CN106674081A - Synthetic method of 3-methylthio indole derivative - Google Patents
Synthetic method of 3-methylthio indole derivative Download PDFInfo
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- CN106674081A CN106674081A CN201611173110.3A CN201611173110A CN106674081A CN 106674081 A CN106674081 A CN 106674081A CN 201611173110 A CN201611173110 A CN 201611173110A CN 106674081 A CN106674081 A CN 106674081A
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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
Abstract
The invention discloses a synthetic method of 3-methylthio indole derivative. In a condition that thiourea and an indole derivative are used as raw materials, iodine and potassium iodide are used as catalysts, and excessive methanol is used as a solvent, a reaction is fully carried out at a room temperature; a sodium hydroxide solution whose mass ratio is 20% is added and heated to 50 DEG C for ten minutes, and iodomethane is added at a room temperature for carrying out a full reaction; after the reaction ends, a reaction solution is separated and purified in order to obtain the 3-methylthio indole derivative. The method has the advantages of simple and safe process and operation, high reaction conversion rate, economical used raw materials, low "three wastes (waste gas, waste water and industrial residue)", environmental friendliness without metal catalysis, and new application of C-H activation.
Description
Technical field
The present invention relates to organic synthesis field, and in particular to have thiourea and iodomethane synthesis 3- methylthioindole analog derivatives
Method.
Background technology
Aromatic yl sulfide is very important as the basic composition of natural materials, medicine and functional material.Therefore, develop
Effectively method becomes the focus of people's research in recent years to construct C-S keys.Wherein, aryl halide is transition metal-catalyzed with mercaptan
Cross-coupling have become one of most important method in the synthesis of aromatic yl sulfide.Sulfidomethyl is used as a kind of auxochrome group
The optical property of compound can be improved.In recent years, greatly concern is caused by the direct sulfenylations of C-H.This
The method of kind can more effectively synthesize and simplify operating procedure.Various sulfurous acid reagents, such as disulphide, sulfenyl halogen, sulfur
Alcohol and arylsulfonyl cyanide are smoothly added electron rich aromatic hydrocarbons.This method is also successfully used for the sulfenylation of indole, and
And various 3- substituted indoles are selectively obtained, can be used to as the effective for the treatment of cancer, acquired immune deficiency syndrome (AIDS), heart disease and allergy
Medicine.Mercaptan, disulphide and other active sulfur reagents can be reacted under the metal such as catalysis such as copper, ferrum and palladium salt with indole.
Sulfinic acid sodium salt is stable, it is easy to processed, and is widely used as sulfonyl agent.Indole and its derivant are extensively divided
Cloth all contains indole ring in nature, in many native compounds, and vital movement is closely related with some indole derivativeses, institute
It is a kind of critically important heterocyclic compound with indole.
For example：
1 (Chen S Q, Wang Q M, Xu P C, et al.Iodine-promoted selective 3- of document
selanylation and 3-sulfenylation of indoles with dichalcogenides under mild
conditions[J].Phosphorus Sulfur&Silicon&the Related Elements,2015,191(1):00-
00.) just by foreign scholar Ranken when this method its tangible 1989, Paul and Mckinnie B.Gary are on JOC
Such article was delivered, the method is most original, other mechanism used by method below are substantially in the method
Complete on basis, its reaction equation is as follows：
2 (Teresa A.Unzner, Thomas Magauer.Carbon-fluorine bond activation of document
for the synthesis offunctionalized molecules[J].Tetrahedron Letters,2015,56:
877-883.) by aryl halide and DMSO reaction production sulfidomethyls, one has been delivered on TL within 2015 with copper as mediation
Use DMSO and aryl halide there is sulfomethylation reaction.With copper fluoride in the reaction, Copper diiodide etc. is medium, adds fluorination
Zinc reacts, and reaction temperature is 130 DEG C, and time 10h, yield can reach more than 80% substantially, and its reaction equation is as follows：
3 (Azizi N, Amiri AK, Bolourtchian M, et al.Agreen and highly of document
efficient alkylation ofthiols in water[J].Journal ofthe Iranian Chemical
Society,2009,6(4):749-753.) there is substitution reaction with iodomethane by mercaptan, the synthesis of this type has had a lot
Scientific research personnel does, is that this we representative from a comparison, is published on Green Chemistry periodical in 2009
Piece article.The reaction is more gentle, the aqueous solution for adding potassium carbonate is stirred at room temperature, but the yield of reaction is very high.So
What this method was substantially presently most approved by everybody at last, its reaction equation is as follows：
4 (Xiao F, Xie H, Liu S, et al.ChemInform Abstract of document:Iodine‐Catalyzed
Regioselective Sulfenylation of Indoles with Sodium Sulfinates.[J].Organic
Letters,2014,16(1):A sulfidomethyl is directly directly connected on the three of indole by methyl sulfinate 50-3.),
Fuhongxiao in 2014, Hao Xie, Saiwen Liu, and Guo-Jun Deng have delivered one with catalysis of iodine, sulfinic acid sodium
There is the article of vulcanization reaction with indole reaction on three of indole in salt.Herein using iodine as catalyst, DMSO is used as oxygen
Agent, toluene are solvent, at 110 DEG C, vulcanization reaction occur on indole three under conditions of nitrogen protection, and the reaction is in nothing
The selectivity of carry out under conditions of metal catalytic and reaction is fairly good, yield also substantially all more than 60%, its reaction equation
It is as follows：
But can all there are some drawbacks in the several method of the above：
(1) serious environmental problem can be produced using the big mercaptan of high-purity zest taste, while also having in safety
Problem
(2) superfluous DMSO can not reach recycling, and substantial amounts of discharge can produce pollution to environment, not meet greenization
Developing direction.
Therefore, in order to find more suitably sulphur source, it is to avoid participating in reaction using the reagent having greater environmental impacts has non-
Often important realistic meaning.
The content of the invention
It is an object of the invention to provide a kind of rational technology, hypotoxicity, good product quality via thiourea and iodomethane
The method of synthesis methylthioindole derivant.
Realization the technical scheme is that：
A kind of 3- methylthioindoles derivative synthesizing process, method is：
The first step, using the indole derivativeses III of III sum of thiourea as raw material, iodine and potassium iodide are used as catalyst, excessive first
Alcohol is fully reacted under room temperature as solvent；
Second step, is heated after adding the sodium hydroxide solution that mass fraction is 20%；
3rd step, adds iodomethane and fully reacts at room temperature, and after reaction terminates, the separated purification of reactant liquor obtains 3-
Methylthioindole derivatives I
In formula I or formula III, R is selected from one of following：Hydrogen, 5 (F), 6 (F), 7 (methyl)
The reaction equation that adopts of the present invention for：
In the present invention, the mol ratio of thiourea II and indole derivatives III is 2：1.
Further, the mol ratio of the consumption of the consumption and indole derivatives III of catalyst potassium iodide and iodine is 1：1.
Further, 30-100 times for III mole of indole derivatives of the consumption of solvent methanol, preferably 50-80
Times.
Further, mass fraction is 20% sodium hydroxide solution, and consumption is the 10-30 of III mole of indole derivativeses
Times.
Further, the mol ratio of the consumption of iodomethane consumption and indole derivatives III is 1：1.
Further, first step reaction temperature is 10-50 DEG C, and preferably 20-30 DEG C, second step reaction temperature is 40-60
DEG C, preferably 45-50 DEG C, three-step reaction temperature is 10-50 DEG C, preferably 20-30 DEG C.
In the present invention, the response time needed for the first step be 8-24h, preferably 10-12h, second step reaction needed for when
Between be 10-50min, the preferred time be 10-20min, the time needed for three-step reaction be 1-5h, preferred position 1-2h.
In 3rd step, the separated purification process of reactant liquor is：After reaction terminates, reactant liquor adds diluted ethyl acetate, satisfies
With brine It 3 times, separation takes organic layer, and the vacuum distillation Jing after anhydrous sodium sulfate drying removes solvent.Crude product is via post
Chromatography.Wherein column chromatography adopts eluant for ethyl acetate and petroleum ether mixed liquor, and the two volume ratio is 15：1.
Compared with prior art, its remarkable advantage is the present invention：
(1) of the invention to avoid using the substrates such as DMSO, disulfide, the three wastes are few, environmental friendliness.
(2) without the need for metal catalytic, it is the application of hydrocarbon priming reaction, and required raw material economics material benefit.
(4) the method reaction conversion rate is high, and the condition needed for reaction is simple, and it is high that easily separated purification obtains product purity.
Description of the drawings
Fig. 1 is the 1H NMR figures of 3- methylthioindoles；
Fig. 2 is the 13C NMR figures of 3- methylthioindoles；
Fig. 3 is the 1H NMR figures of the fluoro- 3- methylthioindoles of 5-；
Fig. 4 is the 13C NMR figures of the fluoro- 3- methylthioindoles of 5-；
Fig. 5 is the 1H NMR figures of the fluoro- 3- methylthioindoles of 6-；
Fig. 6 is the 13C NMR figures of the fluoro- 3- methylthioindoles of 6-；
Fig. 7 is the 1H NMR figures of 7- methyl -3- methylthioindoles；
Fig. 8 is the 13C NMR figures of 7- methyl -3- methylthioindoles.
Specific embodiment
For a better understanding of the present invention, below by specific embodiment illustrating technical scheme.
Embodiment 1
2.34g (20mmol) indole, 6.08g (40mmol) thiourea, 3.32g (20mmol) iodate are added in the reactor
Potassium, 5.08g (20mmol) iodine, 60ml methanol, after stirring 12h at normal temperatures, the sodium hydroxide for adding mass ratio to be 20% is water-soluble
Liquid 20ml is heated to 50 DEG C of 10min, adds 1.2ml, 20mmol, iodomethane, normal-temperature reaction 1h.After reaction terminates, reaction
Liquid adds 100mL diluted ethyl acetates, saturated common salt water washing 3 times, separation to take organic layer, reduces pressure Jing after anhydrous sodium sulfate drying
Solvent is distilled off.Via column chromatography wherein, eluant is ethyl acetate and petroleum ether mixed liquor to crude product, and the two volume ratio is
15：1, isolated 3- methylthioindoles 2.96g, yield is 91%.
3- methylthioindole 1HNMR figures are shown in Fig. 1, and 3- methylthioindole 13C NMR figures are shown in Fig. 2.
1H NMR (500MHz, CDCl3) δ 8.18 (s, 1H), 7.84 (d, J=7.5Hz, 1H), 7.36 (d, J=7.5Hz,
1H),7.33–7.24(m,3H),2.43(s,3H)；
13C NMR (126MHz, CDCl3) δ 136.47 (s), 129.74 (s), 128.63 (d, J=53.1Hz), 128.07
(s), 122.87 (s), 120.51 (s), 119.34 (s), 111.81 (s), 108.03 (s), 77.43 (d, J=31.9Hz),
77.05(s),20.38(s).
Embodiment 2
2.7g (20mmol) 5- fluoro indoles, 6.08g (40mmol) thiourea, 3.32g (20mmol) iodine are added in the reactor
Change potassium, 5.08g (20mmol) iodine, 60ml methanol, after stirring 12h at normal temperatures, add the sodium hydroxide that mass fraction is 20%
Aqueous solution 20ml is heated to 50 DEG C of 10min, adds 1.2ml, the iodomethane of 20mmol, normal-temperature reaction 1h.After reaction terminates, instead
Liquid is answered to add 100mL diluted ethyl acetates, saturated common salt water washing 3 times, separation to take organic layer, subtract Jing after anhydrous sodium sulfate drying
Pressure is distilled off solvent.Crude product is ethyl acetate and petroleum ether mixed liquor via column chromatography, eluant, and the two volume ratio is
15：1, isolated 5- fluorine 3- methylthioindole 3.0g, yield is 83%.
The fluoro- 3- methylthioindoles 1H NMR figures of 5- are shown in Fig. 3, and the fluoro- 3- methylthioindoles 13C NMR figures of 5- are shown in Fig. 4
1HNMR (500MHz, CDCl3) δ 8.26 (s, 1H), 7.43 (dd, J=9.3,2.4Hz, 1H), 7.37 (d, J=
2.3Hz, 1H), 7.31 (dd, J=8.8,4.2Hz, 1H), 7.01 (td, J=9.0,2.5Hz, 1H), 2.37 (s, 3H)；
13C NMR (126MHz, CDCl3) δ 159.44 (s), 157.57 (s), 132.83 (s), 129.70 (d, J=
20.5Hz), 112.35 (d, J=8.7Hz), 111.42 (s), 111.21 (s), 108.47 (s), 104.48 (s), 104.29 (s),
77.39(s),77.13(s),76.88(s),20.32(s).
Embodiment 3
2.7g (20mmol) 6- fluoro indoles, 6.08g (40mmol) thiourea, 3.32g (10mmol) iodine are added in the reactor
Change potassium, 5.08g (20mmol) iodine, 60ml methanol, after stirring 12h at normal temperatures, add the sodium hydroxide that mass fraction is 20%
Aqueous solution 20ml is heated to 50 DEG C of 10min, adds 1.2ml, the iodomethane of 20mmol, normal-temperature reaction 1h.After reaction terminates, instead
Liquid is answered to add 100mL diluted ethyl acetates, saturated common salt water washing 3 times, separation to take organic layer, subtract Jing after anhydrous sodium sulfate drying
Pressure is distilled off solvent.Crude product is ethyl acetate and petroleum ether mixed liquor via column chromatography, eluant, and the two volume ratio is
15：1, isolated 6 fluoro- 3- methylthioindoles 2.6g, yield is 72%.
The fluoro- 3- methylthioindoles 1H NMR figures of 6- are shown in Fig. 5, and the fluoro- 3- methylthioindoles 13C NMR figures of 6- are shown in Fig. 6
1HNMR (500MHz, CDCl3) δ 8.18 (s, 1H), 7.68 (dd, J=8.7,5.3Hz, 1H), 7.30 (d, J=
2.4Hz, 1H), 7.09 (dd, J=9.4,2.2Hz, 1H), 6.98 (ddd, J=9.5,8.9,2.2Hz, 1H), 2.39 (s, 3H)；
13C NMR (126MHz, CDCl3) δ 127.92 (s), 120.22 (d, J=9.9Hz), 97.95 (d, J=
26.4Hz),77.74–76.59(m),76.59–76.29(m),20.25(s).
Embodiment 4
2.62g (20mmol) 7- methylindole, 6.08g (40mmol) thiourea, 3.32g (10mmol) are added in the reactor
Potassium iodide, 5.08g (20mmol) iodine, 60ml methanol, after stirring 12h at normal temperatures, add the hydroxide that mass fraction is 20%
Sodium water solution 20ml is heated to 50 DEG C of 10min, adds 1.2ml, the iodomethane of 20mmol, normal-temperature reaction 1h.After reaction terminates,
Reactant liquor adds 100mL diluted ethyl acetates, and saturated common salt water washing 3 times, separation take organic layer, Jing after anhydrous sodium sulfate drying
Vacuum distillation removes solvent.Crude product is ethyl acetate and petroleum ether mixed liquor via column chromatography, eluant, and the two volume ratio is
15：1, isolated 3- methylthioindoles 2.98g, yield is 84%.
7- methyl -3- methylthioindole 1H NMR figures are shown in Fig. 7, and 7- methyl -3- methylthioindole 13C NMR figures are shown in Fig. 8
1H NMR (500MHz, CDCl3) δ 8.13 (s, 1H), 7.66 (d, J=7.9Hz, 1H), 7.29 (d, J=2.3Hz,
1H), 7.17 (t, J=7.5Hz, 1H), 7.08 (d, J=7.0Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H)；
13C NMR(126MHz,CDCl3)δ136.01(s),128.42(s),127.65(s),123.39(s),120.79
(d, J=26.2Hz), 117.07 (s), 108.71 (s), 78.03-76.48 (m), 20.35 (s), 16.54 (s).
Above-described embodiment limits the present invention never in any form, every to be obtained by the way of equivalent or equivalent transformation
Technical scheme all fall within protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of 3- methylthioindoles derivant, it is characterised in that the method is：
The first step, using the indole derivativeses III of III sum of thiourea as raw material, used as catalyst, excessive methanol is made for iodine and potassium iodide
For solvent, fully react under room temperature；
Second step, is heated after adding the sodium hydroxide solution that mass fraction is 20%；
3rd step, adds iodomethane and fully reacts at room temperature, and after reaction terminates, the separated purification of reactant liquor obtains 3- first sulfur
Base indole derivativeses I；
Wherein, in formula I or formula III, R is selected from one of following：Hydrogen, 5 (F), 6 (F), 7 (methyl).
2. the method for claim 1, it is characterised in that the mol ratio of III consumption of described thiourea III and indole derivativeses
For 1：2.
3. the method for claim 1, it is characterised in that the consumption and indoles of described catalyst potassium iodide and iodine spreads out
The mol ratio of biological III consumption is 1：1.
4. the method for claim 1, it is characterised in that described solvent methanol, consumption rub for indole derivatives III
30-100 times of that amount.
5. the method for claim 1, it is characterised in that described mass fraction is 20% sodium hydroxide solution, uses
Measure 10-30 times for III mole of indole derivatives.
6. the method for claim 1, it is characterised in that the consumption of described iodomethane consumption and indole derivatives III
Mol ratio be 1：1.
7. the method for claim 1, it is characterised in that the temperature needed for first step reaction is 20-30 DEG C, and second step adds
Temperature needed for heat is 45-50 DEG C, and the temperature needed for the 3rd step is 20-30 DEG C.
8. the method for claim 1, it is characterised in that the response time needed for the first step is 8-24h, second step reaction
The required time is 10-50min, and the response time needed for the 3rd step is 1-5h.
9. the method for claim 1, it is characterised in that the separated purification process of the reactant liquor is：After reaction terminates,
Reactant liquor adds diluted ethyl acetate, saturated common salt water washing 3 times, separation to take organic layer, reduces pressure Jing after anhydrous sodium sulfate drying
Solvent is distilled off, and adds eluant column chromatography for separation to be carried out to crude product.
10. method as claimed in claim 9, it is characterised in that eluant is ethyl acetate and petroleum ether mixed liquor, the two body
Product is than being 15：1 to 20：1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109942478A (en) * | 2017-12-21 | 2019-06-28 | 南京理工大学 | A kind of synthetic method of 3- methylthioindole analog derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109942478A (en) * | 2017-12-21 | 2019-06-28 | 南京理工大学 | A kind of synthetic method of 3- methylthioindole analog derivative |
| CN109942478B (en) * | 2017-12-21 | 2022-07-22 | 南京理工大学 | Synthetic method of 3-methylthio indole derivative |
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