spectrum of compound 7.
FIG. 2 (a) shows a nuclear magnetic resonance hydrogen spectrum of Compound 8; fig. 2 (b) shows a nuclear magnetic resonance spectrum of the compound 8.
FIG. 3 (a) shows a nuclear magnetic resonance hydrogen spectrum of Compound 9; fig. 3 (b) shows a nuclear magnetic carbon spectrum of the compound 9.
FIG. 4 (a) shows a nuclear magnetic resonance hydrogen spectrum of the complex 10; fig. 4 (b) shows a nuclear magnetic resonance spectrum of the complex 10.
FIG. 5 (a) shows a nuclear magnetic resonance hydrogen spectrum of the complex 11; fig. 5 (b) shows a nuclear magnetic resonance spectrum of the complex 11.
FIG. 6 (a) shows a nuclear magnetic resonance hydrogen spectrum of the complex 12; fig. 6 (b) shows a nuclear magnetic resonance spectrum of the complex 12.
Fig. 7 shows a single crystal structure of the complex 10.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
In the embodiment of the invention, the obtained final product contains the flexible large-steric hindrance N-heterocyclic carbene palladium complex 10-12 (complex 10-12) with halogenated benzene ring, and the preparation methods of the complex are respectively and independently carried out without interference. In this example, for the sake of simplicity and illustration only, the preparation methods of N-heterocyclic carbene palladium complexes 10-12 with similar preparation conditions are described in the same examples; and not in the same experiment, three products of the flexible large-steric hindrance N-heterocyclic carbene palladium complex 10-12 containing halogenated benzene rings can be obtained simultaneously.
Similarly, in the examples of the present invention, the reaction substrates and the raw materials used in the respective steps were also carried out independently and without interfering with each other. For example, in the examples, "halogenated aromatic amine 1-3" means that halogenated aromatic amine 1, halogenated aromatic amine 2 and halogenated aromatic amine 3 are taken as reaction substrates in three independent experiments which do not interfere with each other, respectively, and it does not mean that halogenated aromatic amine 1-3 is simultaneously taken as a reaction substrate in the same experiment.
Example 1
The chemical synthetic route of the flexible, highly sterically hindered N-heterocyclic carbene palladium complex containing halogenated benzene rings is shown below.
(1) Synthesis of alpha-diimine Compound 4-6 (Compound 4-6)
Acenaphthoquinone (10.0 mmol), halogenated aromatic amine 1-3 (20.0 mmol) and anhydrous zinc chloride (20.0 mmol) are sequentially added into a 100mL flask under the protection of nitrogen, 40mL glacial acetic acid is added, and the reactants are heated, refluxed and reacted for 5 hours, and then cooled to room temperature. The orange solid was obtained by filtration, then washed with a small amount of glacial acetic acid and dried in vacuo. The orange solid obtained was dissolved in 200mL of dichloromethane, and an aqueous potassium oxalate solution was added thereto and stirred for 12 hours. The white solid precipitate was removed, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a crude product, which was then recrystallized from methylene chloride and ethanol to give the product α -diimine compound 4-6 (yield 63-75%).
(2) Synthesis of imidazole salt intermediate 7-9 (Compound 7-9)
Under the protection of nitrogen, adding 4-6 (1 mmol) of alpha-diimine compound and 3mL of chloromethyl ether into a thick-wall branch bottle, performing airtight reaction for 24 hours at 100 ℃, cooling to room temperature, adding 20mL of anhydrous ether, vigorously stirring, generating a large amount of yellow powder, repeatedly washing for three times, and filtering to obtain the product imidazole salt intermediate 7-9.
The yield of compound 7 was 65%. FIG. 1 (a) shows a nuclear magnetic resonance hydrogen spectrum of Compound 7; fig. 1 (b) shows a nuclear magnetic carbon spectrum of compound 7.
1H NMR(400MHz,CDCl3)δ12.16(s,1H),7.85(d,J＝8.2Hz,2H),7.41(t,J＝7.5Hz,2H),7.28(s,6H),7.26(s,2H),7.20(s,2H),7.09(d,J＝6.9Hz,2H),6.93(d,J＝6.8Hz,2H),6.82–6.71(m,8H),6.65(dd,J＝14.8,8.0Hz,4H),5.84(s,2H),2.21(s,6H).13C NMR(101MHz,CDCl3)δ164.7,162.2,144.2,140.7,140.5,138.1,136.4,129.8,129.8,129.0,128.9,128.3,127.4,127.2,126.6,122.7,122.6,117.1,116.9,116.7,51.6,18.9.
The yield of compound 8 was 66%. FIG. 2 (a) shows a nuclear magnetic resonance hydrogen spectrum of Compound 8; fig. 2 (b) shows a nuclear magnetic resonance spectrum of the compound 8.
1H NMR(400MHz,CDCl3)δ11.90(s,1H),7.87(dd,J＝18.9,8.3Hz,3H),7.41–7.35(m,3H),7.09(t,J＝7.7Hz,8H),7.00(d,J＝7.7Hz,2H),6.94(d,J＝7.8Hz,2H),6.83(t,J＝6.8Hz,3H),6.71(dd,J＝9.3,2.5Hz,2H),6.63(s,5H),6.47(d,J＝7.8Hz,3H),5.63(s,1H),5.31(s,1H),2.27(d,J＝9.1Hz,12H),2.18(s,3H),1.75(s,3H).13C NMR(101MHz,CDCl3)δ164.7,162.3,162.2,144.9,144.8,144.2,144.1,143.0,138.6,138.5,138.1,138.0,137.8,137.8,137.7,137.5,136.8,136.6,136.6,136.5,136.2,129.8,129.7,129.4,129.2,129.1,128.9,128.9,128.0,127.5,127.2,122.7,122.3,117.3,117.0,116.8,116.6,116.4,116.2,116.0,51.1,21.0,20.9,20.6,20.4,18.7,18.5.
The yield of compound 9 was 74%. FIG. 3 (a) shows a nuclear magnetic resonance hydrogen spectrum of Compound 9; fig. 3 (b) shows a nuclear magnetic carbon spectrum of the compound 9.
1H NMR(400MHz,CDCl3)δ11.52(s,1H),7.31(d,J＝7.5Hz,5H),7.21(d,J＝7.2Hz,4H),7.16(d,J＝7.4Hz,2H),7.04(d,J＝7.6Hz,4H),6.98(s,2H),6.93(d,J＝6.6Hz,4H),6.65(d,J＝9.0Hz,1H),6.60(d,J＝9.1Hz,2H),6.53(s,1H),6.44(s,2H),5.59(s,2H),5.39(s,1H),2.22(d,J＝13.2Hz,12H).13C NMR(101MHz,CDCl3)δ142.3,142.2,141.6,141.4,139.9,139.7,135.1,134.9,131.0,130.7,130.2,129.8,129.6,129.3,128.8,128.6,127.2,127.0,126.9,124.2,51.4,21.4,18.0.
(3) Synthesis of flexible large-steric-hindrance N-heterocyclic carbene palladium complex 10-12 containing halogenated benzene ring
Imidazole salt intermediate 7-9 (1 mmol), palladium chloride (1.1 mmol), potassium carbonate (10 mmol) and 3mL 3-chloropyridine were added sequentially to a 25mL thick-walled vial. The reaction was allowed to cool to room temperature under nitrogen at 90℃for 24 h. The reaction mixture was subjected to rapid dry column chromatography with methylene chloride, and the solvent was removed under reduced pressure to give a solid. The resulting solid was dissolved with methylene chloride and then precipitated with a large amount of n-hexane until a solid powder was precipitated. And finally, repeatedly washing with N-hexane for three times, and performing suction filtration and drying to obtain the flexible large-steric hindrance N-heterocyclic carbene palladium complex 10-12 containing halogenated benzene rings.
The yield of complex 10 was 48%. FIG. 4 (a) shows a nuclear magnetic resonance hydrogen spectrum of the complex 10; fig. 4 (b) shows a nuclear magnetic resonance spectrum of the complex 10.
1H NMR(400MHz,CDCl3)δ9.09(d,J＝2.2Hz,1H),8.94(d,J＝4.7Hz,1H),7.78(d,J＝8.2Hz,1H),7.53(d,J＝8.3Hz,2H),7.43(d,J＝6.9Hz,4H),7.32(dd,J＝8.1,5.7Hz,2H),7.27(dd,J＝8.8,5.7Hz,8H),7.17–7.12(m,2H),7.03(dd,J＝8.6,2.8Hz,2H),6.94(d,J＝7.4Hz,4H),6.75(dd,J＝9.6,2.8Hz,2H),6.59(t,J＝7.6Hz,4H),6.48(d,J＝6.9Hz,2H),6.42(t,J＝7.4Hz,2H),2.29(s,6H).13C NMR(101MHz,CDCl3)δ163.9,161.4,154.8,150.7,149.4,145.6,145.5,142.9,140.9,140.2,140.1,138.6,138.0,132.6,132.5,130.0,129.3,128.5,128.4,127.7,127.6,126.5,126.4,124.8,124.6,120.7,116.3,116.1,116.0,115.8,50.9,19.9.
Fig. 7 shows a single crystal structure of the complex 10.
The yield of complex 11 was 46%. FIG. 5 (a) shows a nuclear magnetic resonance hydrogen spectrum of the complex 11; fig. 5 (b) shows a nuclear magnetic resonance spectrum of the complex 11.
1H NMR(400MHz,CDCl3)δ9.05(d,J＝2.2Hz,1H),8.91(dd,J＝5.5,1.1Hz,1H),7.77(ddd,J＝8.2,2.1,1.3Hz,1H),7.54(d,J＝8.2Hz,2H),7.32(d,J＝7.8Hz,5H),7.15(dd,J＝8.2,7.1Hz,2H),7.08(d,J＝7.9Hz,4H),7.02(dd,J＝8.5,2.7Hz,2H),6.97(s,2H),6.79(dd,J＝9.7,2.8Hz,2H),6.75(d,J＝7.9Hz,4H),6.41(d,J＝6.9Hz,2H),6.32(d,J＝7.8Hz,4H),2.38(s,6H),2.33(s,6H),1.58(s,2H),1.56(s,6H).13C NMR(101MHz,CDCl3)δ163.9,161.4,155.1,150.7,149.4,146.5,146.5,140.1,140.0,139.7,138.6,138.1,137.9,135.9,135.3,132.5,132.4,132.4,129.8,129.3,128.4,127.2,126.3,124.8,124.3,120.8,116.1,115.9,115.7,115.4,50.2,21.0,20.3,20.1.
The yield of complex 12 was 39%. FIG. 6 (a) shows a nuclear magnetic resonance hydrogen spectrum of the complex 12; fig. 6 (b) shows a nuclear magnetic resonance spectrum of the complex 12.
1H NMR(400MHz,CDCl3)δ8.83(s,1H),8.71(d,J＝5.5Hz,1H),7.74(dd,J＝15.6,7.8Hz,6H),7.66(d,J＝8.1Hz,1H),7.40(t,J＝7.6Hz,2H),7.26–7.16(m,8H),6.94(d,J＝6.9Hz,2H),6.88(d,J＝7.3Hz,2H),6.50(d,J＝9.5Hz,2H),5.60(d,J＝7.0Hz,2H),2.22(s,6H),1.29(d,J＝7.1Hz,6H).13C NMR(101MHz,CDCl3)δ164.2,161.7,157.4,150.6,149.5,148.6,148.5,143.6,139.8,139.7,139.6,137.9,132.3,131.5,129.8,129.3,129.0,128.7,128.0,127.9,126.5,125.4,124.6,121.1,116.0,115.8,114.4,114.2,38.8,20.7,19.6.
Test example 1
In order to test the effect of a flexible, highly sterically hindered N-heterocyclic carbene palladium complex 10-12 containing a halogenated benzene ring in a Suzuki-Miyaura coupling inversion reaction, the following experiment was set up.
To a parallel reactor, 4-chlorophenyl triflate (1.0 mmol), p-methylphenylboronic acid (1.1 mmol), variable substrate (catalytic amount), and potassium carbonate (2.0 mmol) were added sequentially. Wherein, the flexible large steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring is provided with a plurality of groups of parallel experiments.
And two different sets of reaction conditions were set:
Reaction condition a: THF, dmac=1:1; water as additive, reaction temperature: 80 ℃; reaction time: 4h.
Reaction condition B: toluene thf=19:1; water as additive, reaction temperature: 100 ℃; reaction time: 4h.
Post-treatment process: after the reaction time was reached, the reaction system was cooled to room temperature, transferred to a separating funnel, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate to remove water, then the solvent was removed by rotary evaporation, and the yield was determined after separation and purification on a thin silica gel plate, and the product was characterized by 1 H NMR and 13 C NMR to confirm the structure of the coupled product.
Wherein, the variable substrates in the reaction are respectively selected from flexible large steric hindrance N-heterocyclic carbene palladium complex 10-12 containing halogenated benzene ring, commercialized catalyst Pd-PEPSI-IMes (control 1) and Pd-PEPSI-IPr (control 2). All of the variable substrates described above were added to the parallel tubes and parallel experiments were performed.
The chemical equation for the parallel experiments described above is as follows:
The chemical equation shows that after the 4-chlorophenyl trifluoro methane sulfonate and p-methylphenyl boric acid are subjected to Suzuki-Miyaura coupling and turning reaction under the reaction condition A or the reaction condition B, the final product is a mixture, and the product M1 and the product M2 are simultaneously contained. However, the ratio of M1 and M2 produced is different depending on the reaction conditions.
The desired result is that the above-described Suzuki-Miyaura coupling inversion reaction is highly selective, i.e. depending on the chosen reaction conditions (reaction conditions a/B), wherein one of the products M1 or M2 exhibits a yield that is clearly advantageous.
In general, it is well known to those skilled in the art that the Suzuki-Miyaura coupling inversion reaction is considered highly selective when the molar ratio of product with a significant dominant yield to product with a non-dominant yield is greater than 10:1 of the two products.
In the parallel experiments described above, the molar ratios of M1 and M2 formed for the different variable substrates under reaction conditions A and B, respectively, are shown in Table 1.
TABLE 1 molar ratio of products M1 to M2 (M1/M2) after reaction under different variables of substrate conditions using reaction conditions A/B
As can be seen from the above table, when complex 10-12 was used as a variable substrate in a Suzuki-Miyaura coupling inversion reaction, the reaction results exhibited high selectivity. Namely: the molar ratio of the product M1 and M2 obtained, with a dominant yield, to the product with a non-dominant yield can be maintained at 10/1 and above, with individual results even approaching 100/1, showing a significant reaction selectivity, regardless of the reaction conditions A or B. All of the above data meet the criteria of high selectivity.
However, when the inverted control 1 or control 2, which was used as a variable substrate in the Suzuki-Miyaura coupling inversion reaction, the resulting product did not fully exhibit high selectivity when the reaction conditions were changed: as in control 1, the molar ratio of product with dominant yield to product with non-dominant yield was only 3/4 at reaction condition B, while the molar ratio of product with dominant yield to product with non-dominant yield was only 59/25 at reaction condition a. The two results are far from the highly selective ideal results. This indicates that control 1 and control 2 did not achieve the desired results.
The reason for the above results is that the aromatic amine moiety of the catalyst in the complex 10-12 is a flexible large steric hindrance, and has good steric expanse. They allow the solvent molecule DMAc to participate in coordination under the reaction conditions a of the polar coordinating solvent. This dual ligand (L 1L2) Pd active center enhances the nucleophilicity of the palladium metal, resulting in high selectivity for the oxidative addition of C-OTf. In the reaction condition B of the nonpolar solvent, the fluorine atom has an electron withdrawing effect, so that the electron donating capability of the metal center can be weakened, and the palladium metal center can only selectively react with the C-Cl bond. Thus, the coupling reaction can be turned over by changing the reaction conditions by using only a single catalyst.
In contrast, since the aromatic amine moiety of commercial control 1 (Pd-PEPSI-IMes) is 2,4, 6-trimethylaniline, the axial steric hindrance is small, the degree of protection of the metal center is insufficient, and the metal center is easily deactivated under low polarity reaction conditions B. Whereas for commercial control 2 (Pd-PEPSI-IPr), it is highly sterically hindered at the axial position of the metal center due to its aromatic amine moiety being 2, 6-diisopropylaniline. When in the reaction condition A of the polar coordination solvent, the large steric hindrance prevents the solvent molecule from participating in coordination, thereby leading to low selectivity of the solvent molecule to C-OTf and C-Cl bonds.
Test example 2
Based on the results of test example 1, we further set up parallel experiments for expanding the screening range of the reaction substrates; and finishing statistics are carried out on the molar ratio of the product with the dominant yield to the product with the non-dominant yield in the obtained product.
The variable substrate was selected only for N-heterocyclic carbene palladium complex 10 and tested for its effect in a Suzuki-Miyaura coupling flip-flop reaction. The parallel experiments were set up as follows:
To a parallel reactor, 4-chlorophenyl triflate (1.0 mmol), phenylboronic acid derivative (1.1 mmol), N-heterocyclic carbene palladium complex 10 (catalytic amount), and potassium carbonate (2.0 mmol) were sequentially added. Among them, phenylboronic acid derivatives have several specific structures, as shown in table 2.
Two different sets of reaction conditions were set:
Reaction condition a: THF, dmac=1:1; water as additive, reaction temperature: 80 ℃; reaction time: 4h.
Reaction condition B: toluene thf=19:1; water as additive, reaction temperature: 100 ℃; reaction time: 4h.
Post-treatment process: after the reaction time was reached, the reaction system was cooled to room temperature, transferred to a separating funnel, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate to remove water, then the solvent was removed by rotary evaporation, and the yield was determined after separation and purification on a thin silica gel plate, and the product was characterized by 1 H NMR and 13 C NMR to confirm the structure of the coupled product.
The chemical equation for the parallel experiments described above is as follows:
The chemical equation shows that after the 4-chlorophenyl trifluoro methane sulfonate and phenylboric acid derivative are subjected to Suzuki-Miyaura coupling and turning reaction under the reaction condition A or the reaction condition B, the final product is a mixture, and the product M3 and the product M4 are contained simultaneously. However, the ratio of M3 to M4 produced varies depending on the reaction substrate phenylboronic acid derivative and the reaction conditions. Table 2 shows the molar ratios of the products M3 and M4 in the molar ratios of the products of the advantageous yields after the reaction of complex 10 as catalyst under the different phenylboronic acid derivatives under reaction conditions A/B.
Table 2 shows the molar ratios of the products M3 and M4, indicated in brackets in the figure, of the advantageous yields of the products M3 and M4 after reaction under the reaction conditions A/B with the complex 10 as catalyst under the different phenylboronic acid derivatives.
As is clear from Table 2, when N-heterocyclic carbene palladium complex 10 is used as a catalyst, the final molar ratio of M3 and M4 obtained is more than 30/1 depending on the reaction substrate. It follows that complex 10 has a large steric hindrance in flexibility, and can achieve selective inversion of the C-OTf bond and the C-Cl bond by a single catalyst with high selectivity by changing the reaction conditions. Meanwhile, the reaction condition is mild, and the defects of poor substrate adaptability, low yield and the like reported in literature are overcome.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (2)

1. The preparation method of the flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing the halogenated benzene ring is characterized in that the flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing the halogenated benzene ring is selected from the following structures:
；
the preparation method of the flexible large-steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring comprises the following steps:
dissolving acenaphthoquinone and halogenated aromatic amine in a solvent, and heating for reaction under the action of a catalyst to obtain a precursor containing halogenated benzene ring, wherein the precursor is used for Suzuki-Miyaura coupling and overturning reaction;
the reaction conditions of the Suzuki-Miyaura coupling and overturning reaction are as follows:
Reaction condition a: the solvent is a mixed solvent of THF and DMAc;
Or (b)
Reaction condition B: the solvent is a mixed solvent of THF and toluene.
2. The method for preparing a flexible large-steric hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring according to claim 1, wherein the acenaphthoquinone has the structure:
。
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