CN108440384A - The preparation method of the trifluoromethyl hydroxylation derivative of isoindolone - Google Patents
The preparation method of the trifluoromethyl hydroxylation derivative of isoindolone Download PDFInfo
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- CN108440384A CN108440384A CN201810316154.XA CN201810316154A CN108440384A CN 108440384 A CN108440384 A CN 108440384A CN 201810316154 A CN201810316154 A CN 201810316154A CN 108440384 A CN108440384 A CN 108440384A
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- trifluoromethyl
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- isoindolone
- indoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Abstract
The present invention relates to a kind of preparation methods of the trifluoromethyl hydroxylation derivative of isoindolone, include the following steps:By 3 benzylidene iso-indoles of substitution N phenyl, 1 ketone derivatives and Sodium trifluoromethanesulfinate of formula (1) under the catalytic action of mantoquita and the oxidation of oxidant, it is reacted at 10~80 DEG C in a solvent, the trifluoromethyl hydroxylation derivative of the isoindolone of formula (2) is obtained, the route of the above reaction is as follows:Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R12Independently selected from hydrogen, alkyl, alkoxy or halogen.The method of the present invention can high yield obtain the trifluoromethyl hydroxylation derivative of a variety of 3 benzylidene iso-indoles of N phenyl, 1 ketone；Reaction condition is mild, operate and last handling process is simple, is suitable for large-scale production.
Description
Technical field
The present invention relates to organic synthesis field more particularly to a kind of systems of the trifluoromethyl hydroxylation derivative of isoindolone
Preparation Method.
Background technology
Nitrogen-containing heterocycle compound is a kind of important, the organic compound with bioactivity and medical value.Especially
3- Hydroxy-isoindole -1- ketone derivatives, are important the structural unit of medicine intermediate and natural products.Has document report
N- phenyl -3- benzylidene iso-indoles -1- ketone derivatives have the function of anesthesia and calmness.On the other hand, trifluoromethylation has been
Through becoming the research emphasis of organic synthesis field, the organic matter containing trifluoromethyl is in fields such as medicine, pesticide, material science
Widely paid attention to, this is because trifluoromethyl has peculiar metabolic stability, electronegativity, lipophile and biological utilisation
Degree.It is contemplated that the trifluoromethyl hydroxylation derivative of N- phenyl -3- benzylidene iso-indoles -1- ketone may will further improve
The physiological activity of Isoindolone compounds.Therefore, exploitation synthesizes a kind of N- phenyl -3- benzylidenes iso-indoles -1- ketone derivatives
Trifluoromethyl hydroxylation derivative synthetic method, synthesize a series of trifluoromethyl hydroxylation derivatives and be very important.
So far, the trifluoromethyl hydroxylating of alkene mainly has following three kinds of methods.One is use Togin reagents as
Trifluoromethyl source；One is use Umemoto reagents as trifluoromethyl source；Still an alternative is that using Sodium trifluoromethanesulfinate
As trifluoromethyl source.
With the trifluoromethyl hydroxylating of alkene synthesis 1- phenyl -2- trifluoromethyls ethyl alcohol most early in
It is had been disclosed in Angew.Chem.Int.Ed.2012,51,8221-8224 articles.Under the action of DEDMPONa, Togin ' s
Reagent generates trifluoromethyl free radical, is then reacted with styrene, then has synthesized 1- phenyl -2- fluoroforms by zinc powder reduction
Base alcohol derivative.
The hydroxylated side of alkene trifluoromethyl is carried out using Togin reagents, Umemoto reagents and Sodium trifluoromethanesulfinate
Method is respectively in J.Am.Chem.Soc.2012,134,12462-12465, Angew.Chem.Int.Ed.2012,51,9567-
9571, on the magazines such as Angew.Chem.Int.Ed.2013,52,14177-14180, Synlett.2014,25,1307-1311
It is open.
The trifluoromethyl hydroxylating of the compound of acrylamide is urged due to its special structure, at present only an example light
Change reaction to disclose in Org.Lett.2014,16,1240-1243.But use expensive ruthenium catalyst and Togin reagents, Er Qiexu
To use special mantoquita and ligand.
Currently, the trifluoromethyl hydroxylating about acrylamide is there is not yet document report, N- phenyl -3- benzylidenes are different
Indoles -1- ketone is a kind of heterocyclic compound with acrylamide structure, and existing trifluoromethyl hydroxylacion method is not suitable for N- benzene
The synthesis of base -3- benzylidene iso-indoles -1- ketone trifluoromethyl hydroxylation derivatives.
Nowadays the relevant report that also there have been no the trifluoromethyl hydroxylating of the double bond of iso-indole ketone, in existing profit
With more cheap CF3SO2It is poor that there is reaction selectivities in reports of the Na as trifluoromethyl source, and reaction condition is complicated, and step is numerous
The shortcomings of trivial.In the synthetic technology of the above existing trifluoromethyl hydroxylation derivative, there are operating technologies to require high, reaction scale
Cannot be too big the deficiencies of.Therefore, find one kind meet Green Chemistry require, reaction condition is mild, universality is good, is suitable for scale
The method of metaplasia production is extremely important.
Invention content
In order to solve the above technical problems, the object of the present invention is to provide a kind of trifluoromethyl hydroxylating of isoindolone derivatives
The preparation method of object, method of the invention can high yield obtain the three of a variety of N- phenyl -3- benzylidenes iso-indoles -1- ketone
Methyl fluoride hydroxylation derivative, raw material sources are simple, reaction condition is mild, universality is good.
The present invention provides a kind of preparation methods of the trifluoromethyl hydroxylation derivative of isoindolone, including following step
Suddenly:
By the substitution N- phenyl -3- benzylidenes iso-indoles -1- ketone derivatives and Sodium trifluoromethanesulfinate of formula (1)
(CF3SO2Na) under the oxidation of the catalytic action of mantoquita and oxidant, reaction half is small at 10~80 DEG C in a solvent
When, the trifluoromethyl hydroxylation derivative of the isoindolone of formula (2) is obtained, the route of the above reaction is as follows:
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R12Independently selected from hydrogen, alkyl, alkoxy or halogen
Element.
Further, R1、R2、R3、R4、R5、R6、R7、R8、R9、R11、R12For hydrogen, R10For hydrogen, alkyl, alkoxy or halogen；
Or R1、R2、R3、R4、R5、R6、R7、R8、R10、R11、R12For hydrogen, R9For hydrogen, alkyl or halogen；
Or R1、R2、R3、R4、R5、R6、R7、R9、R10、R11、R12For hydrogen, R8For hydrogen, alkyl or halogen；
Or R1、R2、R4、R6、R7、R8、R9、R10、R11、R12For hydrogen, R5For hydrogen, alkyl or halogen；
Or R1、R2、R3、R5、R7、R8、R9、R10、R11、R12For hydrogen, R4For hydrogen, alkyl, alkoxy or halogen；
Or R1、R2、R4、R5、R7、R8、R9、R10、R11、R12For hydrogen, R3For hydrogen, alkyl or halogen；
Or R3、R4、R5、R6、R7、R8、R9、R10、R11、R12For hydrogen, R1And R2Respectively hydrogen or alkyl.
Further, alkyl is methyl, ethyl or propyl.Preferably, alkyl is methyl.
Further, alkoxy is methoxy or ethoxy.Preferably, alkoxy is methoxyl group.
Further, halogen is fluorine, chlorine or bromine.
Further, mantoquita is cuprous bromide, cuprous iodide, copper oxide, stannous chloride, copper acetate or copper bromide.It is preferred that
Ground, mantoquita are cuprous bromide.
Further, oxidant is potassium peroxydisulfate.
Further, solvent N, N '-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) and water, acetone and water, second
One kind in nitrile and water, tetrahydrofuran (THF) and water.Preferably, solvent is acetonitrile and water.
Further, the volume ratio of acetonitrile and water is 1-7:1-2.Preferably, the volume ratio of acetonitrile and water is 2:1.
Further, substitution N- phenyl -3- benzylidene iso-indoles -1- ketone derivatives, Sodium trifluoromethanesulfinate, mantoquita
Molar ratio with oxidant is 1:1-3:0.2-1.0:3.0-5.0.Preferably, substitution N- phenyl -3- benzylidene iso-indoles -1-
Ketone derivatives, Sodium trifluoromethanesulfinate, mantoquita and oxidant molar ratio be 1:3:0.2:4.
Preferably, reaction temperature is 20-25 DEG C.It is highly preferred that reaction temperature is 25 DEG C.
Further, further include the steps that column chromatography for separation purification processes are carried out to product after reaction.
According to the above aspect of the present invention, the present invention has at least the following advantages:
1. the present invention is starting material using substitution N- phenyl -3- benzylidene iso-indoles -1- ketone derivatives, raw material is easy to get,
There are many type；Copper salt catalyst, Sodium trifluoromethanesulfinate and oxidant are used for N- phenyl -3- benzene methylenes by the present invention for the first time
The trifluoromethyl hydroxylating of base iso-indoles -1- ketone derivatives, due to having selected suitable copper salt catalyst, oxidant and molten
Agent can make this kind of radical reaction efficiently carry out trifluoromethyl hydroxylating, and the present invention also tests reaction temperature,
It was found that especially at room temperature, this radical reaction is easy to carry out, temperature increases or declines to this kind of radical reaction not
Profit.
2. reaction condition of the present invention is mild, operation and last handling process are simple, yield is higher, is suitable for scale life
Production.
Above description is only the general introduction of technical solution of the present invention, in order to better understand the technical means of the present invention,
And can be implemented in accordance with the contents of the specification, below with presently preferred embodiments of the present invention and after coordinating detailed description such as.
Specific implementation mode
With reference to embodiment, the embodiment of the present invention is furthur described in detail.Following embodiment is used for
Illustrate the present invention, but is not limited to the scope of the present invention.
In following embodiment, volume ratio that the ratio of solvent refers both to.
Embodiment one:The synthesis (2a) of 3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone
(1) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), stannous chloride (0.020g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
60%.
(2) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous iodide (0.038g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
28%.
(3) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), copper oxide (0.016g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile solutions
(acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction terminates
Crude on silica gel column chromatography for separation (petroleum ether afterwards:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
30%.
(4) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), copper acetate (0.040g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile solutions
(acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction terminates
Crude on silica gel column chromatography for separation (petroleum ether afterwards:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
55%.
(5) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), copper bromide (0.045g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile solutions
(acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction terminates
Crude on silica gel column chromatography for separation (petroleum ether afterwards:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
50%.
(6) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
72%.
(7) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=7:2) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
35%.
(8) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=1:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
28%.
(9) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), it is water-soluble that potassium peroxydisulfate (1.081g, 4mmol) is dissolved in 9mL DMF
Liquid (DMF:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction terminates
Crude on silica gel column chromatography for separation (petroleum ether afterwards:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
10%.
(10) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL DMSO water
Solution (DMSO:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction
After crude on silica gel column chromatography for separation (petroleum ether:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detach yield
It is 6%.
(11) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), it is water-soluble that potassium peroxydisulfate (1.081g, 4mmol) is dissolved in 9mL acetone
Liquid (acetone:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
55%.
(12) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), it is water-soluble that potassium peroxydisulfate (1.081g, 4mmol) is dissolved in 9mL THF
Liquid (THF:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction terminates
Crude on silica gel column chromatography for separation (petroleum ether afterwards:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
37%.
(13) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=2:1) in.Mixture is stirred to react at 80 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
60%.
(14) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=2:1) in.Mixture is stirred to react at 10 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
56%.
(15) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (0.811g, 3mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
46%.
(16) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.351g, 5mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
70%.
(17) 3- benzylidene -2- phenyl iso-indoles -1- ketone 1a (0.297g, 1mmol), Sodium trifluoromethanesulfinate are weighed
(0.312g, 2mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL aqueous acetonitriles
Liquid (acetonitrile:Water=2:1) in.Mixture is stirred to react at 10 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction knot
Crude on silica gel column chromatography for separation (petroleum ether after beam:Ethyl acetate=1:6) compound 2a is obtained after purifying.Detaching yield is
57%.
2a:Faint yellow solid, 70%yield；1H NMR(400MHz,DMSO-d6)δ:7.98 (s, 1H), 7.91 (d, J=
7.7Hz, 1H), 7.87-7.81 (m, 1H), 7.68 (dd, J=8.8,6.9Hz, 2H), 7.40 (t, J=7.0Hz, 4H), 7.32
(d, J=3.3Hz, 1H), 7.21 (t, J=7.4Hz, 1H), 7.05 (t, J=7.7Hz, 2H), 6.41 (d, J=7.5Hz, 2H),
4.12 (q, J=10.5Hz, 1H)；13C NMR(101MHz,DMSO-d6)δ:165.00(s),145.40(s),136.80(s),
135.92(s),135.80(s),134.79(s),134.70(s),133.80(s),132.02(s),131.75(s),130.65
(s),130.25(s),130.17(s),129.53(s),128.60(s),128.14(s),128.02(s),127.78(s),
127.67(s),127.07(s),126.86(s),126.51(s),125.70(s),122.05(s),95.88(s),51.33
(s),50.64(s)；19F NMR(376MHz,DMSO-d6)δ:-59.31(s).HRMS(ESI-TOF)calcd for
C22H16F3NO2Na+(M+Na)+:406.1031,found:406.1029。
Embodiment two:The conjunction of 3- hydroxyls -2- (4- fluorophenyls) -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone
At the synthesis of (2b)
Weigh 3- benzylidenes -2- (4- fluorophenyls) iso-indoles -1- ketone 1b (0.316g, 1mmol), trifluoromethanesulpacidc acidc
Sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile water
Solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction
After crude on silica gel column chromatography for separation (petroleum ether:Ethyl acetate=1:6) compound 2b is obtained after purifying.Detach yield
It is 67%.
2b:Faint yellow solid, 67%yield；1H NMR(400MHz,DMSO-d6)δ:8.00 (s, 1H), 7.93 (d, J=
7.5Hz, 1H), 7.87-7.83 (m, 1H), 7.72 (d, J=6.8Hz, 1H), 7.68 (d, J=7.2Hz, 1H), 7.37 (dd, J=
8.6,5.1Hz, 2H), 7.29 (d, J=9.8Hz, 1H), 7.26-7.22 (m, 2H), 7.07 (t, J=7.6Hz, 2H), 6.47 (d,
J=7.4Hz, 2H), 4.15 (q, J=10.4Hz, 1H)；13C NMR(101MHz,DMSO-d6)δ:164.95(s),160.31(d,
), J=244.0Hz 144.10 (s), 132.86 (s), 131.48 (s), 131.40 (d, J=2.7Hz), 130.36 (s), 130.06
(q, J=204.0Hz), 130.05 (s), 129.64 (s), 128.62 (s), 128.37 (d, J=8.4Hz), 127.79 (s),
124.62-124.39 (m), 122.91 (s), 115.18 (d, J=22.3Hz), 92.31 (s), 55.49 (q, J=26.2Hz)；19F
NMR(376MHz,DMSO-d6)δ:-59.46(s),-114.98(s).HRMS(ESI-TOF)calcd for C22H15F4NO2Na
(M+Na)+:424.0937,found:424.0935。
Embodiment three:3- hydroxyls -2- (4- methoxyphenyls) -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone
The synthesis of (2c)
3- benzylidenes -2- (4- methoxyphenyls) iso-indoles -1- ketone 1c (0.327g, 1mmol) is weighed, trifluoromethyl is sub-
Sodium sulfonate (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL second
Nitrile aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.
Crude on silica gel column chromatography for separation (petroleum ether after reaction:Ethyl acetate=1:6) compound 2c is obtained after purifying.Separation
Yield is 78%.
2c:Faint yellow solid, 78%yield；1H NMR(400MHz,DMSO-d6)δ:7.89 (d, J=7.4Hz, 1H),
7.85 (s, 1H), 7.69-7.63 (m, 2H), 7.24 (dd, 4H), 7.07 (t, J=7.7Hz, 2H), 6.98 (d, J=9.0Hz,
2H), 6.46 (d, J=7.5Hz, 2H), 4.05 (q, J=10.5Hz, 1H), 3.80 (s, 3H)；13C NMR(101MHz,DMSO-
d6)δ:164.90(s),157.74(s),144.15(s),132.60(s),131.78(s),130.25(s),130.11(s),
129.71 (d, J=4.7Hz), 128.57 (s), 128.01 (d, J=8.1Hz), 127.75 (s), 127.56 (s), 127.47 (q,
), J=253.5Hz 124.41 (q, J=6.5Hz), 122.75 (s), 113.72 (d, J=27.1Hz), 92.16 (s), 55.44
(q, J=25.1Hz), 55.23 (s)；19F NMR(376MHz,DMSO-d6)δ:-59.29(s)；HRMS(ESI-TOF)calcd
for C23H18F3NO3Na(M+Na)+:436.1136,found:436.1143。
Example IV:3- hydroxyls -2- (4- aminomethyl phenyls) -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone
The synthesis of (2d)
Weigh 3- benzylidenes -2- (4- aminomethyl phenyls) iso-indoles -1- ketone 1d (0.311g, 1mmol), trifluoromethyl Asia sulphur
Sour sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitriles
Aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Instead
Crude on silica gel column chromatography for separation (petroleum ether after answering:Ethyl acetate=1:6) compound 2d is obtained after purifying.Separation production
Rate is 75%.
2d:Faint yellow solid, 78%yield；1H NMR(400MHz,DMSO-d6)δ:7.92(s,1H),7.85–7.80
(m, 1H), 7.66 (t, J=6.5Hz, 2H), 7.33 (d, J=4.8Hz, 1H), 7.29 (d, J=8.2Hz, 2H), 7.22 (dd, J
=12.4,7.8Hz, 3H), 7.06 (t, J=7.5Hz, 2H), 6.45 (d, J=7.4Hz, 2H), 4.09 (q, J=10.5Hz,
1H),2.35(s,3H)；13C NMR(101MHz,DMSO-d6)δ:164.87(s),144.15(s),135.93(s),132.67
(s),132.55(s),131.71(s),130.26(s),130.06(s),129.66(s),128.87(s),128.56(s),
127.73 (s), 126.93 (q, J=272.1Hz), 126.27 (s), 124.43 (d, J=3.9Hz), 122.79 (s), 92.40
(s), 55.41 (q, J=25.7Hz), 20.68 (s)；19F NMR(376MHz,DMSO-d6)δ:-59.24(s)；HRMS(ESI-
TOF)calcd for C23H18F3NO2Na(M+Na)+:420.1187,found:420.1193。
Embodiment five:3- hydroxyls -2- (3- aminomethyl phenyls) -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone
The synthesis of (2e)
Weigh 3- benzylidenes -2- (3- aminomethyl phenyls) iso-indoles -1- ketone 1e (0.311g, 1mmol), trifluoromethyl Asia sulphur
Sour sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitriles
Aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Instead
Crude on silica gel column chromatography for separation (petroleum ether after answering:Ethyl acetate=1:6) compound 2e is obtained after purifying.Separation production
Rate is 65%.
2e:Faint yellow solid, 65%yield；1H NMR(400MHz,DMSO-d6)δ:7.94 (s, 1H), 7.84 (t, J=
7.2Hz, 1H), 7.69 (dd, J=13.5,7.1Hz, 2H), 7.35-7.28 (m, 2H), 7.24 (dd, J=15.4,7.9Hz,
2H), 7.15 (d, J=7.2Hz, 1H), 7.10-7.02 (m, 3H), 6.42 (d, J=7.4Hz, 2H), 4.11 (q, J=10.4Hz,
1H),2.29(s,3H)；13C NMR(101MHz,DMSO-d6)δ:164.95(s),144.11(s),137.43(s),135.13
(s), 132.74 (s), 131.70 (s), 130.50 (s), 130.30 (s), 130.06 (s), 129.71 (s), 128.64 (q, J=
254.5Hz), 128.57 (s), 128.14 (s), 127.66 (s), 127.24 (d, J=5.2Hz), 124.49 (d, J=3.1Hz),
123.29 (s), 122.84 (s), 92.34 (s), 55.59 (q, J=25.7Hz), 21.12 (s)；19F NMR(376MHz,DMSO-
d6)δ:-59.43(s)；HRMS(ESI-TOF)calcd for C23H18F3NO2Na(M+Na)+:420.1187,found:
420.1184。
Embodiment six:3- hydroxyls -2- (3- chlorphenyls) -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone (2f)
Synthesis
Weigh 3- benzylidenes -2- (3- chlorphenyls) iso-indoles -1- ketone 1f (0.331g, 1mmol), trifluoromethanesulpacidc acidc
Sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile water
Solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction
After crude on silica gel column chromatography for separation (petroleum ether:Ethyl acetate=1:6) compound 2f is obtained after purifying.Detach yield
It is 60%.
2f:Faint yellow solid, 60%yield；1H NMR(400MHz,DMSO-d6)δ:8.12 (s, 1H), 7.94 (d, J=
7.8Hz, 1H), 7.89-7.85 (m, 1H), 7.75 (d, J=7.2Hz, 1H), 7.70 (d, J=7.1Hz, 1H), 7.48-7.44
(m, 2H), 7.40 (dd, J=5.0,2.3Hz, 1H), 7.31 (s, 2H), 7.24 (t, J=7.4Hz, 1H), 7.07 (t, J=
7.7Hz, 2H), 6.44 (d, J=7.5Hz, 2H), 4.26 (q, J=10.3Hz, 1H)；13C NMR(101MHz,DMSO-d6)δ:
165.40 (s), 144.44 (s), 137.25 (s), 133.58 (s), 133.15 (d, J=20.2Hz), 131.68 (s), 130.85
(d, J=23.8Hz), 130.43 (q, J=257.3Hz), 130.31 (d, J=27.3Hz), 130.02 (s), 129.47 (s),
129.14(s),128.23(s),126.82(s),126.21(s),125.05(s),124.68(s),123.51(s),93.06
(s), 56.01 (q, J=25.2Hz)；19F NMR(376MHz,DMSO-d6)δ:-59.55(s)；HRMS(ESI-TOF)calcd
for C22H16ClF3NO2(M+H)+:418.0822,found:418.0819。
Embodiment seven:3- hydroxyls -2- (2- chlorphenyls) -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone (2g)
Synthesis
Weigh 3- benzylidenes -2- (2- chlorphenyls) iso-indoles -1- ketone 1g (0.331g, 1mmol), trifluoromethanesulpacidc acidc
Sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile water
Solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction
After crude on silica gel column chromatography for separation (petroleum ether:Ethyl acetate=1:6) compound 2g is obtained after purifying.Detach yield
It is 60%.
2g:Faint yellow solid, 60%yield；1H NMR(400MHz,DMSO-d6)δ:8.50 (d, J=6.6Hz, 1H),
8.05 (s, 1H), 7.60 (d, J=7.3Hz, 1H), 7.52 (t, J=6.8Hz, 1H), 7.46-7.41 (m, 2H), 7.41-7.37
(m, 4H), 7.33 (dd, J=5.0,1.7Hz, 3H), 7.12 (td, J=7.9,1.4Hz, 1H), 5.14 (q, J=8.4Hz, 1H)
；13C NMR(101MHz,DMSO-d6)δ:194.22(s),165.98(s),137.76(s),135.62(s),134.38(s),
131.81 (s), 130.79 (d, J=20.3Hz), 130.63 (q, J=240.3Hz), 130.24 (s), 129.14 (t, J=
6.6Hz),128.50(s),127.96(s),127.29(s),125.49(s),125.31(s),124.21(s),123.24(s),
122.70 (s), 122.00 (s), 59.33 (q, J=26.3Hz)；19F NMR(376MHz,DMSO-d6)δ:-65.94(s)；HRMS
(ESI-TOF)calcd for C22H15ClF3NO2Na(M+Na)+:440.0641,found:440.0631。
Embodiment eight:3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- of 2,2,2- (4- chlorobenzene ethyls)) iso-indoles -1- ketone (2h)
Synthesis
Weigh 3- (4- chlorobenzenes methylene) -2- phenyl) iso-indoles -1- ketone 1h (0.331g, 1mmol), trifluoromethyl Asia sulphur
Sour sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitriles
Aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Instead
Crude on silica gel column chromatography for separation (petroleum ether after answering:Ethyl acetate=1:6) compound 2h is obtained after purifying.Separation production
Rate is 56%.
2h:Faint yellow solid, 56%yield；1H NMR(400MHz,DMSO-d6)δ:8.04 (s, 1H), 7.91 (d, J=
7.6Hz, 1H), 7.84 (dd, J=11.5,4.7Hz, 1H), 7.72 (d, J=6.9Hz, 1H), 7.68 (d, J=7.2Hz, 1H),
7.43 (d, J=4.2Hz, 4H), 7.35-7.31 (m, 1H), 7.15 (d, J=8.5Hz, 2H), 6.46 (d, J=8.2Hz, 2H),
4.23 (q, J=10.4Hz, 1H)；13C NMR(101MHz,DMSO-d6)δ:164.91(s),143.93(s),135.24(s),
133.46 (s), 132.94 (s), 131.42 (s), 130.39 (d, J=15.6Hz), 129.03 (s), 128.54 (q, J=
266.6Hz), 128.52 (d, J=8.4Hz), 127.99 (s), 127.83 (s), 126.64 (s), 126.15 (s), 124.44 (d,
), J=3.3Hz 122.98 (s), 92.30 (s), 54.72 (q, J=25.6Hz)；19F NMR(376MHz,DMSO-d6)δ:-
59.45(s)；HRMS(ESI-TOF)calcd for C22H15ClF3NO2Na(M+Na)+:440.0641,found:440.0629。
Embodiment nine:3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- of 2,2,2- (4- fluorobenzene ethyl)) iso-indoles -1- ketone (2i)
Synthesis
Weigh 3- (4- fluorobenzylidenes) -2- phenyl iso-indoles -1- ketone 1i (0.316g, 1mmol), trifluoromethanesulpacidc acidc
Sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile water
Solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction
After crude on silica gel column chromatography for separation (petroleum ether:Ethyl acetate=1:6) compound 2i is obtained after purifying.Detach yield
It is 67%.
2i:Faint yellow solid, 67%yield；1H NMR(400MHz,DMSO-d6)δ:8.04 (s, 1H), 7.94 (d, J=
7.5Hz, 1H), 7.85 (d, J=7.3Hz, 1H), 7.83-7.80 (m, 1H), 7.74 (d, J=7.2Hz, 1H), 7.68 (d, J=
7.4Hz, 1H), 7.44 (d, J=6.8Hz, 3H), 7.36-7.32 (m, 1H), 6.91 (t, J=8.6Hz, 2H), 6.53-6.44
(m, 2H), 4.23 (q, J=10.3Hz, 1H)；13C NMR(101MHz,DMSO-d6)δ:164.94(s),163.20(s),
160.75 (s), 143.98 (s), 135.32 (s), 132.87 (s), 131.60 (d, J=16.4Hz), 130.40 (s), 128.43
(s), 128.39 (q, J=255.7Hz), 126.59 (s), 126.35 (s), 126.13 (s), 124.46 (d, J=3.1Hz),
122.95 (s), 114.70 (d, J=21.5Hz), 92.43 (s), 54.65 (q, J=25.4Hz)；19F NMR(376MHz,DMSO-
d6)δ:-59.60(s)；HRMS(ESI-TOF)calcd for C22H15F4NO2Na(M+Na)+:424.0937,found:
424.0935。
Embodiment ten:3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- of 2,2,2- (4- methylphenethyls)) iso-indoles -1- ketone (2j)
Synthesis
Weigh 3- (4- methyl benzylidenes) -2- phenyl iso-indoles -1- ketone 1j (0.311g, 1mmol), trifluoromethyl Asia sulphur
Sour sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitriles
Aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Instead
Crude on silica gel column chromatography for separation (petroleum ether after answering:Ethyl acetate=1:6) compound 2j is obtained after purifying.Separation production
Rate is 74%.
2j:Faint yellow solid, 74%yield；1H NMR(400MHz,DMSO-d6)δ:7.95 (s, 1H), 7.90 (d, J=
7.5Hz, 1H), 7.84 (d, J=6.5Hz, 1H), 7.67 (dd, J=8.5,6.8Hz, 2H), 7.46-7.39 (m, 4H), 7.35-
7.32 (m, 1H), 6.85 (d, J=7.8Hz, 2H), 6.29 (d, J=7.6Hz, 2H), 4.04 (q, J=10.6Hz, 1H), 2.17
(s,3H)；13C NMR(101MHz,DMSO-d6)δ:165.41(s),144.64(s),138.45(s),135.77(s),133.24
(s), 132.09 (s), 130.80 (d, J=6.9Hz), 129.97 (s), 129.74 (q, J=216.1Hz), 129.04 (s),
128.83 (d, J=5.7Hz), 127.42 (s), 127.08 (s), 126.76 (s), 124.91 (d, J=3.1Hz), 123.34
(s), 93.04 (s), 55.56 (q, J=25.4Hz), 20.98 (s)；19F NMR(376MHz,DMSO-d6)δ:-59.34(s)；
HRMS(ESI-TOF)calcd for C23H19F3NO2(M+H)+:398.1368,found:398.1327。
Embodiment 11:3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- of 2,2,2- (4- methoxyphenethyls)) iso-indoles -1- ketone
The synthesis of (2k)
3- (4- methoxybenzylidenes) -2- phenyl iso-indoles -1- ketone 1k (0.327g, 1mmol) are weighed, trifluoromethyl is sub-
Sodium sulfonate (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL second
Nitrile aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.
Crude on silica gel column chromatography for separation (petroleum ether after reaction:Ethyl acetate=1:6) compound 2k is obtained after purifying.Separation
Yield is 76%.
2k:Faint yellow solid, 76%yield；1H NMR(400MHz,DMSO-d6)δ:7.93 (s, 1H), 7.89 (d, J=
7.7Hz,1H),7.86–7.80(m,1H),7.70–7.65(m,2H),7.44–7.39(m,4H),7.35–7.31(m,1H),
6.61 (d, J=8.9Hz, 2H), 6.31 (d, J=8.2Hz, 2H), 4.02 (q, J=10.6Hz, 1H), 3.64 (s, 3H)；13C
NMR(101MHz,DMSO-d6)δ:164.95 (s), 159.17 (s), 144.15 (s), 135.30 (s), 132.63 (d, J=
26.4Hz), 131.62 (s), 131.05-130.45 (m), 130.30 (s), and 128.38 (s), 128.21 (q, J=263.5Hz),
126.57 (d, J=6.9Hz), 126.30 (s), 124.41 (s), 122.88 (s), 121.79 (s), 113.46-112.34 (m),
92.59 (s), 54.95 (s), 54.67 (q, J=51.1,25.4Hz)；19F NMR(376MHz,DMSO-d6)δ:-59.53(s)；
HRMS(ESI-TOF)calcd for C23H18F3NO3Na(M+Na)+:436.1136,found:436.1136。
Embodiment 12:3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- of 2,2,2- (3- methylphenethyls)) iso-indoles -1- ketone
The synthesis of (2l)
Weigh 3- (3- methyl benzylidenes) -2- phenyl iso-indoles -1- ketone 1l (0.311g, 1mmol), trifluoromethyl Asia sulphur
Sour sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitriles
Aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Instead
Crude on silica gel column chromatography for separation (petroleum ether after answering:Ethyl acetate=1:6) compound 2l is obtained after purifying.Separation production
Rate is 76%.
2l:Faint yellow solid, 76%yield；1H NMR(400MHz,DMSO-d6)δ:8.02 (s, 1H), 7.95 (d, J=
7.5Hz, 1H), 7.84 (t, J=7.2Hz, 1H), 7.72 (d, J=7.2Hz, 1H), 7.68 (d, J=7.3Hz, 1H), 7.48-
7.41 (m, 4H), 7.36-7.32 (m, 1H), 7.04 (d, J=7.5Hz, 1H), 6.93 (t, J=7.6Hz, 1H), 6.29-6.12
(m, 2H), 4.10 (q, J=10.5Hz, 1H), 2.03 (s, 3H)；13C NMR(101MHz,DMSO-d6)δ:164.94(s),
144.16 (s), 136.79 (s), 135.46 (s), 132.57 (d, J=25.5Hz), 131.70 (s), and 130.24 (s), 129.78
(s), 129.59 (q, J=247.5Hz), 129.08 (s), 128.56 (s), 128.24 (s), 127.55 (s), 126.66 (d, J=
13.3Hz), 126.50 (s), 126.17 (s), 124.76-124.14 (m), 122.78 (s), 92.57 (s), 55.57 (q, J=
25.5Hz),20.66(s)；19F NMR(376MHz,DMSO-d6)δ:-59.31(s)；HRMS(ESI-TOF)calcd for
C23H18F3NO2Na(M+Na)+:420.1187,found:420.1196。
Embodiment 13:3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- of 2,2,2- (3- chlorobenzene ethyls)) iso-indoles -1- ketone (2m)
Synthesis
Weigh 3- (3- chlorobenzenes methylene) -2- phenyl iso-indoles -1- ketone 1m (0.331g, 1mmol), trifluoromethanesulpacidc acidc
Sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile water
Solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction
After crude on silica gel column chromatography for separation (petroleum ether:Ethyl acetate=1:6) compound 2m is obtained after purifying.Detach yield
It is 64%.
2m:Faint yellow solid, 64%yield；1H NMR(400MHz,DMSO-d6)δ:8.07 (s, 1H), 7.93 (d, J=
7.6Hz, 1H), 7.89-7.85 (m, 1H), 7.78-7.66 (m, 3H), 7.44-7.38 (m, 4H), 7.31 (d, J=7.6Hz,
1H), 7.10 (t, J=7.9Hz, 1H), 6.42 (d, J=10.2Hz, 2H), 4.28 (q, J=10.3Hz, 1H)；13C NMR
(101MHz,DMSO-d6)δ:164.92(s),143.93(s),135.28(s),132.94(s),132.34(s),132.21(d,
), J=0.8Hz 131.42 (s), 130.49 (s), 130.18 (q, J=279.3Hz), 129.91 (s), 129.52 (s), 128.56
(s), 128.39 (s), 126.81 (s), 126.65 (s), 126.08 (s), 124.44 (d, J=2.9Hz), 122.94 (s),
92.22 (s), 54.98 (q, J=25.2Hz)；19F NMR(376MHz,DMSO-d6)δ:-59.46(s)；HRMS(ESI-TOF)
calcd for C22H16ClF3NO2(M+H)+:418.0822,found:418.0823。
Embodiment 14:3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- of 2,2,2- (2- chlorobenzene ethyls)) iso-indoles -1- ketone (2n)
Synthesis
Weigh 3- (2- chlorobenzenes methylene) -2- phenyl iso-indoles -1- ketone 1n (0.331g, 1mmol), trifluoromethanesulpacidc acidc
Sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile water
Solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction
After crude on silica gel column chromatography for separation (petroleum ether:Ethyl acetate=1:6) compound 2n is obtained after purifying.Detach yield
It is 42%.
2n:Faint yellow solid, 42%yield；1H NMR(400MHz,DMSO-d6)δ:8.06 (s, 1H), 7.89 (d, J=
3.8Hz, 2H), 7.84 (d, J=7.4Hz, 1H), 7.76 (dd, J=7.8,3.9Hz, 2H), 7.51 (dd, J=20.8,
13.0Hz, 1H), 7.31 (d, J=7.5Hz, 4H), 7.07 (d, J=7.4Hz, 2H), 6.22 (d, J=7.8Hz, 1H), 4.78
(q, J=9.7Hz, 1H)；13C NMR(101MHz,DMSO-d6)δ:164.84(s),143.67(s),136.56(s),134.81
(s), 133.16 (s), 131.72 (s), 131.41 (q, J=245.6Hz), 130.68 (s), 130.51 (s), 129.44 (s),
128.66 (s), 128.37 (s), 128.18 (s), 126.81 (s), 126.13 (s), 124.62 (d, J=2.9Hz), 124.13
(d, J=9.2Hz), 123.15 (s), 92.04 (s), 51.20 (q, J=26.3Hz)；19F NMR(376MHz,DMSO-d6)δ:-
60.81(s)；HRMS(ESI-TOF)calcd for C22H15ClF3NO2Na(M+Na)+:440.0641,found:440.0645。
Embodiment 15:5- methyl -3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone
The synthesis of (2o)
Weigh 5- methyl -3- benzylidene -2- phenyl iso-indoles -1- ketone 1o (0.311g, 1mmol), trifluoromethyl Asia sulphur
Sour sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitriles
Aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Instead
Crude on silica gel column chromatography for separation (petroleum ether after answering:Ethyl acetate=1:6) compound 2o is obtained after purifying.Separation production
Rate is 80%.
2o:Faint yellow solid, 80%yield；1H NMR(400MHz,DMSO-d6)δ:7.92(s,1H),7.70(s,
1H), 7.58 (d, J=7.7Hz, 1H), 7.47 (d, J=7.7Hz, 1H), 7.38 (dd, J=9.8,7.2Hz, 4H), 7.34-
7.30 (m, 1H), 7.21 (t, J=7.4Hz, 1H), 7.05 (t, J=7.7Hz, 2H), 6.42 (d, J=7.6Hz, 2H), 4.10
(q, J=10.5Hz, 1H), 2.54 (s, 3H)；13C NMR(101MHz,DMSO-d6)δ:165.39(s),144.98(s),
143.55(s),135.91(s),131.51(s),130.52(s),130.11(s),129.62(s),129.04(s),128.78
(s), 128.20 (s), 129.11 (q, J=200.0Hz), 126.97 (d, J=13.7Hz), 126.60 (s), 125.24 (s),
123.26 (s), 92.73 (s), 55.99 (q, J=25.5Hz), 22.16 (s)；19F NMR(376MHz,DMSO-d6)δ:-59.30
(s)；HRMS(ESI-TOF)calcd for C23H18F3NO2Na(M+Na)+:420.1187,found:420.1200。
Embodiment 16:The chloro- 3- of 3- hydroxyl -2- phenyl -5- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone
The synthesis of (2p)
Weigh 3- benzylidene -2- phenyl -5- chlorine iso-indoles -1- ketone 1p (0.331g, 1mmol), trifluoromethanesulpacidc acidc
Sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitrile water
Solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Reaction
After crude on silica gel column chromatography for separation (petroleum ether:Ethyl acetate=1:6) compound 2p is obtained after purifying.Detach yield
It is 42%.
2p:Faint yellow solid, 42%yield；1H NMR(400MHz,DMSO-d6)δ:8.16(s,1H),7.87(s,
1H), 7.75 (d, J=9.8Hz, 2H), 7.41 (d, J=5.6Hz, 4H), 7.33 (d, J=2.6Hz, 1H), 7.23 (t, J=
7.3Hz, 1H), 7.08 (t, J=7.5Hz, 2H), 6.49 (d, J=7.5Hz, 2H), 4.20 (q, J=10.4Hz, 1H)；13C NMR
(101MHz,DMSO-d6)δ:163.90(s),146.18(s),137.61(s),135.09(s),130.69(s),130.31
(s), 129.67 (d, J=11.9Hz), 128.67 (s), 128.48 (d, J=7.2Hz), 127.88 (s), 127.34 (q, J=
241.0Hz), 126.72 (d, J=9.0Hz), 126.58 (s), 126.11 (s), 124.83 (s), 124.42 (d, J=3.0Hz),
92.01 (s), 55.30 (q, J=25.9Hz)；19F NMR(376MHz,DMSO-d6)δ:-59.35(s)；HRMS(ESI-TOF)
calcd for C22H16ClF3NO2(M+H)+:418.0822,found:418.0835。
Embodiment 17:6- methyl -3- hydroxyl -2- phenyl -3- (tri- fluoro- 1- phenylethyls of 2,2,2-) iso-indoles -1- ketone
The synthesis of (2q)
Weigh 6- methyl -3- benzylidene -2- phenyl iso-indoles -1- ketone 1q (0.311g, 1mmol), trifluoromethyl Asia sulphur
Sour sodium (0.468g, 3mmol), cuprous bromide (0.028g, 0.2mmol), potassium peroxydisulfate (1.081g, 4mmol) are dissolved in 9mL acetonitriles
Aqueous solution (acetonitrile:Water=2:1) in.Mixture is stirred to react at 25 DEG C, and TLC tracking reaction terminates until the reaction was complete.Instead
Crude on silica gel column chromatography for separation (petroleum ether after answering:Ethyl acetate=1:6) compound 2q is obtained after purifying.Separation production
Rate is 83%.
2q:Faint yellow solid, 83%yield；1H NMR(400MHz,DMSO-d6)δ:7.90 (s, 1H), 7.80 (d, J=
8.0Hz, 1H), 7.65 (d, J=7.5Hz, 1H), 7.53 (s, 1H), 7.40 (d, J=5.3Hz, 4H), 7.34-7.32 (m, 1H),
7.22 (t, J=7.3Hz, 1H), 7.06 (t, J=7.6Hz, 2H), 6.43 (d, J=7.6Hz, 2H), 4.12 (q, J=10.5Hz,
1H),2.46(s,3H)；13C NMR(101MHz,DMSO-d6)δ:165.52(s),141.89(s),140.65(s),135.93
(s),134.00(s),132.31(s),130.62(s),130.08(s),129.03(s),128.77(s),128.21(s),
128.04 (q, J=276.2Hz), 126.93 (s), 126.58 (s), 124.74 (d, J=3.2Hz), 123.51 (s), 92.84
(s), 56.04 (q, J=25.6Hz), 21.31 (s)；19F NMR(376MHz,DMSO-d6)δ:-59.42(s)；HRMS(ESI-
TOF)calcd for C23H18F3NO2Na(M+Na)+:420.1187,found:420.1181。
In short, the invention discloses a kind of trifluoromethyl hydroxylating of N- phenyl -3- benzylidenes iso-indoles -1- ketone derivatives
The preparation method of object, it is excellent using mantoquita as catalyst to replace N- phenyl -3- benzylidene iso-indoles -1- ketone derivatives as substrate
Selection of land is reacted with Sodium trifluoromethanesulfinate, oxidant at 10-80 DEG C in the in the mixed solvent of organic solvent and water, is made
The trifluoromethyl hydroxylation derivative of N- phenyl -3- benzylidene iso-indoles -1- ketone.The present invention provides a completely new bodies
System, the trifluoromethyl hydroxylating of acrylamide is realized using radical reaction.
The above is only a preferred embodiment of the present invention, it is not intended to restrict the invention, it is noted that for this skill
For the those of ordinary skill in art field, without departing from the technical principles of the invention, can also make it is several improvement and
Modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (9)
1. a kind of preparation method of the trifluoromethyl hydroxylation derivative of isoindolone, which is characterized in that include the following steps:
By the substitution N- phenyl -3- benzylidenes iso-indoles -1- ketone derivatives and Sodium trifluoromethanesulfinate of formula (1) in mantoquita
It under the oxidation of catalytic action and oxidant, is reacted at 10~80 DEG C in a solvent, obtains the isoindolone of formula (2)
The route of trifluoromethyl hydroxylation derivative, the above reaction is as follows：
Wherein, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R12Independently selected from hydrogen, alkyl, alkoxy or halogen.
2. the preparation method of the trifluoromethyl hydroxylation derivative of isoindolone according to claim 1, it is characterised in that:
R1、R2、R3、R4、R5、R6、R7、R8、R9、R11、R12For hydrogen, R10For hydrogen, alkyl, alkoxy or halogen；
Or R1、R2、R3、R4、R5、R6、R7、R8、R10、R11、R12For hydrogen, R9For hydrogen, alkyl or halogen；
Or R1、R2、R3、R4、R5、R6、R7、R9、R10、R11、R12For hydrogen, R8For hydrogen, alkyl or halogen；
Or R1、R2、R4、R6、R7、R8、R9、R10、R11、R12For hydrogen, R5For hydrogen, alkyl or halogen；
Or R1、R2、R3、R5、R7、R8、R9、R10、R11、R12For hydrogen, R4For hydrogen, alkyl, alkoxy or halogen；
Or R1、R2、R4、R5、R7、R8、R9、R10、R11、R12For hydrogen, R3For hydrogen, alkyl or halogen；
Or R3、R4、R5、R6、R7、R8、R9、R10、R11、R12For hydrogen, R1And R2Respectively hydrogen or alkyl.
3. the preparation method of the trifluoromethyl hydroxylation derivative of isoindolone according to claim 1 or 2, feature exist
In:The alkyl is methyl, ethyl or propyl.
4. the preparation method of the trifluoromethyl hydroxylation derivative of isoindolone according to claim 1 or 2, feature exist
In:The alkoxy is methoxy or ethoxy.
5. the preparation method of the trifluoromethyl hydroxylation derivative of isoindolone according to claim 1 or 2, feature exist
In:The halogen is fluorine, chlorine or bromine.
6. the preparation method of the trifluoromethyl hydroxylation derivative of isoindolone according to claim 1, it is characterised in that:
The mantoquita is cuprous bromide, cuprous iodide, copper oxide, stannous chloride, copper acetate or copper bromide.
7. the preparation method of the trifluoromethyl hydroxylation derivative of isoindolone according to claim 1, it is characterised in that:
The oxidant is potassium peroxydisulfate.
8. the preparation method of the trifluoromethyl hydroxylation derivative of isoindolone according to claim 1, it is characterised in that:
The solvent is N, one in N '-dimethyl formamide, dimethyl sulfoxide and water, acetone and water, acetonitrile and water, tetrahydrofuran and water
Kind.
9. the preparation method of the trifluoromethyl hydroxylation derivative of isoindolone according to claim 1, it is characterised in that:
It is described to replace rubbing for N- phenyl -3- benzylidene iso-indoles -1- ketone derivatives, Sodium trifluoromethanesulfinate, mantoquita and oxidant
You are than being 1:1-3:0.2-1.0:3.0-5.0.
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| CN115246798A (en) * | 2022-08-02 | 2022-10-28 | 浙江工业大学 | Method for synthesizing photocatalytic beta-C heteroaryl substituted alcohol |
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| CN113801054A (en) * | 2021-09-30 | 2021-12-17 | 西南大学 | Preparation method of 3-alkyl-3-hydroxyindole-2-ketone and derivatives thereof and products thereof |
| CN115246798A (en) * | 2022-08-02 | 2022-10-28 | 浙江工业大学 | Method for synthesizing photocatalytic beta-C heteroaryl substituted alcohol |
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