CN106242935A - A kind of synthetic method of triaryl substituted chiral compound - Google Patents

A kind of synthetic method of triaryl substituted chiral compound Download PDF

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CN106242935A
CN106242935A CN201610628195.3A CN201610628195A CN106242935A CN 106242935 A CN106242935 A CN 106242935A CN 201610628195 A CN201610628195 A CN 201610628195A CN 106242935 A CN106242935 A CN 106242935A
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formula
synthetic method
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methyl
toluenesulfonyl
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CN106242935B (en
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王益锋
章程
许丹倩
徐振元
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

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Abstract

The invention provides the synthetic method of the triaryl substituted chiral compound shown in a kind of formula (1); described synthetic method is: in water phase and an oil phase system; 2 (aryl (p-toluenesulfonyl) methyl) phenol shown in starting materials of formulae (2) and 2 naphthols shown in formula (3) acid binding agent, chiral catalyst effect under react; TLC tracking and monitoring is to reaction completely; reactant liquor is post-treated afterwards, obtains the triaryl substituted chiral compound shown in product formula (1)；The present invention with containing at least one tertiary amine, nitrogen side's acid function group chiral catalyst as catalyst system and catalyzing, water phase and an oil phase is reacted, post processing isolated product triaryl substituted chiral compound, can be applied to the field such as medicine, pesticide as the organic intermediate that a class is important；The inventive method solvent contamination is little, response speed is fast, yield is high, asymmetric selectivity is good, reaction substrate is in extensive range, reaction reagent is cheap and easy to get, has important using value；

Description

A kind of synthetic method of triaryl substituted chiral compound
(1) technical field
The present invention relates to the synthetic method of a kind of triaryl substituted chiral compound, especially a kind of in water phase and an oil phase system Under, raw material beta naphthal and 2-(aryl (p-toluenesulfonyl) methyl) phenol are through being catalyzed asymmetric Friedel-Crafts alkylation The method of synthesis triaryl substituted chiral compound.
(2) background technology
Asymmetry catalysis is one of field of enlivening the most of current chemical developer, is exploitation chiral drug, material and spice Powerful theoretical basis and academic foundation Deng chemicals.Enzyme and metal complex are the main and maximally effective catalyst of two classes, Wherein metal complex is the most universal chemical catalyst of research, and obtains the achievement caught people's attention, and some is answered For commercial production, the Nobel chemistry Prize of calendar year 2001 is granted by terms of metal organic catalysis asymmetric reaction making outstanding tribute William S.Knowles, the Ryoji Noyori offered and K.Barry Sharpless tri-people, it is sufficient to show asymmetry catalysis The significance of synthesis.By the development of last decade, asymmetric organocatalysis (Asymmetric organocatalysis), Through one of important branch developing into asymmetry catalysis, have become as metal organic catalysis and two kinds of traditional methods of enzyme catalysis Important supplement (A.Berkessel and H.Asymmetric Organocatalysis,Wiley VCH, Weinheim,2005.；P.I.Dalko,Enantioselective Organocatalysis,Wiley-VCH,Weinheim, 2007.)。
In recent years, water phase and an oil phase (Water-Oil phases) has become as reaction system important in organic synthesis, because of It can make organic compound efficiently and quickly separate in course of reaction with water-soluble ionic compounds or combine and be subject to wide General concern.Wherein, the asymmetric catalysis under water phase and an oil phase system especially has important research and practical value.Current For research, organic reaction based on water phase and an oil phase system, mainly quaternary ammonium salt, crown ether-like phase transfer catalysts are to organic end The facilitation that thing reacts with reaction of ionic type thing.For the asymmetric organocatalysis under two-phase system, be limited only at present from Sub-liquid.Therefore, development is more based on biphase asymmetry catalysis system, has important practical significance.
(3) summary of the invention
It is an object of the invention to provide the synthesis side of a kind of triaryl substituted chiral compound carried out in water phase and an oil phase Method.
For achieving the above object, the present invention adopts the following technical scheme that
A kind of synthetic method of the triaryl substituted chiral compound shown in formula (1), described synthetic method is:
In water phase and an oil phase system, 2-(aryl (p-toluenesulfonyl) methyl) phenol shown in starting materials of formulae (2) and formula (3) institute The beta naphthal shown acid binding agent, chiral catalyst effect under react, TLC tracking and monitoring to reaction completely, reacts afterwards Liquid is post-treated, obtains the triaryl substituted chiral compound shown in product formula (1).
Reaction equation is as follows:
In formula (2), Ts represents p-toluenesulfonyl；
In formula (1), (2) or (3),
R1、R2Each stand alone as H, methoxyl group or halogen；
Ar is furyl, thienyl, naphthyl, phenyl or the phenyl being substituted with one or more substituents, and described takes Methyl, methoxyl group, trifluoromethyl or halogen is each stood alone as base.
In synthetic method of the present invention:
Described reaction is generally carried out under room temperature (20～30 DEG C).
The material of beta naphthal shown in the phenol of 2-(aryl (p-toluenesulfonyl) methyl) shown in described formula (2) and formula (3) The ratio of amount be 0.2～5: 1, preferably 0.5～2: 1.
The amount of the material of 2-(aryl (p-toluenesulfonyl) methyl) phenol shown in described chiral catalyst and formula (2) it Ratio is 0.01～100: 100, preferably 0.1～20: 1.
Described acid binding agent with the ratio of the amount of the material of 2-shown in formula (2) (aryl (p-toluenesulfonyl) methyl) phenol is 0.5～20: 1, preferably 1～10: 1.
Described water phase and an oil phase system is mixed to form with volume ratio 1: 0.1～10 by water and organic solvent, and described is organic Solvent is selected from dichloromethane, 1,2-dichloroethanes, ether, toluene, ethyl acetate or isopropyl acetate.
Described acid binding agent is conventional inorganic base, such as: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, bicarbonate Potassium, sodium hydroxide, potassium hydroxide or disodium hydrogen phosphate.
The post-processing approach of described reactant liquor is: after reaction terminates, by reactant liquor separatory, take organic facies concentrating under reduced pressure laggard Row silica gel column chromatography separates, and is that eluant carries out gradient elution with the mixed liquor of petrol ether/ethyl acetate volume ratio 1～10: 1, Collect the eluent containing target compound, solvent be evaporated off and be dried, obtaining the triaryl substituted chiral chemical combination shown in product formula (1) Thing.
In the present invention, described chiral catalyst contains at least one in tertiary amine, nitrogen side's acid function group.
Concrete, described chiral catalyst is selected from one of compound shown in following formula (4)～(8):
In formula (4), (5), the carbon atom indicating * is chiral carbon atom.
In formula (4), (5), (6), (7) or (8),
R3、R6、R9、R12Each stand alone as C1～C20 alkyl, or the phenyl that is substituted with one or more substituents or benzyl Base, described substituent group each stands alone as trifluoromethyl, nitro or halogen；
R4、R5、R7、R8Each stand alone as C1～C10 alkyl；
R10、R13、R16Each stand alone as ethyl or vinyl；
R11、R14、R15Each stand alone as H, hydroxyl or methoxyl group.
More preferably, described chiral catalyst is selected from one of following:
The beneficial effects of the present invention is:
In synthetic method of the present invention, with containing at least one tertiary amine, the chiral catalyst of nitrogen side's acid function group For catalyst system and catalyzing, react in water phase and an oil phase, post processing isolated product triaryl substituted chiral compound, can conduct The important organic intermediate of one class is applied to the field such as medicine, pesticide.The synthetic method that the present invention provides, solvent contamination is little, anti- Answer that speed is fast, yield is high, asymmetric selectivity is good, reaction substrate is in extensive range, reaction reagent is cheap and easy to get, have important should By value.
(4) detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not limited in This.
Reaction embodiment 1:
Catalyst (6)-a (0.005mmol, 3mg), 6-methoxyl group-2-(phenyl it is sequentially added in dry glass tubing (p-toluenesulfonyl) methyl) phenol (0.1mmol, 36.8mg), betanaphthol (0.12mmol, 17.3mg), potassium carbonate (0.25mmol, 34.5mg), dichloromethane (1ml), water (1ml), feed intake complete, reactor is airtight, exist with magnetic stirring apparatus Stir 6h, TLC display 6-methoxyl group-2-(phenyl (p-toluenesulfonyl) methyl) phenol under room temperature to be exhausted, by reactant liquor Separatory, takes organic facies concentrating under reduced pressure, and upper silica gel column chromatography separates, and is 1～10: 1 with the volume ratio of petroleum ether and ethyl acetate Mixed liquor is that eluant carries out gradient elution, collects the eluent containing target compound, solvent is evaporated off and is dried, obtains white solid Body product 32.7mg (yield 92%),1H NMR(500MHz,CDCl3) δ 8.10 (d, J=8.6Hz, 1H), 7.82 (dd, J= 8.1,0.7Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.46 (ddd, J=8.4,6.8,1.3Hz, 1H), 7.41 7.22 (m, 6H), 7.12 (d, J=8.9Hz, 1H), 6.87 6.77 (m, 3H), 6.74 (s, 1H), 5.98 (s, 1H), 5.58 (s, 1H), 3.91 (s,3H).13C NMR(125MHz,CDCl3)δ153.07,146.51,143.45,141.29,133.51,129.54,129.39, 129.15,128.59,128.50,127.14,126.94,126.70,123.08,122.98,121.79,120.20,119.81, 119.68,109.60,55.98,42.39；By chiral HPLC, actual conditions is (IC-H, 1%iPrOH in hexane,flow rate 1.0ml/min):tR(leading)=56.6min, tR(secondary)=70.7min, 96%ee.
Take identical reactant, under identical operating procedure, respectively with below 0.005mmol catalyst alternative catalysts (6)-a reacts, and result is as shown in table 1 below:
Table 1
Numbering Catalyst Response time (h) Productivity (%)c Ee value (%)d
1 (4)-a 6 87 -83
2 (5)-a 6 68 -85
3 (6)-a 6 92 96
4 (6)-b 6 79 92
5 (6)-c 6 82 76
6 (6)-d 6 56 81
7 (6)-e 6 79 78
8 (7)-a 6 51 -72
9 (8)-a 6 59 66
In table 1, subscriptcRepresent separation yield,dRepresent the enantiomeric excess obtained by chiral high performance liquid chromatography analysis Value.
Take identical reactant, under identical operating procedure, substitute potassium carbonate with below 0.25mol inorganic base respectively and carry out Reaction, result is as shown in table 2 below:
Table 2
Numbering Inorganic base Response time (h) Productivity (%)c Ee value (%)d
1 K2CO3 6 92 96
2 CsCO3 6 79 91
3 KOH 6 92 16
4 Na2HPO4 6 45 91
5 NaHCO3 6 48 89
In table 2, subscriptcRepresent separation yield,dRepresent the enantiomeric excess obtained by chiral high performance liquid chromatography analysis Value.
Take identical reactant, under identical operating procedure, substitute dichloromethane with below 1ml organic solvent respectively and carry out Reaction, result is as shown in table 3 below:
Table 3
Numbering Solvent Response time (h) Productivity (%)c Ee value (%)d
1 CH2Cl2 6 92 96
2 Toluene 6 89 90
3 Ethyl acetate 6 68 36
4 ClCH2CH2Cl 6 81 92
In table 3, subscriptcRepresent separation yield,dRepresent the enantiomeric excess obtained by chiral high performance liquid chromatography analysis Value.
Reaction embodiment 2:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-4-bromo-2-(phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 44.7mg), other reaction conditions and operating procedure and reaction embodiment 1 phase With, obtain white solid product 36.5mg (yield 84%),1H NMR(500MHz,CDCl3) δ 8.01 (d, J=8.6Hz, 1H), 7.81 (d, J=7.9Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.49 7.42 (m, 1H), 7.34 (dt, J=12.9, 7.0Hz, 4H), 7.22 (d, J=7.5Hz, 2H), 7.10 (d, J=8.8Hz, 1H), 6.95 (d, J=2.1Hz, 1H), 6.91 (d, J=2.1Hz, 1H), 6.69 (s, 1H), 5.88 (s, 1H), 5.33 (s, 1H), 3.91 (s, 3H).13C NMR(125MHz,CDCl3) δ153.01,147.04,142.52,140.71,133.44,129.73,129.58,129.35,128.69,128.48, 128.27,127.43,126.87,124.60,123.25,122.73,119.94,119.26,113.14,112.07,56.30, 41.96；By chiral HPLC, actual conditions is (IC-H, 1%iPrOH in hexane, flow rate 1.0ml/ min):tR(leading)=46.6min, tR(secondary)=38.0min, 97%ee.
Reaction embodiment 3:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-4-iodo-2-(phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 49.5mg), other reaction conditions and operating procedure and reaction embodiment 1 phase With, obtain yellow solid product 44.6mg (yield 92%),1H NMR(500MHz,CDCl3) δ 8.01 (d, J=8.6Hz, 1H), 7.82 (dd, J=8.1,0.6Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.46 (ddd, J=8.4,6.9,1.3Hz, 1H), 7.40 7.30 (m, 4H), 7.21 (d, J=7.6Hz, 2H), 7.15 7.00 (m, 3H), 6.67 (s, 1H), 5.92 (s, 1H), 5.34(s,1H),3.90(s,3H).13C NMR(125MHz,CDCl3)δ152.98,147.12,143.34,140.69, 133.42,130.67,129.72,129.55,129.34,129.03,128.68,128.25,127.42,126.87,123.24, 122.72,119.94,119.22,118.74,81.58,56.26,41.79；By chiral HPLC, actual conditions is (IC- H, 2%iPrOH in hexane, flow rate 1.0ml/min): tR(leading)=21.2min, tR(secondary)=17.7min, 97% ee。
Reaction embodiment 4:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-2-(4-aminomethyl phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 38.2mg), other reaction conditions and operating procedure and reaction embodiment 1 phase With, obtain white solid product 35mg (yield 95%),1H NMR(500MHz,CDCl3) δ 8.06 (d, J=8.6Hz, 1H), 7.79 (d, J=7.9Hz, 1H), 7.74 (d, J=8.9Hz, 1H), 7.47 7.39 (m, 1H), 7.32 (dd, J=11.0, 4.0Hz, 1H), 7.15 (q, J=8.2Hz, 4H), 7.09 (d, J=8.9Hz, 1H), 6.79 (ddt, J=9.3,7.6,4.0Hz, 3H),6.67(s,1H),5.92(s,1H),5.57(s,1H),3.92(s,3H),2.35(s,3H).13C NMR(125MHz, CDCl3)δ153.17,146.49,143.39,138.11,136.93,133.53,129.99,129.51,129.34,128.57, 128.35,127.02,126.71,123.06,122.94,121.82,120.14,119.84,119.78,109.53,56.01, 41.99,21.04；By chiral HPLC, actual conditions is (IC-H, 1%iPrOH in hexane, flow rate 1.0ml/min):tR(leading)=33.8min, tR(secondary)=61.6min, 91%ee.
Reaction embodiment 5:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-2-(3-aminomethyl phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 38.2mg), other reaction conditions and operating procedure and reaction embodiment 1 phase With, obtain white solid product 31.7mg (yield 86%),1H NMR(500MHz,CDCl3) δ 8.10 (d, J=8.6Hz, 1H), 7.81 (d, J=7.2Hz, 1H), 7.76 (d, J=8.9Hz, 1H), 7.46 (ddd, J=8.4,6.9,1.3Hz, 1H), 7.39 7.31 (m, 1H), 7.28 7.24 (m, 1H), 7.17 7.08 (m, 3H), 7.05 (d, J=7.7Hz, 1H), 6.87 6.76 (m, 3H),6.71(s,1H),5.97(s,1H),5.62(s,1H),3.92(s,3H),2.32(s,3H).13C NMR(125MHz, CDCl3)δ153.16,146.47,143.37,141.28,138.99,133.53,129.49,129.33,129.24,129.09, 128.56,128.12,126.93,126.72,125.34,123.06,122.93,121.85,120.11,119.84,119.83, 109.53,55.96,42.26,21.49；By chiral HPLC, actual conditions be (IC-H, 1%iPrOH in hexane, flow rate 1.0ml/min):tR(leading)=32.5min, tR(secondary)=43.5min, 94%ee.
Reaction embodiment 6:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-2-(4-methoxybenzene Base (p-toluenesulfonyl) methyl) phenol (0.1mmol, 39.8mg), other reaction conditions and operating procedure and reaction embodiment 1 Identical, obtain yellow solid product 34mg (yield 88%),1H NMR(500MHz,CDCl3) δ 8.06 (d, J=8.6Hz, 1H), 7.79 (d, J=7.5Hz, 1H), 7.74 (d, J=8.9Hz, 1H), 7.44 (ddd, J=8.5,6.9,1.3Hz, 1H), 7.33 (dd, J=11.1,4.1Hz, 1H), 7.16 (d, J=8.6Hz, 2H), 7.10 (d, J=8.9Hz, 1H), 6.93 6.72 (m, 5H),6.65(s,1H),5.95(s,1H),5.63(s,1H),3.91(s,3H),3.80(s,3H).13C NMR(125MHz, CDCl3)δ158.70,153.15,146.51,143.39,133.49,132.87,129.58,129.52,129.33,128.57, 127.25,126.69,123.06,122.93,121.75,120.16,119.81,119.76,114.63,109.55,56.00, 55.21,41.57；By chiral HPLC, actual conditions is (IC-H, 3%iPrOH in hexane, flow rate 0.6ml/min):tR(leading)=58.9min, tR(secondary)=73.5min, 92%ee.
Reaction embodiment 7:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-2-(2-methoxybenzene Base (p-toluenesulfonyl) methyl) phenol (0.1mmol, 39.8mg), other reaction conditions and operating procedure and reaction embodiment 1 Identical, obtain white solid product 22.2mg (yield 58%),1H NMR(500MHz,CDCl3) δ 8.04 (d, J=8.6Hz, 1H), 7.82 7.72 (m, 1H), 7.69 (d, J=8.8Hz, 1H), 7.42 (ddd, J=8.4,6.8,1.3Hz, 1H), 7.35 7.18 (m, 3H), 7.09 (dd, J=7.6,1.5Hz, 1H), 7.04 (d, J=8.8Hz, 1H), 6.98 6.93 (m, 1H), 6.90 (td, J=7.6,0.8Hz, 1H), 6.86 6.76 (m, 3H), 6.64 (s, 1H), 5.81 (s, 1H), 5.73 (s, 1H), 3.89 (s, 3H),3.71(s,3H).13C NMR(125MHz,CDCl3)δ157.50,153.18,146.60,143.69,133.46, 129.51,129.38 128.84,128.57,128.48,127.44,126.48,123.07,122.86,121.01,120.05, 119.45,118.92,111.11,109.68,55.95,55.66,37.66；By chiral HPLC, actual conditions is (IC- H, 3%iPrOH in hexane, flow rate 0.6ml/min): tR(leading)=35.4min, tR(secondary)=43.5min, 91% ee。
Reaction embodiment 8:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-2-(3-methoxybenzene Base (p-toluenesulfonyl) methyl) phenol (0.1mmol, 39.8mg), other reaction conditions and operating procedure and reaction embodiment 1 Identical, obtain yellow solid product 33mg (yield 88%),1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.6Hz, 1H), 7.78 (dd, J=8.1,0.7Hz, 1H), 7.73 (d, J=8.9Hz, 1H), 7.43 (ddd, J=8.4,6.9,1.3Hz, 1H), 7.36 7.30 (m, 1H), 7.30 7.24 (m, 2H), 7.08 (d, J=8.8Hz, 1H), 6.87 6.71 (m, 5H), 6.66 (s, 1H),5.92(s,1H),5.59(s,1H),3.92(s,3H),3.73(s,3H).13C NMR(125MHz,CDCl3)δ160.32, 153.22,146.49,143.39,143.18,133.54,130.24,129.41,128.59,126.74,123.08,122.94, 121.82,120.68,120.19,119.86,119.60,114.51,112.46,109.62,56.01,55.15,42.36.；Logical Crossing chiral HPLC, actual conditions is (AD-H, 5%iPrOH in hexane, flow rate 1.0ml/min): tR(leading) =89.8min, tR(secondary)=97.0min, 91%ee.
Reaction embodiment 9:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-2-(3,4-methylene oxygen Base phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 41.2mg), other reaction conditions and operating procedure are real with reaction Execute example 1 identical, obtain white solid product 34.6mg (yield 87%),1H NMR(500MHz,CDCl3) δ 8.03 (d, J= 8.6Hz, 1H), 7.79 (dd, J=8.1,0.6Hz, 1H), 7.74 (d, J=8.9Hz, 1H), 7.44 (ddd, J=8.4,6.9, 1.3Hz, 1H), 7.37 7.30 (m, 1H), 7.10 (d, J=8.9Hz, 1H), 6.89 6.69 (m, 5H), 6.69 6.64 (m, 1H),6.61(s,1H),5.97–5.93(m,3H),5.71(s,1H),3.91(s,3H).13C NMR(125MHz,CDCl3)δ 153.14,148.57,146.84,146.49,143.33,135.09,133.42,129.48,129.42,128.59,126.91, 126.75,123.09,122.82,121.68,121.20,120.20,119.76,119.57,109.62,109.25,108.62, 101.17,55.99,42.01；By chiral HPLC, actual conditions is (IC-H, 2%iPrOH in hexane, flow rate 1.0ml/min):tR(leading)=73.3min, tR(secondary)=97.4min, 94%ee.
Reaction embodiment 10:
It is with reaction embodiment 1 difference: substrate fortified phenol used is that (4-fluorophenyl is (right for 6-methoxyl group-2- Tosyl) methyl) phenol (0.1mmol, 38.6mg), other reaction conditions and operating procedure are identical with reaction embodiment 1, Obtain white solid product 34.3mg (yield 92%),1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.6Hz, 1H), 7.81 (dd, J=8.0,0.8Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 7.44 (ddd, J=8.5,6.9,1.3Hz, 1H), 7.39 7.31 (m, 1H), 7.25 7.17 (m, 2H), 7.10 (d, J=8.9Hz, 1H), 7.07 6.99 (m, 2H), 6.88 6.79 (m, 2H), 6.76 (dd, J=7.0,2.3Hz, 1H), 6.66 (s, 1H), 5.98 (s, 1H), 5.58 (s, 1H), 3.91 (s, 3H).13C NMR(125MHz,CDCl3) δ 161.78 (d, J=245Hz), 152.90,146.57,143.49,136.90 (d, J= 3.75Hz), 133.37,130.13 (d, J=7.5Hz), 129.60,129.52,128.66,126.98,126.73,123.15, (122.94,121.58,120.32,119.73,119.40,115.85 d, J=22.5Hz), 109.74,56.00,41.80；Logical Crossing chiral HPLC, actual conditions is (AS-H, 10%iPrOH in hexane, flow rate 1.0ml/min): tR (leading)=42.4min, tR(secondary)=31.3min, 95%ee.
Reaction embodiment 11:
It is with reaction embodiment 1 difference: substrate fortified phenol used is that (4-chlorphenyl is (right for 6-methoxyl group-2- Tosyl) methyl) phenol (0.1mmol, 40.25mg), other reaction conditions and operating procedure and reaction embodiment 1 phase With, obtain white solid product 30mg (yield 77%),1H NMR(500MHz,CDCl3) δ 8.03 (d, J=8.6Hz, 1H), (7.81 d, J=8.0Hz, 1H), 7.75 (d, J=8.8Hz, 1H), 7.44 (ddd, J=8.5,6.9,1.2Hz, 1H), 7.38 7.28 (m, 3H), 7.18 (d, J=8.4Hz, 2H), 7.10 (d, J=8.8Hz, 1H), 6.89 6.80 (m, 2H), 6.77 (dd, J =7.0,2.3Hz, 1H), 6.65 (s, 1H), 6.00 (s, 1H), 5.61 (s, 1H), 3.91 (s, 3H).13C NMR(125MHz, CDCl3)δ152.83,146.57,143.51,139.93,133.34,132.71,129.93,129.61,129.56,129.04, 128.67,126.73,126.69,123.16,122.97,121.59,120.33,119.68,119.20,109.77,55.99, 41.97；By chiral HPLC, actual conditions is (AS-H, 10%iPrOH in hexane, flow rate 1.0ml/ min):tR(leading)=46.2min, tR(secondary)=34.5min, 95%ee.
Reaction embodiment 12:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-2-(4-trifluoromethyl Phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 43.6mg), other reaction conditions and operating procedure are implemented with reaction Example 1 is identical, obtains white solid product 33mg (yield 78%),1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.6Hz, 1H), 7.83 (d, J=7.8Hz, 1H), 7.78 (d, J=8.9Hz, 1H), 7.59 (d, J=8.3Hz, 2H), 7.48 7.43 (m, 1H), 7.36 (dd, J=11.2,4.2Hz, 3H), 7.12 (d, J=8.8Hz, 1H), 6.86 (dd, J=9.1,5.5Hz, 2H), 6.80 (dd, J=6.5,2.9Hz, 1H), 6.74 (s, 1H), 6.05 (s, 1H), 5.62 (s, 1H), 3.91 (s, 3H).13C NMR (125MHz,CDCl3)δ152.71,146.63,145.88,143.58,133.34,129.70,128.90,128.75, (126.79,126.43,125.66 q, J=3.75Hz), 125.26,123.24,123.02,121.65,120.41,119.63, 119.06,109.88,55.99,42.48；By chiral HPLC, actual conditions is (AD-H, 3%iPrOH in hexane,flow rate 0.6ml/min):tR(leading)=150.9min, tR(secondary)=167.9min, 92%ee.
Reaction embodiment 13:
It is with reaction embodiment 1 difference: substrate fortified phenol used is 6-methoxyl group-2-(3,5-double trifluoros Aminomethyl phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 50.4mg), other reaction conditions and operating procedure and reaction Embodiment 1 is identical, obtains white solid product 43mg (yield 87%),1H NMR(500MHz,CDCl3) δ 8.01 (d, J= 8.6Hz, 1H), 7.83 (d, J=7.7Hz, 1H), 7.80 7.71 (m, 2H), 7.65 (s, 2H), 7.46 (ddd, J=8.4,6.9, 1.2Hz, 1H), 7.36 (dd, J=11.1,4.0Hz, 1H), 7.08 (d, J=8.8Hz, 1H), 6.90 6.83 (m, 2H), 6.78 (dd, J=6.8,2.5Hz, 1H), 6.73 (s, 1H), 6.03 (s, 1H), 5.56 (s, 1H), 3.92 (s, 3H).13C NMR (125MHz,CDCl3) δ 152.31,146.66,145.05,143.50,133.25,131.44 (q, J=33.75Hz), 130.07,129.78,128.91,128.65,126.99,125.72,124.49,123.41,122.91,122.32,121.76, (120.52,120.36 q, J=3.75Hz), 119.49,118.72,110.05,56.06,42.41；By chiral HPLC, Actual conditions is (IC-H, 1%iPrOH in hexane, flow rate 0.5ml/min): tR(leading)=23.2min, tR(secondary) =18.0min, 94%ee.
Reaction embodiment 14:
It is with reaction embodiment 1 difference: substrate fortified phenol used is that (1-naphthyl is (to first for 6-methoxyl group-2- Benzenesulfonyl) methyl) phenol (0.1mmol, 41.8mg), other reaction conditions and operating procedure are identical with reaction embodiment 1, To white solid product 26mg (yield 64%),1H NMR(500MHz,CDCl3) δ 8.08 (s, 1H), 7.90 (d, J=8.1Hz, 1H), 7.83 (dd, J=14.5,7.8Hz, 3H), 7.72 (d, J=8.9Hz, 1H), 7.47 (dd, J=14.0,6.3Hz, 2H), 7.42 7.32 (m, 3H), 7.27 7.21 (m, 2H), 6.98 (d, J=8.8Hz, 1H), 6.85 (dd, J=8.1,1.3Hz, 1H), (6.79 t, J=7.9Hz, 1H), 6.69 (s, 1H), 5.90 (s, 1H), 5.72 (s, 1H), 3.92 (s, 3H).13C NMR (125MHz,CDCl3)δ154.06,146.67,134.27,133.12,131.92,129.64,129.38,128.87, 128.73,127.04,126.60,126.09,125.56,124.10,123.14,122.63,120.24,119.60,118.60, 109.72,55.97,40.34；By chiral HPLC, actual conditions is (IC-H, 2%iPrOH in hexane, flow rate 1.0ml/min):tR(leading)=41.6min, tR(secondary)=20.7min, 88%ee.
Reaction embodiment 15:
It is with reaction embodiment 1 difference: substrate fortified phenol used is that (2-furan is (to first for 6-methoxyl group-2- Benzenesulfonyl) methyl) phenol (0.1mmol, 35.8mg), other reaction conditions and operating procedure are identical with reaction embodiment 1, To yellow solid product 33.7mg (yield 97%),1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.7Hz, 1H), 7.79 (d, J=7.8Hz, 1H), 7.75 (d, J=8.9Hz, 1H), 7.54 7.40 (m, 2H), 7.34 (t, J=7.2Hz, 1H), 7.14 (d, J=8.9Hz, 1H), 6.90 6.79 (m, 3H), 6.62 (s, 1H), 6.37 (dd, J=3.1,1.9Hz, 1H), 6.28 (s, 1H), 6.06 (d, J=3.2Hz, 1H), 6.02 (s, 1H), 3.89 (s, 3H).13C NMR(125MHz,CDCl3)δ154.95, 153.28,146.54,143.18,142.96,133.09,129.56,129.48,128.63,126.72,125.49,123.09, 122.61,121.14,120.21,119.62,117.09,110.35,109.80,108.59,55.98,37.21；Pass through chirality HPLC analyzes, and actual conditions is (IC-H, 10%iPrOH in hexane, flow rate 1.0ml/min): tR(leading)= 22.3min,tR(secondary)=46.2min, 91%ee.
Reaction embodiment 16:
It is with reaction embodiment 1 difference: substrate fortified phenol used is that (2-thiophene is (to first for 6-methoxyl group-2- Benzenesulfonyl) methyl) phenol (0.1mmol, 37.4mg), other reaction conditions and operating procedure are identical with reaction embodiment 1, To white solid product 35mg (yield 97%),1H NMR(500MHz,CDCl3) δ 8.08 (d, J=8.6Hz, 1H), 7.78 (dd, J=21.2,8.3Hz, 2H), 7.46 (ddd, J=8.4,6.9,1.2Hz, 1H), 7.39 7.26 (m, 2H), 7.14 (d, J= 8.9Hz, 1H), 6.96 (ddd, J=14.5,5.5,3.4Hz, 2H), 6.86 (d, J=6.8Hz, 1H), 6.84 (s, 1H), 6.83 (t, J=5.5Hz, 2H), 6.02 (s, 2H), 3.91 (s, 3H).13C NMR(125MHz,CDCl3)δ153.33,146.47, (145.83,143.07,132.95,129.66,129.43,128.62,127.19,126.84 d, J=11.8Hz), 126.54, 126.15,123.16,122.66,121.12,120.20,119.90,119.31,109.82,56.00,38.00；Pass through chirality HPLC analyzes, and actual conditions is (IC-H, 2%iPrOH in hexane, flow rate 1.0ml/min): tR(leading)= 41.4min,tR(secondary)=62.8min, 65%ee.
Reaction embodiment 17:
With reaction embodiment 1 difference be: substrate substituted naphthol used be the bromo-beta naphthal of 3-(0.12mmol, 36.8mg), other reaction conditions and operating procedure are identical with reaction embodiment 1, obtain white solid product 40.3mg (yield 93%),1H NMR(500MHz,CDCl3) δ 8.08 8.01 (m, 2H), 7.71 (d, J=7.8Hz, 1H), 7.40 (t, J= 7.7Hz, 1H), 7.33 (dd, J=14.8,7.6Hz, 3H), 7.29 7.26 (m, 1H), 7.21 (d, J=7.3Hz, 2H), 6.85 6.76(m,4H),6.01(s,1H),5.91(s,1H),3.91(s,3H).13C NMR(125MHz,CDCl3)δ148.57, 146.40,143.54,141.36,132.91,131.52,129.94,128.76,128.51,127.69,126.96,126.84, 126.73,124.00,123.84,122.20,122.14,119.87,113.68,109.46,56.00,42.86；Pass through chirality HPLC analyzes, and actual conditions is (IC-H, 2%iPrOH in hexane, flow rate 1.0ml/min): tR(leading)= 19.2min,tR(secondary)=54.9min, 89%ee.
Reaction embodiment 18:
With reaction embodiment 1 difference be: substrate substituted naphthol used be the bromo-beta naphthal of 6-(0.12mmol, 36.8mg), other reaction conditions and operating procedure are identical with reaction embodiment 1, obtain white solid product 36.8mg (yield 85%),1H NMR(500MHz,CDCl3) δ 7.95 7.90 (m, 2H), 7.64 (d, J=8.9Hz, 1H), 7.48 (dd, J=9.1, 2.2Hz, 1H), 7.38 7.29 (m, 3H), 7.23 (d, J=7.4Hz, 2H), 7.10 (d, J=8.8Hz, 1H), 6.86 6.80 (m, 2H), 6.72 (dd, J=7.5,1.7Hz, 1H), 6.63 (s, 1H), 5.94 (s, 1H), 5.59 (s, 1H), 3.92 (s, 3H) .13C NMR(125MHz,CDCl3)δ153.35,146.55,143.41,140.83,132.07,130.81,130.41, 129.81,129.23,128.49,128.45,127.30,126.69,124.98,121.61,121.01,120.31,119.95, 116.84,109.72,56.02,42.44；By chiral HPLC, actual conditions is (IC-H, 2%iPrOH in hexane,flow rate 1.0ml/min):tR(leading)=27.3min, tR(secondary)=32.8min, 94%ee.
Reaction embodiment 19:
With reaction embodiment 1 difference be: substrate substituted naphthol used be the bromo-beta naphthal of 7-(0.12mmol, 36.8mg), other reaction conditions and operating procedure are identical with reaction embodiment 1, obtain white solid product 35.6mg (yield 85%),1H NMR(500MHz,CDCl3) δ 8.26 (d, J=1.1Hz, 1H), 7.67 (dd, J=23.7,8.7Hz, 2H), 7.41 (dd, J=8.6,1.8Hz, 1H), 7.39 7.33 (m, 2H), 7.32 (d, J=7.1Hz, 1H), 7.24 (d, J=7.5Hz, 2H), 7.10 (d, J=8.9Hz, 1H), 6.89 6.80 (m, 2H), 6.75 (dd, J=7.3,2.0Hz, 1H), 6.59 (s, 1H), 5.98 (s,1H),5.65(s,1H),3.92(s,3H).13C NMR(125MHz,CDCl3)δ153.82,146.61,143.49, 140.68,134.85,130.15,129.27,129.22,128.45,127.94,127.31,126.46,125.44,121.55, 121.36,120.27,119.17,109.76,56.01,42.33；By chiral HPLC, actual conditions be (IC-H, 2% iPrOH in hexane,flow rate 1.0ml/min):tR(leading)=20.8min, tR(secondary)=25.5min, 93%ee.

Claims (8)

1. the synthetic method of the triaryl substituted chiral compound shown in a formula (1), it is characterised in that described synthetic method For:
In water phase and an oil phase system, shown in 2-(aryl (p-toluenesulfonyl) methyl) phenol shown in starting materials of formulae (2) and formula (3) Beta naphthal acid binding agent, chiral catalyst effect under react, TLC tracking and monitoring to reaction completely, reactant liquor warp afterwards Post processing, obtains the triaryl substituted chiral compound shown in product formula (1)；
Reaction equation is as follows:
In formula (2), Ts represents p-toluenesulfonyl；
In formula (1), (2) or (3),
R1、R2Each stand alone as H, methoxyl group or halogen；
Ar is furyl, thienyl, naphthyl, phenyl or the phenyl being substituted with one or more substituents, described substituent group Each stand alone as methyl, methoxyl group, trifluoromethyl or halogen；
In described synthetic method:
The amount of the material of beta naphthal shown in the phenol of 2-(aryl (p-toluenesulfonyl) methyl) shown in described formula (2) and formula (3) Ratio be 0.2～5:1；
Described chiral catalyst with the ratio of the amount of the material of 2-shown in formula (2) (aryl (p-toluenesulfonyl) methyl) phenol is 0.01～100:100；
Described acid binding agent is 0.5 with the ratio of the amount of the material of 2-(aryl (p-toluenesulfonyl) methyl) phenol shown in formula (2) ～20:1；
Described water phase and an oil phase system is mixed to form with volume ratio 1:0.1～10 with organic solvent by water；Described organic solvent Selected from dichloromethane, 1,2-dichloroethanes, ether, toluene, ethyl acetate or isopropyl acetate；
Described acid binding agent is inorganic base；
Described chiral catalyst is selected from one of compound shown in following formula (4)～(8):
In formula (4), (5), the carbon atom indicating * is chiral carbon atom；
In formula (4), (5), (6), (7) or (8),
R3、R6、R9、R12Each stand alone as C1～C20 alkyl, or the phenyl that is substituted with one or more substituents or benzyl, institute The substituent group stated each stands alone as trifluoromethyl, nitro or halogen；
R4、R5、R7、R8Each stand alone as C1～C10 alkyl；
R10、R13、R16Each stand alone as ethyl or vinyl；
R11、R14、R15Each stand alone as H, hydroxyl or methoxyl group.
2. the synthetic method of the triaryl substituted chiral compound shown in formula (1) as claimed in claim 1, it is characterised in that Described reaction is carried out at normal temperatures.
3. the synthetic method of the triaryl substituted chiral compound shown in formula (1) as claimed in claim 1, it is characterised in that The ratio of the amount of the material of beta naphthal shown in the phenol of 2-(aryl (p-toluenesulfonyl) methyl) shown in described formula (2) and formula (3) It is 0.5～2:1.
4. the synthetic method of the triaryl substituted chiral compound shown in formula (1) as claimed in claim 1, it is characterised in that Described chiral catalyst is 0.1 with the ratio of the amount of the material of 2-(aryl (p-toluenesulfonyl) methyl) phenol shown in formula (2) ～20:1.
5. the synthetic method of the triaryl substituted chiral compound shown in formula (1) as claimed in claim 1, it is characterised in that Described acid binding agent is 1～10:1 with the ratio of the amount of the material of 2-(aryl (p-toluenesulfonyl) methyl) phenol shown in formula (2).
6. the synthetic method of the triaryl substituted chiral compound shown in formula (1) as claimed in claim 1, it is characterised in that Described acid binding agent is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or phosphoric acid Disodium hydrogen.
7. the synthetic method of the triaryl substituted chiral compound shown in formula (1) as claimed in claim 1, it is characterised in that Described chiral catalyst is selected from one of following:
8. the synthetic method of the triaryl substituted chiral compound shown in formula (1) as claimed in claim 1, it is characterised in that The post-processing approach of described reactant liquor is: after reaction terminates, by reactant liquor separatory, carry out silicagel column after taking organic facies concentrating under reduced pressure Chromatography, carries out gradient elution with the mixed liquor of petrol ether/ethyl acetate volume ratio 1～10:1 for eluant, collects containing mesh The eluent of mark compound, is evaporated off solvent and is dried, obtaining the triaryl substituted chiral compound shown in product formula (1).
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109896999A (en) * 2019-01-31 2019-06-18 浙江工业大学 Containing adjacent tertiary carbon-quaternary carbon chiral centre pyrazolone compound synthetic method shown in a kind of formula (3)
CN110950793A (en) * 2019-12-31 2020-04-03 浙江工业大学 Preparation method of chiral diaryl indole methane compound
CN113004109A (en) * 2021-02-09 2021-06-22 浙江工业大学 Asymmetric synthesis method of chiral alpha-hydroxy-beta-ketonic acid ester compound

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CN102557955A (en) * 2012-01-18 2012-07-11 浙江工业大学 Green synthetic method of nitro-substitution chiral compound

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Publication number Priority date Publication date Assignee Title
CN102557955A (en) * 2012-01-18 2012-07-11 浙江工业大学 Green synthetic method of nitro-substitution chiral compound

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109896999A (en) * 2019-01-31 2019-06-18 浙江工业大学 Containing adjacent tertiary carbon-quaternary carbon chiral centre pyrazolone compound synthetic method shown in a kind of formula (3)
CN109896999B (en) * 2019-01-31 2020-10-23 浙江工业大学 Synthesis method of pyrazolone compound containing adjacent tertiary carbon-quaternary carbon chiral center
CN110950793A (en) * 2019-12-31 2020-04-03 浙江工业大学 Preparation method of chiral diaryl indole methane compound
CN110950793B (en) * 2019-12-31 2021-07-27 浙江工业大学 Preparation method of chiral diaryl indole methane compound
CN113004109A (en) * 2021-02-09 2021-06-22 浙江工业大学 Asymmetric synthesis method of chiral alpha-hydroxy-beta-ketonic acid ester compound

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