CN108689895A - A kind of thioamide derivatives and preparation method thereof - Google Patents

A kind of thioamide derivatives and preparation method thereof Download PDF

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CN108689895A
CN108689895A CN201810385848.9A CN201810385848A CN108689895A CN 108689895 A CN108689895 A CN 108689895A CN 201810385848 A CN201810385848 A CN 201810385848A CN 108689895 A CN108689895 A CN 108689895A
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formula
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thioamide derivatives
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product
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CN108689895B (en
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陈万芝
张平顺
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings

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Abstract

The invention discloses a kind of thioamide derivatives, shown in structural formula such as formula (I) or formula (II);The present invention also provides the preparation methods of the thioamide derivatives, including:Using alkali metal salt as alkali, amine and alkene and sulphur are directly coupled, by the selection of alkali, same materials composite structure formula two kinds of different thioamide derivatives as shown in formula (I) or formula (II) can be used.Preparation method provided by the invention, raw material is cheap and easy to get, and synthetic method is simple, can substantially reduce cost.Thioamide derivatives provided by the invention can be applied to the fields such as bioactive molecule and pharmaceutical synthesis, and tool has been widely used.

Description

A kind of thioamide derivatives and preparation method thereof
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of thioamide derivatives and preparation method thereof.
Background technology
Compound containing thio amide structure is widely present in bioactive molecule and some drugs, is such as clinically used for The sulfonyl amine drug for the treatment of hyperthyroidism has carbimazole (CMZ), methylthiourea pyridine, methimazol (MMI) and propyl thiocarbamide pyridine (PTU)。
In addition, in organic synthesis, thioamides as a kind of important synthon, many organic compounds such as amide, Sulfur heterocyclic ring (such as thiophene, thiadiazoles, thiazole and thiazoline) amidine can be used as raw material by thioamides and be synthesized, therefore Chemist is also being continually striving to explore new structure and its new synthetic method based on thioamides.
Currently, including by method of the Material synthesis containing thioamide derivatives of organic amine:
(1) be coupled and obtain under potassium carbonate effect with aniline and benzaldehyde and sulphur (H.Xu, H.Deng, Z.Li, H.Xiang, X.Zhou, Eur.J.Org.Chem.2013,7054.), main problem existing for this method is benzene in reaction raw materials Formaldehyde easily pollutes the environment.(2) benzaldehyde and secondary amine and sulphur generated under the action of microwave (O.I.Zubruyev, N.Stiasni, C.O.Kappe, J.Comb.Chem.2003,5,145.), this method needs microwave to promote the progress of reaction, Industrialized production can increase production cost, while there are the potential impacts of ionising radiation to environment.(3) benzaldehyde and amide and sulphur Sulphur obtained under the catalytic action of alkali DBU (W.Liu, C.Cui, H.Liu, Beilstein J.Org.Chem.2015,11, 1721), the raw material in this method pollutes the environment and DBU is as highly basic, has very strong corrosivity, is wanted to process equipment Ask high.(4) benzene acetonitrile and N,N-dimethylformamide and sulphur generated under the catalytic action of copper (Y.Qu, Z.Li, H.Xiang, X.Zhou, Adv.Synth.Catal.2013,355,3141.), this method needs metallic copper as catalyst.(5) Benzylamine directly generates (T.B.Nguyen, L. Ermolenko, A.Al- at 110-130 DEG C with 2- phenyl ethylamines and sulphur Mourabit,Org.Lett.2012,14,4274.);This method is easy to operate, easy, but is suitable only for benzylamine, applicable surface It is narrow.(6) be coupled under pyridine effect with phenylacetylene and amine and sulphur and can also synthesize (T.B.M.Q.Tran, L.Ermolenko, A.Al-Mourabit, Org.Lett.2014,16,310.), but the raw material alkynes in this method is expensive, and production cost is high.
There is many deficiencies in above method:Including reaction agents useful for same toxicity or corrosivity relatively strong, raw material be not easy to obtain, Reaction process requires harshness, production cost height, environmental pollution etc..Therefore exploitation new method is needed to prepare thioamide derivatives.
Invention content
The present invention provides a kind of and its important, organic synthesis intermediate --- thioamide derivatives provide simultaneously Preparation method, it is most important that, preparation method provided by the invention can be closed by the selection of different alkali using same materials At entirely different thioamide derivatives.
Shown in the thioamide derivatives, structural formula such as formula (I) or formula (II):
Wherein, R1For aromatic radical;R3For H, C1~12Alkyl or aromatic radical;
R2The saturated alkyl or halogen atom for being 1~3 for H, carbon atom number.
The aromatic radical, abbreviation aryl refer to any functional group derived from simple aromatic rings or substituent group.It is most simple Aryl be phenyl (Phenyl), be used to describe unsubstituted aryl, but for summarizing and terse reason is containing substituted The aromatic rings of base is still referred to as aryl.
A kind of preparation method of thioamide derivatives, including:
In organic solvent, under inert gas shielding, potassium fluoride or acetic acid salt action, aromatic amine, alkene and sulphur are anti- It answers, it is after reaction, post-treated to obtain structural formula thioamide derivatives as shown in formula (I);Or,
In organic solvent, under the action of inert gas shielding, tripotassium phosphate, aromatic amine, alkene and sulfur reaction, instead It is post-treated to obtain structural formula thioamide derivatives as shown in formula (II) after answering;Or,
In organic solvent, under the action of inert gas shielding, carbonate or hydroxide, aromatic amine, alkene and sulphur Sulphur reacts, after reaction, post-treated to obtain structural formula thioamide derivatives as shown in formula (I) and (II);Or,
In organic solvent, under the action of inert gas shielding, tripotassium phosphate, carbonate or hydroxide, fatty amine/ Ammonium salt, alkene and sulfur reaction, it is after reaction, post-treated to obtain structural formula thioamide derivatives as shown in formula (II).
The ammonium salt is ammonium hydrogen carbonate;
The fatty amine is that carbon atom number is 1~12;
Shown in the structural formula of the aromatic amine such as formula (III):
Shown in the structural formula of the alkene such as formula (IV):
Wherein, R4Saturated alkyl, halogen atom, hydroxyl, nitro trifluoromethyl or the benzene oxygen for being 1~3 for H, carbon atom number Base;R2Definition and formula (I) or formula (II) in R2Definition it is identical.
The reaction principle of preparation method provided by the invention is:Sulphur S8S is first generated under the action of KF or acetate3From By base anion, the 1,2,3-trithiolane of amine substitution is formed with alkene addition in the presence of aromatic amine, is obtained after decomposition Structural formula thioamide derivatives as shown in formula (I).And aromatic amine/fatty amine/ammonium salt and alkene are in K3PO4The lower Mr. of effect At N- aryl phenyl ethylamine/N- alkyl phenyl ethylamine/phenyl ethylamine, then nitrogen-atoms ortho position methylene is aoxidized to form C=S keys by sulphur, from And obtain structural formula thioamide derivatives as shown in formula (II).And aromatic amine, alkene and sulphur S8In carbonate or hydroxide Under object effect, above-mentioned two classes reaction can occur simultaneously, generating structure formula thioamides as shown in formula (I) and formula (II) derives Object.But fatty amine/ammonium salt, alkene and sulphur S8Under the effect of tripotassium phosphate, carbonate or hydroxide, structure can be only generated Formula thioamide derivatives as shown in formula (II).
The molar ratio of the aromatic amine and alkene, sulphur is 1:1~4:1~6;Fatty amine/the ammonium salt and alkene, The molar ratio of sulphur is also 1:1~4:1~6.
The molar ratio of the potassium fluoride, tripotassium phosphate, acetate, carbonate or hydroxide and aromatic amine is 1~3:1; The molar ratio of the potassium fluoride, tripotassium phosphate, acetate, carbonate or hydroxide and fatty amine/ammonium salt is also 1~3:1.
Alkali metal salt is good as the catalytic action of alkali, and the yield of target product is high, while considering the cost of catalyst, described Acetate be preferably sodium acetate or potassium acetate;The carbonate is preferably sodium carbonate or potassium carbonate;The hydroxide Preferably sodium hydroxide or potassium hydroxide.
The reaction temperature is 60~120 DEG C, and the time of reaction is 10~30 hours;Further, it is reacted to increase Degree improves target product yield, and the reaction temperature is preferably 100~120 DEG C, and the time of reaction is preferably 24~30 small When.
The organic solvent is ethyl alcohol, dimethyl sulfoxide (DMSO) or acetone.
The dosage of the organic solvent, can be by the fully dispersed dissolving of raw material, generally without particularly severe requirement The Materials Solvents dosage of 100mg is 2.5mL or so.
The post-processing operation, including:It is filtered to remove insoluble matter, is washed, extraction is spin-dried for solvent, then uses column color Spectrum is detached.
Each step of post-processing of the present invention uses existing conventional method, and the eluent of extractant or pillar layer separation is Common organic solvent, if do not react with product can, preferably, extractant used is ethyl acetate;Column chromatography The eluent of separation is that volume ratio is 1:50-1:3 ethyl acetate and petroleum ether mixed liquor.
Thioamide derivatives provided by the invention can be applied to the fields such as bioactive molecule and pharmaceutical synthesis, have Extensive purposes.
Further, above-mentioned thioamide derivatives provided by the invention can be applied to prepare the sulfonyl amine for the treatment of hyperthyroidism Drug etc..
Compared with prior art, the present invention has the following advantages:
(1) amine and alkene and sulphur are directly coupled by the method for the present invention using alkali metal salt as alkali, by the selection of alkali, Two kinds of different thioamide derivatives can be synthesized with same materials;
(2) preparation method provided by the invention, easy to operate, easy, raw material is cheap and easy to get, the different sulphur of industrialized production For amide derivatives process equipment without change, process costs are greatly reduced.
Specific implementation mode
For a further understanding of the present invention, with reference to embodiment to a kind of thioamide derivatives provided by the invention and Preparation method is specifically described, and however, the present invention is not limited to these examples, and field technology personnel are in core of the present invention The non-intrinsically safe modifications and adaptations made under guiding theory, still fall within protection scope of the present invention.
Embodiment 1
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 73.2mg, is obtained, yield 95%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 2
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 60 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 9.3mg, is obtained, yield 12%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 3
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 120 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 42.4mg, is obtained, yield 55%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 4
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 10 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 43.2mg, is obtained, yield 56%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 5
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 30 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 73.2mg, is obtained, yield 95%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 6
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 17.4mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 61.7mg, is obtained, yield 80%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 7
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 52.2mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 74.0mg, is obtained, yield 96%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 8
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methyl of 35.5mg is added The sulphur of styrene, 9.6mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 27.0mg, is obtained, yield 35%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 9
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 142mg is added The sulphur of ethylene, 57.6mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 73.2mg, is obtained, yield 95%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 10
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the ethyl alcohol of 1.5mL.Under nitrogen protection, it stirs 24 hours for 100 DEG C.Reaction After be cooled to room temperature, be filtered to remove insoluble matter, wash, ethyl acetate extraction, directly cross silicagel column (ethyl acetate and oil The volume ratio of ether is 1:50-1:3) product 10.8mg, is obtained, yield 14%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 11
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the acetone of 1.5mL.Under nitrogen protection, it stirs 24 hours for 100 DEG C.Reaction After be cooled to room temperature, be filtered to remove insoluble matter, wash, ethyl acetate extraction, directly cross silicagel column (ethyl acetate and oil The volume ratio of ether is 1:50-1:3) product 15.4mg, is obtained, yield 20%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 12
In the Schlenk reaction tubes of dry 25mL, the 4- methylanilines of 32.1mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 68.7mg, is obtained, yield 95%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ2.36(s,3H),2.39(s,3H),7.20-7.23(m,4H), 7.58(d,J =8.0Hz, 2H), 7.75d, J=7.6Hz, 2H), 8.98 (br, 1H)13C NMR(100MHz, CDCl3):δ198.19, 141.88,140.22,136.93,136.61,129.61,129.24,126.77,124.00, 21.42.
Embodiment 13
In the Schlenk reaction tubes of dry 25mL, be added the aniline of 27.9mg, the 4- methyl styrenes of 71mg, The sulphur of 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, it stirs 24 hours for 100 DEG C.Instead It is cooled to room temperature after answering, is filtered to remove insoluble matter, washed, silicagel column (ethyl acetate and stone are directly crossed in ethyl acetate extraction The volume ratio of oily ether is 1:50-1:3) product 64.7mg, is obtained, yield 95%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.38 (s, 3H), 7.19 (d, J=6.8Hz, 2H), 7.26-7.28 (m, 1H), 7.38-7.45(m,2H),7.62-7.81(m,4H),9.05(br,1H).13C NMR(100MHz, CDCl3):δ198.30, 141.95,140.28,139.13,129.25,129.03,126.91,126.81,123.89, 21.44.
Embodiment 14
In the Schlenk reaction tubes of dry 25mL, the 4- tertiary butyls aniline of 44.8mg, the 4- methyl of 71mg is added The sulphur of styrene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 79.8mg, is obtained, yield 94%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 1.26 (s, 9H), 2.32 (s, 3H), 7.15 (d, J=7.6Hz, 2H), 7.37 (d, J=8.0Hz, 2H), 7.61 (d, J=8.0Hz, 2H), 7.68 (d, J=7.6Hz, 2H), 8.90 (br, 1H)13C NMR (100MHz,CDCl3):δ197.83,149.98,141.87,140.44,136.54, 129.27,126.73,125.93, 123.30,34.71,31.33,21.42.
Embodiment 15
In the Schlenk reaction tubes of dry 25mL, the 4- fluoroanilines of 33.3mg, the 4- methylbenzene second of 71mg is added The sulphur of alkene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, it stirs 24 hours for 100 DEG C. Be cooled to room temperature after reaction, be filtered to remove insoluble matter, wash, ethyl acetate extraction, directly cross silicagel column (ethyl acetate with The volume ratio of petroleum ether is 1:50-1:3) product 72.0mg, is obtained, yield 98%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,d6-DMSO):δ 2.37 (s, 3H), 7.28 (d, J=8.0Hz, 2H), 7.50 (d, J= 8.8Hz, 2H), 7.78 (d, J=8.0Hz, 2H), 7.87 (d, J=8.8Hz, 2H), 11.72 (br, 1H)13C NMR(100MHz, d6-DMSO):δ197.60,141.05,139.61,138.95,129.89,128.51, 128.38,127.55,125.91, 20.89.
Embodiment 16
In the Schlenk reaction tubes of dry 25mL, the 4- chloroanilines of 38.3mg, the 4- methylbenzene second of 71mg is added The sulphur of alkene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, it stirs 24 hours for 100 DEG C. Be cooled to room temperature after reaction, be filtered to remove insoluble matter, wash, ethyl acetate extraction, directly cross silicagel column (ethyl acetate with The volume ratio of petroleum ether is 1:50-1:3) product 70.0mg, is obtained, yield 92%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,d6-DMSO):δ 2.37 (s, 3H), 7.28 (d, J=8.0Hz, 2H), 7.50 (d, J= 8.8Hz, 2H), 7.78 (d, J=8.0Hz, 2H), 7.87 (d, J=8.8Hz, 2H), 11.72 (br, 1H)13C NMR(100MHz, d6-DMSO):δ197.60,141.05,139.60,138.95,129.89,128.51, 128.38,127.54,125.92, 20.88.
Embodiment 17
In the Schlenk reaction tubes of dry 25mL, the 4- bromanilines of 51.7mg, the 4- methylbenzene second of 71mg is added The sulphur of alkene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, it stirs 24 hours for 100 DEG C. Be cooled to room temperature after reaction, be filtered to remove insoluble matter, wash, ethyl acetate extraction, directly cross silicagel column (ethyl acetate with The volume ratio of petroleum ether is 1:50-1:3) product 86.9mg, is obtained, yield 95%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,d6-DMSO):δ 2.37 (s, 3H), 7.28 (d, J=8.0Hz, 2H), 7.63 (d, J= 8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 7.81 (d, J=8.4Hz, 2H), 11.71 (br, 1H)13C NMR(100MHz, d6-DMSO):δ197.57,141.07,139.61,139.36,131.32,128.52, 127.54,126.22,118.20, 20.88.
Embodiment 18
In the Schlenk reaction tubes of dry 25mL, the 4- nitroanilines of 41.4mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 44.1mg, is obtained, yield 54%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,d6-DMSO):δ 2.38 (s, 3H), 7.31 (d, J=8.0Hz, 2H), 7.77 (d, J= 8.0Hz, 2H), 8.21 (d, J=8.4Hz, 2H), 8.31 (d, J=9.2Hz, 2H), 12.06 (br, 1H)13C NMR(100MHz, d6-DMSO):δ198.89,145.87,144.04,141.53,139.80,128.61, 127.68,124.22,123.81, 20.92.
Embodiment 19
In the Schlenk reaction tubes of dry 25mL, the 4- hydroxyanilines of 32.7mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 67.8mg, is obtained, yield 93%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,d6-DMSO):δ 2.36 (s, 3H), 6.80 (d, J=8.8Hz, 2H), 7.26d, J= 8.0Hz, 2H), 7.56 (d, J=8.8Hz, 2H), 7.75d, J=8.4Hz, 2H), 9.58 (br, 1H), 11.46 (br, 1H)13C NMR(100MHz,d6-DMSO):δ196.16,155.51,140.56,139.66,131.64, 128.41,127.44, 125.82,114.78,20.85.
Embodiment 20
In the Schlenk reaction tubes of dry 25mL, the 4- 5-trifluoromethylanilines of 48.3mg, the 4- first of 71mg is added The sulphur of base styrene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 hours.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (second is directly crossed in ethyl acetate extraction The volume ratio of acetoacetic ester and petroleum ether is 1:50-1:3) product 80.5mg, yield 91%, reaction process such as following formula institute, are obtained Show:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,d6-DMSO):δ 2.38 (s, 3H), 7.30 (d, J=8.0Hz, 2H), 7.78-7.82 (m, 4H), 8.10 (d, J=7.2Hz, 2H), 11.91 (br, 1H)13C NMR(100MHz, d6-DMSO):δ198.37,143.55, (141.27,139.66,128.09,127.62,125.63 q, J=3.6Hz), 124.34,20.89.
Embodiment 21
In the Schlenk reaction tubes of dry 25mL, the 3- methylanilines of 32.1mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 69.4mg, is obtained, yield 96%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.31 (s, 6H), 7.02 (d, J=7.2Hz, 1H), 7.13 (d, J=6.8Hz, 2H), 7.21-7.25 (m, 1H), 7.39-7.54 (m, 2H), 7.67 (d, J=7.2Hz, 2H), 8.91 (br, 1H)13C NMR (100MHz,CDCl3):δ198.19,141.90,140.37,139.06,129.25, 128.85,127.77,126.76, 124.40,121.01,21.46,21.43.
Embodiment 22
In the Schlenk reaction tubes of dry 25mL, the 3- nitroanilines of 41.4mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 37.5mg, is obtained, yield 46%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.41 (s, 3H), 7.25 (d, J=9.2Hz, 2H), 7.60 (t, J=8.4Hz, 1H), 7.76 (d, J=7.6Hz, 2H), 8.12-8.17 (m, 2H), 8.65 (br, 1H), 9.15 (s, 1H)13C NMR (100MHz,CDCl3):δ199.34,148.44,142.68,140.06,129.76,129.60, 129.45,126.80, 121.31,118.73,21.47.
Embodiment 23
In the Schlenk reaction tubes of dry 25mL, the 2- chloroanilines of 38.1mg, the 4- methylbenzene second of 71mg is added The sulphur of alkene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, it stirs 24 hours for 100 DEG C. Be cooled to room temperature after reaction, be filtered to remove insoluble matter, wash, ethyl acetate extraction, directly cross silicagel column (ethyl acetate with The volume ratio of petroleum ether is 1:50-1:3) product 75.2mg, is obtained, yield 96%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.41 (s, 3H), 7.21-7.25 (m, 4H), 7.35 (t, J=7.6 Hz, 1H), 7.48 (dd, J=1.2,8.0Hz, 1H), 7.81 (d, J=7.6Hz, 2H), 9.29 (br, 1H)13C NMR(100MHz, CDCl3):δ198.04,142.25,135.86,129.56,129.40,127.40,127.20, 126.93,126.90, 125.07,21.45.
Embodiment 24
In the Schlenk reaction tubes of dry 25mL, the 2- ethyl aniline of 36.4mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 74.2mg, is obtained, yield 97%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 1.25 (t, J=7.6Hz, 3H), 2.42 (s, 3H), 2.66 (q, J=7.6Hz, 2H), 7.24 (d, J=7.6Hz, 2H), 7.30-7.35 (m, 3H), 7.49 (d, J=7.6Hz, 1H), 7.81 (d, J=7.6Hz, 2H),8.88(br,1H).13C NMR(100MHz,CDCl3):δ199.72, 142.09,139.91,139.28,137.19, 129.30,129.12,128.37,127.46,126.87,126.71, 24.52,21.47,14.38.
Embodiment 25
In the Schlenk reaction tubes of dry 25mL, the 2- phenoxybenzamines of 55.6mg, the 4- methyl of 71mg is added The sulphur of styrene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 88.0mg, is obtained, yield 92%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.38 (s, 3H), 6.94-6.97 (m, 1H), 7.07 (d, J=7.6 Hz, 2H), 7.16-7.21 (m, 5H), 7.36-7.40 (m, 2H), 7.67 (d, J=7.6Hz, 2H), 9.12 (br, 1H), 9.56 (s, 1H) .13C NMR(100MHz,CDCl3):δ196.88,156.13,148.13,141.82, 130.74,130.13,129.28, 126.77,124.29,123.35,123.04,118.86,118.00,21.41.
Embodiment 26
In the Schlenk reaction tubes of dry 25mL, the 2,6-DIPA of 53.2mg, the 4- of 71mg is added The sulphur of methyl styrene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, it stirs for 100 DEG C It mixes 24 hours.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column is directly crossed in ethyl acetate extraction (volume ratio of ethyl acetate and petroleum ether is 1:50-1:3) product 79.3mg, yield 85%, reaction process such as following formula, are obtained It is shown:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 1.21 (d, J=6.8Hz, 6H), 1.29 (d, J=6.8Hz, 6H), 2.44 (s, 3H), 3.05-3.12 (m, 2H), 7.27 (s, 2H), 7.29 (s, 2H), 7.42 (t, J=7.6Hz, 1H), 7.87 (d, J= 8.4Hz,2H),8.62(br,1H).13C NMR(100MHz,CDCl3):δ200.60, 145.92,142.12,138.84, 134.03,129.37,129.30,126.76,123.98,28.91,24.57,23.30, 21.46.
Embodiment 27
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- chlorobenzenes of 83.2mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 64.8mg, is obtained, yield 78%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,d6-DMSO):δ 3.79 (s, 3H), 7.00 (d, J=9.2Hz, 2H), 7.54 (d, J= 8.8Hz, 2H), 7.72 (d, J=8.8Hz, 2H), 7.86 (d, J=8.8Hz, 2H), 11.72 (br, 1H)13C NMR(100MHz, d6-DMSO):δ195.11,157.32,141.07,135.36,132.87,129.23, 127.95,125.60,113.58, 55.27.
Embodiment 28
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- fluorobenzene of 73.3mg is added The sulphur of ethylene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 65.0mg, is obtained, yield 83%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 3.83 (s, 3H), 6.94 (d, J=8.8Hz, 2H), 7.09 (t, J=8.4Hz, 2H), 7.57 (d, J=8.8Hz, 2H), 7.83-7.87 (m, 2H), 8.94 (br, 1H)13C NMR (100MHz,CDCl3):δ 196.96,164.60(d,JC-F=251.1Hz, 1C), 158.34,138.97,131.93,129.00 (d, JC-F=8.8Hz, 1C),125.75,115.56(d,JC-F=21.8Hz, 1C), 114.23,55.52.
Embodiment 29
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the tertiary fourths of 4- of 96.2mg is added The sulphur of base styrene, 38.4mg, the potassium fluoride of 35mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 hours.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (second is directly crossed in ethyl acetate extraction The volume ratio of acetoacetic ester and petroleum ether is 1:50-1:3) product 87.9mg, is obtained, yield 98%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 1.34 (s, 9H), 3.82 (s, 3H), 6.93 (d, J=9.2Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.78 (d, J=8.4Hz, 2H), 9.00 (br, 1H)13C NMR (100MHz,CDCl3):δ198.13,158.17,154.91,140.00,132.15, 126.61,125.71,125.57, 114.16,55.52,34.94,31.18.
Embodiment 30
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the tripotassium phosphate of 127mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 69.1mg, is obtained, yield 85%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.37 (s, 3H), 3.78 (s, 3H), 4.22 (s, 2H), 6.86 (d, J= 9.2Hz, 2H), 7.23 (s, 4H), 7.40 (d, J=9.2Hz, 2H), 8.45 (br, 1H)13C NMR(100 MHz,CDCl3):δ 201.59,158.24,137.91,131.76,131.49,130.14,129.62,125.55, 114.01,55.48,54.07, 21.20.
Embodiment 31
In the Schlenk reaction tubes of dry 25mL, the ammonium hydrogen carbonate of 23.7mg, the 4- methylbenzene second of 71mg is added The sulphur of alkene, 38.4mg, the potassium phosphate and 1.5mL dimethyl sulfoxide (DMSO)s of 127mg.Under nitrogen protection, it stirs 24 hours for 100 DEG C. Be cooled to room temperature after reaction, be filtered to remove insoluble matter, wash, ethyl acetate extraction, directly cross silicagel column (ethyl acetate with The volume ratio of petroleum ether is 1:50-1:3) product 22.3mg, is obtained, yield 45%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ2.35(s,3H),4.07(s,2H),6.73(br,1H), 7.05-7.08(m, 1H),7.14-7.20(m,2H),7.25-7.29(m,1H),7.80(br,1H).13C NMR (100MHz,CDCl3):δ 207.84,207.61,139.18,137.82,134.74,131.76,130.18,130.01, 129.37,129.23, 128.75,126.45,52.05,51.69,21.37,21.13.
Embodiment 32
In the Schlenk reaction tubes of dry 25mL, be added the n-butylamine of 21.9mg, the 4- methyl styrenes of 71mg, The sulphur of 38.4mg, the potassium phosphate and 1.5mL dimethyl sulfoxide (DMSO)s of 127mg.Under nitrogen protection, it stirs 24 hours for 100 DEG C.Reaction After be cooled to room temperature, be filtered to remove insoluble matter, wash, ethyl acetate extraction, directly cross silicagel column (ethyl acetate and oil The volume ratio of ether is 1:50-1:3) product 41.1mg, is obtained, yield 62%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 0.88 (t, J=7.2Hz, 2H), 1.22-1.31 (m, 2H), 1.47-1.54 (m, 2H), 2.36 (s, 3H), 3.58-3.63 (m, 2H), 4.10 (s, 2H), 6.98 (br, 1H), 7.12 (d, J=8.0Hz, 2H), 7.19 (d, J=7.6Hz, 2H)13C NMR(100MHz,CDCl3):δ201.98, 137.70,131.54,129.98, 129.56,52.77,45.91,29.82,21.15,20.04,13.69.
Embodiment 33
In the Schlenk reaction tubes of dry 25mL, the 4- methylanilines of 32.3mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the tripotassium phosphate of 127mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 53.6mg, is obtained, yield 70%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.33 (s, 3H), 2.38 (s, 3H), 4.23 (s, 2H), 7.15 (d, J= 8.4Hz, 2H), 7.23 (s, 4H), 7.40 (d, J=8.4Hz, 2H), 8.46 (br, 1H)13C NMR(100 MHz,CDCl3):δ 201.52,137.92,137.01,135.99,131.76,130.15,129.62,129.45, 123.78,54.34,21.19, 21.15.
Embodiment 34
In the Schlenk reaction tubes of dry 25mL, the 4- chloroanilines of 38.3mg, the 4- methylbenzene second of 71mg is added The sulphur of alkene, 38.4mg, the tripotassium phosphate of 127mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 are small When.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid second is directly crossed in ethyl acetate extraction The volume ratio of ester and petroleum ether is 1:50-1:3) product 61.9mg, is obtained, yield 75%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.38 (s, 3H), 4.23 (s, 2H), 7.23 (s, 4H), 7.30 (d, J= 8.8Hz, 2H), 7.51 (d, J=8.8Hz, 2H), 8.41 (br, 1H)13C NMR(100MHz,CDCl3): δ201.89, 138.14,136.95,132.16,131.43,130.27,129.61,128.97,124.92,54.58, 21.20.
Embodiment 35
In the Schlenk reaction tubes of dry 25mL, the 4- tertiary butyls aniline of 44.8mg, the 4- methyl of 71mg is added The sulphur of styrene, 38.4mg, the tripotassium phosphate of 127mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 hours.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (second is directly crossed in ethyl acetate extraction The volume ratio of acetoacetic ester and petroleum ether is 1:50-1:3) product 65.0mg, is obtained, yield 73%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ1.28(s,9H),2.36(s,3H),4.23(s,2H),7.22(s, 4H), 7.35 (d, J=8.8Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 8.46 (br, 1H)13C NMR(100 MHz,CDCl3):δ 201.13,150.08,137.93,135.90,131.73,130.15,129.62,125.76, 123.19,54.47,34.64, 31.28,21.19.
Embodiment 36
In the Schlenk reaction tubes of dry 25mL, the 3- methylanilines of 32.1mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the tripotassium phosphate of 127mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 44.4mg, is obtained, yield 58%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.33 (s, 3H), 2.37 (s, 3H), 4.24 (s, 2H), 7.04 (d, J= 8.0Hz, 1H), 7.21-7.23 (m, 5H), 7.32 (s, 1H), 7.36 (d, J=8.0Hz, 1H), 8.41 (br, 1H)13C NMR (100MHz,CDCl3):δ200.98,138.43,137.90,137.49,131.15,129.70, 129.14,128.21, 127.36,123.69,120.35,54.05,20.87,20.69.
Embodiment 37
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the tertiary fourths of 4- of 96.2mg is added The sulphur of base styrene, 38.4mg, the tripotassium phosphate of 127mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, it stirs for 100 DEG C It mixes 24 hours.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column is directly crossed in ethyl acetate extraction (volume ratio of ethyl acetate and petroleum ether is 1:50-1:3) product 70.4mg, yield 75%, reaction process such as following formula, are obtained It is shown:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 1.33 (s, 9H), 3.78 (s, 3H), 4.23 (s, 2H), 6.86 (d, J= 8.8Hz, 2H), 7.28 (d, J=8.4Hz, 2H), 7.39-7.44 (m, 4H), 8.47 (br, 1H)13C NMR (100MHz, CDCl3):δ201.68,158.28,151.10,131.76,131.52,129.41,126.40,125.69, 114.03, 55.49,53.99,34.64,31.33.
Embodiment 38
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium acetate of 58.9mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 38.6mg, is obtained, yield 50%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 39
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium carbonate of 82.8mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 21.6mg, is obtained, yield 28%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 40
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium carbonate of 82.8mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 16.3mg, is obtained, yield 20%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.37 (s, 3H), 3.78 (s, 3H), 4.22 (s, 2H), 6.86 (d, J= 9.2Hz, 2H), 7.23 (s, 4H), 7.40 (d, J=9.2Hz, 2H), 8.45 (br, 1H)13C NMR(100 MHz,CDCl3):δ 201.59,158.24,137.91,131.76,131.49,130.14,129.62,125.55, 114.01,55.48,54.07, 21.20.
Embodiment 41
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium hydroxide of 34mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 11.6mg, is obtained, yield 15%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.40 (s, 3H), 2.83 (s, 3H), 6.95 (d, J=9.2Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.60 (d, J=8.8Hz, 2H), 7.77 (d, J=8.0Hz, 2H), 8.95 (br, 1H)13C NMR (100MHz,CDCl3):δ198.23,158.20,141.90,140.06,132.12, 129.26,126.75,125.77, 114.18,55.51,21.42.
Embodiment 42
In the Schlenk reaction tubes of dry 25mL, the 4- aminoanisoles of 37mg, the 4- methylbenzenes of 71mg is added The sulphur of ethylene, 38.4mg, the potassium hydroxide of 34mg and the dimethyl sulfoxide (DMSO) of 1.5mL.Under nitrogen protection, 100 DEG C of stirrings 24 Hour.It is cooled to room temperature after reaction, is filtered to remove insoluble matter, wash, silicagel column (acetic acid is directly crossed in ethyl acetate extraction The volume ratio of ethyl ester and petroleum ether is 1:50-1:3) product 15.4mg, is obtained, yield 19%, reaction process is shown below:
Nuclear magnetic resonance spectroscopy is carried out to the product that the present embodiment is prepared:
1H NMR(400MHz,CDCl3):δ 2.37 (s, 3H), 3.78 (s, 3H), 4.22 (s, 2H), 6.86 (d, J= 9.2Hz, 2H), 7.23 (s, 4H), 7.40 (d, J=9.2Hz, 2H), 8.45 (br, 1H)13C NMR(100 MHz,CDCl3):δ 201.59,158.24,137.91,131.76,131.49,130.14,129.62,125.55, 114.01,55.48,54.07, 21.20。

Claims (10)

1. shown in a kind of thioamide derivatives, structural formula such as formula (I) or formula (II):
Wherein, R1For aromatic radical;R3For H, C1~12Alkyl or aromatic radical;
R2The saturated alkyl or halogen atom for being 1~3 for H, carbon atom number.
2. the preparation method of thioamide derivatives according to claim 1, including:
In organic solvent, under inert gas shielding, potassium fluoride or acetic acid salt action, aromatic amine, alkene and sulfur reaction, instead It is post-treated to obtain structural formula thioamide derivatives as shown in formula (I) after answering;Or,
In organic solvent, under the action of inert gas shielding, tripotassium phosphate, aromatic amine, alkene and sulfur reaction, reaction knot Shu Hou, it is post-treated to obtain structural formula thioamide derivatives as shown in formula (II);Or,
In organic solvent, under the action of inert gas shielding, carbonate or hydroxide, aromatic amine, alkene and sulphur are anti- It answers, it is after reaction, post-treated to obtain structural formula thioamide derivatives as shown in formula (I) and (II);Or,
In organic solvent, under the action of inert gas shielding, tripotassium phosphate, carbonate or hydroxide, ammonium salt/fat Amine, alkene and sulfur reaction, it is after reaction, post-treated to obtain structural formula thioamide derivatives as shown in formula (II).
3. the preparation method of thioamide derivatives according to claim 2, which is characterized in that the ammonium salt is carbonic acid Hydrogen ammonium;
The fatty amine is that carbon atom number is 1~12;
Shown in the structural formula of the aromatic amine such as formula (III):
Shown in the structural formula of the alkene such as formula (IV):
Wherein, R4Saturated alkyl, halogen atom, hydroxyl, nitro trifluoromethyl or the phenoxy group for being 1~3 for H, carbon atom number;R2 Definition and formula (I) or formula (II) in R2Definition it is identical.
4. the preparation method of thioamide derivatives according to claim 2, which is characterized in that the potassium fluoride, phosphoric acid The molar ratio of tripotassium, acetate, carbonate or hydroxide and aromatic amine is 1~3:1;The potassium fluoride, tripotassium phosphate, acetic acid The molar ratio of salt, carbonate or hydroxide and fatty amine is 1~3:1;The potassium fluoride, tripotassium phosphate, acetate, carbonate Or the molar ratio of hydroxide and ammonium salt is 1~3:1.
5. the preparation method of thioamide derivatives according to claim 4, which is characterized in that the acetate is vinegar Sour sodium or potassium acetate;The carbonate is sodium carbonate or potassium carbonate;The hydroxide is sodium hydroxide or potassium hydroxide.
6. the preparation method of thioamide derivatives according to claim 2, which is characterized in that the aromatic amine/fat The molar ratio of fat amine/ammonium salt and alkene, sulphur is 1:1~4:1~6.
7. the preparation method of thioamide derivatives according to claim 2, which is characterized in that the reaction temperature is 60~120 DEG C, the time of reaction is 10~30 hours.
8. the preparation method of thioamide derivatives according to claim 2, which is characterized in that the organic solvent is second Alcohol, dimethyl sulfoxide (DMSO) or acetone.
9. the preparation method of thioamide derivatives according to claim 2, which is characterized in that the post-processing includes Filtering, washing, extraction and pillar layer separation, it is 1 that the eluent of the pillar layer separation, which is volume ratio,:50-1:3 ethyl acetate With petroleum ether mixed liquor.
10. application of the thioamide derivatives according to claim 1 in the sulfonyl amine drug for preparing treatment hyperthyroidism.
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CN111303079A (en) * 2020-02-02 2020-06-19 郑州大学 Method for aqueous phase synthesis of thioamide by promoting elemental sulfur with mixed alkali
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