CN108409630A - The preparation method of 3- hydroxyl -2- indolone derivatives in a kind of water phase - Google Patents
The preparation method of 3- hydroxyl -2- indolone derivatives in a kind of water phase Download PDFInfo
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- CN108409630A CN108409630A CN201810158489.3A CN201810158489A CN108409630A CN 108409630 A CN108409630 A CN 108409630A CN 201810158489 A CN201810158489 A CN 201810158489A CN 108409630 A CN108409630 A CN 108409630A
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- XCHBYBKNFIOSBB-UHFFFAOYSA-N CC(c1ccccc1N1)(C1=O)O Chemical compound CC(c1ccccc1N1)(C1=O)O XCHBYBKNFIOSBB-UHFFFAOYSA-N 0.000 description 1
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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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
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Abstract
The present invention relates to a kind of synthetic methods of 3 hydroxyl, 2 indolone derivatives in water phase.This method is by the way that 32 indole ketone compounds of substitution (1a), the compound of formula 2a, lauryl sodium sulfate (SDS) and aqueous solvent are added into Schlenk reaction bulbs, reaction bulb is placed under the conditions of certain temperature, air atmosphere and is stirred to react, reaction process is monitored through TLC or GC, to raw material, the reaction was complete, post-treated to obtain 3 hydroxyl of target product, 2 indolone derivatives (I)；
Description
Technical field
The application belongs to organic synthesis field, and in particular to a kind of synthetic method of 3- hydroxyls -2- indolone derivatives.
Background technology
There are many various chemical functionals and property for natural products, they play an important role to the exploitation of drug.At these
In substance, indolone has unprecedented structure diversity and bioactivity, therefore causes chemist and biologist
Extensive and long-term concern.As a subclass of indolone natural products, the skeletons of 3- hydroxyl -2- indolones is also very
Important biological unit.There are more and more 3- hydroxyls -2- indolone structures to be found to be the core for constituting many natural products
Heart skeleton, and there is extensive bioactivity.
Since 3- hydroxyl -2- indole ketone compounds and its derivative are very important organic intermediate, and it is many
Native compound all contains these skeletons, shows with good pharmaceutical activity, in medicine, biology etc. using very
Extensively.Therefore, development is convenient, environmental-friendly, is efficiently synthesized 3- hydroxyl -2- indolones and its method of derivative seems suitable
It is important.
Inventor has found that the route of synthesis for being synthetically prepared 3- hydroxyl -2- indole ketone compounds in the prior art mainly wraps
Include the following two kinds：First, being prepared by ring-closure reaction, prepared by addition reaction that is another then being isatin.In recent years, also there is scientific research
Worker has developed the side that 3- hydroxyl -2- indole ketone compounds are prepared using 3- substitution -2- indole ketone compounds as raw material
Method.For example, reference can be made to following document：
(1)“A Dinuclear Palladium Catalyst for r-Hydroxylation of Carbonyls
with O2", Tobias Ritter et.al., J.Am.Chem.Soc.2011,133,1760-1762；
(2) " A catalytic, mild and efficient protocol for the C-3aerial
Hydroxylation of oxindoles ", Benjamin R.Buckley et.al., Tetrahedron Letters 54
(2013)843-846；
(3) " Ruthenium-catalyzed direct α-alkylation of amides using alcohols ",
Boopathy Gnanaprakasam et.al., Org.Biomol.Chem., 2016,14,9215；
(4)“Literature Survey and Further Studies on the 3-Alkylation of N-
Unprotected 3-Monosubstituted Oxindoles.Practical Synthesis of N-Unprotected
3,3-Disubstituted Oxindoles and Subsequent Transformations on the Aromatic
Ring ",Volk et.al., Molecules 2017,22,24；
(5) " Transition-Metal-Free C-H Hydroxylation of Carbonyl Compounds ",
Boopathy Gnanaprakasam et.al., Org.Lett.2017,19,3628-3631；
(6) CN103613478A, 20140305.
However, the 3- substitution -2- indole ketone compounds in these prior arts report are that raw material prepares 3- hydroxyl -2- Yin
In diindyl ketone compounds method, reaction condition is more harsh, such as using -78 DEG C of low temperature, uses butyl lithium, potassium tert-butoxide
Equal highly basic, and/or use expensive catalyst system and catalyzings such as precious metal palladium, ruthenium, phosphorus ligand etc..Therefore, find it is a kind of it is more efficient,
The project more cheap, more green synthetic method is still a challenge.In the patent application (application that applicant is previously proposed
Number it is：CN201710956656.4 in), it is proposed that a kind of new side preparing 3- substitution -3- hydroxyl -2- indole ketone compounds
Method, this method is using 3- substitution -2- indole ketone compounds as reaction raw materials, and react C in the case where room temperature and TEMPO promote
(sp3)-H hydroxylatings, to obtain a series of target product (formula two) in high yield.
Inventor has carried out 3- substitution -3- hydroxyl -2- indole ketone compounds the research of series, it is further proposed that one
The new method for preparing 3- hydroxyl -2- indole ketone compounds of kind.According to the inventors knowledge, there is presently no the prior arts to report
Using tertbutanol peroxide (t-BuOOH) as the C (sp of source of hydroxyl groups3)-H hydroxylatings.
Invention content
The purpose of the present invention is to overcome the deficiency in the prior art, provides one kind simple for process, green high-efficient, Atom economy
The good synthetic method for preparing 3- hydroxyl -2- indole ketone compounds, this method are original with 3- substitution -2- indole ketone compounds
Material, using tertbutanol peroxide (t-BuOOH) and the like as source of hydroxyl groups, water is solvent, easily and with excellent yield
Prepare 3- hydroxyl -2- indole ketone compounds.
The preparation method of 3- hydroxyls -2- indole ketone compounds provided by the invention, this method is with 3- substitution -2- indolones
Class compound is raw material, is prepared through the following steps：
The compound and aqueous solvent of 3- substitution -2- indolone derivatives (1a), formula 2a are added into Schlenk reaction bulbs,
Reaction bulb is placed under the conditions of certain temperature, air atmosphere and is stirred to react, reaction process is monitored through TLC or GC, until raw material reacts
Completely, post-treated to obtain target product 3- hydroxyl -2- indole ketone compounds (I).
The preparation method of 3- hydroxyls -2- indole ketone compounds provided by the invention, chemical equation can be expressed as (see
Formula three)；
In the reaction of above-mentioned formula three, the reaction atmosphere is the air atmosphere of 1atm, can also replace with the nitrogen of 1atm
Gas atmosphere or other inert gas atmospheres consider, preferably air atmosphere from economic cost etc..
The post-processing operation is as follows：Reaction solution after the completion of reaction is extracted with ethyl acetate, organic phase is with anhydrous
Sodium sulphate is dried, and removing solvent is filtered and be concentrated under reduced pressure, and by residue, through column chromatography for separation, (eluting solvent is：Ethyl acetate/just
Hexane) obtain target product 3- hydroxyl -2- indole ketone compounds (I).
The product 3- hydroxyl -2- indoles that the raw material 3- substitution -2- indole ketone compounds and Formulas I that above-mentioned formula 1a is indicated indicate
In ketone compounds, R1Indicate one or more substituent groups on phenyl ring that it is connected, each R1It is independently from each other hydrogen, C1-
C6Alkyl, C1-C6Alkoxy, C1-C6Acyl group, C1-C6Ester group, halogen, cyano, nitro, C3-C6Naphthenic base, C5-C14Aryl, C5-
C14Heteroaryl ,-NRaRb.Wherein, Ra, RbIt is independently from each other C1-C6Alkyl or hydrogen；The hetero atom of the heteroaryl is selected from O, S
Or N.
R2Indicate hydrogen, C1-C6Alkyl, halogen, cyano, C3-C6Naphthenic base, C5-C14Aryl, C5-C14Heteroaryl；The heteroaryl
The hetero atom of base is selected from O, S or N.
R3Indicate hydrogen, tertbutyloxycarbonyl (Boc), C1-C6Alkyl, C1-C6Acyl group, C3-C6Naphthenic base, C5-C14Aryl, C5-
C14Aryl-C1-C6Alkyl, C5-C14The hetero atom of heteroaryl, the heteroaryl is selected from O, S or N.
Wherein, above-mentioned each alkyl, alkoxy, naphthenic base, aryl and heteroaryl can be further substituted with a substituent, institute
The substituent group stated is selected from halogen or C1-C6Alkyl.
Preferably, R1Indicate one or more substituent groups on phenyl ring that it is connected, each R1Be independently from each other hydrogen,
C1-C6Alkyl, halogen, C1-C6Alkoxy, nitro, C5-C14Aryl；The wherein described C1-C6Alkyl and/or C5-C14Aryl can be into
One step is substituted, and the substituent group is selected from halogen or C1-C6Alkyl.
Preferably, R2Indicate hydrogen, C1-C6Alkyl, halogen, cyano, C5-C14Aryl, wherein the C1-C6Alkyl and/or C5-
C14Aryl can be further substituted, and the substituent group is selected from halogen or C1-C6Alkyl.
Preferably, R3Indicate hydrogen, tertbutyloxycarbonyl (Boc), C1-C6Alkyl, C1-C6Acyl group, phenyl, benzyl, wherein described
C1-C6Alkyl and/or C1-C6Acyl group, phenyl and/or benzyl can be further substituted, and the substituent group is selected from halogen or C1-C6
Alkyl.
In the compound that above-mentioned formula 2a is indicated, the R4Expression hydrogen, tertiary butyl,(this two substitutions
" " in based structures formula indicates the R4The link position of group and " OOH ").Preferably, R4Indicate tertiary butyl, at this time formula 2a
Compound be tertbutanol peroxide, i.e., t-BuOOH herein.
In the reaction of the present invention, the reaction temperature of the reaction be 40-100 DEG C, preferably 40-80 DEG C, most preferably
60℃。
In the reaction of the present invention, it is preferably added lauryl sodium sulfate (SDS) and is used as surfactant.
In the reaction of the present invention, the molar ratio of the compound of the compound and formula 2a of the formula 1a is 1: 1~4, preferably
The molar ratio of ground, the compound of formula 1a and the compound of formula 2a is 1: 2~3.It is highly preferred that the change of the compound of formula 1a and formula 2a
The molar ratio for closing object is 1: 2.The compound of formula 1a and the molar ratio of SDS are 1: 0.1~0.3, it is preferable that the compound of formula 1a with
The molar ratio of SDS is 1: 0.2.
In the reaction of the present invention, water does not limit particularly as solvent, dosage, and those skilled in the art can be with
Conventional selection is carried out according to the actual conditions of reaction and/or adjusts its dosage.
The beneficial effects of the invention are as follows：
1) report tertbutanol peroxide (t-BuOOH) realizes C (sp as source of hydroxyl groups for the first time3)-H keys hydroxylating.
2) tertbutanol peroxide is not only used as radical initiator in the reaction, but also as reaction substrate, has higher original
Subeconomy.
3) reaction is not necessarily to transition-metal catalyst, is not necessarily to other additives.
4) using green solvent water as reaction medium, C (sp be can be achieved in air3)-H keys hydroxylating.
5) easy to operate, it is easy to purify.
Specific implementation mode
Below in conjunction with specific embodiment, further detailed description is carried out to the present invention.
The synthesis of 1 compound 3- methyl -3- hydroxyl -2- indolones of embodiment
3- methyl -2- indolones (, 29.4mg, 0.2mmol), tertbutanol peroxide are added into Schlenk reaction bulbs
(36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), reaction bulb is placed in
60 DEG C, be stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until the reaction was complete that (reaction time 24 is small for raw material
When), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, is filtered and is depressurized
Concentration removes solvent, and by residue, through column chromatography for separation, (eluting solvent is：Ethyl acetate/n-hexane) obtain target product 3- first
Base -3- hydroxyl -2- indolones.White solid (83%yield)；1H NMR (400MHz, CDCl3)δ：8.18 (s, 1H), 7.39
(d, J=5.6Hz, 1H), 7.26 (t, J=6.0Hz, 1H), 7.08 (t, J=6.0Hz, 1H), 6.89 (d, J=6.4Hz, 1H),
1.61 (s, 3H)；13C NMR (100MHz, CDCl3)δ：180.6,139.8,131.8,129.6,123.9,123.2,110.4,
74.0 24.8.
Embodiment 2
It is added without surfactant SDS, remaining condition is the same as embodiment 1, target product 3- methyl -3- hydroxyl -2- indolones
Yield be 31%, the 3- methyl -2- indolone rate of recovery be 57%.
Embodiment 3
The inventory of surfactant SDS is reduced, and is the 10mol% (i.e. 28.8mg) of 3- methyl -2- indolone inventorys,
For remaining condition with embodiment 1, the yield of target product 3- methyl -3- hydroxyl -2- indolones is 57%.
Embodiment 4
The inventory of surfactant SDS increases, and is the 30mol% (i.e. 28.8mg) of 3- methyl -2- indolone inventorys,
For remaining condition with embodiment 1, the yield of target product 3- methyl -3- hydroxyl -2- indolones is 84%.
Embodiment 5
Reaction temperature is 40 DEG C, remaining condition is the same as embodiment 1, the yield of target product 3- methyl -3- hydroxyl -2- indolones
It is 41%.
Embodiment 6
Reaction temperature is 80 DEG C, remaining condition is the same as embodiment 1, the yield of target product 3- methyl -3- hydroxyl -2- indolones
It is 84%.
Embodiment 7
The inventory of tertbutanol peroxide is 1.2 equivalents (0.24mmol), remaining condition is the same as embodiment 1, target product 3-
The yield of methyl -3- hydroxyl -2- indolones is 69%.
Embodiment 8
The inventory of tertbutanol peroxide is 3 equivalents (0.6mmol), remaining condition is the same as embodiment 1, target product 3- first
The yield of base -3- hydroxyl -2- indolones is 84%.
Embodiment 9
Reaction is set to be carried out under the conditions of argon gas, remaining condition is the same as embodiment 1, target product 3- methyl -3- hydroxyl -2- indoles
The yield of ketone is 83%.
Embodiment 10
The tert-Butanol peroxide in embodiment 1 is replaced with hydrogen peroxide, remaining condition is the same as embodiment 1, target product 3- methyl -3-
The yield of hydroxyl -2- indolones is 16%.
Embodiment 11
The tertbutanol peroxide in embodiment 1 is replaced with tertiary amyl hydrogen peroxide, remaining condition is the same as embodiment 1, target production
The yield of object 3- methyl -3- hydroxyl -2- indolones is 75%.
Embodiment 12
The tertbutanol peroxide in embodiment 1 is replaced with alpha, alpha-dimethylbenzyl hydrogen peroxide, the same embodiment of remaining condition
1, the yield of target product 3- methyl -3- hydroxyl -2- indolones is 61%.
The synthesis of 13 compound 3- ethyl -3- hydroxyl -2- indolones of embodiment
3- ethyl -2- indolones (32.2mg, 0.2mmol), tertbutanol peroxide are added into Schlenk reaction bulbs
(36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), reaction bulb is placed in
60 DEG C, be stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until the reaction was complete that (reaction time 24 is small for raw material
When), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, is filtered and is depressurized
Concentration removes solvent, and by residue, through column chromatography for separation, (eluting solvent is：Ethyl acetate/n-hexane) obtain target product 3- second
Base -3- hydroxyl -2- indolones.White solid (74%yield)；1H NMR (400MHz, DMSO-d6) δ：10.20 (s, 1H),
(7.25-7.17 m, 2H), 6.96（T, J=7.6Hz, 1H), 6.79 (d, J=7.6Hz, 1H), 5.80 (s, 1H), 1.79-1.73
(m, 2H), 0.61 (t, J=7.6Hz, 3H)；13C NMR (100MHz, DMSO-d6) δ：179.8,142.4,132.3,129.3,
124.3,122.0,109.9,76.7,31.1,8.0.
The synthesis of 14 compound 3- phenyl -3- hydroxyl -2- indolones of embodiment
3- phenyl -2- indolones (41.8mg, 0.2mmol), tertbutanol peroxide are added into Schlenk reaction bulbs
(36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), reaction bulb is placed in
60 DEG C, be stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until the reaction was complete that (reaction time 24 is small for raw material
When), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, is filtered and is depressurized
Concentration removes solvent, and by residue, through column chromatography for separation, (eluting solvent is：Ethyl acetate/n-hexane) obtain target product 3- benzene
Base -3- hydroxyl -2- indolones.White solid (87%yield)；1H NMR (400MHz, DMSO-d6) δ：10.39 (s, 1H),
7.33-7.22 (m, 6H), 7.09 (d, J=7.2,1H), 6.96 (t, J=7.6Hz, 1H), 6.89 (d, J=7.6Hz, 1H),
6.61 (s, 1H)；13C NMR (100MHz, DMSO-d6) δ：178.9,142.4,142.0,134.2,129.7,128.5,127.9,
125.9,125.2,122.5,110.3,77.8.
The synthesis of embodiment 15 compound 3- (2,5- 3,5-dimethylphenyl) -3- hydroxyl -2- indolones
3- (2,5- 3,5-dimethylphenyl) -2- indolones (47.4mg, 0.2mmol), peroxide are added into Schlenk reaction bulbs
Change the tert-butyl alcohol (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), it will be anti-
It answers bottle to be placed in 60 DEG C, be stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until raw material the reaction was complete (reaction
24 hours time), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, mistake
Removing solvent is filtered and is concentrated under reduced pressure, (eluting solvent is through column chromatography for separation by residue：Ethyl acetate/n-hexane) obtain target
Product 3- (2,5- 3,5-dimethylphenyl) -3- hydroxyl -2- indolones.White solid (86%yield)；1H NMR (400MHz,
DMSO-d6)δ：10.51 (s, 1H), 7.70 (s, 1H), 7.23 (t, J=7.6Hz, 1H), 6.99 (d, J=7.6Hz, 1H),
6.92-6.87 (m, 3H), 6.82 (d, J=7.2Hz, 1H), 6.53 (s, 1H), 2.32 (s, 3H), 1.72 (s, 3H)；13C NMR
(100MHz, DMSO-d6) δ：177.3,142.1,138.4,133.7,132.0,130.6,130.4,128.9,127.5,
126.8,123.9,121,5,109.2,76.1,20.5,17.9.
The synthesis of 16 compound 5- methoxyl group -3- phenyl -3- hydroxyl -2- indolones of embodiment
Into Schlenk reaction bulbs be added compound 5- methoxyl group -3- phenyl -2- indolones (47.8mg, 0.2mmol),
Tertbutanol peroxide (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL),
Reaction bulb is placed in 60 DEG C, is stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until the reaction was complete for raw material
(24 hours reaction time), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dry with anhydrous sodium sulfate
It is dry, removing solvent is filtered and is concentrated under reduced pressure, (eluting solvent is through column chromatography for separation by residue：Ethyl acetate/n-hexane)
To target product 5- methoxyl group -3- phenyl -3- hydroxyl -2- indolones.White solid (89%yield)；1H NMR (400MHz,
DMSO-d6)δ：10.28 (s, 1H), 7.37-7.23 (m, 6H), 6.84 (d, J=7.2Hz, 1H), 6.74 (d, J=8.4Hz,
1H), 5.81 (s, 1H), 3.35 (s, 3H)；13C NMR (100MHz, DMSO-d6) δ：175.7,153.5,136.1,130.9,
129.9,127.7,126.7,125.5,114.2,113.7,110.0,77.2,55.2..
The synthesis of the chloro- 3- phenyl -3- hydroxyls -2- indolones of 17 compound 5- of embodiment
The chloro- 3- phenyl -2- indolones (48.6mg, 0.2mmol) of compound 5-, peroxide are added into Schlenk reaction bulbs
Change the tert-butyl alcohol (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), it will be anti-
It answers bottle to be placed in 60 DEG C, be stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until raw material the reaction was complete (reaction
24 hours time), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, mistake
Removing solvent is filtered and is concentrated under reduced pressure, (eluting solvent is through column chromatography for separation by residue：Ethyl acetate/n-hexane) obtain target
The chloro- 3- phenyl -3- hydroxyls -2- indolones of product 5-.White solid (86%yield)；1H NMR (400MHz, DMSO-d6) δ：
10.55 (s, 1H), 7.35-7.27 (m, 6H), 7.10 (s, 1H), 6.92 (d, J=8.0Hz, 1H), 6.79 (s, 1H)；13C NMR
(100MHz, DMSO-d6) δ：178.6,141.3,136.2,129.6,128.8,128.3,128.2,126.5,125.8,
125.2,112.0,77.9..
The synthesis of the bromo- 3- phenyl -3- hydroxyls -2- indolones of 18 compound 5- of embodiment
The bromo- 3- phenyl -2- indolones (57.4mg, 0.2mmol) of compound 5-, peroxide are added into Schlenk reaction bulbs
Change the tert-butyl alcohol (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), it will be anti-
It answers bottle to be placed in 60 DEG C, be stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until raw material the reaction was complete (reaction
24 hours time), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, mistake
Removing solvent is filtered and is concentrated under reduced pressure, (eluting solvent is through column chromatography for separation by residue：Ethyl acetate/n-hexane) obtain target
The bromo- 3- phenyl -3- hydroxyls -2- indolones of product 5-.White solid (84%yield)：1H NMR (400MHz, DMSO-d6) δ：
10.57 (s, 1H), 7.44 (d, J=8.0Hz, 1H), 7.36-7.27 (m, 5H), 7.21 (s, 1H), 6.88 (d, J=8.0Hz,
1H), 6.78 (s, 1H)；13C NMR (100MHz, DMSO-d6) δ：178.4,141.7,141.3,136.6,132.5,128.8,
128.2,127.9,125.8,114.1,112.5,77.8..
The synthesis of 19 compound 5- nitro -3- phenyl -3- hydroxyl -2- indolones of embodiment
Compound 5- nitro -3- phenyl -2- indolones (50.8mg, 0.2mmol), mistake are added into Schlenk reaction bulbs
The tert-butyl alcohol (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL) are aoxidized, it will
Reaction bulb is placed in 60 DEG C, is stirred to react under the conditions of air atmosphere, and reaction process is monitored through TLC or GC, until that the reaction was complete is (anti-for raw material
24 hours between seasonable), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate,
Removing solvent is filtered and is concentrated under reduced pressure, (eluting solvent is through column chromatography for separation by residue：Ethyl acetate/n-hexane) obtain mesh
Mark product 5- nitro -3- phenyl -3- hydroxyl -2- indolones.White solid (68%yield)；1H NMR (400MHz, DMSO-
d6)δ：11.16 (s, 1H), 8.25 (d, J=10.4Hz, 1H), 7.90 (s, 1H), 7.36-7.30 (m, 5H), 7.13 (d, J=
8.8Hz, 1H), 7.00 (s, 1H)；13C NMR (100MHz, DMSO-d6) δ：179.0,149.0,143.0,140.5,135.0,
128.9,128.5,127.1,125.8,120.6,110.9,77.4..
The synthesis of 20 compound N-methy -3- phenyl -3- hydroxyl -2- indolones of embodiment
Compound N-methy -3- phenyl -2- indolones (44.6mg, 0.2mmol), mistake are added into Schlenk reaction bulbs
The tert-butyl alcohol (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL) are aoxidized, it will
Reaction bulb is placed in 60 DEG C, is stirred to react under the conditions of air atmosphere, and reaction process is monitored through TLC or GC, until that the reaction was complete is (anti-for raw material
24 hours between seasonable), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate,
Removing solvent is filtered and is concentrated under reduced pressure, (eluting solvent is through column chromatography for separation by residue：Ethyl acetate/n-hexane) obtain mesh
Mark product N- methyl-3-phenyl-3-hydroxy -2- indolones.White solid (62%yield)；1H NMR (400MHz, DMSO-
d6)δ：7.37-7.24 (m, 6H), 7.14 (d, J=7.2Hz, 1H), 7.09-7.03 (m, 2H), 6.68 (s, 1H), 3.15 (s,
3H)；13C NMR (100MHz, DMSO-d6) δ：177.2,143.9,141.8,133.5,129.8,128.6,128.0,125.9,
124.8,123.2,109.3,77.5,26.6..
The synthesis of 21 compound Ns of embodiment-benzyl -3- phenyl -3- hydroxyl -2- indolones
Compound N-methy -3- phenyl -2- indolones (60mg, 0.2mmol), peroxide are added into Schlenk reaction bulbs
Change the tert-butyl alcohol (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), it will be anti-
It answers bottle to be placed in 60 DEG C, be stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until raw material the reaction was complete (reaction
24 hours time), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, mistake
Removing solvent is filtered and is concentrated under reduced pressure, (eluting solvent is through column chromatography for separation by residue：Ethyl acetate/n-hexane) obtain target
Product 3- methyl -3- hydroxyl -2- indolones.White solid (63%yield)；1H NMR (400MHz, DMSO-d6) δ：7.35-
7.24 (m, 11H), 7.17 (d, J=7.2Hz, 1H), 7.02 (t, J=7.6Hz, 1H), 6.96 (d, J=8.0Hz, 1H), 6.84
(s, 1H), 4.91 (s, 2H)；13C NMR (100MHz, DMSO-d6) δ：177.3,142.9,141.8,136.8,133.5,
129.7,129.1,128.6,128.1,127.9,127.7,125.9,125.0,123.3,109.9,77.5,43.2..
The synthesis of 22 compound Ns of embodiment-phenyl -3- phenyl -3- hydroxyl -2- indolones
Compound N-phenyl -3- phenyl -2- indolones (57mg, 0.2mmol), peroxide are added into Schlenk reaction bulbs
Change the tert-butyl alcohol (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), it will be anti-
It answers bottle to be placed in 60 DEG C, be stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until raw material the reaction was complete (reaction
24 hours time), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, mistake
Removing solvent is filtered and is concentrated under reduced pressure, (eluting solvent is through column chromatography for separation by residue：Ethyl acetate/n-hexane) obtain target
Product 3- methyl -3- hydroxyl -2- indolones.White solid (56%yield)；1H NMR (400MHz, DMSO-d6) δ：7.60
(t, J=7.6Hz, 2H), 7.48 (t, J=8.4Hz, 3H), 7.41-7.34 (m, 4H), 7.30 (t, J=7.6Hz, 2H), 7.24
(d, J=7.6Hz, 1H), 7.10 (t, J=7.6Hz, 1H), 6.92 (s, 1H), 6.81 (d, J=8.0Hz, 1H)；13C NMR
(100MHz, DMSO-d6) δ：176.7,143.6,141.7,134.7,133.5,130.2,129.9,128.8,128.6,
128.2,127.1,125.9,125.4,123.9,109.7,77.5..
The synthesis of embodiment 23 the bromo- 3- of compound 5- (2,5- 3,5-dimethylphenyl) -3- hydroxyl -2- indolones
Into Schlenk reaction bulbs be added compound 5- bromo- 3- (2,5- 3,5-dimethylphenyl) -2- indolones (63mg,
0.2mmol), tertbutanol peroxide (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and solvent
Water (2mL), is placed in 60 DEG C by reaction bulb, is stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until raw material
The reaction was complete (24 hours reaction time), and the reaction solution after the completion of reaction is extracted with ethyl acetate three times, and organic phase is with anhydrous
Sodium sulphate is dried, and removing solvent is filtered and be concentrated under reduced pressure, and by residue, through column chromatography for separation, (eluting solvent is：Ethyl acetate/just
Hexane) obtain target product 3- methyl -3- hydroxyl -2- indolones.White solid (81%yield)；1H NMR (400MHz,
DMSO-d6)δ：10.69 (s, 1H), 7.69 (s, 1H), 7.43 (d, J=8.0Hz, 1H), 7.03 (d, J=7.6Hz, 1H), 6.94
(d, J=8.0Hz, 1H), 6.91 (s, 1H), 6.87, (d, J=8.4Hz, 1H), 6.75, (s, 1H), and 2.33 (s, 3H), 1.74
(s, 3H)；13C NMR (100MHz, DMSO-d6) δ：177.7,142.3,138.6,135.2,134.8,132.5,131.4 (2),
128.7,127.7,127.4,114.0,112.3,76.9,21.4,18.8..
The synthesis of the chloro- 3- ethyls -3- hydroxyls -2- indolones of 24 compound 5- of embodiment
The chloro- 3- ethyls -2- indolones (39mg, 0.2mmol) of compound 5-, peroxidating are added into Schlenk reaction bulbs
The tert-butyl alcohol (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and aqueous solvent (2mL), will react
Bottle is placed in 60 DEG C, is stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until the reaction was complete (when reaction for raw material
Between 24 hours), the reaction solution after the completion of reaction is extracted with ethyl acetate three times, organic phase is dried with anhydrous sodium sulfate, filtering
And removing solvent is concentrated under reduced pressure, by residue, through column chromatography for separation, (eluting solvent is：Ethyl acetate/n-hexane) obtain target production
Object 3- methyl -3- hydroxyl -2- indolones.White solid (72%yield)；1H NMR (400MHz, DMSO-d6) δ：10.35 (s,
1H), 7.26 (d, J=11.2Hz, 2H), 6.81 (d, J=8.4Hz, 1H), 5.97 (s, 1H), 1.81-1.76 (m, 2H), 0.61
(t, J=7.6Hz, 3H)；13C NMR (100MHz, DMSO-d6) δ：179.4,141.2,134.4,129.1,126.1,124.4,
111.4,76.9,30.9,7.9..
The synthesis of the chloro- 3- phenyl -3- hydroxyls -2- indolones of 25 compound N-methy -5- of embodiment
Be added into Schlenk reaction bulbs compound N-methy -5- chloro- 3- phenyl -2- indolones (51.4mg,
0.2mmol), tertbutanol peroxide (36mg, 0.4mmol), SDS (lauryl sodium sulfate, 57.6mg, 0.04mmol) and solvent
Water (2mL), is placed in 60 DEG C by reaction bulb, is stirred to react under the conditions of air atmosphere, reaction process is monitored through TLC or GC, until raw material
The reaction was complete (24 hours reaction time), and the reaction solution after the completion of reaction is extracted with ethyl acetate three times, and organic phase is with anhydrous
Sodium sulphate is dried, and removing solvent is filtered and be concentrated under reduced pressure, and by residue, through column chromatography for separation, (eluting solvent is：Ethyl acetate/just
Hexane) obtain target product 3- methyl -3- hydroxyl -2- indolones.White solid (60%yield)：1H NMR (400MHz,
DMSO-d6)δ：7.43 (d, J=8.4Hz, 1H), 7.35-7.27 (m, 5H), 7.16-7.12 (m, 2H), 6.84 (s, 1H), 3.16
(s, 3H)；13C NMR (100MHz, DMSO-d6) δ：176.8,142.8,141.1,135.4,129.6,128.7,128.3,
127.2,125.9,124.8,111.0,77.5,26.8..
26 reaction mechanism Control experiment of embodiment
(1) tert-Butanol peroxide in embodiment 14 is replaced with di-tert-butyl peroxide, remaining condition is the same as embodiment 14.Through
GC is detected, and reaction does not obtainProduct, and raw material 3- phenyl -2- indolones are with the rate of recovery more than 90%
Recycling.
(2) H is used2 18O replaces the aqueous solvent in embodiment 14, remaining condition to analyze and measure through HRMS with embodiment 14, mesh
Hydroxyl oxygen atom in mark product " 3- phenyl -3- hydroxyl -2- indolones " is still16O, it is known that in present invention reaction, hydroxyl source
In tert-Butanol peroxide.
(3) BHT (2,6- the di-t-butyl) -4- methylphenols of 2.4 equivalents are added into the reaction of embodiment 14 or to benzene
Diphenol significantly falls to 28% and 21% respectively as free radical scavenger, the target product yield of the reaction.
It follows that the possible reaction mechanism of the present invention can be derived and is shown below：
Embodiment described above is merely a preferred embodiment of the present invention, and the simultaneously exhaustion of the feasible implementation of non-present invention.For
It is any apparent to made by it under the premise of without departing substantially from the principle of the invention and spirit for those skilled in the art
Change, should all be contemplated as falling with the present invention claims within.
Claims (8)
1. a kind of preparation method of 3- hydroxyls -2- indolone derivatives, which is characterized in that include the following steps：It is anti-to Schlenk
The compound and aqueous solvent that 3- substitution -2- indole ketone compounds, formula 2a shown in formula 1a are added in bottle are answered, reaction bulb is placed in
It is stirred to react under the conditions of certain temperature and air atmosphere, target product 3- hydroxyl -2- indoles is obtained through post-processing after the reaction was complete
Ketone compounds (I)；Reaction equation is as follows：
In the compound that formula 1a and Formulas I indicate, R1Indicate one or more substituent groups on phenyl ring that it is connected, each R1Each other solely
On the spot it is selected from hydrogen, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Acyl group, C1-C6Ester group, halogen, cyano, nitro, C3-C6Naphthenic base,
C5-C14Aryl, C5-C14Heteroaryl ,-NRaRb；Wherein, Ra, RbIt is independently from each other C1-C6Alkyl or hydrogen；
R2Indicate hydrogen, C1-C6Alkyl, halogen, cyano, C3-C6Naphthenic base, C5-C14Aryl, C5-C14Heteroaryl；
R3Indicate hydrogen, tertbutyloxycarbonyl (Boc), C1-C6Alkyl, C1-C6Acyl group, C3-C6Naphthenic base, C5-C14Aryl, C5-C14Virtue
Base-C1-C6Alkyl, C5-C14Heteroaryl；
Wherein, the hetero atom of the heteroaryl is selected from O, S or N；
And above-mentioned each alkyl, alkoxy, naphthenic base, aryl and heteroaryl can be further substituted with a substituent, it is described
Substituent group is selected from halogen or C1-C6Alkyl；
In the compound that formula 2a is indicated, the R4Indicate hydrogen, tertiary butyl,
2. according to the method described in claim 1, it is characterized in that, R1Indicate one or more substitutions on phenyl ring that it is connected
Base, each R1It is independently from each other hydrogen, C1-C6Alkyl, halogen, C1-C6Alkoxy, nitro, C5-C14Aryl；The wherein described C1-
C6Alkyl and/or C5-C14Aryl can be further substituted, and the substituent group is selected from halogen or C1-C6Alkyl；
R2Indicate hydrogen, C1-C6Alkyl, halogen, cyano, C5-C14Aryl, wherein the C1-C6Alkyl and/or C5-C14Aryl can be with
It is further substituted, the substituent group is selected from halogen or C1-C6Alkyl；
R3Indicate hydrogen, tertbutyloxycarbonyl (Boc), C1-C6Alkyl, C1-C6Acyl group, phenyl, benzyl, wherein the C1-C6Alkyl and/
Or C1-C6Acyl group, phenyl and/or benzyl can be further substituted, and the substituent group is selected from halogen or C1-C6Alkyl；
R4Preferably tertiary butyl.
3. method according to claim 1 or 2, which is characterized in that be preferably added dodecyl sulphate in the method
Sodium (SDS) is used as surfactant.
4. according to the method described in claim 1-3 any one, which is characterized in that the certain temperature is 40-100 DEG C.
5. according to the method described in claim 4, it is characterized in that, temperature is most preferably 60 DEG C.
6. according to the method for claim 1-5 any one, which is characterized in that the compound of the formula 1a is with formula 2a's
The molar ratio of compound is 1: 1~4；The compound of formula 1a and the molar ratio of SDS are 1: 0.1~0.3.
7. according to the method described in claim 1-6 any one, which is characterized in that the change of the compound and formula 2a of the formula 1a
The molar ratio for closing object is 1: 2；The compound of formula 1a and the molar ratio of SDS are 1: 0.2.
8. according to the method described in claim 1-7 any one, which is characterized in that the post-processing operation is as follows：It will be anti-
Reaction solution after the completion of answering is extracted with ethyl acetate, and organic phase is dried with anhydrous sodium sulfate, filters and be concentrated under reduced pressure removing solvent,
By residue through column chromatography for separation, eluting solvent is：Ethyl acetate/n-hexane obtains target product 3- hydroxyl -2- indole ketones
Compound (I).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1135576A (en) * | 1997-07-16 | 1999-02-09 | Kao Corp | Production of 3-alkylflavanonol derivative |
| CN103153951A (en) * | 2010-10-13 | 2013-06-12 | 默克专利股份公司 | Pyrrolidinones as MetAP-2 inhibitors |
| CN103613478A (en) * | 2013-10-25 | 2014-03-05 | 北京大学 | Synthetic method of alpha-hydroxyl carbonyl compound |
| CN107141246A (en) * | 2017-05-20 | 2017-09-08 | 宁波大学 | A kind of preparation method of Isatine derivatives |
-
2018
- 2018-02-07 CN CN201810158489.3A patent/CN108409630B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1135576A (en) * | 1997-07-16 | 1999-02-09 | Kao Corp | Production of 3-alkylflavanonol derivative |
| CN103153951A (en) * | 2010-10-13 | 2013-06-12 | 默克专利股份公司 | Pyrrolidinones as MetAP-2 inhibitors |
| CN103613478A (en) * | 2013-10-25 | 2014-03-05 | 北京大学 | Synthetic method of alpha-hydroxyl carbonyl compound |
| CN107141246A (en) * | 2017-05-20 | 2017-09-08 | 宁波大学 | A kind of preparation method of Isatine derivatives |
Non-Patent Citations (2)
| Title |
|---|
| GUNAGANTI NARESH ET AL.: "Silver(I)-Catalyzed Regioselective Construction of Highly Substituted α-Naphthols and Its Application toward Expeditious Synthesis of Lignan Natural Products", 《ORG. LETT.》 * |
| WEN-MING ZHU ET AL.: "TEMPO-Promoted C(sp3)-H Hydroxylation of 2-Oxindoles at Room Temperature", 《ASIAN J. ORG. CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776387A (en) * | 2019-03-14 | 2019-05-21 | 宁波大学 | The preparation method of 3- peroxy -2- indole ketone compound in a kind of water phase |
| CN109776387B (en) * | 2019-03-14 | 2022-04-05 | 宁波大学 | Preparation method of 3-peroxy-2-indolone compounds in aqueous phase |
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