CN108456172B - Chiral N-heterocyclic carbene precursor compound with benzimidazole skeleton and preparation method and application thereof - Google Patents

Chiral N-heterocyclic carbene precursor compound with benzimidazole skeleton and preparation method and application thereof Download PDF

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CN108456172B
CN108456172B CN201810361990.XA CN201810361990A CN108456172B CN 108456172 B CN108456172 B CN 108456172B CN 201810361990 A CN201810361990 A CN 201810361990A CN 108456172 B CN108456172 B CN 108456172B
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李�杰
杨帆
周碧辉
何卫平
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Zhejiang University City College ZUCC
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
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    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B01J2231/4233—Kumada-type, i.e. RY + R'MgZ, in which Ris optionally substituted alkyl, alkenyl, aryl, Y is the leaving group and Z is halide

Abstract

The invention discloses a chiral nitrogen heterocyclic carbene precursor compound with a benzimidazole skeleton and a preparation method and application thereof.

Description

Chiral N-heterocyclic carbene precursor compound with benzimidazole skeleton and preparation method and application thereof
Technical Field
The invention relates to the field of organic synthesis, in particular to a chiral N-heterocyclic carbene precursor compound with a benzimidazole skeleton, and a preparation method and application thereof.
Background
The research history of N-heterocyclic carbenes (NHCs) can be traced back to the first report of Wanzlick in 1962, but the research of NHC ligand has not attracted extensive attention until Arduengo et al isolated stable NHC monomer-imidazole-2-carbene for the first time in 1991. Compared with phosphine ligands, the azacarbene ligands have the following characteristics: 1) the stronger σ donating and weaker pi acceptance enable NHCs to form more stable metal complexes with transition metals and exhibit better air and thermodynamic stability; 2) different from the space layout of phosphine ligand 'edge-to-face', the five-membered N-heterocyclic carbene ligand mostly has a wedge-shaped near-planar space structure, and the electrical factor and the space layout can be separated relatively independently. Based on this, the n-heterocyclic carbene ligands play an increasingly important role in the fields of organic chemistry and metal-organic chemistry, and the catalytic performance of the n-heterocyclic carbene ligands has exceeded that of traditional phosphine ligands in many important reactions.
At present, no matter whether a monodentate or bidentate chiral NHC ligand is developed by a subject group at home and abroad, a basic structural unit of the ligand is mainly based on structures such as five-membered ring imidazole or dihydroimidazole, and a benzimidazole carbene ligand which is one of representative frameworks is less researched and is still in a starting stage.
Figure GDA0002694100800000011
The chemical shift value of the carbene carbon in the carbon spectrum of the benzimidazole carbene ligand is 231.47ppm, and the chemical shift value is equal to that of unsaturated imidazole carbene delta (C)NHC210-220ppm) was significantly different, closer to the chemical shift δ C of the saturated imidazoline carbene carbonNHC240ppm, it is speculated that this demasking effect of the carbene centres may be due to a reduction in five-membered ring electron delocalisation. Furthermore, the geometric parameters of the five-membered rings in such ligands are also within the range of values for saturated imidazoline-2-carbenes, whose C ═ C bond length is close to that of saturated imidazole rings.
In 1999, Hahn et al reported the synthesis of benzimidazole carbene ligands for the first time on Chemistry-A European Journal, and examined the electrical and structural characteristics, the structures of which are as follows.
Figure GDA0002694100800000021
The research of chiral benzimidazole carbene ligands began in 2001, and a carver topic group reported on Organic Letters a benzimidazole carbene precursor salt with a chiral side chain connected to an N atom for the first time, but the chiral benzimidazole carbene precursor salt is not applied to asymmetric catalytic reaction, and the structure of the chiral carbene precursor salt is as follows.
Figure GDA0002694100800000022
In 2003, Jung project group at university of California, south reported a chiral tridentate benzimidazole palladium carbene complex with a characteristic structure and its dimer on Angewandte Chemie International Edition, and achieved excellent enantioselectivity (ee > 90%) in asymmetric oxidation Heck reaction, which has the following structure. Subsequently, the Sakaguchi topic group applies the same type of chiral ligand to iridium-catalyzed asymmetric hydrosilylation reaction of ketone, ruthenium-catalyzed asymmetric hydrogen transfer reaction of ketone, copper-catalyzed asymmetric conjugate addition reaction of unsaturated ketene and the like, and obtains relatively good enantioselectivity.
Figure GDA0002694100800000023
During the period from 2003 to 2013, the sensitization subject group of Shanghai organic institute of Chinese academy of sciences applies the benzimidazole carbene ligand with axial chirality designed by the inventor to various asymmetric reactions catalyzed by transition metals, including asymmetric hydrosilylation reaction catalyzed by rhodium, asymmetric conjugate addition reaction catalyzed by palladium on unsaturated ketene, asymmetric addition reaction catalyzed by palladium on imine, asymmetric oxidation kinetic resolution catalyzed by palladium on alcohol and the like, and obtains better enantioselectivity. The structure of such ligands is as follows.
Figure GDA0002694100800000024
Recently, this group designed and synthesized a series of new chiral benzimidazole carbene precursor salts, and obtained a moderate partial enantioselectivity in the non-addition reaction of rhodium catalyzed aromatic aldehyde, and constructed a series of chiral diaryl secondary alcohol compounds with important role.
Figure GDA0002694100800000031
Throughout the development of benzimidazole carbene ligands, the field is still in the beginning. Nevertheless, the use of carbene ligands of such frameworks in partially catalytic reactions has shown certain advantages. Therefore, the development of a novel synthesis method of the chiral benzimidazole carbene ligand and the metal complex thereof has important significance, not only can enrich the meaning of carbene chemical taxonomy, but also can be applied to asymmetric reaction to reduce the production cost of part of chiral drug synthesis intermediates.
Disclosure of Invention
The invention aims to develop a chiral N-heterocyclic carbene precursor compound with a benzimidazole skeleton and a preparation method and application thereof through a simple organic synthesis route, thereby expanding the application range of the chiral N-heterocyclic carbene precursor compound in the synthesis reaction of a drug intermediate and the organic asymmetric synthesis reaction.
A chiral N-heterocyclic carbene precursor compound with a benzimidazole skeleton is characterized in that the chiral N-heterocyclic carbene precursor compound is:
Figure GDA0002694100800000032
or an enantiomer thereof
Figure GDA0002694100800000033
Wherein the content of the first and second substances,
R1selected from phenyl, benzyl, tert-butyl, isopropyl, methyl, isobutyl;
R2selected from phenyl, 1-naphthyl, 2-naphthyl, benzyl, isopropyl, tert-butyl and cyclohexyl;
R4selected from hydrogen, 1-naphthoyl, 2,4, 6-trimethylbenzoyl, p-methoxybenzoyl and p-tert-butylbenzoyl;
R3selected from chloride ion, bromide ion, tetrafluoroborate ion, hexafluorophosphate ion.
Preferably, the structure of the compound is selected from:
Figure GDA0002694100800000041
Figure GDA0002694100800000051
the preparation method of the chiral N-heterocyclic carbene precursor compound is characterized by comprising the following steps:
reacting chiral amine alcohol shown as a general formula (I) with tert-butyldimethylsilyl chloride in an aprotic solvent under the action of 4-dimethylaminopyridine and triethylamine, and collecting a compound shown as a formula (II) from a reaction product, wherein the reaction general formula is as follows:
Figure GDA0002694100800000052
(ii) in an aprotic solvent, heating TBS protective amine alcohol compounds shown as a general formula (II) and 1,2 dibromobenzene to react under the action of alkali and a catalyst, and then collecting compounds shown as a formula (III) from reaction products;
Figure GDA0002694100800000053
(iii) heating the optically pure 2-bromoaniline compound shown as the general formula (III) and the aromatic amine compound in an aprotic solvent under the action of alkali and a catalyst to react, and collecting the compound shown as the general formula (IV) from a reaction product, wherein the general formula is as follows:
Figure GDA0002694100800000054
(iv) dissolving chiral diamine shown as a general formula (IV) in trimethyl orthoformate or triethyl orthoformate in an aprotic solvent, reacting under the action of Lewis acid, and collecting a compound shown as a formula (V-A) from a reaction product; the reaction formula is as follows:
Figure GDA0002694100800000061
(v) reacting the N-heterocyclic carbene precursor salt of the general formula (V-A) with acyl chloride under alkaline conditions, and collecting the compound of the general formula (V-B) from the reaction product, wherein the general reaction formula is as follows:
Figure GDA0002694100800000062
preferably, the molar ratio of the compound of formula (I) in step (i) to tert-butyldimethylsilyl chloride is 1:1.1, the reaction temperature is 20-30 ℃ and the reaction time is 3-5 hours.
Preferably, the reaction temperature of the step (ii) is 80-120 ℃, the reaction time is 5-12 hours, and the molar ratio of the compound of the formula (II), 1,2 dibromobenzene, the catalyst and the alkali is 1.2:1: 0.1-0.01: 1-2; the alkali is preferably sodium tert-butoxide or potassium tert-butoxide.
Preferably, the reaction temperature in the step (iii) is 80-120 ℃, the reaction time is 12-16 hours, and the molar ratio of the compound of formula (III), the aromatic amine compound, the catalyst and the base is 1:1.2: 0.1-0.05: 2-3; the alkali is preferably sodium tert-butoxide or potassium tert-butoxide.
Preferably, the reaction temperature of step (iv) is 80-120 ℃, the reaction time is 5-20 hours, and the molar ratio of the compound of formula (IV) and the Lewis acid is 1: 1-10.
The application of the chiral N-heterocyclic carbene precursor compound is characterized in that the compound is used as a catalyst for the following reactions:
Figure GDA0002694100800000063
wherein Ar is phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl respectively; the reaction process of the reaction is as follows: in an aprotic solution, reacting palladium acetate with the N-heterocyclic carbene precursor compound, 4-benzylpyridine and a compound shown as a general formula (VI) under the action of alkali, and collecting a compound shown as a formula (VII) from a reaction product; the reaction temperature is 60-80 ℃, the reaction time is 12-18h, and the molar ratio of the 4-benzylpyridine, the compound (VI), the alkali, the N-heterocyclic carbene precursor compound and the palladium acetate is 1:1.2:1:3:0.075: 0.05.
Preferably, the aprotic solvent is any one of benzene, toluene, xylene, tetrahydrofuran, ethylene glycol dimethyl ether and 1, 4-dioxane, and the used base is any one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and lithium bis (trimethylsilyl) amide.
The application of a chiral N-heterocyclic carbene precursor compound is characterized in that the compound is used as a catalyst for the following reactions:
Figure GDA0002694100800000071
wherein Ar is1And Ar2Respectively, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, and the like; the reaction process of the reaction is as follows: adding a compound shown as a general formula (VIII), nickel metal and the N-heterocyclic carbene precursor compound in sequence into an aprotic solution, finally adding a compound shown as a general formula (IX), and collecting a compound shown as a formula (X) from a reaction product. The reaction conditions are as follows: the reaction temperature is 24-50 ℃, and the reaction is carried outThe time is 1-10h, wherein the molar ratio of the (VIII) compound, the (IX) azacarbene precursor compound and the metallic nickel is 1:1.2:0.05: 0.05.
The invention has the beneficial effects that:
the invention can simply and effectively synthesize a series of chiral benzimidazole carbene precursor compounds with novel structures through five-step reaction, introduces oxygen-containing functional groups (hydroxyl or ester groups) containing lone pair electrons into chiral side chain substituent groups, can be used as bidentate ligands to form a complex with a metal center, can show excellent reaction activity in a metal catalytic reaction system, and is expected to obtain a catalytic product of high enantiomer in asymmetric reaction.
Detailed Description
The present invention will be described in detail below based on preferred embodiments, and objects and effects of the present invention will become more apparent, and the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The synthetic route of the chiral N-heterocyclic carbene precursor compound is as follows:
Figure GDA0002694100800000081
t-butyldimethylsilyl chloride, 4-dimethylaminopyridine; (ii) 1, 2-dibromobenzene, BINAP, palladium metal, base (sodium tert-butoxide, potassium tert-butoxide, etc.); (iii) arylamines, BINAP, palladium metal, bases (sodium tert-butoxide, potassium tert-butoxide, etc.); (iv) triethyl or trimethyl orthoformate, ammonium salts; (v) triethylamine, acyl chloride.
Representative synthesis of compound ii (general method 1):
Figure GDA0002694100800000082
4mmol of Compound I (1eq) and 8mmol of triethylamine (2eq) were dissolved in dry dichloromethane (40mL), and after stirring at room temperature for 5 minutes, 4 was added.4mmol of tert-butyldimethylsilyl chloride (1.1eq), stirring for 5 minutes, adding 4mmol of 4-dimethylaminopyridine (1eq), stirring at 20 ℃ for 3 hours, evaporating the reaction mixture under reduced pressure, and separating the mixture by column Chromatography (CH)2Cl2:CH3OH 80: 1-50: 1) to obtain a product II.
Representative synthesis of compound iii (general method 2):
Figure GDA0002694100800000083
mixing 0.02mmol of tris (dibenzylideneacetone) dipalladium (1.0% eq), 0.04mmol of (+/-) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (2.0% eq) and 2.6mmol of sodium tert-butoxide (1.3eq), adding redistilled toluene (15mL), sequentially adding 2mmol of 1, 2-dibromobenzene (1eq) and 2.4mmol of compound II (1.2eq) under stirring, stirring at 95 ℃ for 12 hours, filtering the reaction solution after the reaction is finished, evaporating under reduced pressure, and performing column chromatography separation on the mixture (petroleum ether: ethyl acetate: 100:1) to obtain a product III.
Representative Synthesis of Compound IV (general method 3):
Figure GDA0002694100800000091
dissolving 0.15mmol of palladium acetate (10% eq) and 0.15mmol of (+/-) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (10% eq) in redistilled toluene (10mL), stirring at 60 ℃ for 10 minutes, cooling the reaction solution to room temperature, sequentially adding 1.5mmol of the compound (III) (1eq), 1.8mmol of arylamine (1.2eq) and 3.75mmol of sodium tert-butoxide (2.5eq), stirring at 80 ℃ for 12 hours, filtering the reaction solution after the reaction is finished, evaporating under reduced pressure, and performing column chromatography separation on the mixture (petroleum ether: ethyl acetate ═ 50: 1-30: 1) to obtain a product IV.
Representative synthesis of compound v (general method 4):
Figure GDA0002694100800000092
1mmol of the compoundIV (1eq) is dissolved in triethyl orthoformate (39mL), 8mmol of concentrated hydrochloric acid (8eq) is slowly added dropwise with stirring, after stirring for 30 minutes at room temperature, the mixture is stirred for 20 hours at 100 ℃, after the reaction is finished, the reaction solution is evaporated to dryness under reduced pressure, and the mixture is separated by column Chromatography (CH)2Cl2:CH3OH is 50: 1-30: 1) to obtain a product V.
Example 1
Preparation and characterization of Compound II-1:
Figure GDA0002694100800000093
compound I-1 (521. mu.L, 4mmol) and triethylamine (1112. mu.L, 8mmol) were dissolved in dry dichloromethane (40mL), stirred at room temperature for 5 minutes, then tert-butyldimethylchlorosilane (663mg,4.4mmol) was added, and after stirring for 5 minutes, 4-dimethylaminopyridine (489. mu.L, 4mmol) was added and reacted at room temperature for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure and the mixture was separated by column Chromatography (CH)2Cl2:CH3OH 80:1 to 50:1) to give ii-1656 mg as a yellow oil in 71% yield.1H NMR(500MHz,CDCl3)δ:3.76(dd,J＝9.8,3.2Hz,1H),3.40–3.31(m,1H),2.57(dd,J＝8.8,3.2Hz,1H),0.91(d,J＝3.0Hz,18H),0.07(s,6H)。
Example 2
Preparation and characterization of Compound II-2:
Figure GDA0002694100800000101
the preparation was carried out under the same conditions as in example 1, yellow oil, yield 85%;1H NMR(500MHz,CDCl3)δ:7.38(dd,J＝8.3,1.3Hz,2H),7.36–7.32(m,2H),7.29–7.24(m,1H),4.08(dd,J＝8.4,3.9Hz,1H),3.73(dd,J＝9.8,4.0Hz,1H),3.53(dd,J＝9.8,8.4Hz,1H),0.94–0.86(m,9H),0.03(t,J＝2.2Hz,6H)。
example 3
Preparation and characterization of Compound II-3:
Figure GDA0002694100800000102
the preparation was carried out under the same conditions as in example 1, yellow oil, yield 88%;1H NMR(500MHz,CDCl3)δ:7.33–7.28(m,2H),7.25–7.19(m,3H),3.59(dd,J＝9.7,4.4Hz,1H),3.45(dd,J＝9.7,6.5Hz,1H),3.10(m,1H),2.80(dd,J＝13.4,5.3Hz,1H),2.52(dd,J＝13.4,8.4Hz,1H),0.94–0.91(m,9H),0.09–0.05(m,6H)。
example 4
Preparation and characterization of Compound II-4:
Figure GDA0002694100800000103
the preparation was carried out under the same conditions as in example 1, yellow oil, yield 74%;1H NMR(500MHz,CDCl3)δ:3.64(dd,J＝9.8,4.0Hz,1H),3.43–3.35(m,1H),2.57(dd,J＝10.9,6.9Hz,1H),1.61(m,1H),0.93–0.89(m,15H),0.06(s,6H)。
example 5
Preparation and characterization of Compound II-5:
Figure GDA0002694100800000111
the preparation was carried out under the same conditions as in example 1, yellow oil, yield 78%;1H NMR(500MHz,CDCl3)δ:3.66(dd,J＝9.8,3.7Hz,1H),3.42–3.35(m,1H),2.70–2.63(m,1H),1.57–1.49(m,1H),1.43–1.36(m,1H),1.18(m,1H),0.93–0.87(m,15H),0.06(s,6H)。
example 6
Preparation and characterization of Compound II-6:
Figure GDA0002694100800000112
the preparation was carried out under the same conditions as in example 1, yellow oil, yield 71%;1H NMR(500MHz,CDCl3)δ:3.51(dd,J＝9.7,4.2Hz,1H),3.27(dd,J＝9.7,7.5Hz,1H),2.97(m,1H),1.01(d,J＝6.5Hz,3H),0.91–0.89(s,9H),0.06(d,J＝2.8Hz,6H)。
example 7
Preparation and characterization of Compound III-1:
Figure GDA0002694100800000113
three of tris (dibenzylideneacetone) dipalladium (18mg,0.02mmol), 0.04mmol (±) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (25mg,0.04mmol) and sodium tert-butoxide (250mg,2.6mmol) were dissolved in toluene (15mL), and 1, 2-dibromobenzene (241mg,2mmol) and a compound ii-1 (554mg,2.4mmol) were sequentially added with stirring, and stirred at 95 ℃ for 12 hours, after completion of the reaction, the reaction mixture was filtered and evaporated to dryness under reduced pressure, and the mixture was subjected to column chromatography (petroleum ether: ethyl acetate ═ 100:1) to obtain colorless oil iii-1463 mg with a yield of 60%.1H NMR(500MHz,CDCl3)δ:1H NMR(500MHz,CDCl3)δ7.42(dd,J＝7.9,1.5Hz,1H),7.16–7.09(m,1H),6.72(dd,J＝8.3,0.9Hz,1H),6.51(m,1H),4.72(d,J＝9.7Hz,1H),3.76(m,2H),1.06(s,9H),0.91–0.84(m,9H),0.03–0.01(m,6H)。
Example 8
Preparation and characterization of Compound III-2:
Figure GDA0002694100800000121
the preparation was carried out under the same conditions as in example 7, colorless oil, yield 75%;1H NMR(500MHz,CDCl3)δ:7.43(dd,J＝7.9,1.5Hz,1H),7.35(m,4H),7.28–7.25(m,1H),6.99–6.93(m,1H),6.52(m,1H),6.33(dd,J＝8.2,1.4Hz,1H),4.42(m,1H),3.95(dd,J＝10.1,4.2Hz,1H),3.72(dd,J＝10.2,7.3Hz,1H),0.93–0.89(m,9H),0.06(d,J＝2.9Hz,3H),0.01(d,J＝1.6Hz,3H)。
example 9
Preparation and characterization of Compound III-3:
Figure GDA0002694100800000122
the preparation was carried out under the same conditions as in example 7, colorless oil, yield 77%;1H NMR(500MHz,CDCl3)δ:7.43(dd,J＝7.9,1.5Hz,1H),7.34–7.29(m,2H),7.27–7.21(m,3H),7.20–7.15(m,1H),6.70(dd,J＝8.2,1.3Hz,1H),6.57–6.53(m,1H),4.78(d,J＝8.9Hz,1H),3.64–3.57(m,2H),2.94(d,J＝6.7Hz,2H),0.99–0.94(m,9H),0.07(t,J＝2.5Hz,6H)。
example 10
Preparation and characterization of Compound III-4:
Figure GDA0002694100800000123
the preparation was carried out under the same conditions as in example 7, colorless oil, yield 93%;1H NMR(500MHz,CDCl3)δ:7.40(m,1H),7.16–7.10(m,1H),6.65(dd,J＝8.2,1.0Hz,1H),6.53–6.47(m,1H),3.74(dd,J＝10.1,3.7Hz,1H),3.63(dd,J＝10.1,5.0Hz,1H),3.25(m,1H),2.06(m,1H),1.01(t,J＝7.0Hz,6H),0.91–0.89(m,9H),0.03(d,J＝1.5Hz,6H)。
example 11
Preparation and characterization of Compound III-5:
Figure GDA0002694100800000131
the preparation was carried out under the same conditions as in example 7, colorless oil, yield 80%;1H NMR(500MHz,CDCl3)δ:7.41(d,J＝7.8Hz,1H),7.13(t,J＝7.7Hz,1H),6.64(d,J＝8.2Hz,1H),6.51(t,J＝7.5Hz,1H),4.65(d,J＝8.9Hz,1H),3.71(m,2H),3.32(m,1H),1.84–1.75(m,1H),1.67–1.58(m,1H),0.96(dd,J＝15.5,7.3Hz,6H),0.90(s,9H),0.03(d,J＝2.4Hz,6H)。
example 12
Preparation and characterization of Compound III-6:
Figure GDA0002694100800000132
the preparation was carried out under the same conditions as in example 1, colorless oil, yield 88%;1H NMR(500MHz,CDCl3)δ:7.42(d,J＝7.9Hz,1H),7.16(t,J＝7.7Hz,1H),6.67(d,J＝8.2Hz,1H),6.54(t,J＝7.6Hz,1H),3.68–3.64(m,2H),3.61(s,1H),1.25(d,J＝6.3Hz,3H),0.92(s,9H),0.07(s,6H)。
example 13
Preparation and characterization of Compound IV-1:
Figure GDA0002694100800000133
palladium acetate (34mg,0.15mmol) and 0.15mmol (±) -2,2 '-bis- (diphenylphosphino) -1,1' -binaphthyl (93mg,0.15mmol) were dissolved in redistilled toluene (10mL), and stirred at 60 ℃ for 10 minutes, the reaction solution was cooled to room temperature, and then compound iii-1 (579mg,1.5mmol), 2-naphthylamine (258mg,1.8mmol) and sodium tert-butoxide (360mg,3.75mmol) were added in this order, and stirred at 80 ℃ for 12 hours, after the reaction was completed, the reaction solution was filtered and evaporated to dryness under reduced pressure, and the mixture was subjected to column chromatography (petroleum ether: ethyl acetate: 50: 1-30: 1) to obtain yellow gum iv-1612 mg with a yield of 91%.1H NMR(500MHz,CDCl3)δ:7.73–7.66(m,2H),7.56(d,J＝8.3Hz,1H),7.35(t,J＝7.1Hz,1H),7.24(t,J＝7.1Hz,1H),7.19–7.09(m,2H),7.04(dd,J＝8.7,2.1Hz,1H),6.92(s,1H),6.83(d,J＝8.1Hz,1H),6.67(s,1H),3.68(m,2H),3.18(s,1H),0.92(s,9H),0.80(s,9H),0.02–0.10(m,6H)。
Example 14
Preparation and characterization of Compound IV-2:
Figure GDA0002694100800000141
the preparation was carried out under the same conditions as in example 13, using a white solid in a yield of 99%;1H NMR(500MHz,CDCl3)δ:7.73(dd,J＝8.2,5.2Hz,2H),7.61(d,J＝8.2Hz,1H),7.42–7.36(m,3H),7.32(t,J＝7.4Hz,2H),7.29–7.23(m,1H),7.19(d,J＝7.3Hz,1H),7.11(dd,J＝8.7,2.0Hz,1H),6.96(dd,J＝16.4,8.2Hz,2H),6.72(t,J＝7.4Hz,1H),6.52(d,J＝7.3Hz,1H),4.45–4.39(m,1H),3.85(dd,J＝10.1,4.1Hz,1H),3.63(s,1H),0.72–0.68(m,9H),0.02–0.01(m,3H),0.13(s,3H)。
example 15
Preparation and characterization of Compound IV-3:
Figure GDA0002694100800000142
the preparation was carried out under the same conditions as in example 13, yellow gum, 97% yield;1H NMR(500MHz,CDCl3)δ:7.70(dd,J＝14.4,8.4Hz,2H),7.55(d,J＝8.2Hz,1H),7.36(t,J＝7.1Hz,1H),7.26–7.13(m,8H),6.99(dd,J＝8.7,1.8Hz,1H),6.86(d,J＝6.8Hz,2H),6.74(t,J＝7.1Hz,1H),3.59(dd,J＝9.9,3.1Hz,1H),3.50(dd,J＝9.9,4.8Hz,1H),2.93–2.81(m,2H),0.80(s,9H),-0.07(d,J＝27.5Hz,6H)。
example 16
Preparation and characterization of Compound IV-4:
Figure GDA0002694100800000151
the preparation was carried out under the same conditions as in example 13, yellow gum, 87% yield;1H NMR(500MHz,CDCl3)δ:7.70(t,J＝9.3Hz,2H),7.56(d,J＝8.3Hz,1H),7.35(t,J＝7.5Hz,1H),7.24(t,J＝7.4Hz,1H),7.19–7.11(m,2H),7.04(d,J＝8.8Hz,1H),6.91(s,1H),6.79(d,J＝7.9Hz,1H),6.68(t,J＝7.3Hz,1H),3.68(dd,J＝10.0,3.6Hz,1H),3.55(dd,J＝10.0,5.3Hz,1H),3.27(d,J＝4.2Hz,1H),1.99(dd,J＝13.2,6.5Hz,1H),0.92(d,J＝6.7Hz,3H),0.87(d,J＝6.7Hz,3H),0.80(s,9H),0.03(s,3H),0.08(s,3H)。
example 17
Preparation and characterization of Compound IV-5:
Figure GDA0002694100800000152
the preparation conditions are the same as those of the practiceExample 13, green gum, 98% yield;1H NMR(500MHz,CDCl3)δ:7.70(t,J＝8.5Hz,2H),7.57(d,J＝8.1Hz,1H),7.36(t,J＝7.4Hz,1H),7.28–7.23(m,3H),7.07(d,J＝16.2Hz,2H),6.99(s,1H),6.83(s,1H),3.69(d,J＝42.2Hz,2H),1.49(dd,J＝60.0,34.7Hz,4H),0.96–0.84(m,6H),0.81(s,9H),0.05(dd,J＝22.0,10.0Hz,6H)。
example 18
Preparation and characterization of Compound IV-6:
Figure GDA0002694100800000161
the preparation was carried out under the same conditions as in example 13, yellow gum, 96% yield;1H NMR(500MHz,CDCl3)δ:7.70(t,J＝8.8Hz,2H),7.56(d,J＝8.2Hz,1H),7.36(t,J＝7.5Hz,1H),7.24(t,J＝7.4Hz,1H),7.20(d,J＝7.6Hz,1H),7.14(t,J＝7.6Hz,1H),7.05(d,J＝8.6Hz,1H),6.92(s,1H),6.83(d,J＝8.0Hz,1H),6.74(t,J＝7.4Hz,1H),3.67–3.58(m,2H),3.58–3.51(m,1H),1.19(d,J＝5.9Hz,3H),0.79(s,9H),0.05(d,J＝14.7Hz,6H)。
example 19
Preparation and characterization of Compound V-1:
Figure GDA0002694100800000162
dissolving compound IV-1 (448mg,1mmol) in triethyl orthoformate (39mL), slowly adding concentrated hydrochloric acid (662. mu.L, 8mmol) dropwise under stirring, stirring at room temperature for 30 min, stirring at 100 deg.C for 20 hr, evaporating the reaction solution under reduced pressure, and separating the mixture by column Chromatography (CH)2Cl2:CH3OH 50: 1-30: 1) gave v-1315 mg as a white solid in 83% yield.1H NMR(500MHz,DMSO)δ:10.52(s,1H),8.57(s,1H),8.42(d,J＝8.4Hz,1H),8.32(d,J＝8.8Hz,1H),8.19–8.13(m,2H),8.02(dd,J＝8.7,1.9Hz,1H),7.95(d,J＝8.2Hz,1H),7.81–7.76(m,1H),7.76–7.71(m,3H),5.38(t,J＝5.6Hz,1H),4.32–4.19(m,1H),4.09(m,1H),1.07(s,9H)；13C NMR(125MHz,DMSO)δ142.21,134.31,133.61,133.17,131.28,131.11,130.57,128.88,128.52,128.45,128.20,127.91,127.52,125.32,123.46,115.24,114.07,70.07,59.51,55.38,35.04,27.12。
Example 20
Preparation and characterization of Compound V-2:
Figure GDA0002694100800000171
the preparation was carried out under the same conditions as in example 19, white gum in 93% yield;1H NMR(500MHz,DMSO)δ:10.69(s,1H),8.59(d,J＝2.0Hz,1H),8.33(d,J＝8.9Hz,1H),8.20–8.12(m,2H),8.09–8.02(m,2H),8.00–7.94(m,1H),7.77–7.70(m,4H),7.69–7.65(m,2H),7.48–7.37(m,3H),6.32–6.22(m,1H),4.57(m,1H),4.24–4.17(m,1H)；13C NMR(125MHz,DMSO)δ142.43,137.87,135.51,133.63,133.20,131.89,131.83,131.10,130.71,129.43,128.91,128.52,128.23,128.16,128.09,127.67,125.82,125.15,123.24,120.83,114.86,114.44,112.51,64.60,62.47,25.94。
example 21
Preparation and characterization of Compound V-3:
Figure GDA0002694100800000172
the preparation was carried out under the same conditions as in example 19, white gum in 93% yield;1H NMR(500MHz,DMSO)δ:10.63(s,1H),8.48(d,J＝2.0Hz,1H),8.32(d,J＝8.8Hz,1H),8.22(d,J＝7.8Hz,1H),8.20–8.13(m,2H),7.96–7.87(m,2H),7.76–7.65(m,4H),7.36(d,J＝7.3Hz,2H),7.26(t,J＝7.6Hz,2H),7.17(t,J＝7.3Hz,1H),5.62(t,J＝6.2Hz,1H),4.03–3.86(m,2H),3.48(m,2H)；13C NMR(125MHz,DMSO)δ142.48,137.15,133.56,133.20,132.30,131.29,131.04,130.84,129.57,129.01,128.91,128.52,128.47,128.25,127.91,127.40,127.33,124.85,123.04,114.81,114.00,79.77,62.58,61.92,36.09。
example 22
Preparation and characterization of Compound V-4:
Figure GDA0002694100800000181
the preparation was carried out under the same conditions as in example 19, white gum in 85% yield;1H NMR(500MHz,DMSO)δ:10.47(s,1H),8.55(s,1H),8.33(d,J＝8.7Hz,2H),8.16(d,J＝2.7Hz,2H),7.99(dd,J＝17.2,8.4Hz,2H),7.77(m,4H),5.46(t,J＝5.8Hz,1H),4.82(d,J＝7.0Hz,1H),4.09(m,1H),3.91(dd,J＝7.6,4.9Hz,1H),1.15(d,J＝6.5Hz,3H),0.88(t,J＝7.8Hz,3H)；13C NMR(125MHz,DMSO)δ142.31,133.58,133.20,132.81,131.62,131.16,130.66,128.87,128.51,128.42,128.20,127.97,127.49,125.12,123.29,114.94,114.20,67.49,60.66,29.40,19.77,19.74。
example 23
Preparation and characterization of Compound V-5:
Figure GDA0002694100800000182
the preparation was carried out under the same conditions as in example 19, white gum in 87% yield;1H NMR(500MHz,DMSO)δ:10.44(s,1H),8.52(s,1H),8.32(dd,J＝8.4,3.9Hz,2H),8.18–8.12(m,2H),8.01–7.95(m,2H),7.82–7.70(m,4H),5.40(t,J＝5.9Hz,1H),4.86(dd,J＝11.4,4.8Hz,1H),4.08(m,1H),3.89(m,1H),2.40–2.31(m,1H),1.39–1.29(m,1H),1.11(d,J＝6.7Hz,3H),0.83(t,J＝7.3Hz,3H)；13C NMR(125MHz,DMSO)δ142.34,133.58,133.19,132.70,131.65,131.16,130.65,128.88,128.51,128.42,128.20,127.98,127.54,125.10,123.30,114.85,114.25,65.86,60.56,35.06,25.35,15.62,10.97。
example 24
Preparation and characterization of Compound V-6:
Figure GDA0002694100800000191
the preparation was carried out under the same conditions as in example 19, white gum in 82% yield;1H NMR(500MHz,DMSO)δ:10.42(s,1H),8.50(d,J＝2.0Hz,1H),8.30(dd,J＝14.9,8.5Hz,2H),8.18–8.12(m,2H),7.99–7.92(m,2H),7.80–7.70(m,4H),5.47(t,J＝6.2Hz,1H),3.87(t,J＝5.6Hz,2H),1.71(d,J＝6.9Hz,3H)；13C NMR(125MHz,DMSO)δ142.29,133.56,133.21,132.03,131.77,131.20,130.72,128.87,128.51,128.42,128.21,127.86,127.28,124.97,123.17,115.03,114.05,63.73,57.25,16.44。
example 25
The example is a catalytic experiment of N-heterocyclic carbene precursors V-1 to V-6, wherein the structural formulas of V-1 to V-6 are shown as follows, and the catalytic effect is shown in Table 1.
Figure GDA0002694100800000192
Preparation and characterization of Compound A-2:
Figure GDA0002694100800000193
under the protection of nitrogen, 0.015mmol of N-heterocyclic carbene precursor is dissolved in 2mL of anhydrous toluene, 0.01mmol of palladium acetate is added, after stirring for 15 minutes, 0.6mmol of bis (trimethylsilyl) sodium amide is added, after stirring for 20 minutes, 0.4mmol of compound A-1, 0.2mmol of 4-tert-butylbromobenzene is added into the reaction solution, and the reaction is carried out for 12 hours at 60 ℃. After the reaction is finished, adding 5 drops of water to perform extraction and quenching reaction, taking a suction filter funnel, filling diatomite, performing suction filtration, leaching with ethyl acetate for three times, combining organic phases, performing reduced pressure rotary removal on the solvent, and performing column chromatography separation (petroleum ether: ethyl acetate is 3:1) to obtain a product A-2, wherein the yield is as follows: 95 percent;1H NMR(500MHz,CDCl3):δ8.50(d,J＝6.0Hz,2H),7.34–7.21(m,5H),7.10(d,J＝7.5Hz,2H),7.07–6.98(m,4H),5.46(s,1H),1.30(s,9H)ppm；13C NMR(125MHz,CDCl3):δ153.2,150.0,149.9,142.6,139.1,129.5,129.1,128.7,127.0,125.7,124.8,56.0,34.6,31.5。
TABLE 1 catalytic yield of N-heterocyclic carbene precursors V-1 to V-6
Figure GDA0002694100800000201
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and although the invention has been described in detail with reference to the foregoing examples, it will be apparent to those skilled in the art that various changes in the form and details of the embodiments may be made and equivalents may be substituted for elements thereof. All modifications, equivalents and the like which come within the spirit and principle of the invention are intended to be included within the scope of the invention.

Claims (9)

1. A chiral N-heterocyclic carbene precursor compound with a benzimidazole skeleton is characterized in that the chiral N-heterocyclic carbene precursor compound is:
Figure FDA0002694100790000011
the structure of the compound is selected from:
Figure FDA0002694100790000012
2. a process for the preparation of a chiral azacyclo-carbene precursor compound as claimed in claim 1, comprising the steps of:
reacting chiral amine alcohol shown as a general formula (I) with tert-butyldimethylsilyl chloride in an aprotic solvent under the action of 4-dimethylaminopyridine and triethylamine, and collecting a compound shown as a formula (II) from a reaction product, wherein the reaction general formula is as follows:
Figure FDA0002694100790000013
(ii) in an aprotic solvent, heating TBS protective amine alcohol compounds shown as a general formula (II) and 1,2 dibromobenzene to react under the action of alkali and a catalyst, and then collecting compounds shown as a formula (III) from reaction products;
Figure FDA0002694100790000021
(iii) heating the optically pure 2-bromoaniline compound shown as the general formula (III) and the aromatic amine compound in an aprotic solvent under the action of alkali and a catalyst to react, and collecting the compound shown as the general formula (IV) from a reaction product, wherein the general formula is as follows:
Figure FDA0002694100790000022
(iv) dissolving chiral diamine shown as a general formula (IV) in trimethyl orthoformate or triethyl orthoformate in an aprotic solvent, reacting under the action of Lewis acid, and collecting a compound shown as a formula (V-A) from a reaction product; the reaction formula is as follows:
Figure FDA0002694100790000023
3. the preparation method of claim 2, wherein the molar ratio of the compound of formula (I) in step (i) to tert-butyldimethylsilyl chloride is 1:1.1, the reaction temperature is 20-30 ℃ and the reaction time is 3-5 hours.
4. The preparation method according to claim 3, wherein the reaction temperature of step (ii) is 80-120 ℃, the reaction time is 5-12 hours, and the molar ratio of the compound of formula (II), 1, 2-dibromobenzene, the catalyst and the base is 1.2:1: 0.1-0.01: 1-2; the alkali is sodium tert-butoxide or potassium tert-butoxide.
5. The preparation method according to claim 4, wherein the reaction temperature in the step (iii) is 80-120 ℃, the reaction time is 12-16 hours, and the molar ratio of the compound of formula (III), the aromatic amine compound, the catalyst and the base is 1:1.2: 0.1-0.05: 2-3; the alkali is sodium tert-butoxide or potassium tert-butoxide.
6. The preparation method of claim 5, wherein the reaction temperature of step (iv) is 80-120 ℃, the reaction time is 5-20 hours, and the molar ratio of the compound of formula (IV) to the Lewis acid is 1: 1-10.
7. Use of a chiral azacyclo-carbene precursor compound as claimed in claim 1, as a catalyst for the following reaction:
Figure FDA0002694100790000031
wherein Ar is phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl respectively; the reaction process of the reaction is as follows: in an aprotic solution, reacting palladium acetate with the N-heterocyclic carbene precursor compound, 4-benzylpyridine and a compound shown as a general formula (VI) under the action of alkali, and collecting a compound shown as a formula (VII) from a reaction product; the reaction temperature is 60-80 ℃, the reaction time is 12-18h, and the molar ratio of the 4-benzylpyridine, the compound (VI), the alkali, the N-heterocyclic carbene precursor compound and the palladium acetate is 1:1.2:1:3:0.075: 0.05.
8. The use of a chiral azacyclo-carbene precursor compound according to claim 7, wherein the aprotic solvent is any one of benzene, toluene, xylene, tetrahydrofuran, ethylene glycol dimethyl ether and 1, 4-dioxane, and the base used is any one of sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide.
9. Use of a chiral azacyclo-carbene precursor compound as claimed in claim 1, as a catalyst for the following reaction:
Figure FDA0002694100790000032
wherein Ar is1And Ar2Respectively phenyl, substituted phenyl, 1-naphthyl and 2-naphthyl; the reaction process of the reaction is as follows: sequentially adding a compound shown as a general formula (VIII), nickel metal and the N-heterocyclic carbene precursor compound into an aprotic solution, finally adding a compound shown as a general formula (IX), and collecting a compound shown as a formula (X) from a reaction product, wherein the reaction conditions are as follows: the reaction temperature is 24-50 ℃, the reaction time is 1-10h, and the molar ratio of the (VIII) compound, the (IX) nitrogen heterocyclic carbene precursor compound and the metallic nickel is 1:1.2:0.05: 0.05.
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