CN108863969A - A kind of synthetic method of two substituted isoxazoles of 4- allyl -3,5- - Google Patents
A kind of synthetic method of two substituted isoxazoles of 4- allyl -3,5- Download PDFInfo
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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Abstract
The invention discloses a kind of synthetic methods of bis- substituted isoxazoles of 4- allyl -3,5-, belong to technical field of organic synthesis.The synthetic method is：In the reactor, Norethisteroneoxime ether substrate, 3- bromopropene, palladium catalyst, additive and solvent is added, is stirred to react at 70-80 DEG C, reaction product is isolated and purified, and bis- substituted isoxazoles of 4- allyl -3,5- are obtained.The product that method of the invention is coupled with acyl chlorides and alkynes simple and easy to get through Sonogashira reacts to obtain a series of Norethisteroneoxime ethers again with methoxy amine hydrochlorate, reaction condition is mild, no pollution to the environment, construct the 4- allyl -3 with latent functionality, bis- substituted isoxazoles compound of 5-, this method has innovative and Atom economy, mild condition, safe operation, and 5 gram-grade scales can be amplified to without influencing yield thus there is potential practical value.
Description
Technical field
The invention belongs to isoxazole preparation fields, and in particular to a kind of synthesis of bis- substituted isoxazoles of 4- allyl -3,5-
Method.
Background technique
Isoxazole structure is widely present in natural products and drug molecule, in drug of many containing isoxazole skeleton
There is N just because of this in molecule, the presence of the five-ring heterocycles structure of O atom and show important physiological activity, it is such as anti-
Bacterium, anti-inflammatory, anticancer etc., therefore the synthesis of this kind of compounds receives significant attention.Up to the present the building of , isoxazole skeleton
[3+2] cycloaddition reaction mainly by (1) under transition metal-catalyzed；(2) using the dipole of preparatory function dough as instead
Substrate is answered to pass through cycloaddition reaction；(3) several methods such as cycloisomerisation strategy synthesize.Although these strategies are varied, according to
Right having some limitations property, such as severe reaction conditions, it usually needs highly basic or high temperature；Reaction substrate is complicated, this is allowed for instead
That answers is inefficient, and low yield, atom utilization is inadequate, does not meet the idea of development of Green Chemistry.
In addition, allyl is introduced into compound structure segment especially as a kind of group with high reaction activity
It is heterocycle structure segment or more abundant molecular structure is obtained by the conversion of allyl always is chemist institute
The target of pursuit.In the synthesis process of many natural products or complex compound, by the introducing of allyl and it can turn
Change and construct its key structure, and the introducing of allyl is but also the physiological activity of these drug molecules greatly improves.It consults related
The introducing strategy of literature, allyl is broadly divided into four kinds：The first is to realize C-H allyl in such a way that C-H is activated
Change；Second is realized by the metal process that turns of organometallic reagent；The third is to migrate to introduce by intramolecular allyl；
4th kind is to pass through transition metal-catalyzed strategy using allyl alcohol or allyl halide as substrate.Literature survey finds this
There is also corresponding limitations, such as the C-H strategy activated to generally require the introducing of homing device and with reaction item for a little methods
The drawbacks such as part harshness；Reaction yield is low and atom utilization is low etc..
Summary of the invention
In order to solve the disadvantage that the above prior art and shortcoming, the purpose of the present invention is to provide a kind of 4- allyls
The synthetic method of two substituted isoxazoles of base -3,5-.
The object of the invention is achieved through the following technical solutions.
A kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5-, includes the following steps：
In the reactor, substrate, 3- bromopropene, palladium catalyst, additive and the solvent of 1 structure of formula is added, at 70-80 DEG C
Under be stirred to react, reaction product is isolated and purified, and bis- substituted isoxazoles of 4- allyl -3,5- are obtained；
Preferably, R in formula 11For methyl, all kinds of electron-donating group phenyl, all kinds of electron-withdrawing group phenyl, thienyl, cyclopenta
Or cyclohexyl；R2For chain alkyl, short-chain alkyl, all kinds of electron-donating group phenyl, all kinds of electron-withdrawing group phenyl, thienyl, ring penta
Base or cyclohexyl.
Preferably, R in formula 11、R2For monosubstituted phenyl or polysubstituted phenyl.
Preferably, R in formula 11、R2For 2- aminomethyl phenyl, 3- aminomethyl phenyl or 4- aminomethyl phenyl.
Preferably, the palladium catalyst refers to palladium acetate；The dosage of palladium catalyst and the molar ratio of substrate are 0.05:1-
0.1:1。
Preferably, the additive is positive butylammonium bromide；The additional amount of the normal-butyl ammonium bromide and rubbing for substrate
You are than being (1-1.2):1, further preferably 1:1.
Preferably, the solvent is n,N-Dimethylformamide.
Preferably, the temperature being stirred to react is 80 DEG C.
Preferably, the time being stirred to react is 10-40min.
Preferably, described isolate and purify is to be cooled to room temperature reaction solution after completion of the reaction, and saturation chlorination is then added
Ammonium salt solution adds ethyl acetate extraction, merges organic phase, with anhydrous MgSO4Dry, filtering, vacuum rotary steam remove solvent, with
Petroleum ether and ethyl acetate are solvent, by TLC contact plate, are then taken by the isolated 4- allyl -3,5- bis- of plate layer chromatography
Dai isoxazole.
Preferably, the plate layer chromatography refers to the plate layer chromatography using the mixed solvent of petroleum ether and ethyl acetate as solvent,
The volume ratio of petroleum ether and ethyl acetate is (100-70):1.
Preferably, a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5-, includes the following steps：
In common test tube, Pd (OAc) is sequentially added2, normal-butyl ammonium bromide (n-Bu4NBr), 3- bromopropene, Norethisteroneoxime ether
Common DMF is then added in class substrate, and opening is stirred to react in a heated condition, and product is through isolating and purifying to obtain after reaction
Two substituted isoxazoles of target product 4- allyl -3,5-.
Above-mentioned synthetic reaction formula is shown below：
Reaction principle of the invention is occurred first under palladium catalyst effect using 3- bromopropene and Norethisteroneoxime ether as raw material
Intramolecular oxygen palladium obtains alkenyl palladium intermediate, then the migration that alkene occurs with 3- bromopropene is inserted into obtain alkyl palladium intermediate,
β-Br finally occurs to eliminate to obtain final product, releases divalent palladium and returns to catalytic cycle system.
Compared with prior art, the invention has the advantages that and beneficial effect：
(1) synthetic method raw material of the invention is easy to get, and can synthesize through simple two step：The first step passes through various substitutions
The acyl chlorides and terminal alkyne of base are coupled to obtain corresponding acetylenic ketone compound through Sonogashira；Second step will be obtained in the previous step
Acetylenic ketone and methoxy amine hydrochlorate using pyridine as alkali, anhydrous sodium sulfate as water absorbing agent, methanol as solvent, be stirred at room temperature
Night can take target compound Norethisteroneoxime ether with the separation yield of 70%-90%.Another one's share of expenses for a joint undertaking substrate 3- bromopropene is also honest and clean
The chemical reagent that valence is easy to get.This method have novelty, mild condition, safe operation, yield height, the reaction time is short, low energy consumption
The advantages that, and 5 gram-grade large-scale production may be implemented, thus there is potential practical value.
(2) synthetic method of the invention has the characteristics that efficient, convenient, substrate wide adaptability, functional group's tolerance are good.
(3) synthetic method of the invention can construct the full substituted isoxazoles structure for containing exposed allyl with a step.
(4) synthetic method of the invention can be with amplification quantity to 5 gram-grade scales.
Detailed description of the invention
Fig. 1 is the hydrogen spectrogram of 1 gained target product of embodiment；
Fig. 2 is the carbon spectrogram of 1 gained target product of embodiment；
Fig. 3 be embodiment 2 target product hydrogen spectrogram；
Fig. 4 be embodiment 2 target product carbon spectrogram；
Fig. 5 be embodiment 3 target product hydrogen spectrogram；
Fig. 6 be embodiment 3 target product carbon spectrogram；
Fig. 7 be embodiment 4 target product hydrogen spectrogram；
Fig. 8 be embodiment 4 target product carbon spectrogram；
Fig. 9 be embodiment 5 target product hydrogen spectrogram；
Figure 10 be embodiment 5 target product carbon spectrogram；
Figure 11 be embodiment 6 target product hydrogen spectrogram；
Figure 12 be embodiment 6 target product carbon spectrogram；
Figure 13 be embodiment 7 target product hydrogen spectrogram；
Figure 14 be embodiment 7 target product carbon spectrogram；
Figure 15 be embodiment 8 target product hydrogen spectrogram；
Figure 16 be embodiment 8 target product carbon spectrogram；
Figure 17 be embodiment 9 target product hydrogen spectrogram；
Figure 18 be embodiment 9 target product carbon spectrogram.
Specific embodiment
Present invention will now be described in further detail with reference to the embodiments and the accompanying drawings, but embodiments of the present invention are unlimited
In this.
The general structure of the Norethisteroneoxime ether of following embodiment such as formula 1：
Embodiment 1
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=R2=Ph) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of n,N-Dimethylformamide (DMF) and exists
Under 600rpm revolving speed, 80 DEG C are stirred to react, and are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room temperature and 3mL is added
The good saturated ammonium chloride solution of configured in advance adds ethyl acetate and extracts 3 merging organic phases, with anhydrous MgSO4Dry, mistake
Filter, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=200:1), pass through thin layer
The isolated final goal product of plate, separation yield 99%.The hydrogen spectrogram and carbon spectrogram of the present embodiment products therefrom are respectively such as
Shown in Fig. 1 and Fig. 2；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.79-7.77 (d, J=4.0Hz, 2H), 7.71-7.69 (m, 2H), 7.50-
7.45 (m, 6H), 6.15-6.05 (m, 1H), 5.26-5.25 (d, J=2.0Hz, 1H), 5.11-5.06 (d, J=8.0Hz, 1H),
3.43-3.42(m,2H)；
13C NMR(100MHz,CDCl3)δ166.8,164.0,135.4,129.8,129.6,129.4,128.9,128.7,
128.4,128.2,126.9,117.1,110.1,27.1；
IR(KBr)νmax 3066,2916,2845,1963,1891,1815,1624,1422 1261,1167,1071,
922,838,757,694,583,484cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C18H15NO,262.1229；found,262.1226.
Tentatively infer through above data and obtains such as flowering structure：
Embodiment 2
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=Ph, R2=4-MePh) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of n,N-Dimethylformamide (DMF)
Under 600rpm revolving speed, 80 DEG C are stirred to react, and are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room temperature addition
The good saturated ammonium chloride solution of 3mL configured in advance adds ethyl acetate and extracts 3 merging organic phases, with anhydrous MgSO4It is dry
Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=200:1), lead to
Cross the isolated final goal product of lamellae, separation yield 99%.The hydrogen spectrogram and carbon spectrogram of the present embodiment products therefrom
It is as shown in Figure 3 and Figure 4 respectively；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.70-7.64 (m, 4H), 7.44-7.43 (d, J=2.0Hz, 3H), 7.26-
7.24 (d, J=4.0Hz, 2H), 6.10-6.01 (m, 1H), 5.22-5.20 (d, J=2.0Hz, 1H), 5.08-5.03 (d, J=
10.0Hz 1H),3.39-3.38(m,1H),2.37(s,3H)；
13C NMR(100MHz,CDCl3)δ167.0,164.0,140.0,135.5,129.6,126.5,128.7,128.4,
126.8,125.4,117.0,109.6,27.1,21.4；
IR(KBr)νmax:3069,2997,2915,2844,2417,1903,1620,1516,1431,1333,1270,
1179,1117,1021,918,830,757,694,572,495cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C19H17NO,276.1386；Found, 276.1383 warp more than
Data, which are tentatively inferred, to be obtained such as flowering structure：
Embodiment 3
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=3,4-diMeOPh, R2=Ph) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of n,N-Dimethylformamide
(DMF) under 600rpm revolving speed, 80 DEG C are stirred to react, and are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room temperature
The good saturated ammonium chloride solution of 3mL configured in advance is added, adds ethyl acetate and extracts 3 merging organic phases, with anhydrous MgSO4
Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=200:1),
Pass through the isolated final goal product of lamellae, separation yield 98%.The hydrogen spectrogram and carbon of the present embodiment products therefrom are composed
Figure is as shown in Figure 4 and Figure 6 respectively；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.77-7.75 (d, J=4.0Hz, 2H), 7.49-7.43 (m, 3H), 7.30-
7.28 (d, J=4.0Hz, 2H), 6.96-6.94 (d, J=4.0Hz, 1H), 3.92-3.91 (d, J=2.0Hz, 6H), 3.44-
3.43(t,2H)；
13C NMR(100MHz,CDCl3)δ166.8,163.9,150.1,149.1,135.8,129.8,128.9,128.1,
126.8,121.9,121.0,117.1,111.4,111.2,109.8,56.0,55.9,27.3；
IR(KBr)νmax:3074,2937,2836,2584,1599,1521,1439,1329,1528,1147,1025,
922,863,757,696,628,518,482cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C20H19NO3,322.1439；found,322.1438
Tentatively infer through above data and obtains such as flowering structure：
Embodiment 4
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=Ph, R2=2-thienyl) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of n,N-Dimethylformamide
(DMF) under 600rpm revolving speed, 80 DEG C are stirred to react, and are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room temperature
The good saturated ammonium chloride solution of 3mL configured in advance is added, adds ethyl acetate and extracts 3 merging organic phases, with anhydrous MgSO4
Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=200:1),
Pass through the isolated final goal product of lamellae, separation yield 95%.The hydrogen spectrogram and carbon of the present embodiment products therefrom are composed
Figure is as shown in Figure 7 and Figure 8 respectively；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.71-7.70 (d, J=2.0Hz, 2H), 7.57-7.51 (d, J=12.0Hz,
5H), 7.19 (s, 1H), 6.12-6.05 (m, 1H), 5.25-5.23 (d, J=2.0Hz, 1H), 5.13-5.09 (d, J=8.0Hz,
1H),3.48(s,2H)；
13C NMR(100MHz,CDCl3)δ163.9,162.4,134.5,129.7,129.1,128.8,128.4,127.9,
127.8,127.1,116.9,109.7,27.0；
IR(KBr)νmax:3079,2985,2913,2841,1965,1816,1617,1522,1437,1339,124,
1165,1068,1000,925,844,754,706,577,485cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C16H13NOS,268.0787；found,268.0791.
Tentatively infer through above data and obtains such as flowering structure：
Embodiment 5
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=2- phenyl vinyl, R2=Ph) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of N, N- dimethyl formyl
Under 600rpm revolving speed, 80 DEG C are stirred to react amine (DMF), are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room
The good saturated ammonium chloride solution of 3mL configured in advance is added in temperature, adds ethyl acetate and extracts 3 merging organic phases, use is anhydrous
MgSO4Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=
200:1), pass through the isolated final goal product of lamellae, separation yield 95%.The hydrogen spectrogram of the present embodiment products therefrom
Distinguish with carbon spectrogram as shown in Figure 9 and Figure 10；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.70-7.68 (d, J=2.0Hz, 2H), 7.53-7.45 (m, 6H), 7.38-
7.30 (m, 3H), 6.96-6.92 (d, J=8.0Hz, 1H), 6.11-6.04 (m, 1H), 5.23-5.21 (d, J=2.0Hz, 1H),
5.12-5.08 (d, J=8.0Hz, 1H), 3.45 (s, 2H)；
13C NMR(100MHz,CDCl3)δ166.5,161.1,136.3,135.6,134.8,129.8,128.9,128.8,
128.1,127.1,127.0,116.9,114.7,110.4,26.9；
IR(KBr)νmax:3057,2918,2849,1961,1888,1817,1629,1499,1431,1272,1197,
1072,973,917,846,756,689,564,496cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C20H17NO,288.1379；found,288.1393.
Tentatively infer through above data and obtains such as flowering structure：
Embodiment 6
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=2-thienyl, R2=Ph) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of n,N-Dimethylformamide
(DMF) under 600rpm revolving speed, 80 DEG C are stirred to react, and are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room temperature
The good saturated ammonium chloride solution of 3mL configured in advance is added, adds ethyl acetate and extracts 3 merging organic phases, with anhydrous MgSO4
Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=200:1),
Pass through the isolated final goal product of lamellae, separation yield 94%.The hydrogen spectrogram and carbon of the present embodiment products therefrom are composed
Figure difference is as is illustrated by figs. 11 and 12；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.73-7.71 (d, J=2.0Hz, 2H), 7.49-7.42 (m, 5H), 7.13 (s,
1H), 6.16-6.08 (m, 1H), 5.26-5.24 (d, J=4.0Hz, 1H), 5.12-5.07 (d, J=8.0Hz, 1H), 3.51-
3.50 (d, J=2.0Hz, 1H)；
13C NMR(100MHz,CDCl3)δ167.4,158.5,134.8,130.1,130.0,128.9,127.9,127.8,
127.7,127.6,127.0,117.2,109.7,27.1；
IR(KBr)νmax:3077,2990,2917,2846,1814,1618,1427,1236,1163,1066,994,919,
842,754,575,483cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C16H13NOS,268.0795；found,268.0791.
Tentatively infer through above data and obtains such as flowering structure：
Embodiment 7
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=4-F-3-MePh, R2=Ph)) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of n,N-Dimethylformamide
(DMF) under 600rpm revolving speed, 80 DEG C are stirred to react, and are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room temperature
The good saturated ammonium chloride solution of 3mL configured in advance is added, adds ethyl acetate and extracts 3 merging organic phases, with anhydrous MgSO4
Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=200:1),
Pass through the isolated final goal product of lamellae, separation yield 94%.The hydrogen spectrogram and carbon of the present embodiment products therefrom are composed
Figure is as shown in Figure 13 and Figure 14 respectively；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.77-7.75 (m, 2H), 7.57-7.55 (d, J=2.0Hz, 1H, 1H), 7.50-
7.44 (m, 4H), 7.11-7.06 (m, 1H), 6.14-6.05 (m, 1H), 5.27-5.25 (d, J=4.0Hz, 1H), 5.10-5.06
(d, J=8.0Hz, 1H), 3.41-3.40 (d, J=2.0Hz, 1H), 2.33 (s, 1H)；
13C NMR(100MHz,CDCl3)δ166.9,163.5,163.4,161.0,135.4,131.7,129.8,128.9,
127.5,127.4,126.9,125.6,125.4,125.2,125.1,117.2,115.5,115.3,109.9,27.1,14.6；
IR(KBr)νmax:3070,2921,2851,1891,1603,1508,1434,1325,1250,1182,1119,
1057,971,970,827,755,692,615,553,441cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C19H16FNO,294.1292；found,294.1289.
Tentatively infer through above data and obtains such as flowering structure：
Embodiment 8
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=Ph, R2=n-propyl) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of n,N-Dimethylformamide
(DMF) under 600rpm revolving speed, 80 DEG C are stirred to react, and are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room temperature
The good saturated ammonium chloride solution of 3mL configured in advance is added, adds ethyl acetate and extracts 3 merging organic phases, with anhydrous MgSO4
Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=200:1),
Pass through the isolated final goal product of lamellae, separation yield 97%.The hydrogen spectrogram and carbon of the present embodiment products therefrom are composed
Figure is as shown in Figure 15 and Figure 16 respectively；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3)δ7.66-7.65(m,2H),7.44(s,3H),5.96-5.87(m,1H),5.11-
5.09 (d, J=2.0Hz, 1H), 5.01-4.97 (d, J=8.0Hz, 1H), 3.24 (s, 2H), 2.74-2.70 (m, 2H), 1.81-
1.76(m,2H),1.04-1.00(m,3H)；
13C NMR(100MHz,CDCl3)δ170.6,162.6,135.5,129.8,129.3,128.6,128.1,116.0,
109.9,27.6,26.4,21.0,13.9；
IR(KBr)νmax:3069,2957,1966,1865,1824,1700,1625,1444,1339,1273,1176,
1063,992,919,761,698,564cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C15H17NO,228.1386；found,228.1383.
Tentatively infer through above data and obtains such as flowering structure：
Embodiment 9
0.025 mM of Pd (OAc) is added in test tube2, 0.5 mM of normal-butyl ammonium bromide, 0.5 mM of Norethisteroneoxime
Ether (R1=cyclohexyl, R2=Ph) and 0.75 mM of 3- bromopropene, it is eventually adding 1.0 milliliters of n,N-Dimethylformamide (DMF)
Under 600rpm revolving speed, 80 DEG C are stirred to react, and are detected and are reacted by TLC, and end of reaction stops stirring, are cooled to room temperature addition
The good saturated ammonium chloride solution of 3mL configured in advance adds ethyl acetate and extracts 3 merging organic phases, with anhydrous MgSO4It is dry
Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether (PE) and ethyl acetate (EA) for solvent (PE:EA=200:1), lead to
Cross the isolated final goal product of lamellae, separation yield 93%.The hydrogen spectrogram and carbon spectrogram of the present embodiment products therefrom
It is as shown in Figure 17 and Figure 18 respectively；Structural characterization data are as follows：
1H NMR(400MHz,CDCl3) δ 7.71-7.69 (d, J=2.0Hz, 2H), 7.48-7.40 (m, 3H), 6.06-
5.97 (m, 1H), 5.18-5.15 (d, J=2.0Hz, 1H), 5.06-5.01 (d, J=8.0Hz, 1H), 3.38-3.35 (m, 2H)；
13C NMR(100MHz,CDCl3)δ168.4,165.3,135.2,129.4,128.7,128.5,126.9,116.4,
108.9,35.6,31.8,26.6,26.5,25.9；
IR(KBr)νmax 3069,2925,2853,1628,1437,1348,1268,1162,1070,980,909,830,
754,690cm-1；
HRMS(ESI,m/z):[M+H]+Calcd.for C18H21NO,268.1697；found,268.1696.
Tentatively infer through above data and obtains such as flowering structure：
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
1. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5-, which is characterized in that include the following steps：
In the reactor, substrate, 3- bromopropene, palladium catalyst, additive and the solvent of 1 structure of formula is added, is stirred at 70-80 DEG C
Reaction is mixed, reaction product is isolated and purified, and bis- substituted isoxazoles of 4- allyl -3,5- are obtained；
2. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
R in formula 11For methyl, all kinds of electron donating group phenyl, all kinds of electron-withdrawing group phenyl, thienyl, cyclopenta or cyclohexyl；R2For
Chain alkyl, short-chain alkyl, all kinds of electron-donating group phenyl, all kinds of electron-withdrawing group phenyl, thienyl, cyclopenta or cyclohexyl.
3. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
R in formula 11、R2For monosubstituted phenyl or polysubstituted phenyl.
4. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
R in formula 11、R2For 2- aminomethyl phenyl, 3- aminomethyl phenyl or 4- aminomethyl phenyl.
5. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
The palladium catalyst refers to palladium acetate；The dosage of palladium catalyst and the molar ratio of substrate are 0.05:1-0.1:1.
6. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
The additive is positive butylammonium bromide；The additional amount of the normal-butyl ammonium bromide and the molar ratio of substrate are (1-1.2):1.
7. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
The solvent is N,N-dimethylformamide.
8. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
The temperature being stirred to react is 80 DEG C.
9. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
The time being stirred to react is 10-40min.
10. a kind of synthetic method of bis- substituted isoxazoles of 4- allyl -3,5- according to claim 1, it is characterised in that：
Described isolate and purify is to be cooled to room temperature reaction solution after completion of the reaction, and saturated ammonium chloride solution is then added, adds second
Acetoacetic ester extraction, merges organic phase, with anhydrous MgSO4Dry, filtering, vacuum rotary steam remove solvent, with petroleum ether and acetic acid second
Ester is solvent, by TLC contact plate, then passes through isolated bis- substituted isoxazoles of 4- allyl -3,5- of plate layer chromatography.
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| CN112645896A (en) * | 2020-12-16 | 2021-04-13 | 华南理工大学 | Method for synthesizing 4-aryl isoxazole derivative |
| CN113185472A (en) * | 2021-04-12 | 2021-07-30 | 华南理工大学 | Method for synthesizing 4-alkoxy alkenyl isoxazole derivative |
| CN115710234A (en) * | 2022-11-02 | 2023-02-24 | 华南理工大学 | 3,4,5-trisubstituted isoxazole compounds with antitumor activity and preparation method and application thereof |
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| CN109761926A (en) * | 2019-01-16 | 2019-05-17 | 华南理工大学 | A kind of β-isoxazolone/aldehyde synthetic method |
| CN109761926B (en) * | 2019-01-16 | 2022-01-18 | 华南理工大学 | Synthesis method of beta-isoxazolidone/aldehyde |
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| CN109705050B (en) * | 2019-01-22 | 2022-12-16 | 华南理工大学 | Method for synthesizing 4-sulfenyl isoxazole |
| CN112645896A (en) * | 2020-12-16 | 2021-04-13 | 华南理工大学 | Method for synthesizing 4-aryl isoxazole derivative |
| CN113185472A (en) * | 2021-04-12 | 2021-07-30 | 华南理工大学 | Method for synthesizing 4-alkoxy alkenyl isoxazole derivative |
| CN115710234A (en) * | 2022-11-02 | 2023-02-24 | 华南理工大学 | 3,4,5-trisubstituted isoxazole compounds with antitumor activity and preparation method and application thereof |
| CN115710234B (en) * | 2022-11-02 | 2024-04-16 | 华南理工大学 | 3,4, 5-trisubstituted isoxazole compound with anti-tumor activity and preparation method and application thereof |
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