CN107141279A - A kind of preparation method of the ketenes derivative of 3 (base of thiophene 2) hexamethylene 2 - Google Patents
A kind of preparation method of the ketenes derivative of 3 (base of thiophene 2) hexamethylene 2 Download PDFInfo
- Publication number
- CN107141279A CN107141279A CN201710482096.3A CN201710482096A CN107141279A CN 107141279 A CN107141279 A CN 107141279A CN 201710482096 A CN201710482096 A CN 201710482096A CN 107141279 A CN107141279 A CN 107141279A
- Authority
- CN
- China
- Prior art keywords
- thiophene
- hexamethylene
- solvent
- ketenes
- bases
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- 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
- C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- 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
- C07D333/28—Halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention relates to thiophene derivant preparation method technical field, and in particular to a kind of preparation method of the ketenes derivative of 3 (base of thiophene 2) hexamethylene 2.The preparation method of one kind ketenes derivative of 3 (base of thiophene 2) hexamethylene 2 of the invention, comprises the following steps：(1) in the reactor, in molar ratio 3:1:0.1:2.5:0.1:0.2 sequentially adds cyclonene, thiophene or substituted thiophene, palladium bichloride, silver carbonate, N acetoglycocolls and silver hexafluoroantimonate, adds solvent and dissolves reactant, be well mixed at room temperature, is then reacted 5~48 hours under the conditions of 60~120 DEG C；(2) reactor is cooled to room temperature after the completion of reacting, is dissolved, is washed successively with saturated ammonium chloride and saturated sodium-chloride water solution with ethyl acetate, organic phase is after anhydrous sodium sulfate drying, filtering, solvent is removed in rotation on a rotary evaporator；(3) the residue silica gel column chromatography separating purification gone after solvent will be revolved, collects target product, rotate away solvent, oil pump is drained.
Description
Technical field
The present invention relates to thiophene derivant preparation method technical field, and in particular to a kind of 3- (thiophene -2- bases) hexamethylene -2-
The preparation method of ketenes derivative.
Technical background
Thiophene is important aromatic heterocycle compounds, and its 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
Thing, agricultural chemicals, polymer and Field of Fine Chemicals.Yet with the strong ortho para position effect by phenolic hydroxy, meta substitution
Phenolic compound is generally relatively difficult to synthesis.Hexamethylene -2- ketenes the analog derivative of the utilization 3- substitutions developed in recent years is by entering
The oxidation of one step prepares the phenolic compound (Angew.Chem.Int.Ed.2013,52,3672-3675 of meta substitution；Green
Chem.,2016,18,6462–6467).However, hexamethylene -2- the ketene compounds of 3- substitutions at present usually require pre- function dough
Substrate, could be prepared by two steps or three steps.The C-H/C-H oxidative coupling reactions of palladium chtalyst prepare the hexamethylene -2- of 3- substitutions
Ketene is undoubtedly a kind of most economical and step most succinct reaction scheme, however cyclonene as coupling reagent in palladium chtalyst
Heck reactions in could occur β-hydrogen elimination reaction in homonymy due to the hydrogen on palladium intermediate and the β-carbon of generation, and ring
Tension force causes carbon-palladium key to rotate freely limited (Angew.Chem.Int.Ed.2013,52,3672-3675), current transition metal
The cyclonene of catalysis and the direct C-H/C-H oxidative coupling reactions of heterocycle construct 3- heterocyclic ring hex- 2- ketenes derivatives still
Do not solve, therefore urgent need exploitation one kind is constructed 3- heterocyclic ring hex- 2- ketenes based on direct C-H/C-H oxidative coupling reactions and spread out
Biological method, then oxidation obtains 3- heterocycle phenol derivatives in acid condition.
The content of the invention
It is an object of the invention to provide a kind of preparation method of 3- (thiophene -2- bases) hexamethylene -2- ketenes derivatives, raw material is honest and clean
Valency is easy to get, method simple, one-step synthesis.
The present invention to achieve the above object and the technical scheme taken is：
A kind of preparation method of 3- (thiophene -2- bases) hexamethylene -2- ketenes derivatives, comprises the following steps：
(1) in the reactor, it is in molar ratio 3:1:0.1:2.5:0.1:0.2 sequentially adds cyclonene, thiophene or takes
Thiophene, palladium bichloride, silver carbonate, N- acetoglycocolls and the silver hexafluoroantimonate in generation, add solvent and dissolve reactant, at room temperature
It is well mixed, then reacted 5~48 hours under the conditions of 60~120 DEG C；
(2) reactor is cooled to room temperature after the completion of reacting, dissolved with ethyl acetate, successively with saturated ammonium chloride and saturation
Sodium-chloride water solution is washed, and organic phase is after anhydrous sodium sulfate drying, filtering, and solvent is removed in rotation on a rotary evaporator；
(3) the residue silica gel column chromatography separating purification gone after solvent will be revolved, collects target product, rotate away molten
Agent, oil pump is drained.
Further, substituted thiophene of the present invention is 3 methyl thiophene, adjacent benzene thiophene, 3- methoxythiophenes, 2-
Chlorothiophene, 2- bromothiophenes, the chloro- 3 methyl thiophenes of 2-, 2- methylthiophenes, 2- acetyl thiophenes or 2-Thiophene Carboxylic Acid ethyl ester.
Further, solvent of the present invention is dimethyl sulfoxide, HFIP or Isosorbide-5-Nitrae-two
One or more kinds of mixtures in the ring of oxygen six.
The technology path of the present invention is the direct step cross-coupling of the c h bond of c h bond and thiophene of cyclonene, its chemistry
Equation is：
Wherein, R is methyl, methoxyl group, phenyl, halogen, acyl group, ester group etc..
Present invention use proton nmr spectra (1H NMR), carbon spectrum (13C NMR) and high resolution mass spectrum confirm 3- (thiophenes
Fen -2- bases) hexamethylene -2- ketenes derivatives structure (such as accompanying drawing) detection instrument be：AVANCE III HD 600MHz types
NMR, wherein deuterochloroform are that internal standard (compose, deuterochloroform by hydrogen：δ 7.26ppm) (compose, deuterochloroform by carbon：δ77ppm).
Thermo Scientific Q Exactive type high-resolution mass spectrometers.
Compared with existing synthetic method, advantages of the present invention is embodied as：
(1) the cross-coupling reaction functional group scope of application that the present invention is used is wider, including：Containing halogen, alkyl, phenyl,
The functional group such as alkoxy, ester group, carbonyl substrate；
(2) present invention synthetic route used is the direct cross-coupling reactions 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 reactions steps are simple, improve synthesis gross production rate, reduce totle drilling cost；
(3) present invention synthetic route used is the direct cross-coupling reactions of C-H/C-H, and any homing device, nothing is not used
Additional step is needed to introduce or removing homing device；
(4) present invention synthetic route used is the direct cross-coupling reactions of C-H/C-H, is that rapidly and efficiently synthesis contains ring-type
The complicated natural products of carbon-to-carbon double bond provides new approach.
Brief description of the drawings
Fig. 1 composes for the hydrogen of 3- (3 methyl thiophene -2- bases) hexamethylene -2- ketenes；
Fig. 2 composes for the carbon of 3- (3 methyl thiophene -2- bases) hexamethylene -2- ketenes；
Fig. 3 composes for the hydrogen of 3- (5- tolylthiophene -2- bases) hexamethylene -2- ketenes；
Fig. 4 composes for the carbon of 3- (5- tolylthiophene -2- bases) hexamethylene -2- ketenes；
Fig. 5 composes for the hydrogen of 3- (4- methoxythiophene -2- bases) hexamethylene -2- ketenes；
Fig. 6 composes for the carbon of 3- (4- methoxythiophene -2- bases) hexamethylene -2- ketenes；
Fig. 7 composes for the hydrogen of 3- (thiophene -2- bases) hexamethylene -2- ketenes；
Fig. 8 composes for the carbon of 3- (thiophene -2- bases) hexamethylene -2- ketenes；
Fig. 9 composes for the hydrogen of 3- (5- chlorothiophene -2- bases) hexamethylene -2- ketenes；
Figure 10 composes for the carbon of 3- (5- chlorothiophene -2- bases) hexamethylene -2- ketenes；
Figure 11 composes for the hydrogen of 3- (5- bromothiophene -2- bases) hexamethylene -2- ketenes；
Figure 12 composes for the carbon of 3- (5- bromothiophene -2- bases) hexamethylene -2- ketenes；
Figure 13 composes for the hydrogen of 3- (the chloro- 4- methylthiophenes -2- bases of 5-) hexamethylene -2- ketenes；
Figure 14 composes for the carbon of 3- (the chloro- 4- methylthiophenes -2- bases of 5-) hexamethylene -2- ketenes；
Figure 15 composes for the hydrogen of 3- (5- methylthiophene -2- bases) hexamethylene -2- ketenes；
Figure 16 composes for the carbon of 3- (5- methylthiophene -2- bases) hexamethylene -2- ketenes；
Figure 17 composes for the hydrogen of 3- (5- acetyl thiophene -2- bases) hexamethylene -2- ketenes；
Figure 18 composes for the carbon of 3- (5- acetyl thiophene -2- bases) hexamethylene -2- ketenes；
Figure 19 composes for the hydrogen of 5- (3- oxocyclohex -1- alkene -1- bases) thiophene -2-carboxylic acid ethyl ester；
Figure 20 composes for the carbon of 5- (3- oxocyclohex -1- alkene -1- bases) thiophene -2-carboxylic acid ethyl ester.
Embodiment
The present invention is described in further detail with reference to embodiment, it will help the understanding of the present invention,
But it is not the interest field that the present invention is limited with this.
Embodiment 1：The synthesis of 3- (3 methyl thiophene -5- bases) hexamethylene -2- ketenes
(1) by 3 methyl thiophene (0.024ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium bichloride
(0.0044g, 0.0025mmol), N- acetoglycocolls (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 being stirred in totally dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained,
Obtain pale yellow oil, target product 33.4mg, yield 70%.The isomer proportion of 5 and 2 substitutions of thiophene is in product
83:17, nuclear magnetic data is the coupled product of 5 substitutions of thiophene, 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-
(dt, J=12.8,6.2Hz, the 2H) of 2.40 (m, 2H), 2.36 (s, 3H), 2.1013C 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.
Embodiment 2：The synthesis of 3- (5- tolylthiophene -2- bases) hexamethylene -2- ketenes
(1) by adjacent benzene thiophene (0.0401g, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium bichloride
(0.0044g, 0.0025mmol), N- acetoglycocolls (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 being stirred in totally dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained,
Obtain yellow solid target product 47.7mg, yield 75%.Fusing point：129-131℃；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.
Embodiment 3：The synthesis of 3- (4- methoxythiophene -2- bases) hexamethylene -2- ketenes
(1) by 3- methoxythiophenes (0.025ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium bichloride
(0.0044g, 0.0025mmol), N- acetoglycocolls (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 to after totally being stirred in dry airtight reactor tube, is reacted 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained,
Obtain yellow solid target product 32.6mg, yield 63%.Fusing point：68-70℃；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),
(m, the 2H) of 2.74 (t, J=5.9Hz, 2H), 2.44-2.40 (m, 2H), 2.11-2.0513C 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.
Embodiment 4：The synthesis of 3- (thiophene -2- bases) hexamethylene -2- ketenes
(1) by thiophene (0.020ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium bichloride
(0.0044g, 0.0025mmol), N- acetoglycocolls (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 being stirred in totally dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained,
Obtain pale 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.
Embodiment 5：The synthesis of 3- (5- chlorothiophene -2- bases) hexamethylene -2- ketenes
(1) by 2- chlorothiophenes (0.023ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium bichloride
(0.0044g, 0.0025mmol), N- acetoglycocolls (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 being stirred in totally dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained,
Obtain yellowish solid material, target product 25.1mg, yield 47%.Fusing point：66-68℃；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.
Embodiment 6：The synthesis of 3- (5- bromothiophene -2- bases) hexamethylene -2- ketenes
(1) by 2- bromothiophenes (0.024ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium bichloride
(0.0044g, 0.0025mmol), N- acetoglycocolls (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 being stirred in totally dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained,
Obtain yellowish solid material, target product 32.2mg, yield 50%.Fusing point：90-93℃；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.
Embodiment 7：The synthesis of 3- (the chloro- 4- methylthiophenes -2- bases of 5-) hexamethylene -2- ketenes
(1) by the chloro- 3 methyl thiophenes of 2- (0.027ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), chlorine
Change palladium (0.0044g, 0.0025mmol), N- acetoglycocolls (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 being stirred in totally dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=15:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained,
Obtain yellowish solid material, target product 37.9mg, yield 67%.Fusing point：82-84℃；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.
Embodiment 8：The synthesis of 3- (5- methylthiophene -2- bases) hexamethylene -2- ketenes
(1) by 2- methylthiophenes (0.024ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium bichloride
(0.0044g, 0.0025mmol), N- acetoglycocolls (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 being stirred in totally dry airtight reactor tube,
Reaction 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=5:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained, obtained
To yellowish solid material, target product 32.6mg, yield 68%.Fusing point：80-82℃；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),
(m, the 2H) of 2.45 (s, 3H), 2.39 (dd, J=9.4,3.8Hz, 2H), 2.08-2.0413C 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.
Embodiment 9：The synthesis of 3- (5- acetyl thiophene -2- bases) hexamethylene -2- ketenes
(1) by 2- acetyl thiophenes (0.027ml, 0.25mmol), cyclonene (0.072ml, 0.75mmol), palladium bichloride
(0.0044g, 0.0025mmol), N- acetoglycocolls (0.0145g, 0.125mmol), silver carbonate (0.1379g, 0.5mmol),
Dimethyl sulfoxide (0.05ml), HFIP (0.5ml), Isosorbide-5-Nitrae-dioxane (0.5ml) is totally being done
110 DEG C are heated to after being stirred in dry airtight reactor tube, is reacted 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, 40ml ethyl acetate is added and reaction system is diluted and moved into
In 100ml separatory funnel, 20ml saturated aqueous ammonium chlorides are added, are rocked, stood, removed after following aqueous phase, add
20ml saturated aqueous common salts, are rocked, and stand, and remove following aqueous phase, by organic phase anhydrous sodium sulfate drying, and solvent is removed in decompression,
Residue silica gel column chromatography (petrol ether/ethyl acetate=5:1, v/v) isolate and purify, revolving removes solvent, oil pump is drained, obtained
To yellow solid matter, target product 26.6mg, yield 48%.Fusing point：140-141℃；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.
Embodiment 10：The synthesis of 5- (3- oxocyclohex -1- alkene -1- bases) 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- acetoglycocolls (0.0145g, 0.125mmol), silver carbonate (0.1379g,
0.5mmol), dimethyl sulfoxide (0.05ml), HFIP (0.5ml), Isosorbide-5-Nitrae-dioxane (0.5ml),
110 DEG C are heated to after being stirred in totally dry airtight reactor tube, is reacted 24 hours.
(2) reaction tube is cooled to room temperature after the completion of reacting, ethyl acetate is added and reaction system is diluted and 100ml is moved into
Separatory funnel in, add saturated aqueous ammonium chloride, rock, stand, remove after following aqueous phase, add saturated common salt
Water, rocks, and stands, after, saturated aqueous common salt is added, is rocked, is stood, following aqueous phase is removed, by organic phase anhydrous sodium sulfate
Dry, solvent, residue silica gel column chromatography (petrol ether/ethyl acetate=5 are removed in decompression:1, v/v) isolate and purify, after drying
Obtain yellow solid matter, target product 37.4mg, yield 60%.Fusing point：94-95℃；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 (3)
1. a kind of preparation method of 3- (thiophene -2- bases) hexamethylene -2- ketenes derivatives, it is characterised in that comprise the following steps：
(1) in the reactor, it is in molar ratio 3:1:0.1:2.5:0.1:0.2 sequentially adds cyclonene, thiophene or substituted
Thiophene, palladium bichloride, silver carbonate, N- acetoglycocolls and silver hexafluoroantimonate, add solvent and dissolve reactant, mix at room temperature
Uniformly, then reacted 5~48 hours under the conditions of 60~120 DEG C；
(2) reactor is cooled to room temperature after the completion of reacting, dissolved with ethyl acetate, successively with saturated ammonium chloride and saturation chlorination
Sodium water solution is washed, and organic phase is after anhydrous sodium sulfate drying, filtering, and solvent is removed in rotation on a rotary evaporator；
(3) the residue silica gel column chromatography separating purification gone after solvent will be revolved, collects target product, rotate away solvent, oil
Pumping is done.
2. a kind of preparation method of 3- (thiophene -2- bases) hexamethylene -2- ketenes derivatives according to claim 1, its feature
It is 3 methyl thiophene, adjacent benzene thiophene, 3- methoxythiophenes, 2- chlorothiophenes, 2- bromothiophenes, 2- to be described substituted thiophene
Chloro- 3 methyl thiophene, 2- methylthiophenes, 2- acetyl thiophenes or 2-Thiophene Carboxylic Acid ethyl ester.
3. a kind of preparation method of 3- (thiophene -2- bases) hexamethylene -2- ketenes derivatives according to claim 1, its feature
Be one kind for dimethyl sulfoxide, 1,1,1,3,3,3- hexafluoro -2- propyl alcohol or in 1,4- dioxane of described solvent or
Two or more mixtures.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710482096.3A CN107141279B (en) | 2017-06-22 | 2017-06-22 | A kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710482096.3A CN107141279B (en) | 2017-06-22 | 2017-06-22 | A kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107141279A true CN107141279A (en) | 2017-09-08 |
| CN107141279B CN107141279B (en) | 2019-04-05 |
Family
ID=59782940
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710482096.3A Active CN107141279B (en) | 2017-06-22 | 2017-06-22 | A kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107141279B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110117246A (en) * | 2019-06-18 | 2019-08-13 | 山西大学 | A kind of preparation method of 3- indoles pimelie kelone compounds |
| CN110117270A (en) * | 2019-06-18 | 2019-08-13 | 山西大学 | A kind of 3-(thiophene -2- base) cyclohexanone framework compound preparation method |
| CN110982806A (en) * | 2019-08-30 | 2020-04-10 | 浙江工业大学 | Protein aryl derivative and preparation method thereof |
-
2017
- 2017-06-22 CN CN201710482096.3A patent/CN107141279B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| A. MITAL等: "Synthesis and Biological Evaluation of Naphthalene-1,4-dione Derivatives as Potent Antimycobacterial Agents", 《MEDICINAL CHEMISTRY》 * |
| MING ZHOU等: "Highly Enantioselective Synthesis of Chiral Cyclic Allylic Amines via Rh-Catalyzed Asymmetric Hydrogenation", 《ORG. LETT.》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110117246A (en) * | 2019-06-18 | 2019-08-13 | 山西大学 | A kind of preparation method of 3- indoles pimelie kelone compounds |
| CN110117270A (en) * | 2019-06-18 | 2019-08-13 | 山西大学 | A kind of 3-(thiophene -2- base) cyclohexanone framework compound preparation method |
| CN110117270B (en) * | 2019-06-18 | 2021-07-27 | 山西大学 | Preparation method of 3- (thiophene-2-yl) cyclohexanone framework compound |
| CN110117246B (en) * | 2019-06-18 | 2022-05-31 | 山西大学 | Preparation method of 3-position indolylated cyclohexenone compound |
| CN110982806A (en) * | 2019-08-30 | 2020-04-10 | 浙江工业大学 | Protein aryl derivative and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107141279B (en) | 2019-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107141279B (en) | A kind of preparation method of 3- (thiophene -2- base) hexamethylene -2- ketenes derivative | |
| CN110078652B (en) | Chiral tetraaryl substituted methane and preparation method thereof | |
| CN108569942B (en) | Preparation method of alpha-trifluoromethylthio substituted acetophenone compound | |
| Guan et al. | Efficient and selective α-bromination of carbonyl compounds with N-bromosuccinimide under microwave | |
| CN108690030A (en) | The loop coil oxidized indole compounds and its synthetic method of pyrroles's thione structure with optical activation | |
| Aikawa et al. | Copper-catalyzed allylic difluoromethylation of allyl carbonates with (difluoromethyl) zinc reagent | |
| CN106977386B (en) | 2-trifluoroethyl-1-indanone and derivatives and preparation method thereof | |
| Wang et al. | Catalytic asymmetric aryl transfer: Highly enantioselective preparation of (R)-and (S)-diarylmethanols catalyzed by the same chiral ferrocenyl aziridino alcohol | |
| CN110294730B (en) | Difluoromethyl sulfuration flavonoid compound and preparation method thereof | |
| WO2011021492A1 (en) | Process for production of formyl-substituted aromatic compounds | |
| CN107118140B (en) | A kind of β-acyl group-allyl methyl sulfide derivative and preparation method thereof | |
| CN107141227B (en) | A kind of preparation method and applications of chirality 4- amido cyclopentenone | |
| CN100436441C (en) | Method for preparing 3-formacyl chromone derivative | |
| CN110294708B (en) | Preparation method of trifluoroethylselenophenanthridine and 3, 4-dihydroisoquinoline derivatives | |
| Kundu et al. | A mild and versatile synthesis of bis (indolyl) methanes and tris (indolyl) alkanes catalyzed by antimony trichloride | |
| CN108218840A (en) | A kind of synthetic method of bisindole derivatives | |
| CN103087039A (en) | Synthesis method of poly-substituted benzene[1,3]meta-ditetrahydrofuran compound | |
| CN106946758A (en) | A kind of synthetic method of 3 (trifluoroacetyl) indole derivativeses | |
| CN106957251B (en) | A method of preparing alkyl thiomethyl ester type compound | |
| CN106810482B (en) | A kind of 3- phenylseleno -1- acetone derivatives and its synthetic method | |
| Prasanna et al. | Quick access to bis (indolyl) methanes: T3P as a novel catalyst system | |
| CN107501234A (en) | A kind of oil-source rock correlation and preparation method thereof | |
| CN107827715A (en) | A kind of method that efficient selective synthesizes 2 hydroxy phenyl styryl ether compounds | |
| Kaur et al. | Applications of metal and non-metal catalysts for the synthesis of oxygen containing five-membered polyheterocylces: a mini review | |
| CN110372718B (en) | Difluoromethane thiochromanonthiophene compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |