CN105622536B - A kind of trifluoromethylation alkenyl isoxazole compound and its preparation method and application - Google Patents
A kind of trifluoromethylation alkenyl isoxazole compound and its preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D261/10—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 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
- C07D261/14—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- 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
- C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
Abstract
It is applied the present invention relates to a kind of trifluoromethylation alkenyl isoxazole compound and preparation method thereof and in organic synthesis, belongs to organofluorine compound synthesis technical field.It is with general formula I：
Description
Technical field
The present invention relates to organofluorine compound synthesis technical fields, and it is different to specifically relate to a kind of trifluoromethylation alkenyl
Oxazole compounds and preparation method thereof and the application in organic synthesis.
Background technology
An important branch of the organic fluorine chemistry as organic chemistry, it has also become the hot spot in chemical research field and order instantly
One of topic that people attractes attention.At present in fields such as medicine, pesticide and materials chemistries by extensive concern and application.Such as
Efavirenz (efavirenz) be hiv reverse transcriptase inhibitor (Antimicrob Agents Chemother.1995,39,
2602.)；Celecoxib (happiness is happy to preserve) is a kind of drug for the treatment of of arthritis (Expert Opin.Investig.Drugs
2008,17,197.)；Trifluranlin (trefanocide) is the herbicide of broad-spectrum high efficacy
(Bioorg.Med.Chem.Lett.2010,20,5179.).Therefore, develop high-efficient simple, safe green, Atom economy, can
The synthetic method of control property is particularly significant to construct and be converted into fluorinated organic compound.
It is a kind of highly effective method to synthesize the compound containing trifluoromethyl by trifluoromethyl building block
(Chem.Rev.2011,111,455.).In recent years, by the unremitting effort of organic chemists, have been developed that some are novel
Trifluoromethyl building block, as β-trifluoromethyl nitroolefin derivative (J.Am.Chem.Soc.2013,135,2983.), β-
Trifluoromethyl ketenes derivative (Angew.Chem.Int.Ed.2010,49,576.) and 2,2,2- trifluoro ethylidene malonates
Derivative (Org Lett.2010,12,4655.) etc..Although the type of trifluoromethyl building block is very much, also obtain
Widely apply, but development structure novel trifluoromethyl building block still there is an urgent need to.
Invention content
The purpose of the present invention is intended to develop the trifluoromethylation alkenyl isoxazole compound of a kind of structure novel, meanwhile, it carries
Preparation method and its application in organic synthesis for above-mentioned trifluoromethylation alkenyl isoxazole compound.
Trifluoromethylation alkenyl isoxazole compound of the present invention has general formula I：
R is hydrogen, methyl, benzyl or aromatic group in general formula I；R ' is methyl or phenyl.
It is preferred that：
R is aromatic group；R ' is methyl or phenyl.
The aromatic group is phenyl, 4- aminomethyl phenyls, 4- methoxyphenyls, 3- methoxyphenyls, 2- methoxybenzenes
Base, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 4- tert-butyl-phenyls, 4- phenyls, 3,5- 3,5-dimethylphenyls, 2- naphthalenes or
2- thienyls.
It is as follows that the preparation method of trifluoromethylation alkenyl isoxazole compound of the present invention includes step：
(1)
3- substituent group -4- nitro -5- methyl-isoxazoles, trifluoromethyl aryl ketones are added in a reactor, in a solvent,
Catalyst is continuously added, lower reaction is stirred at room temperature, after completion of the reaction, washed, extraction, separation, purifying obtain intermediate A；
The catalyst is triethylamine, DABCO (1,4- diazabicylos [2,2,2] octane), N, N- lutidines or DBU (1,
11 carbon -7- alkene of 8- diazabicylos).The solvent is water, methanol, ethyl alcohol, Ν, Ν-dimethylformamide, acetonitrile, four
Hydrogen furans or toluene etc..
(2)
Above-mentioned intermediate A is added in another reactor, in a solvent, acid binding agent, thionyl chloride are continuously added, in heating
Stirring is lower to react, and after completion of the reaction, washed, extraction, separation, purifying obtain target product trifluoromethylation alkenyl isoxazole
Compound.
The acid binding agent is triethylamine or pyridine.The solvent is water, methanol, ethyl alcohol, Ν, Ν-dimethyl formyl
Amine, acetonitrile, tetrahydrofuran or toluene.
3- substituent group -4- nitro -5- methyl-isoxazoles the compound, trifluoromethyl aromatic ketone compound, catalyst,
Acid binding agent, thionyl chloride molar ratio are：3- substituent group -4- nitro -5- methyl-isoxazole compounds：Trifluoromethyl aryl ketones chemical combination
Object：Catalyst：Acid binding agent：Thionyl chloride=1：1.5-2：0.1~1：3~6：2~4.
R, R in synthetic method ' it is consistent with above-mentioned general formula I characterization ranges.
Application 1 of the trifluoromethylation alkenyl isoxazole compound of the present invention in organic synthesis：As reaction
Substrate reacts with nitromethane class compound under the effect of catalyst tetrabutylammonium bromide, inorganic base and toluene and prepares general formula II
Organofluorine compound containing trifluoromethyl group, reaction are as follows：
R is hydrogen, methyl, benzyl or aromatic group in general formula II, and preferably R is aromatic group；R ' is methyl or phenyl；R " is
Hydrogen, methyl, ethyl, isopropyl, benzyl or aromatic group；The aromatic group is phenyl, 4- aminomethyl phenyls, 4- methoxybenzenes
Base, 3- methoxyphenyls, 2- methoxyphenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 4- tert-butyl-phenyls, 4- phenyl benzene
Base, 3,5- 3,5-dimethylphenyls, 2- naphthalenes or 2- thienyls.
Application 2 of the trifluoromethylation alkenyl isoxazole compound of the present invention in organic synthesis：As reaction
Substrate react with malononitrile derivative preparation general formula III under the effect of catalyst tetrabutylammonium bromide, inorganic base and toluene and contains
The organofluorine compound of trifluoromethyl group, reaction are as follows：
R is hydrogen, methyl, benzyl or aromatic group in general formula III, and preferably R is aromatic group；R ' is methyl or phenyl；It is described
Aromatic group for phenyl, 4- aminomethyl phenyls, 4- methoxyphenyls, 3- methoxyphenyls, 2- methoxyphenyls, 4- fluorophenyls,
4- chlorphenyls, 4- bromophenyls, 4- tert-butyl-phenyls, 4- phenyls, 3,5- 3,5-dimethylphenyls, 2- naphthalenes or 2- thienyls.
Application 3 of the trifluoromethylation alkenyl isoxazole compound of the present invention in organic synthesis：As reaction
Substrate in the presence of catalyst dinaphthol phosphate and dichloromethane, reacts with Benzazole compounds and prepares general formulae IV containing trifluoro
The organofluorine compound of methyl group, reaction are as follows：
R is hydrogen, methyl, benzyl or aromatic group in general formulae IV, and preferably R is aromatic group；R ' is methyl or phenyl；R”’
For hydrogen, methyl, methoxyl group, fluorine, chlorine or bromine；The aromatic group is phenyl, 4- aminomethyl phenyls, 4- methoxyphenyls, 3- first
Phenyl, 2- methoxyphenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 4- tert-butyl-phenyls, 4- phenyls, 3,5-
3,5-dimethylphenyl, 2- naphthalenes or 2- thienyls.
The present invention provides one kind from simple substrate, trifluoromethylation alkenyl isoxazole is simply, efficiently synthesized
The method of compound, and this method has that mild easy to operate, reaction condition, high income, substrate universality be good, atom utilization
High, the advantages that environment compatibility is good.In addition, such compound is the trifluoromethyl synthesis that a kind of structure is completely new, highly useful
Building block, can be as trifluoromethyl synthon and nitromethane class compound, malonic acid ester type compound or malononitrile class
It closes object etc. to be acted on, for building a series of complicated organofluorine compounds containing trifluoromethyl group, is conducive to contain
The research and development of the organofluorine compound of trifluoromethyl group.
Specific embodiment
The present invention is further described with reference to example, contributes to further understand the present invention by following examples, but
It does not limit the scope of the invention.
Example 1：The preparation of 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- phenyl propyl- 1- alkene -1- bases) isoxazole
It is weighed into 3,5- dimethyl -4- nitros isoxazoles (0.14g, 1.0mmol) in Schlenk bottles of a 25mL, 2,2,2-
Three fluoro- 1- Phenyl ethyl ketones (0.26g, 1.5mmol) add in 5.0mL water and triethylamine (0.05g, 0.5mmol) into system, put
It is stirred at room temperature for 24 hours.The reaction was complete for TLC detections, and 10mL ethyl acetate and 5mL water, liquid separation, water phase acetic acid second are added in system
Ester extracts (10mL x 2), merges organic phase, anhydrous MgSO4It is dry, column chromatography (leacheate：Petrol ether/ethyl acetate=10/
1to 5/1), obtain corresponding intermediate.
The intermediate is added in a 50mL round-bottomed bottles, adds 10.0mL dry toluenes, ice-water bath cooling adds successively
The thionyl chloride (0.36g, 3.0mmol) for enter anhydrous pyridine (0.32g, 4.0mmol), steaming again, finishes, load onto reflux condensing tube and
Drying tube containing anhydrous calcium chloride is placed in 80 DEG C of stirrings for 24 hours.Reaction finishes, and the dilution of 20mL ethyl acetate is added in system, according to
Secondary water, saturated common salt water washing, liquid separation, anhydrous MgSO4It is dry, column chromatography (leacheate：Petrol ether/ethyl acetate=30/
1to 20/1), you can obtain target product 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- phenyl propyl- 1- alkene -1- bases) different Evil
Azoles 0.25g, light yellow solid, yield 86%.Z:E=3:97；1H NMR(400MHz,CDCl3)δ2.52(s,3H),7.30(d,J
=6.8Hz, 2H), 7.41-7.48 (m, 3H), 7.72 (s, 1H)；13C NMR(100MHz,CDCl3)δ163.7,155.5,142.5
(q,JC-F=31.5Hz), 130.5,130.0,128.7,128.6,127.9,122.3 (q, JC-F=273.4Hz), 116.0 (q,
JC-F=6.4Hz), 11.4；19F NMR(376MHz,CDCl3)δ-67.14(s,3F),-59.66。
Example 2：The system of 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- fluorophenyls) propyl- 1- alkene -1- bases) isoxazole
It is standby
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (4- fluorophenyls) second
Ketone, 1,4- diazabicylos [2,2,2] octane, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.5：3：4, it obtains
Target product 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- fluorophenyls) propyl- 1- alkene -1- bases) isoxazoles 0.29g, it is pale yellow
Color solid, yield 93%.Z:E=3:97；1H NMR(400MHz,CDCl3) δ 2.53 (s, 3H), 7.13 (dd, J=8.8Hz,
2H), 7.30 (dd, J=5.2Hz, 2H), 7.74 (d, J=1.2Hz, 1H)；13C NMR(100MHz,CDCl3)δ163.7(d,JC-F
=249.2Hz), 163.5,155.6,141.3 (q, JC-F=31.5Hz), 130.8,130.7,126.4 (d, JC-F=4.4Hz),
122.2(q,JC-F=273.3Hz), 116.4 (q, JC-F=6.2Hz), 115.9 (d, JC-F=21.9Hz), 11.4；19F NMR
(376MHz,CDCl3)δ-67.30(s,3F),-59.90,-109.97(s,1F)。
Example 3：The system of 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- chlorphenyls) propyl- 1- alkene -1- bases) isoxazole
It is standby
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (4- chlorphenyls) second
Ketone, N, the mol ratio that feeds intake of N- lutidines, thionyl chloride and triethylamine is 1：1.5：0.5：3：4, obtain target product
3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- chlorphenyls) propyl- 1- alkene -1- bases) isoxazole 0.30g, light yellow solid,
Yield 89%.Z:E=4:96；1H NMR(400MHz,CDCl3) δ 2.53 (s, 3H), 7.25 (d, J=8.0Hz, 2H), 7.42 (d,
J=8.4Hz, 2H), 7.75 (s, 1H)；13C NMR(100MHz,CDCl3)δ163.3,155.6,141.2(q,JC-F=
31.5Hz),136.5,130.0,129.0,128.9,122.1(q,JC-F=273.4Hz), 116.4 (q, JC-F=6.1Hz),
11.4；19F NMR(376MHz,CDCl3)δ-67.14(s,3F),-59.77。
Example 4：The system of 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- fluorophenyls) propyl- 1- alkene -1- bases) isoxazole
It is standby
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (4- bromophenyls) second
Ketone, 11 carbon -7- alkene of 1,8- diazabicylos, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.5：3：4, it obtains
Target product 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- fluorophenyls) propyl- 1- alkene -1- bases) isoxazoles 0.33g, it is pale yellow
Color solid, yield 87%.Z:E=3:97；1H NMR(400MHz,CDCl3) δ 2.53 (s, 3H), 7.18 (d, J=8.0Hz, 2H),
7.58 (d, J=8.4Hz, 2H), 7.75 (s, 1H)；13C NMR(100MHz,CDCl3)δ163.3,155.6,141.1(q,JC-F=
31.3Hz),131.9,130.2,129.3,124.7,122.0(q,JC-F=273.5Hz), 116.4 (q, JC-F=6.4Hz),
11.4；19F NMR(376MHz,CDCl3)δ-67.12(s,3F),-59.75。
Example 5：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- aminomethyl phenyls) propyl- 1- alkene -1- bases) isoxazole
It prepares
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (4- aminomethyl phenyls) second
Ketone, triethylamine, thionyl chloride and pyridine the mol ratio that feeds intake be 1：2：0.5：4：3, obtain target product 3- methyl -4- nitre
Base -5- (3,3,3- tri- fluoro- 2- (4- aminomethyl phenyls) propyl- 1- alkene -1- bases) isoxazole 0.26g, light yellow solid, yield 83%.
Z:E=5:95；1H NMR(400MHz,CDCl3) δ 2.36 (s, 3H), 2.49 (s, 3H), 7.18 (dd, J=17.6Hz, 7.6Hz,
4H), 7.65 (d, J=1.2Hz, 1H)；13C NMR(100MHz,CDCl3)δ163.9,155.5,142.6(q,JC-F=
30.9Hz),140.3,129.3,128.5,127.6,122.4(q,JC-F=273.4Hz), 115.6 (q, JC-F=6.4Hz),
21.3,11.4；19F NMR(376MHz,CDCl3)δ-67.07(s,3F),-59.65。
Example 6：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- methoxyphenyls) propyl- 1- alkene -1- bases) isoxazole
Preparation
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (4- methoxyphenyls)
Ethyl ketone, triethylamine, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.3：3：2, obtain target product 3- methyl -4-
Nitro -5- (3,3,3- tri- fluoro- 2- (4- methoxyphenyls) propyl- 1- alkene -1- bases) isoxazole 0.27g, light yellow solid, yield
80%.Z:E=7:93；1H NMR(400MHz,CDCl3) δ 2.61 (s, 3H), 3.92 (s, 3H), 7.01 (d, J=8.8Hz, 2H),
7.32 (d, J=8.4Hz, 2H), 7.73 (s, 1H)；13C NMR(100MHz,CDCl3)δ164.1,161.0,155.5,142.4
(q,JC-F=30.8Hz), 130.2,122.6,122.4 (q, JC-F=273.5Hz), 115.3 (q, JC-F=6.3Hz), 114.1,
55.2,11.5；19F NMR(376MHz,CDCl3)δ-66.94(s,3F),-59.61。
Example 7：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (3- methoxyphenyls) propyl- 1- alkene -1- bases) isoxazole
Preparation
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (3- methoxyphenyls)
Ethyl ketone, triethylamine, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.5：3：5, obtain target product 3- methyl -4-
Nitro -5- (3,3,3- tri- fluoro- 2- (3- methoxyphenyls) propyl- 1- alkene -1- bases) isoxazole 0.25g, light yellow solid, yield
77%.Z:E=3:97；1H NMR(400MHz,CDCl3)δ2.52(s,3H),3.80(s,3H),6.83(s,1H),6.85(d,J
=8.0Hz, 1H), 7.00 (dd, J=8.0Hz, 2.4Hz, 1H), 7.33 (t, J=8.0Hz, 1H), 7.71 (s, 1H)；13C NMR
(100MHz,CDCl3)δ163.7,159.5,155.5,142.2(q,JC-F=31.1Hz), 131.6,129.8,128.6,
127.9,122.2(q,JC-F=273.4Hz), 120.9,116.0 (q, JC-F=6.4Hz), 115.4,114.3,55.2,11.4；19F NMR(376MHz,CDCl3)δ-67.11(s,3F),-59.74。
Example 8：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (2- methoxyphenyls) propyl- 1- alkene -1- bases) isoxazole
Preparation
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (2- methoxyphenyls)
Ethyl ketone, triethylamine, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.5：3：4, obtain target product 3- methyl -4-
Nitro -5- (3,3,3- tri- fluoro- 2- (2- methoxyphenyls) propyl- 1- alkene -1- bases) isoxazole 0.28g, light yellow solid, yield
85%.Z:E=3:97；1H NMR(400MHz,CDCl3) δ 2.51 (s, 3H), 3.71 (s, 3H), 6.96 (d, J=8.0Hz, 1H),
7.01 (t, J=7.2Hz, 1H), 7.21 (d, J=6.8Hz, 1H), 7.44 (t, J=7.2Hz, 1H), 7.82 (s, 1H)；13C NMR
(100MHz,CDCl3)δ164.1,157.2,155.3,138.8(q,JC-F=31.9Hz), 131.5,129.5,122.4 (q, JC-F
=273.5Hz), 120.5,119.6,117.2 (q, JC-F=6.0Hz), 111.2,55.5,11.5；19F NMR(376MHz,
CDCl3)δ-67.12(s,3F),-60.65。
Example 9：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- tert-butyl-phenyls) propyl- 1- alkene -1- bases) isoxazole
Preparation
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (4- tert-butyl-phenyls)
Ethyl ketone, triethylamine, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.5：3：4, obtain target product 3- methyl -4-
Nitro -5- (3,3,3- tri- fluoro- 2- (4- tert-butyl-phenyls) propyl- 1- alkene -1- bases) isoxazole 0.30g, light yellow solid, yield
84%.Z:E=4:96；1H NMR(400MHz,CDCl3) δ 1.26 (s, 9H), 2.45 (s, 3H), 7.15 (d, J=8.0Hz, 2H),
7.35 (d, J=8.0Hz, 2H), 7.61 (s, 1H)；13C NMR(100MHz,CDCl3)δ164.0,155.5,153.3,142.7
(q,JC-F=30.8Hz), 128.4,127.5,125.5,122.4 (q, JC-F=273.6Hz), 115.5 (q, JC-F=6.3Hz),
34.7,31.1,11.4；19F NMR(376MHz,CDCl3)δ-66.89(s,3F),-59.60。
Example 10：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (4- phenyls) propyl- 1- alkene -1- bases) isoxazole
Preparation
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (4- phenyls) second
Ketone, triethylamine, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.5：3：4, obtain target product 3- methyl -4- nitre
Base -5- (3,3,3- tri- fluoro- 2- (4- phenyls) propyl- 1- alkene -1- bases) isoxazole 0.30g, light yellow solid, yield 81%.
Z:E=9:91；1H NMR(400MHz,CDCl3) δ 2.50 (s, 3H), 7.34-7.36 (m, 3H), 7.43 (t, J=7.2Hz, 2H),
7.58-7.63(m,4H),7.72(s,1H)；13C NMR(100MHz,CDCl3)δ163.8,155.5,142.9,142.3(q,JC-F
=30.9Hz), 139.9,129.3,129.1,128.8,127.9,127.4,127.2,127.1,122.3 (q, JC-F=
273.5Hz),115.9(q,JC-F=6.4Hz), 11.4；19F NMR(376MHz,CDCl3)δ-66.81(s,3F),-59.48。
Example 11：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (3,5- 3,5-dimethylphenyl) propyl- 1- alkene -1- bases) is different
The preparation of oxazole
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (3,5- dimethyl benzenes
Base) ethyl ketone, triethylamine, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.5：3：4, obtain target product 3- first
Base -4- nitros -5- (3,3,3- tri- fluoro- 2- (3,5- 3,5-dimethylphenyl) propyl- 1- alkene -1- bases) isoxazoles 0.23g, it is light yellow solid
Body, yield 72%.Z:E=2:98；1H NMR(400MHz,CDCl3)δ2.32(s,6H),2.53(s,3H),6.89(s,2H),
7.09(s,1H),7.68(s,1H)；13C NMR(100MHz,CDCl3)δ164.0,155.4,143.0(q,JC-F=30.7Hz),
138.2,131.7,130.4,126.1,122.3(q,JC-F=273.6Hz), 115.5 (q, JC-F=6.4Hz), 21.2,11.5；19F NMR(376MHz,CDCl3)δ-67.11(s,3F),-59.64。
Example 12：The system of 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (naphthalene -2- bases) propyl- 1- alkene -1- bases) isoxazole
It is standby
With test 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (naphthalene -2- bases) ethyl ketones,
The mol ratio that feeds intake of triethylamine, thionyl chloride and pyridine is 1：1.5：0.5：3：4, obtain target product 3- methyl -4- nitros -
5- (3,3,3- tri- fluoro- 2- (naphthalene -2- bases) propyl- 1- alkene -1- bases) isoxazole 0.29g, light yellow solid, yield 82%.Z:E=8:
92；1H NMR(400MHz,CDCl3) δ 2.49 (s, 3H), 7.35 (d, J=7.2Hz, 1H), 7.52-7.58 (m, 2H), 7.82-
7.91(m,5H)；13C NMR(100MHz,CDCl3)δ163.7,155.5,142.5(q,JC-F=31.1Hz), 133.6,132.7,
128.6,128.5,128.4,127.9,127.8,127.3,126.7,125.5,122.4(q,JC-F=273.5Hz), 116.1
(q,JC-F=6.4Hz), 11.4；19F NMR(376MHz,CDCl3)δ-66.75(s,3F),-59.30。
Example 13：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (thiophene -2- bases) propyl- 1- alkene -1- bases) isoxazole
It prepares
With testing 1 similar method, 3,5- dimethyl -4- nitros isoxazoles, 2,2,2- tri- fluoro- 1- (thiophene -2- bases) second
Ketone, triethylamine, thionyl chloride and pyridine the mol ratio that feeds intake be 1：1.5：0.5：3：4, obtain target product 3- methyl -4- nitre
Base -5- (3,3,3- tri- fluoro- 2- (thiophene -2- bases) propyl- 1- alkene -1- bases) isoxazole 0.26g, light yellow solid, yield 86%.Z:
E=35:65；1H NMR(400MHz,CDCl3) δ 2.57 (s, 3H), 7.10 (dd, J=3.6Hz, 1.2Hz, 1H), 7.26 (d, J=
2.0Hz, 1H), 7.53 (d, J=4.0Hz, 1H), 7.61 (s, 1H)；13C NMR(100MHz,CDCl3)δ163.6,155.7,
135.5(q,JC-F=31.9Hz), 131.2,129.9,129.7,128.6,127.6,121.8 (q, JC-F=274.0Hz),
115.8(q,JC-F=6.2Hz), 11.5；19F NMR(376MHz,CDCl3)δ-67.05(s,3F),-60.47。
Example 14：The preparation of 3- phenyl -4- nitros -5- (3,3,3- tri- fluoro- 2- phenyl propyl- 1- alkene -1- bases) isoxazole
With testing 1 similar method, 5- methyl -3- phenyl -4- nitros isoxazole, 2,2,2- tri- fluoro- 1- Phenyl ethyl ketones, three
The mol ratio that feeds intake of ethamine, thionyl chloride and pyridine is 1：1.5：0.5：3：4, obtain target product 3- phenyl -4- nitros -5-
(3,3,3- tri- fluoro- 2- phenyl propyl- 1- alkene -1- bases) isoxazole 0.31g, light yellow solid, yield 86%.Z:E=2:98；1H
NMR(400MHz,CDCl3) δ 7.38 (d, J=8.0Hz, 2H), 7.47-7.55 (m, 8H), 7.75 (s, 1H)；13C NMR
(100MHz,CDCl3)δ164.4,157.5,142.6(q,JC-F=31.2Hz), 130.9,130.7,130.5,130.1,
129.1,128.7,128.6,128.5,124.9,122.3(q,JC-F=273.5Hz), 115.8 (q, JC-F=6.4Hz)；19F
NMR(376MHz,CDCl3)δ-67.10(s,3F),-59.52。
Example 15：The preparation of 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (nitromethyla) -2- phenylpropyls) isoxazole
3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- phenyl propyl- 1- alkene -1- are added in into Schlenk bottles of a 10mL
Base) isoxazole (0.06g, 0.2mmol), tetrabutylammonium bromide (0.013g, 0.04mmol), Anhydrous potassium carbonate (0.083g,
0.6mmol) with 1.0mL dry toluenes, then the addition nitromethane (0.061g, 1.0mmol) into system, finish, be placed in room temperature
It is stirred to react for 24 hours.TLC detection reactions finish, direct column chromatography (leacheate：Petrol ether/ethyl acetate=10/1), you can it obtains
Target product 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (nitromethyla) -2- phenylpropyls) isoxazole 0.069g, white are solid
Body, yield 96%.1H NMR(400MHz,CDCl3) δ 2.55 (s, 3H), 4.49 (dd, J=34.0Hz, 16.8Hz, 2H), 5.38
(s,2H),7.42(s,5H)；13C NMR(100MHz,CDCl3)δ168.7,155.7,131.6,131.3,129.7,129.3,
126.5,125.2(q,JC-F=283.7Hz), 74.8,51.1 (q, JC-F=25.3Hz), 28.1,11.5；19F NMR(376MHz,
CDCl3)δ-72.06(s,3F)。
Example 16：2- (1,1,1- tri- fluoro- 3- (3- methyl -4- isoxazole -5- bases) -2- phenyl propyl- 2- yls) malononitrile
It prepares
3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- phenyl propyl- 1- alkene -1- are added in into Schlenk bottles of a 10mL
Base) isoxazole (0.06g, 0.2mmol), tetrabutylammonium bromide (0.013g, 0.04mmol), Anhydrous potassium carbonate (0.083g,
0.6mmol) with 1.0mL dry toluenes, then the addition malononitrile (0.066g, 1.0mmol) into system, finish, be placed in room temperature and stir
Mix reaction for 24 hours.TLC detection reactions finish, direct column chromatography (leacheate：Petrol ether/ethyl acetate=10/1), you can obtain mesh
Product 2- (1,1,1- tri- fluoro- 3- (3- methyl -4- isoxazole -5- bases) -2- phenyl propyl- 2- yls) malononitrile 0.069g is marked, it is pale yellow
Color solid, yield 95%.1H NMR(400MHz,CDCl3) δ 2.52 (s, 3H), 4.37 (dd, J=34.4Hz, 16.4Hz, 2H),
4.98(s,1H),7.50-7.56(m,5H)；13C NMR(100MHz,CDCl3)δ165.9,155.9,132.0,130.5,
129.7,129.6,126.5,124.7(q,JC-F=285.3Hz), 109.5,54.7 (q, JC-F=25.2Hz), 30.2,28.5,
11.4；19F NMR(376MHz,CDCl3)δ-67.78(s,3F)。
Example 17：3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (1 Η-indol-3-yl) -2- phenylpropyls) isoxazole
Preparation
3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- phenyl propyl- 1- alkene -1- are added in into Schlenk bottles of a 10mL
Base) isoxazole (0.060g, 0.2mmol), indoles (0.036g, 0.3mmol), dinaphthol phosphate (0.014g, 0.04mmol)
It with 1.0mL dichloromethane, finishes, is placed in and reaction is stirred at room temperature for 24 hours.TLC detection reactions finish, direct column chromatography (leacheate：Stone
Oily ether/ethyl acetate=10/1), you can obtain target product 3- methyl -4- nitros -5- (3,3,3- tri- fluoro- 2- (1 Η-indoles -
3- yls) -2- phenylpropyls) isoxazole 0.077g, light yellow solid, yield 92%.1H NMR(400MHz,CDCl3)δ2.53(s,
3H), 4.32 (dd, J=32.0Hz, 14.4Hz, 2H), 6.65 (d, J=8.5Hz, 1H), 6.91 (t, J=8.0Hz, 1H), 7.18
(t, J=8.0Hz, 1H), 7.35-7.43 (m, 6H), 7.45 (d, J=1.5Hz, 1H), 8.34 (s, 1H)；13C NMR(100MHz,
CDCl3)δ168.6,155.5,136.3,134.5,129.6,128.9,128.7,128.5,127.1,125.4,124.9(q,
JC-F=283.5Hz), 122.6,120.6,120.1,111.6,109.3,54.5 (q, JC-F=25.8Hz), 28.3,11.5；19F
NMR(376MHz,CDCl3)δ-67.76(s,3F)。
It can realize that one-step method prepares the above-mentioned organofluorine compound containing trifluoromethyl group and gives birth to using the compounds of this invention
Object, high income, by-product are few.
Claims (3)
1. the preparation method of the organofluorine compound containing trifluoromethyl group shown in a kind of below formula III, it is characterised in that include
Following steps：
(1)
3- substituent group -4- nitro -5- methyl-isoxazoles, trifluoromethyl ketone are added in reactor, in a solvent, add in catalysis
Lower reaction is stirred at room temperature in agent, and after completion of the reaction, washed, extraction, separation, purifying obtain intermediate A；
The catalyst is triethylamine, 1,4- diazabicylos [2,2,2] octane, N, N- lutidines or 1,8- diazas
Two rings, 11 carbon -7- alkene；The solvent is water, methanol, ethyl alcohol, N,N-dimethylformamide, acetonitrile, tetrahydrofuran or first
Benzene；
(2)
Above-mentioned intermediate A is added in another reactor, in a solvent, adds in acid binding agent, thionyl chloride, it is anti-under heating stirring
Should, after completion of the reaction, washed, extraction, separation, purifying obtain target product trifluoromethylation alkenyl isoxazole compound；
The acid binding agent is triethylamine or pyridine；The solvent is water, methanol, ethyl alcohol, N,N-dimethylformamide, second
Nitrile, tetrahydrofuran or toluene；
(3)
Under the effect of catalyst tetrabutylammonium bromide, inorganic base and toluene, by trifluoromethylation alkenyl isoxazole compound and third
Dinitrile compound reacts, and prepares organofluorine compound of the general formula III containing trifluoromethyl group；
Wherein, R is hydrogen, methyl, benzyl or aromatic group；R ' is methyl or phenyl；The aromatic group is phenyl, 4- methyl
Phenyl, 4- methoxyphenyls, 3- methoxyphenyls, 2- methoxyphenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, the tertiary fourths of 4-
Base phenyl, 4- phenyls, 3,5- 3,5-dimethylphenyls, 2- naphthalenes or 2- thienyls.
2. the preparation method of the organofluorine compound containing trifluoromethyl group as described in claim 1, which is characterized in that reactant
Molar ratio is：3- substituent group -4- nitro -5- methyl-isoxazole compounds：Trifluoromethyl ketone compound：Catalyst：Acid binding agent：Two
Chlorine sulfoxide=1：1.5-2：0.1~1：3~6：2~4.
3. the preparation method of the organofluorine compound containing trifluoromethyl group as described in claim 1, it is characterised in that：R choosing virtues
Perfume base group；R ' is methyl or phenyl；The aromatic group is phenyl, 4- aminomethyl phenyls, 4- methoxyphenyls, 3- methoxybenzenes
Base, 2- methoxyphenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 4- tert-butyl-phenyls, 4- phenyls, 3,5- dimethyl
Phenyl, 2- naphthalenes or 2- thienyls.
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