CN106986841A - A kind of synthetic method of the dihydro-oxazole of 2 thiophenyl 4,5 - Google Patents
A kind of synthetic method of the dihydro-oxazole of 2 thiophenyl 4,5 Download PDFInfo
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- CN106986841A CN106986841A CN201710171529.3A CN201710171529A CN106986841A CN 106986841 A CN106986841 A CN 106986841A CN 201710171529 A CN201710171529 A CN 201710171529A CN 106986841 A CN106986841 A CN 106986841A
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- dihydro
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- thiophenyls
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 a kind of synthetic method of the dihydro-oxazole of 2 thiophenyl 4,5, using 2 oxazolidine thioketones, aryne precursor and cesium fluoride as raw material, heating response, the dihydro-oxazole of 2 thiophenyl 4,5 can be prepared by by one-step method, reaction raw materials are easy to get, easy to operate, mild condition, yield is higher.
Description
Technical field
The invention belongs to chemical pharmacy and fine chemistry industry preparing technical field, it is related to a kind of 2- thiophenyls -4,5- bis- Qing Evil
The synthetic method of azoles.
Background technology
2- thiophenyl -4,5- dihydro-oxazole class compounds are the important organic compound of a class, the chemical combination with the fragment
Thing is omnipresent in some natural products and artificial chemistry product, particularly in some have the molecule of bioactivity.
The synthetic method of current such compound reported in the literature may be summarized to be following two：
(1) using benzenethiol as initiation material, 4,4- dimethyl -2- benzene sulphur is synthesized by a series of processes such as acylation, condensation
Base -4,5- dihydro-oxazole, synthetic route is as shown in equation A.The shortcoming of this method is that gross production rate is too low, has one during amplification
Fixed difficulty.
Equation A：
Wherein, BTC is triphosgene, and Py is pyridine, and DCM is dichloromethane.
(2) with 4,4- dimethyl -4,5- dihydro-oxazole -2- lithiums for initiation material, reacted with diphenyl disulfide, needed for obtaining
Product, its synthetic route is as shown in equation B.Its feature is to need to add highly basic in course of reaction, and severe reaction conditions are secondary
Product is more.
Equation B：
Wherein, R alkyl or halogen (bromine, chlorine).
The content of the invention
The technical problem to be solved in the present invention is：Based on above mentioned problem, the present invention provides a kind of 2- thiophenyls -4,5- dihydro
The synthetic method of oxazole.
The present invention solves a technical scheme being used of its technical problem：A kind of 2- thiophenyls -4,5- dihydro-oxazoles
Synthetic method, be specifically：Under nitrogen protective condition, 2- oxazolidines thioketones and aryne precursor mixed dissolution are added in solvent
Alkali, heating response, vacuum distillation removes solvent, and residue with Ethyl acetate and petroleum ether are eluant, eluent, silica gel column chromatography separation
Purifying, obtains 2- thiophenyl -4,5- dihydro-oxazoles.
The synthetic route of the present invention is as follows：
Further, the general structure of 2- oxazolidines thioketones is：Wherein, R1For hydrogen, methyl, R2For hydrogen, first
Base, isopropyl, benzyl, phenyl.
Further, the general structure of aryne precursor is：Wherein, R3For hydrogen, methyl, the tert-butyl group, benzyl
Base, methoxyl group, piperonyl, fluorine, chlorine, bromine, iodine, phenyl, naphthyl, the aryne precursor can be the mono-substituted structures of above group,
It can also be disubstituted structure.
Further, alkali is cesium fluoride.
Further, solvent is non-protonic solvent acetonitrile.
Further, the mol ratio of 2- oxazolidines thioketones, aryne precursor and alkali is 1：1~1.5：1~3.
Further, reaction temperature is 60~90 DEG C, and the reaction time is 10~12h.
The beneficial effects of the invention are as follows：Using 2- oxazolidines thioketones, aryne precursor and cesium fluoride as raw material, heating response is led to
Cross one-step method and can be prepared by 2- thiophenyl -4,5- dihydro-oxazoles, reaction raw materials are easy to get, easy to operate, mild condition, yield compared with
It is high.
Embodiment
Presently in connection with specific embodiment, the invention will be further described, following examples be intended to illustrate invention rather than
Limitation of the invention further.
Reagent used in the present invention is prepared with reference to pertinent literature, and solvent is by purifying and refines.
Embodiment 1
10 milliliters of tube sealings are taken, 50 milligrams of 1a are weighed, 140 milligrams of 2a, 388 milligrams of cesium fluorides add 2 milliliters of acetonitriles, take out true
Change nitrogen, 90 DEG C of reaction 12h.Then vacuum distillation removes solvent, and residue is using petroleum ether and ethyl acetate as eluant, eluent, silica gel
Column chromatography separating purification, obtains colourless liquid 3aa, and yield is 91%.3aa:1H NMR(400MHz,CDCl3)δ7.61–7.58
(m, 2H), 7.37-7.35 (m, 3H), 4.38 (t, J=8.4Hz, 1H), 4.25-4.16 (m, 1H), 3.84 (t, J=7.6Hz,
1H), 1.24 (d, J=6.6Hz, 3H)13C NMR(100MHz,CDCl3)δ163.9,134.4,129.3,128.1,75.4,
62.5,21.3.HRMS (ESI) m/z calculated values C10H12NOS+[M+H]+194.0634, measured value 194.0637.
Embodiment 2
10 milliliters of tube sealings are taken, 50 milligrams of 1a are weighed, 190 milligrams of 2b, 236 milligrams of cesium fluorides add 2 milliliters of acetonitriles, take out true
Change nitrogen, 90 DEG C of reaction 12h.Then vacuum distillation removes solvent, and residue is using petroleum ether and ethyl acetate as eluant, eluent, silica gel
Column chromatography separating purification, obtains 3ab, and yield is 52%.3ab:1H NMR(300MHz,CDCl3) δ 7.43 (d, J=1.6Hz,
2H), 7.41 (d, J=1.5Hz, 1H), 4.41 (dd, J=9.0,7.9Hz, 1H), 4.29-4.17 (m, 1H), 3.87 (t, J=
7.6,1H), 1.32 (s, 18H), 1.28 (d, J=6.5Hz, 3H)13C NMR(75MHz,CDCl3)δ164.2,151.5,
128.4,127.0,123.4,75.3,62.4,35.0,31.3,21.3.HRMS (ESI) m/z calculated values C18H28NOS+[M+H]+
306.1886, measured value 306,1891.
Embodiment 3
10 milliliters of tube sealings are taken, 50 milligrams of 1a are weighed, 200 milligrams of 2c, 236 milligrams of cesium fluorides add 2 milliliters of acetonitriles, take out true
Change nitrogen, 90 DEG C of reaction 12h.Then vacuum distillation removes solvent, and residue is using petroleum ether and ethyl acetate as eluant, eluent, silica gel
Column chromatography separating purification, obtains 3ac and 3ac ', and gross production rate is 59%.3ac and 3ac ' mixture:1H NMR(400MHz,
CDCl3) δ 7.51 (d, J=8.0Hz, 1H), 7.46-7.42 (m, 1H), 7.29 (dd, J=14.9,7.5Hz, 3H), 7.23-
7.18 (m, 4H), 4.40 (td, J=8.5,4.3Hz, 1H), 4.26-4.17 (m, 1H), 3.99 (s, 2H), 3.86 (td, J=
7.6,4.9Hz, 1H), 1.25 (d, J=6.6Hz, 3H)13C NMR(100MHz,CDCl3)δ164.0,142.3,142.2,
140.3,140.2,134.7,134.6,132.0,129.9,129.8,129.2,129.1,12 9.0,128.59 (d, J=
2.0Hz),128.1,126.4,126.3,125.3,75.5,75.4,62.5,41.7,21.3.HRMS (ESI) m/z calculated values
C17H18NOS+[M+H]+284.1104, measured value 284.1107.
Embodiment 4
10 milliliters of tube sealings are taken, 50 milligrams of 1a are weighed, 170 milligrams of 2d, 236 milligrams of cesium fluorides add 2 milliliters of acetonitriles, take out true
Change nitrogen, 90 DEG C of reaction 12h.Then vacuum distillation removes solvent, and residue is using petroleum ether and ethyl acetate as eluant, eluent, silica gel
Column chromatography separating purification, obtains 3ad, and yield is 71%.3ad:1H NMR(300MHz,CDCl3) δ 7.22 (d, J=8.0Hz,
1H), 7.16-7.08 (m, 2H), 6.86 (m, 1H), 4.36 (dd, J=9.0,7.9Hz, 1H), 4.23-4.10 (m, 1H), 3.82
(t, J=7.6Hz, 1H), 3.75 (s, 3H), 1.21 (d, J=6.5Hz, 3H)13C NMR(75MHz,CDCl3)δ163.8,
159.7,130.0,128.9,126.5,119.5,115.4,75.4,62.5,55.4,21.3.HRMS (ESI) m/z calculated values
C10H14NO2S+[M+H]+210.0583, measured value 210.0586.
Embodiment 5
10 milliliters of tube sealings are taken, 50 milligrams of 1a are weighed, 172 milligrams of 2e, 236 milligrams of cesium fluorides add 2 milliliters of acetonitriles, take out true
Change nitrogen, 90 DEG C of reaction 12h.Then vacuum distillation removes solvent, and residue is using petroleum ether and ethyl acetate as eluant, eluent, silica gel
Column chromatography separating purification, obtains 3ae, and yield is 78%.3ae:1H NMR(400MHz,CDCl3)δ7.17-7.14(m,2H),
6.83-6.76 (m, 1H), 4.47 (dd, J=9.0,8.1Hz, 1H), 4.31-4.22 (m, 1H), 3.92 (t, J=7.7Hz, 1H),
1.29 (d, J=6.6Hz, 3H)13C NMR(100MHz,CDCl3)δ161.4,117.0,116.7,105.1,75.7,62.4,
21.1.HRMS (ESI) m/z calculated values C10H10F2NOS+[M+H]+230.0446, measured value 230.0443.
Embodiment 6
10 milliliters of tube sealings are taken, 50 milligrams of 1a are weighed, 193 milligrams of 2e, 236 milligrams of cesium fluorides add 2 milliliters of acetonitriles, take out true
Change nitrogen, 90 DEG C of reaction 12h.Then vacuum distillation removes solvent, and residue is using petroleum ether and ethyl acetate as eluant, eluent, silica gel
Column chromatography separating purification, obtains 3af and 3af ', and gross production rate is 85%.3af and 3af ' mixture:1H NMR(400MHz,
CDCl3) δ 7.84 (s, 1H), 7.68 (d, J=8.3Hz, 2H), 7.61-7.56 (m, 8H), 7.48-7.43 (m, 5H), 7.37 (t,
J=7.3Hz, 2H), 4.46-4.41 (m, 2H), 4.25 (m, 2H), 3.92-3.87 (m, 2H), 1.29 (d, J=1.7Hz, 3H),
1.28 (d, J=1.7Hz, 3H)13C NMR(75MHz,CDCl3)δ164.2,164,1,142.3,142.2,140.1,140.0,
134.8,133.2,133.1,129.6,128.9,128.4,128.2 127.9,127.8,27.7,127.2 127.2,126.7,
75.6,75.5,62.4,21.3,21.2.HRMS (ESI) m/z calculated values C16H16NOS+[M+H]+270.0749, measured value
270.0950。
Embodiment 7
10 milliliters of tube sealings are taken, 50 milligrams of 1b are weighed, 100 milligrams of 2e, 255 milligrams of cesium fluorides add 2 milliliters of acetonitriles, take out true
Change nitrogen, 90 DEG C of reaction 10h.Then vacuum distillation removes solvent, and residue is using petroleum ether and ethyl acetate as eluant, eluent, silica gel
Column chromatography separating purification, obtains 3ba, and yield is 80%.3ba:1H NMR(300MHz,CDCl3)δ7.68-7.64(m,2H),
7.39-7.37 (m, 3H), 7.35-7.26 (m, 3H), 7.24-7.19 (m, 2H), 5.22 (dd, J=9.8,7.7Hz, 1H), 4.67
(dd, J=9.8,8.2Hz, 1H), 4.16 (t, J=7.9Hz, 1H)13C NMR(100MHz,CDCl3)δ165.7,142.0,
(134.6,129.5,129.3,128.7,127.8,127.7,126.5,76.3,70.2.HRMS ESI) m/z calculated values
C15H14NOS+[M+H]+256.0718, measured value 256.0791.
Using the above-mentioned desirable embodiment according to the present invention as enlightenment, by above-mentioned description, relevant staff is complete
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property scope is not limited to the content on specification, it is necessary to its technical scope is determined according to right.
Claims (7)
1. a kind of synthetic method of 2- thiophenyls -4,5- dihydro-oxazole, it is characterized in that：Under nitrogen protective condition, 2- oxazolidine sulphur
Ketone and aryne precursor mixed dissolution add alkali in solvent, and heating response, vacuum distillation removes solvent, residue acetic acid second
Ester and petroleum ether are eluant, eluent, and silica gel column chromatogram separating purification obtains 2- thiophenyl -4,5- dihydro-oxazoles.
2. a kind of synthetic method of 2- thiophenyls -4,5- dihydro-oxazole according to claim 1, it is characterized in that：Described
The general structure of 2- oxazolidine thioketones is：Wherein, R1For hydrogen, methyl, R2For hydrogen, methyl, isopropyl, benzyl, benzene
Base.
3. a kind of synthetic method of 2- thiophenyls -4,5- dihydro-oxazole according to claim 1, it is characterized in that：Described
The general structure of aryne precursor is：Wherein, R3For hydrogen, methyl, the tert-butyl group, benzyl, methoxyl group, piperonyl,
Fluorine, chlorine, bromine, iodine, phenyl, naphthyl, the aryne precursor can be the mono-substituted structure of above group or disubstituted knot
Structure.
4. a kind of synthetic method of 2- thiophenyls -4,5- dihydro-oxazole according to claim 1, it is characterized in that：Described
Alkali is cesium fluoride.
5. a kind of synthetic method of 2- thiophenyls -4,5- dihydro-oxazole according to claim 1, it is characterized in that：Described
Solvent is non-protonic solvent acetonitrile.
6. a kind of synthetic method of 2- thiophenyls -4,5- dihydro-oxazole according to claim 1, it is characterized in that：Described
The mol ratio of 2- oxazolidines thioketones, aryne precursor and alkali is 1：1~1.5：1~3.
7. a kind of synthetic method of 2- thiophenyls -4,5- dihydro-oxazole according to claim 1, it is characterized in that：Described
Reaction temperature is 60~90 DEG C, and the reaction time is 10~12h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382091A (en) * | 2011-09-05 | 2012-03-21 | 浙江大学 | Method for synthesizing multi-substituted chromone compound |
| CN104177395A (en) * | 2014-07-31 | 2014-12-03 | 重庆大学 | Benzyne precursor and synthesis method thereof |
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2017
- 2017-03-22 CN CN201710171529.3A patent/CN106986841A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382091A (en) * | 2011-09-05 | 2012-03-21 | 浙江大学 | Method for synthesizing multi-substituted chromone compound |
| CN104177395A (en) * | 2014-07-31 | 2014-12-03 | 重庆大学 | Benzyne precursor and synthesis method thereof |
Non-Patent Citations (2)
| Title |
|---|
| KALLOLMAY BISWAS等: "Insertion of Arynes into Thioureas: A New Amidine Synthesis", 《ORGANIC LETTERS》 * |
| 陈静: "苯炔前体的合成及其应用进展", 《合成材料老化与应用》 * |
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Application publication date: 20170728 |