CN106749077B - A method of synthesis oxazoline compound - Google Patents

A method of synthesis oxazoline compound Download PDF

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Publication number
CN106749077B
CN106749077B CN201710185877.6A CN201710185877A CN106749077B CN 106749077 B CN106749077 B CN 106749077B CN 201710185877 A CN201710185877 A CN 201710185877A CN 106749077 B CN106749077 B CN 106749077B
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compound
oxazoline compound
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copper
solvent
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CN106749077A (en
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黄兵
潘英明
王恒山
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Guangxi Normal University
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Guangxi Normal University
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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
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a kind of new methods for synthesizing oxazoline compound; 0.1 mmol enamine ketone compound is added in flask under oxygen protection; the copper salt catalyst (such as copper bromide, copper chloride, cupric iodide) of 30%mmol; in solvent (such as DMF, DMSO solution); 2 h, TLC tracking reaction are stirred to react at 80-100 DEG C；After ruing out of to enamine ketone compound, be cooled to room temperature, filter by decompression and remove solvent, then analyse layer by silicagel column and use ethyl acetate: petroleum ether=1: 100 purifying obtain product.This method is activated using enamine ketone compound and oxygen as raw material based on C-H, under the catalytic action of the copper salts, one pot process oxazoline compound.The method of the present invention raw material is easy to get, easy to operate, mild condition, obtains good yield, is with a wide range of applications.

Description

A method of synthesis oxazoline compound
Technical field
It is specifically a kind of using enamine ketone compound and oxygen as Material synthesis the present invention relates to the synthesis of oxazoline compound The method of oxazoline compound.
Background technique
Oxazole structure is widely present in natural products, active medicine and organic functional material, these natural products and work Property drug there is very important medical value, while disliking azole compounds is also the critically important raw material of industry.
But currently, synthesis oxazoline compound method it is long there are the reaction time, yield is lower, reaction raw materials catalyst compared with For expensive disadvantage.
Summary of the invention
The object of the present invention is to provide one kind using enamine ketone compound and oxygen as raw material, is activated based on C-H, in mantoquita Catalytic action under, the new method of one pot process oxazoline compound.This method raw material is easy to get, easy to operate, and mild condition obtains To good yield, it is with a wide range of applications.
Realizing the technical solution of the object of the invention is:
A kind of new method synthesizing oxazoline compound, synthetic method general formula are as follows:
Wherein, R1 =aryl, heterocycle；
Catalyst are as follows: cupric, such as copper chloride, copper bromide, cupric iodide；
Solvent are as follows: non-protonic solvent, such as DMF, DMSO；
The universal synthesis method of the oxazoline compound is:
Oxygen is protected in lower flask and 0.1 mmol enamine ketone compound, copper salt catalyst (such as bromination of 30%mmol is added Copper, copper chloride, cupric iodide etc.), in non-protonic solvent (such as DMF, DMSO solution), 2 h are stirred to react at 80-100 DEG C, TLC tracking reaction；It after being run out of to enamine ketone compound, is cooled to room temperature, is filtered by decompression and remove solvent, then passed through Silicagel column analyses layer and uses ethyl acetate: petroleum ether=1: 100 purifying obtain product.
The structural formula of the evil azole compounds of synthesis is as follows:
。
In order to which We conducted following experiments for the source of verifying oxygen in the reaction product:
(1) 30%(6.7 mg is added in open flask) copper bromide, 0.1 mmol (31.3 mg) 3-(benzylamino) -1, 3- diphenylprop -2- alkene -1- ketone reacts 2 h in 3 mL DMF solutions at 80 DEG C；After to consumption of raw materials, it is cooled to room Temperature filters by decompression and removes solvent, then analyses layer by silicagel column and use ethyl acetate: petroleum ether=1: 100 purifying obtain light Yellow is solid
10.23 mg of body compound 4a, yield 32.68%, structural formula be,。
(2) argon gas is protected in lower flask and 30%(6.7 mg is added) copper bromide, 0.1 mmol (31.3 mg) 3-(benzyl ammonia Base) -1,3- diphenylprop -2- alkene -1- ketone in 3 mL DMF solutions, reacts 2 h at 80 DEG C, and that there is no product 4a is raw for discovery At.
(3) oxygen is protected in lower flask and 30%(6.7 mg is added) copper bromide, 0.1 mmol (31.3 mg) 3-(benzyl ammonia Base) -1,3- diphenylprop -2- alkene -1- ketone reacts 2 h at 3 mL DMF solutions, 80 DEG C, and it is cooling after consumption of raw materials To room temperature, filter by decompression and remove solvent, then analyse layer by silicagel column and use ethyl acetate: petroleum ether=1: 100 purifying obtain To 23.48 mg of faint yellow solid compound 4a, yield 75%.
By being tested above it can be concluded that being reacted under the conditions of open flask Plays, there is target production The generation of object 4a, but yield is lower；It is reacted under standard conditions under protection of argon gas, absolutely not detects target product The generation of 4a；It is reacted under standard conditions under oxygen protection, target product 4a is received with high yield, this illustrates that the reaction produces Oxygen of the oxygen in oxygen in object oxazole.
The new method raw material that the present invention synthesizes oxazoline compound is easy to get, and easy to operate, mild condition obtains good receipts Rate is with a wide range of applications, and is suitable for commodity production.
Specific embodiment
Below with reference in embodiment seven kinds evil azole compounds synthetic method and Characterization of The Products to the content of present invention make into The explanation of one step, but be not limitation of the invention.
Embodiment 1
The synthesis of (2,4- diphenyl -5- oxazolyl) phenyl ketone:
30%(6.7 mg is added in flask) copper bromide, 0.1 mmol (31.3 mg) 3-(benzylamino) -1,3- hexichol Base propyl- 2- alkene -1- ketone reacts 2 h in 3 mLDMF solution in oxygen atmosphere at 80 DEG C；It is cooling after consumption of raw materials To room temperature, filtered by decompression and remove solvent, then by silicagel column analyse layer purify (ethyl acetate: petroleum ether=1: 100) obtain it is light 23.48 mg of yellow solid compound 4a, yield 75%, structural formula be,；
1H NMR (400 MHz, CDCl3) δ 8.13 – 8.10 (m, 2H), 8.02 (ddd, J = 5.4, 2.9, 1.5 Hz, 2H), 7.89 (dd, J = 8.4, 1.3 Hz, 2H), 7.52 (d, J = 7.4 Hz, 1H), 7.48 – 7.44 (m, 3H), 7.42 – 7.39 (m, 2H), 7.35 (dd, J = 5.1, 1.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 183.19, 161.96, 148.84, 143.50, 137.58, 132.87, 131.75, 130.63, 129.84, 129.58, 129.32, 129.00, 128.36, 128.22, 127.45, 126.35。
Embodiment 2
(2-(4- methoxyphenyl) -4- phenyl -5- oxazolyl) phenyl ketone synthesis:
30%(6.7 mg is added in flask) copper bromide, 0.1 mmol (34.3mg) 3-(3- methoxy-benzyl) amino)- 1,3- diphenylprop -2- alkene -1- ketone reacts 2 h in 3 mLDMF solution in oxygen atmosphere at 80 DEG C；It is complete to consumption of raw materials Bi Hou is cooled to room temperature, by decompression filter remove solvent, then by silicagel column analyse layer purify (ethyl acetate: petroleum ether=1: 100) 28.15 mg of crocus solid chemical compound 4b, yield 82%, structural formula are obtained are as follows:
；
1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 6.5, 3.0 Hz, 2H), 7.95 (d, J = 7.3 Hz, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.41 (ddd, J = 13.9, 8.5, 5.5 Hz, 5H), 3.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 183.09, 161.81, 159.99, 148.81, 143.52, 137.58, 132.95, 130.16, 129.90, 129.65, 129.41, 128.40, 128.26, 119.88, 118.14, 112.18, 55.51。
Embodiment 3
(2-(4- fluorophenyl) -4- phenyl -5- oxazolyl) phenyl ketone synthesis:
30%(4.1 mg is added in flask) copper chloride, 0.1 mmol (33.1mg) 3-((4- luorobenzyl) amino)-1, 3- diphenylprop -2- alkene -1- ketone reacts 2 h in 3 mL DMF solutions in oxygen atmosphere at 80 DEG C；It is finished to consumption of raw materials Afterwards, be cooled to room temperature, by decompression filter remove solvent, then by silicagel column analyse layer purify (ethyl acetate: petroleum ether=1: 100) 22.28 mg of crocus solid chemical compound 4c, yield 67.3%, structural formula are obtained are as follows:
；
1H NMR (400 MHz, CDCl3) δ 8.21 – 8.15 (m, 2H), 8.08 – 8.03 (m, 2H), 7.95 – 7.91 (m, 2H), 7.61 – 7.55 (m, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.41 (dd,J = 4.1, 2.5 Hz, 3H), 7.23 – 7.15 (m, 2H).13CNMR (400 MHz,CDCl3)δ 183.18, 166.20, 163.68, 161.13, 148.81, 143.55, 137.54, 134.89, 132.93, 130.54, 129.91, 129.80, 129.71, 129.56, 129.32, 129.04, 128.39, 128.26, 122.75, 122.72, 116.45, 116.23。
Embodiment 4
(2-(4- chlorphenyl) -4- phenyl -5- oxazolyl) phenyl ketone synthesis:
30%(4.1mg is added in flask) copper chloride, 0.1 mmol (34.8mg) 3-((4- chlorobenzyl) amino)-1,3- Diphenylprop -2- alkene -1- ketone reacts 2 h in 3 mLDMF solution in oxygen atmosphere at 80 DEG C；After to consumption of raw materials, Be cooled to room temperature, by decompression filter remove solvent, then by silicagel column analyse layer purifying (ethyl acetate: petroleum ether=1: 100) obtain To 23.70 mg of orange/yellow solid compound 4d, yield 68.1%, structural formula are as follows:；
1H NMR (400 MHz, CDCl3) δ 8.10 – 8.07 (m, 2H), 8.07 – 8.03 (m, 2H), 7.92 (dd, J = 8.3, 1.2 Hz, 2H), 7.59 – 7.53 (m, 1H), 7.48 – 7.44 (m, 4H), 7.40 (dd, J = 6.4, 2.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 183.18, 161.03, 148.81, 143.59, 138.09, 137.44, 133.03, 130.44, 129.97, 129.60, 129.41, 129.34, 128.72, 128.43, 128.29, 124.81。
Embodiment 5
(2-(4- bromophenyl) -4- phenyl -5- oxazolyl) phenyl ketone synthesis:
30%(9.5 mg is added in branch mouth pipe) cupric iodide, 0.1 mmol (39.2mg) 3-((4- bromobenzyl) amino)- 1,3- diphenylprop -2- alkene -1- ketone reacts 2 h in 3 mLDMF solution in oxygen atmosphere at 80 DEG C；It is complete to consumption of raw materials Bi Hou is cooled to room temperature, by decompression filter remove solvent, then by silicagel column analyse layer purify (ethyl acetate: petroleum ether=1: 100) 26.93 mg of Chinese red solid chemical compound 4e, yield 68.7%, structural formula are obtained are as follows:
；
1H NMR (400 MHz, CDCl3) δ 8.07 – 8.01 (m, 4H), 7.93 (dd, J = 8.3, 1.2 Hz, 2H), 7.69 – 7.62 (m, 2H), 7.61 – 7.55 (m, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.40 (dd, J = 5.4, 2.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 183.17, 161.08, 148.80, 143.60, 137.43, 133.03, 132.37, 130.43, 129.97, 129.59, 129.33, 128.85, 128.43, 128.29, 126.57, 125.25。
Embodiment 6
(2-(4- bromophenyl) -4- phenyl -5- oxazolyl) phenyl ketone synthesis:
30%(9.5 mg is added in flask) cupric iodide, ((4- trifluoromethyl benzyl) ammonia of 0.1 mmol (38.1mg) 3- Base) -1,3- diphenylprop -2- alkene -1- ketone in 3 mL DMSO solutions, reacts 2 h in oxygen atmosphere at 80 DEG C；To raw material It after being exhausted, is cooled to room temperature, is filtered by decompression and remove solvent, then layer is analysed by silicagel column and purifies (ethyl acetate: petroleum Ether=1: 100) 26.25 mg of yellow solid compound 4f, yield 68.9%, structural formula are obtained are as follows:
；
1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.1 Hz, 2H), 8.09 – 8.03 (m, 2H), 7.94 (dt, J = 8.5, 1.6 Hz, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.62 – 7.56 (m, 1H), 7.49 – 7.44 (m, 2H), 7.44 – 7.40 (m, 3H). 13C NMR (100 MHz, CDCl3) δ 183.24, 160.37, 148.67, 143.91, 137.31, 133.39, 133.15, 133.06, 130.28, 130.03, 129.59, 129.54, 129.30, 128.46, 128.32, 127.71, 126.07, 126.03, 125.99。
Embodiment 7
(2-(1- naphthalene) -4- phenyl -5- oxazolyl) phenyl ketone synthesis:
30%(9.5 mg is added in flask) cupric iodide, 0.1 mmol (36.3mg) 3-((naphthalene-1- ylmethyl) amino)- 1,3- diphenylprop -2- alkene -1- ketone reacts 2 h in 3mL DMSO solution in oxygen atmosphere at 80 DEG C；It is complete to consumption of raw materials Bi Hou is cooled to room temperature, by decompression filter remove solvent, then by silicagel column analyse layer purify (ethyl acetate: petroleum ether=1: 100) orange/yellow solid compound 4j 26.27mg, yield 72.3%, structural formula are obtained are as follows:
；
1H NMR (400 MHz, CDCl3) δ 9.46 (d, J = 8.7 Hz, 1H), 8.35 (dd, J = 7.3, 1.1 Hz, 1H), 8.23 – 8.18 (m, 2H), 8.06 – 7.99 (m, 3H), 7.94 (d, J = 8.1 Hz, 1H), 7.69 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.63 – 7.57 (m, 3H), 7.51 – 7.45 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 183.41, 161.90, 148.53, 143.08, 137.70, 134.02, 132.96, 132.75, 130.74, 130.45, 129.93, 129.65, 129.44, 129.17, 128.80, 128.43, 128.30, 128.14, 126.61, 126.15, 125.00, 122.61。

Claims (2)

1. a kind of method for synthesizing oxazoline compound, which is characterized in that oxazoline compound synthetic method general formula is as follows:
Wherein, R1 =aryl, heterocycle；
Catalyst are as follows: copper chloride, copper bromide, one of cupric iodide；
Solvent are as follows: a kind of in non-protonic solvent DMF, DMSO；
The universal synthesis method of the oxazoline compound is:
Oxygen is protected and 0.1 mmol enamine ketone compound is added in lower flask, the copper salt catalyst of 30%mmol, in a solvent, 2 h, TLC tracking reaction are stirred to react at 80-100 DEG C；It after being run out of to enamine ketone compound, is cooled to room temperature, passes through Decompression, which filters, removes solvent, then uses ethyl acetate: petroleum ether=1 by silica gel column chromatography: 100 purifying obtain product.
2. the method for synthesis oxazoline compound according to claim 1, it is characterised in that: the oxazoline compound of the synthesis Structural formula it is as follows:
。
CN201710185877.6A 2017-03-27 2017-03-27 A method of synthesis oxazoline compound Expired - Fee Related CN106749077B (en)

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