CN107141279B - A kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative - Google Patents
A kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative Download PDFInfo
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention relates to thiophene derivant preparation method technical fields, and in particular to a kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative.A kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative of the present invention, include the following steps: (1) in the reactor, 3:1:0.1:2.5:0.1:0.2 sequentially adds cyclonene, thiophene or substituted thiophene, palladium chloride, silver carbonate, N- acetoglycocoll and silver hexafluoroantimonate in molar ratio, solvent is added to dissolve reactant, it is uniformly mixed, is then reacted 5~48 hours under the conditions of 60~120 DEG C at room temperature；(2) reactor is cooled to room temperature after the reaction was completed, is dissolved with ethyl acetate, successively washed with saturated ammonium chloride and saturated sodium-chloride water solution, after organic phase is dried over anhydrous sodium sulfate, filtering, solvent is removed in rotation on a rotary evaporator；(3) rotation is gone to the residue silica gel column chromatography separating purification after solvent, target product is collected, rotates away solvent, oil pump is drained.
Description
Technical field
The present invention relates to thiophene derivant preparation method technical fields, and in particular to a kind of 3- (thiophene -2- base) hexamethylene -2-
The preparation method of ketenes derivative.
Technical background
Thiophene is important aromatic heterocycle compounds, and derivative is conduct in various bioactive molecules and functional material
Key component [referring to: (a) Acc.Chem.Res.2001,34,359-369；(b)Angew.Chem.,Int.Ed.2005,44,
5452–5456.].Substituted phenol derivatives are that a kind of very important chemical intermediate is widely used in preparing various medicines
Object, pesticide, polymer and Field of Fine Chemicals.However replaced due to the strong ortho para position effect by phenolic hydroxy, meta position
Phenolic compound, which usually compares, to be difficult to synthesize.Develop in recent years using 3- replace hexamethylene -2- ketenes analog derivative pass through into
Phenolic compound (the Angew.Chem.Int.Ed.2013,52,3672-3675 that one step oxidation preparation meta position replaces；Green
Chem.,2016,18,6462–6467).However, hexamethylene -2- the ketene compound that 3- replaces at present usually requires pre- function dough
Substrate, could be prepared by two steps or three steps.The C-H/C-H oxidative coupling reaction of palladium chtalyst prepares the hexamethylene -2- of 3- substitution
Ketene is undoubtedly a kind of most economical and most succinct reaction route of step, however cyclonene as coupling reagent in palladium chtalyst
Heck reaction in could occur β-hydrogen elimination reaction ipsilateral due to the hydrogen on the palladium intermediate and β-carbon of generation, and ring
Tension makes carbon-palladium key rotate freely limited (Angew.Chem.Int.Ed.2013,52,3672-3675), at present transition metal
The cyclonene of catalysis and the direct C-H/C-H oxidative coupling reaction of heterocycle construct 3- heterocyclic ring hex- 2- ketenes derivative still
It does not solve, therefore is badly in need of developing and a kind of 3- heterocyclic ring hex- 2- ketenes is constructed based on direct C-H/C-H oxidative coupling reaction spread out
The method of biology, then oxidation obtains 3- heterocycle phenol derivatives in acid condition.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative, raw material is honest and clean
Valence is easy to get, method is simple, one-step synthesis.
The technical solution that the present invention takes to achieve the above object are as follows:
A kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative, includes the following steps:
(1) in the reactor, cyclonene, thiophene are sequentially added for 3:1:0.1:2.5:0.1:0.2 in molar ratio or taken
Thiophene, palladium chloride, silver carbonate, N- acetoglycocoll and the silver hexafluoroantimonate in generation are added solvent and dissolve reactant, at room temperature
It is uniformly mixed, is then reacted 5~48 hours under the conditions of 60~120 DEG C；
(2) reactor is cooled to room temperature after the reaction was completed, is dissolved with ethyl acetate, successively use saturated ammonium chloride and saturation
Sodium-chloride water solution washing, after organic phase is dried over anhydrous sodium sulfate, filtering, solvent is removed in rotation on a rotary evaporator；
(3) rotation is gone to the residue silica gel column chromatography separating purification after solvent, target product is collected, rotates away molten
Agent, oil pump are drained.
Further, substituted thiophene of the present invention is 3 methyl thiophene, adjacent benzene thiophene, 3- methoxythiophene, 2-
Chlorothiophene, 2- bromothiophene, the chloro- 3 methyl thiophene of 2-, 2- methylthiophene, 2- acetyl thiophene or 2-Thiophene Carboxylic Acid ethyl ester.
Further, solvent of the present invention is dimethyl sulfoxide, 1,1,1,3,3,3-hexafluoro-2-propanol or Isosorbide-5-Nitrae-two
One of six ring of oxygen or two or more mixtures.
Technology path of the invention is the direct step cross-coupling of c h bond of the c h bond and thiophene of cyclonene, chemistry
Equation are as follows:
Wherein, R is methyl, methoxyl group, phenyl, halogen, acyl group, ester group etc..
The present invention using nuclear magnetic resonance spectroscopy (1H NMR), carbon spectrum (13C NMR) and high resolution mass spectrum confirm 3- (thiophene
Pheno -2- base) hexamethylene -2- ketenes derivative structure (such as attached drawing) detect instrument are as follows: AVANCE III HD 600MHz type
Nuclear Magnetic Resonance, wherein deuterated chloroform is internal standard (hydrogen spectrum, deuterated chloroform: δ 7.26ppm) (carbon spectrum, deuterated chloroform: δ 77ppm).
Thermo Scientific Q Exactive type high-resolution mass spectrometer.
Compared with existing synthetic method, advantages of the present invention is embodied are as follows:
(1) the cross-coupling reaction functional group scope of application that uses of the present invention is wider, comprising: containing halogen, alkyl, phenyl,
The functional groups such as alkoxy, ester group, carbonyl substrate；
(2) synthetic route used in the present invention is the direct cross-coupling reaction of C-H/C-H, is reacted with conventional synthesis, C-X/C-
The technologies of preparing such as M, C-X/C-H compare, and reaction step is simple, improve synthesis gross production rate, reduce totle drilling cost；
(3) synthetic route used in the present invention is the direct cross-coupling reaction of C-H/C-H, and any homing device, nothing is not used
Additional step is needed to introduce or remove homing device；
(4) synthetic route used in the present invention is the direct cross-coupling reaction of C-H/C-H, contains ring-type for rapidly and efficiently synthesis
The complicated natural products of carbon-to-carbon double bond provides new approach.
Detailed description of the invention
Fig. 1 is that the hydrogen of 3- (3 methyl thiophene -2- base) hexamethylene -2- ketenes is composed；
Fig. 2 is that the carbon of 3- (3 methyl thiophene -2- base) hexamethylene -2- ketenes is composed；
Fig. 3 is that the hydrogen of 3- (5- tolylthiophene -2- base) hexamethylene -2- ketenes is composed；
Fig. 4 is that the carbon of 3- (5- tolylthiophene -2- base) hexamethylene -2- ketenes is composed；
Fig. 5 is that the hydrogen of 3- (4- methoxythiophene -2- base) hexamethylene -2- ketenes is composed；
Fig. 6 is that the carbon of 3- (4- methoxythiophene -2- base) hexamethylene -2- ketenes is composed；
Fig. 7 is that the hydrogen of 3- (thiophene -2- base) hexamethylene -2- ketenes is composed；
Fig. 8 is that the carbon of 3- (thiophene -2- base) hexamethylene -2- ketenes is composed；
Fig. 9 is that the hydrogen of 3- (5- chlorothiophene -2- base) hexamethylene -2- ketenes is composed；
Figure 10 is that the carbon of 3- (5- chlorothiophene -2- base) hexamethylene -2- ketenes is composed；
Figure 11 is that the hydrogen of 3- (5- bromothiophene -2- base) hexamethylene -2- ketenes is composed；
Figure 12 is that the carbon of 3- (5- bromothiophene -2- base) hexamethylene -2- ketenes is composed；
Figure 13 is that the hydrogen of 3- (the chloro- 4- methylthiophene -2- base of 5-) hexamethylene -2- ketenes is composed；
Figure 14 is that the carbon of 3- (the chloro- 4- methylthiophene -2- base of 5-) hexamethylene -2- ketenes is composed；
Figure 15 is that the hydrogen of 3- (5- methylthiophene -2- base) hexamethylene -2- ketenes is composed；
Figure 16 is that the carbon of 3- (5- methylthiophene -2- base) hexamethylene -2- ketenes is composed；
Figure 17 is that the hydrogen of 3- (5- acetyl thiophene -2- base) hexamethylene -2- ketenes is composed；
Figure 18 is that the carbon of 3- (5- acetyl thiophene -2- base) hexamethylene -2- ketenes is composed；
Figure 19 is that the hydrogen of 5- (3- oxocyclohex -1- alkene -1- base) thiophene -2-carboxylic acid ethyl ester is composed；
Figure 20 is that the carbon of 5- (3- oxocyclohex -1- alkene -1- base) thiophene -2-carboxylic acid ethyl ester is composed.
Specific embodiment
Present invention is further described in detail With reference to embodiment, it will help the understanding of the present invention,
It but is not that interest field of the invention is limited with this.
The synthesis of embodiment 1:3- (3 methyl thiophene -5- base) hexamethylene -2- ketenes
(1) by 3 methyl thiophene (0.024ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium chloride
(0.0044g, 0.0025mmol), N- acetoglycocoll (0.0029g, 0.0025mmol), silver carbonate (0.1723g,
0.625mmol), silver hexafluoroantimonate (0.0172g, 0.05mmol), dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3- hexafluoro -2-
Propyl alcohol (0.05ml), Isosorbide-5-Nitrae-dioxane (1ml), is heated to 60 DEG C after mixing evenly in clean and dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v), and revolving removes solvent, and oil pump is drained,
Obtain light yellow oil, target product 33.4mg, yield 70%.The isomer proportion of 5 and 2, thiophene substitutions is in product
83:17, nuclear magnetic data are the coupled product of 5, thiophene substitutions, as depicted in figs. 1 and 2,1H NMR(600MHz,CDCl3)δ7.30
(d, J=5.1Hz, 1H), 6.89 (d, J=5.1Hz, 1H), 6.24 (s, 1H), 2.72 (t, J=11.2,5.4Hz, 2H), 2.45-
2.40 (m, 2H), 2.36 (s, 3H), 2.10 (dt, J=12.8,6.2Hz, 2H)13C NMR(151MHz,CDCl3)δ199.19,
153.74,137.64,136.45,132.58,126.16,125.24,36.86,30.76,22.62,16.93.HRMS(ESI+):
Calculated value C11H13OS[M+H]+193.0682 measured value 193.0683.
The synthesis of embodiment 2:3- (5- tolylthiophene -2- base) hexamethylene -2- ketenes
(1) by adjacent benzene thiophene (0.0401g, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium chloride
(0.0044g, 0.0025mmol), N- acetoglycocoll (0.0029g, 0.0025mmol), silver carbonate (0.1723g,
0.625mmol), silver hexafluoroantimonate (0.0172g, 0.05mmol), dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3- hexafluoro -2-
Propyl alcohol (0.05ml), Isosorbide-5-Nitrae-dioxane (1ml), is heated to 60 DEG C after mixing evenly in clean and dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v), and revolving removes solvent, and oil pump is drained,
Obtain yellow solid target product 47.7mg, yield 75%.Fusing point: 129-131 DEG C；As shown in Figure 3 and Figure 4,1H NMR
(600MHz,CDCl3) δ 7.61 (d, J=7.8Hz, 2H), 7.40 (t, J=7.5Hz, 2H), 7.36-7.30 (m, 2H), 7.29
(d, J=3.7Hz, 1H), 6.43 (s, 1H), 2.78 (t, J=6.0Hz, 2H), 2.47 (t, J=6.6Hz, 2H), 2.17-2.12
(m,2H).13C NMR(151MHz,CDCl3)δ199.26,152.22,147.66,141.51,133.42,129.02,128.54,
128.44,125.91,124.08,122.32,37.22,27.61,22.40.HRMS(ESI+): calculated value C16H15OS[M+H]+
255.0838 measured value 255.0836.
The synthesis of embodiment 3:3- (4- methoxythiophene -2- base) hexamethylene -2- ketenes
(1) by 3- methoxythiophene (0.025ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium chloride
(0.0044g, 0.0025mmol), N- acetoglycocoll (0.0029g, 0.0025mmol), silver carbonate (0.1723g,
0.625mmol), silver hexafluoroantimonate (0.0172g, 0.05mmol), dimethyl sulfoxide (0.05ml), Isosorbide-5-Nitrae-dioxane (1ml),
60 DEG C are heated in clean and dry airtight reactor tube after mixing evenly, is reacted 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v), and revolving removes solvent, and oil pump is drained,
Obtain yellow solid target product 32.6mg, yield 63%.Fusing point: 68-70 DEG C；As shown in Figure 5 and Figure 6,1H NMR
(600MHz,CDCl3) δ 7.34 (d, J=5.6Hz, 1H), 6.90 (d, J=5.6Hz, 1H), 6.78 (s, 1H), 3.92 (s, 3H),
2.74 (t, J=5.9Hz, 2H), 2.44-2.40 (m, 2H), 2.11-2.05 (m, 2H)13C NMR(151MHz,CDCl3)δ
199.96,158.43,152.10,126.81,122.51,118.54,116.82,58.54,37.11,29.29,22.62.HRMS
(ESI+): calculated value C11H13O2S[M+H]+209.0631 measured value 209.0631.
The synthesis of embodiment 4:3- (thiophene -2- base) hexamethylene -2- ketenes
(1) by thiophene (0.020ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium chloride
(0.0044g, 0.0025mmol), N- acetoglycocoll (0.0029g, 0.0025mmol), silver carbonate (0.1723g,
0.625mmol), silver hexafluoroantimonate (0.0172g, 0.05mmol), dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3- hexafluoro -2-
Propyl alcohol (0.05ml), Isosorbide-5-Nitrae-dioxane (1ml), is heated to 60 DEG C after mixing evenly in clean and dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v), and revolving removes solvent, and oil pump is drained,
Obtain light yellow oil, target product 19mg, yield 43%.As shown in Figure 7 and Figure 8,1H NMR(600MHz,CDCl3)δ
7.42 (d, J=5.1Hz, 1H), 7.37 (d, J=3.7Hz, 1H), 7.10-7.05 (m, 1H), 6.41 (s, 1H), 2.77 (t, J=
6.0Hz,2H),2.48–2.42(m,2H),2.15–2.09(m,2H).13C NMR(151MHz,CDCl3)δ199.39,152.38,
142.70,128.71,128.22,127.28,122.68,37.19,27.96,22.39.HRMS(ESI+): calculated value C11H11OS
[M+H]+179.0525 measured value 179.0525.
The synthesis of embodiment 5:3- (5- chlorothiophene -2- base) hexamethylene -2- ketenes
(1) by 2- chlorothiophene (0.023ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium chloride
(0.0044g, 0.0025mmol), N- acetoglycocoll (0.0029g, 0.0025mmol), silver carbonate (0.1723g,
0.625mmol), silver hexafluoroantimonate (0.0172g, 0.05mmol), dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3- hexafluoro -2-
Propyl alcohol (0.05ml), Isosorbide-5-Nitrae-dioxane (1ml), is heated to 60 DEG C after mixing evenly in clean and dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v), and revolving removes solvent, and oil pump is drained,
Obtain yellowish solid material, target product 25.1mg, yield 47%.Fusing point: 66-68 DEG C；As shown in Figure 9 and Figure 10,1H
NMR(600MHz,CDCl3) δ 7.15 (d, J=4.0Hz, 1H), 6.90 (d, J=4.0Hz, 1H), 6.26 (s, 1H), 2.71-
2.68(m,2H),2.46–2.44(m,2H),2.14–2.10(m,2H).13C NMR(151MHz,CDCl3)δ199.00,
151.32,141.08,133.67,127.49,126.84,122.63,37.17,27.24,22.26.HRMS(ESI+): calculated value
C10H10ClOS[M+H]+213.0135 measured value 213.0134.
The synthesis of embodiment 6:3- (5- bromothiophene -2- base) hexamethylene -2- ketenes
(1) by 2- bromothiophene (0.024ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium chloride
(0.0044g, 0.0025mmol), N- acetoglycocoll (0.0029g, 0.0025mmol), silver carbonate (0.1723g,
0.625mmol), silver hexafluoroantimonate (0.0172g, 0.05mmol), dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3- hexafluoro -2-
Propyl alcohol (0.05ml), Isosorbide-5-Nitrae-dioxane (1ml), is heated to 60 DEG C after mixing evenly in clean and dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v), and revolving removes solvent, and oil pump is drained,
Obtain yellowish solid material, target product 32.2mg, yield 50%.Fusing point: 90-93 DEG C；As is illustrated by figs. 11 and 12,1H
NMR(600MHz,CDCl3) δ 7.12 (d, J=4.0Hz, 1H), 7.05 (d, J=4.0Hz, 1H), 6.29 (s, 1H), 2.71-
2.69(m,2H),2.46–2.44(m,2H),2.16–2.10(m,2H).13C NMR(151MHz,CDCl3)δ199.04,
151.17,143.99,131.20,127.56,122.81,116.37,37.17,27.36,22.29.HRMS(ESI+): calculated value
C10H10BrOS[M+H]+256.9630 measured value 256.9625.
The synthesis of embodiment 7:3- (the chloro- 4- methylthiophene -2- base of 5-) hexamethylene -2- ketenes
(1) by the chloro- 3 methyl thiophene of 2- (0.027ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), chlorine
Change palladium (0.0044g, 0.0025mmol), N- acetoglycocoll (0.0029g, 0.0025mmol), silver carbonate (0.1723g,
0.625mmol), silver hexafluoroantimonate (0.0172g, 0.05mmol), dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3- hexafluoro -2-
Propyl alcohol (0.05ml), Isosorbide-5-Nitrae-dioxane (1ml), is heated to 60 DEG C after mixing evenly in clean and dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v), and revolving removes solvent, and oil pump is drained,
Obtain yellowish solid material, target product 37.9mg, yield 67%.Fusing point: 82-84 DEG C；As shown in Figure 13 and Figure 14,1H
NMR(600MHz,CDCl3)δ7.06(s,1H),6.24(s,1H),2.69–2.65(m,2H),2.45–2.41(m,2H),2.17
(s,3H),2.13–2.07(m,2H).13C NMR(151MHz,CDCl3)δ199.02,151.44,135.85,129.04,
128.82,122.23,37.16,27.14,22.27,13.59.HRMS(ESI+): calculated value C11H12ClOS[M+H]+
227.0292 measured value 227.0290.
The synthesis of embodiment 8:3- (5- methylthiophene -2- base) hexamethylene -2- ketenes
(1) by 2- methylthiophene (0.024ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium chloride
(0.0044g, 0.0025mmol), N- acetoglycocoll (0.0029g, 0.0025mmol), silver carbonate (0.1723g,
0.625mmol), silver hexafluoroantimonate (0.0172g, 0.05mmol), dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3- hexafluoro -2-
Propyl alcohol (0.05ml), Isosorbide-5-Nitrae-dioxane (1ml), is heated to 60 DEG C after mixing evenly in clean and dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=5:1, v/v), and revolving removes solvent, and oil pump is drained, obtained
To yellowish solid material, target product 32.6mg, yield 68%.Fusing point: 80-82 DEG C；As shown in Figure 15 and Figure 16,1H NMR
(600MHz,CDCl3) δ 7.15 (s, 1H), 6.71 (d, J=0.9Hz, 1H), 6.26 (s, 1H), 2.70 (t, J=6.0Hz, 2H),
2.45 (s, 3H), 2.39 (dd, J=9.4,3.8Hz, 2H), 2.08-2.04 (m, 2H)13C NMR(151MHz,CDCl3)δ
199.19,152.56,144.19,140.13,127.80,126.61,121.51,37.07,27.38,22.27,15.59.HRMS
(ESI+): calculated value C11H13OS[M+H]+193.0682 measured value 193.0682.
The synthesis of embodiment 9:3- (5- acetyl thiophene -2- base) hexamethylene -2- ketenes
(1) by 2- acetyl thiophene (0.027ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium chloride
(0.0044g, 0.0025mmol), N- acetoglycocoll (0.0145g, 0.125mmol), silver carbonate (0.1379g, 0.5mmol),
Dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3-hexafluoro-2-propanol (0.5ml), Isosorbide-5-Nitrae-dioxane (0.5ml) are completely being done
110 DEG C are heated in dry airtight reactor tube after mixing evenly, is reacted 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, 40ml ethyl acetate is added, reaction system is diluted and moved into
In the separatory funnel of 100ml, 20ml saturated aqueous ammonium chloride is added, rocks, stands, after removing following water phase, add
20ml saturated salt solution, rocks, and stands, removes following water phase, and organic phase is dry with anhydrous sodium sulfate, and solvent is removed in decompression,
Residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=5:1, v/v), and revolving removes solvent, and oil pump is drained, obtained
To yellow solid matter, target product 26.6mg, yield 48%.Fusing point: 140-141 DEG C；As shown in Figure 17 and Figure 18,1H NMR
(600MHz,CDCl3) δ 7.63 (d, J=3.7Hz, 1H), 7.36 (d, J=3.7Hz, 1H), 6.48 (s, 1H), 2.76 (t, J=
5.9Hz, 2H), 2.56 (s, 3H), 2.48 (t, J=6.6Hz, 2H), 2.18-2.13 (m, 2H)13C NMR(151MHz,CDCl3)
δ199.04,190.48,151.13,149.83,145.52,132.67,127.20,124.74,37.14,27.89,26.74,
22.29.HRMS(ESI+): calculated value C12H13O2S[M+H]+221.0631 measured value 221.0629.
The synthesis of embodiment 10:5- (3- oxocyclohex -1- alkene -1- base) thiophene -2-carboxylic acid ethyl ester
(1) by 2-Thiophene Carboxylic Acid ethyl ester (0.033ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), chlorination
Palladium (0.0044g, 0.0025mmol), N- acetoglycocoll (0.0145g, 0.125mmol), silver carbonate (0.1379g,
0.5mmol), dimethyl sulfoxide (0.05ml), 1,1,1,3,3,3-hexafluoro-2-propanol (0.5ml), Isosorbide-5-Nitrae-dioxane (0.5ml),
It is heated to 110 DEG C after mixing evenly in clean and dry airtight reactor tube, reacts 24 hours.
(2) reaction tube is cooled to room temperature after the reaction was completed, ethyl acetate is added, reaction system is diluted and moves into 100ml
Separatory funnel in, be added saturated aqueous ammonium chloride, rock, stand, after removing following water phase, add saturated common salt
Water rocks, and stands, after, saturated salt solution is added, is rocked, stands, following water phase is removed, by organic phase anhydrous sodium sulfate
Dry, solvent is removed in decompression, and residue is isolated and purified with silica gel column chromatography (petrol ether/ethyl acetate=5:1, v/v), after dry
Obtain yellow solid matter, target product 37.4mg, yield 60%.Fusing point: 94-95 DEG C；As illustrated in figures 19 and 20,1H NMR
(600MHz,CDCl3) δ 7.72 (d, J=4.0Hz, 1H), 7.33 (d, J=4.0Hz, 1H), 6.46 (s, 1H), 4.35 (q, J=
7.1Hz, 2H), 2.76 (t, J=6.0Hz, 2H), 2.49-2.46 (m, 2H), 2.17-2.13 (m, 2H), 1.37 (t, J=
7.1Hz,3H).13C NMR(151MHz,CDCl3)δ199.00,161.65,151.23,148.43,135.64,133.65,
126.91,124.32,61.52,37.14,27.83,22.28,14.23.HRMS(ESI+): calculated value C13H15O3S[M+H]+
251.0736 measured value 251.0735.
Claims (2)
1. a kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative, it is characterised in that include the following steps:
(1) in the reactor, cyclonene, thiophene or substituted are sequentially added for 3:1:0.1:2.5:0.1:0.2 in molar ratio
Thiophene, palladium chloride, silver carbonate, N- acetoglycocoll and silver hexafluoroantimonate are added solvent and dissolve reactant, mix at room temperature
Uniformly, it is then reacted 5~48 hours under the conditions of 60~120 DEG C；
(2) reactor is cooled to room temperature after the reaction was completed, is dissolved with ethyl acetate, successively with saturated ammonium chloride and saturation chlorination
Sodium water solution washing, after organic phase is dried over anhydrous sodium sulfate, filtering, solvent is removed in rotation on a rotary evaporator；
(3) rotation is gone to the residue silica gel column chromatography separating purification after solvent, target product is collected, rotates away solvent, oil
Pumping is dry；
Wherein the solvent is one of dimethyl sulfoxide, 1,1,1,3,3,3- hexafluoro -2- propyl alcohol or 1,4- dioxane
Or two or more mixture.
2. a kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative according to claim 1, feature
It is that the substituted thiophene is 3 methyl thiophene, adjacent benzene thiophene, 3- methoxythiophene, 2- chlorothiophene, 2- bromothiophene, 2-
Chloro- 3 methyl thiophene, 2- methylthiophene, 2- acetyl thiophene or 2-Thiophene Carboxylic Acid ethyl ester.
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