CN106220581B - Fluorine-containing heterocycles and preparation method thereof - Google Patents

Fluorine-containing heterocycles and preparation method thereof Download PDF

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CN106220581B
CN106220581B CN201610532601.6A CN201610532601A CN106220581B CN 106220581 B CN106220581 B CN 106220581B CN 201610532601 A CN201610532601 A CN 201610532601A CN 106220581 B CN106220581 B CN 106220581B
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nmr
cdcl
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trifluoromethyl
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CN106220581A (en
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余达刚
叶剑衡
颜思顺
周文俊
宋磊
鞠涛
殷珠宝
张振
李静
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Sichuan University
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    • 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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    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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    • 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
    • C07D263/18—Oxygen atoms
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    • C07B2200/09—Geometrical isomers

Abstract

The present invention relates to a kind of methods for preparing the 2 oxazoline ketone compounds containing trifluoromethyl by propylamine compound using carbon dioxide, specifically, propylamine compound and CO shown in formula 12It reacts in solvent in the presence of copper catalyst, alkali and trifluoromethyl reagent, the 2 oxazoline ketone compounds as shown in Equation 2 containing trifluoromethyl is prepared, wherein, R1、R2、R4And R5H, halogen, cyano, alkyl, carbonyl, ester group, aryl and heteroaryl etc. are each independently, further R4Or R5Optionally with R1Cyclization, the alkyl, carbonyl, ester group, aryl and heteroaryl are optionally by substitutions such as halogen, alkyl；R3For H, halogen, alkyl, aryl etc.,

Description

Fluorine-containing heterocycles and preparation method thereof
Technical field
The present invention relates to the synthesis of fluorine-containing heterocycles, and in particular to a kind of to utilize CO2By propylamine compound system The preparation method of the standby 2-oxazolidinone class compound containing trifluoromethyl.
Background technology
It is well known that CO2Greenhouse effects cause many detrimental effects to global environment, how by CO2It carries out effective It utilizes, is a urgent problem to be solved.It is a very effective approach to realize that it is efficiently utilized by chemical conversion, and This approach can also provide possibility to solve resource problem.In organic synthesis, CO2A kind of cheap and easy to get, peace can be used as Atoxic, and the repeatable C1 synthons utilized, have broad application prospects.But it up to the present, can efficiently utilize The chemical means of carbon dioxide are extremely limited, this is undivided with its thermodynamic stability and kinetic inertness.
Due to CO2Thermodynamic stability and kinetic inertness, realize 4 kinds of strategies below its chemical conversion generally use： (1) using the higher raw material of energy, such as the substances such as epoxide, hydrogen, alkynes, alkene and amine, (2) are by CO2Pass through Chemical conversion generates low energy product, such as carbonate, carbaminate, aromatic acid and ester substance；(3) by removing in reaction Other products with promote react balanced sequence, make reaction to generation target product direction move；(4) the additional energy is provided Such as electric energy or luminous energy activation CO2.In CO2Various chemical conversions in, the use of catalyst is typically essential, so far A variety of catalyst system and catalyzings have been developed, mainly have transition metal-type catalyst, N-heterocyclic carbine class catalyst, amines catalyst and " Lewis Acids and Bases being obstructed to " class catalyst etc..By the use of different catalysts, chemist has correspondingly developed more Kind CO2The new way of synthesis high valuable chemicals is participated in, obtains the chemicals of numerous species.Although in CO2In terms of chemical conversion Carry out numerous studies work, but realize CO in a mild condition2Trans-utilization there are still lot of challenges.
On the other hand, due to the peculiar property of heterocyclic compound, have in all kinds of medicine, pesticide and special material etc. Irreplaceable important function.In various heterocyclic compounds, fluorine-containing heterocycles are due to having extensive physiological activity With unique physicochemical properties, always be synthetic methodology research especially organic fluorine chemistry research important directions it One.Fluorine-containing heterocycles it is unique, it is considered that be caused by the peculiar property of fluorine atom.
2-oxazolidinone is a kind of highly useful centre in organic synthesis as a kind of important heterocyclic compound Body.Because having good bacteriostatic activity, it is widely present in various antibacterials.Moreover, by the introducing of trifluoromethyl, it can To promote its physiological activity, a series of fluorine-containing oxazolinones heterocyclic compounds are synthesized, basis is provided for drug screening.Mesh Before, the various methods for introducing trifluoromethyl, especially C (sp3)—CF3The structure of key has been reported.In complicated molecule structure Middle bifunctional dough such as carbon trifluoromethylation, halogen trifluoromethylation, the oxygen fluoroform for realizing the trifluoromethylation about alkene Base, nitrogen trifluoromethylation have been achieved with significantly being in progress.Although it has been reported that excessively it is many synthesis 2-oxazolidinone method, The method of the 2-oxazolidinone containing trifluoromethyl is synthesized by cheap and easy to get and convenient for processing raw material there is presently no a kind of.
Invention content
To solve the above-mentioned problems, inventor proposes a kind of utilization carbon dioxide by allyl on the basis of extensive research The method that aminated compounds prepares the 2-oxazolidinone class compound containing trifluoromethyl.
According to the method for the present invention, as shown in scheme 1, the propylamine compound and CO shown in formula 12In copper catalyst, alkali With react in solvent in the presence of trifluoromethyl reagent, the 2- Evil as shown in Equation 2 containing trifluoromethyl are prepared Oxazoline ketone compounds.
Scheme 1：
Wherein, R1、R2、R4And R5It is each independently H, halogen, cyano, alkyl, carbonyl, ester group, aryl and heteroaryl Deng further R4Or R5Optionally with R1Cyclization, the alkyl, carbonyl, ester group, aryl and heteroaryl are optionally by halogen The substitutions such as element, alkyl；R3For H, halogen, alkyl, aryl etc..
The copper catalyst includes organic copper catalyst, such as cupric acetylacetonate or tetrem cyanogen copper hexafluorophosphate；With And inorganic copper catalyst, such as stannous chloride or cuprous bromide.Preferably, the copper catalyst is stannous chloride or protobromide Copper.
The alkali includes common weak base and highly basic, such as cesium fluoride, sodium carbonate, cesium carbonate, sodium tert-butoxide or 1,8- bis- 11 carbon -7- alkene (DBU) of azabicyclic etc..Preferably, the alkali is cesium carbonate, sodium tert-butoxide or DBU.It is it is highly preferred that described Alkali is DBU.
The trifluoromethyl reagent is Tognis reagents and Umemoto reagents, such as a generation or two generation Tognis reagents. Preferably, the trifluoromethyl reagent is two generation Tognis reagents.
The solvent is any organic solvent that can dissolve contained substance in reaction system, including intensive polar solvent and weak Polar solvent, such as 1,2- dichloroethanes, dichloromethane, tetrahydrofuran, methanol, n,N-Dimethylformamide, acetonitrile etc..It is preferred that Ground, the solvent are n,N-Dimethylformamide or acetonitrile.
The molar ratio of substrate and catalyst is 20:1~5:1, preferably 10:1；The molar ratio of substrate and alkali is 1:1~1:3, preferably 1:2；The molar ratio of substrate and trifluoromethyl reagent is 1:1~1:2, preferably 1:1.1.
The method of the present invention reaction condition is mild, and reaction temperature, pressure are not required particularly.Preferably, present invention side Method carries out under 25 degrees Celsius and under 1atm reaction pressures.
It, can be in redox electroneutral when building the 2-oxazolidinone compound containing trifluoromethyl by the method for the present invention Under conditions of it is achieved that and reaction condition it is mild, can efficiently realize oxygen trifluoromethylation, structure includes spirocyclization Close the important compound including object.In addition, the introducing of carbon dioxide causes the chemo-selective of reaction by nitrogen trifluoro in this method It methylates and is changed into oxygen trifluoromethylation, reaction has extraordinary chemo-selective simultaneously, and regioselectivity and diastereomeric are different Structure body selectivity；Therefore noxious material such as one can be avoided from 2-oxazolidinone of the simple Material synthesis containing trifluoromethyl The use of carbonoxide, phosgene etc..That is, the method for the present invention is not only able to simply and efficiently synthesize the 2- Evil containing trifluoromethyl Imidzole phenanthroline ketone compound, and can be the reasonable efficient using an important approach is opened of greenhouse gases, realize energy-saving ring The purpose of guarantor.
Description of the drawings
Fig. 1 is the reaction schematic diagram that the present invention prepares the 2-oxazolidinone compound containing trifluoromethyl；
Fig. 2 is the structure chart of compound 2ae.
Specific embodiment
Present invention offer is a kind of to prepare the 2-oxazolidinone containing trifluoromethyl using carbon dioxide by propylamine compound The method of class compound.
According to the method for the present invention, as shown in scheme 1, the propylamine compound and CO shown in formula 12In copper catalyst, alkali With react in solvent in the presence of trifluoromethyl reagent, the 2- Evil as shown in Equation 2 containing trifluoromethyl are prepared Oxazoline ketone compounds.
Scheme 1：
Wherein, R1、R2、R4And R5It is each independently H, halogen, cyano, alkyl, carbonyl, ester group, aryl and heteroaryl Deng further R4Or R5Optionally with R1Cyclization, the alkyl, carbonyl, ester group, aryl and heteroaryl are optionally by halogen The substitutions such as element, alkyl；R3For H, halogen, alkyl, aryl etc..
Halogen includes fluorine, chlorine, bromine, iodine.The alkyl is preferably straight chained alkyl, branched alkane with 1-20 carbon atom Base, cycloalkyl, such as methyl, ethyl, isopropyl, normal-butyl, isobutyl group etc..The aryl preferably has 6-20 carbon atom Aryl, such as phenyl, benzyl, naphthalene etc..The heteroaryl is the heteroaryl with 6-20 carbon atom, such as quinoline, different Quinoline, pyridine, thiophene etc..
The copper catalyst includes organic copper catalyst, such as cupric acetylacetonate or tetrem cyanogen copper hexafluorophosphate；With And inorganic copper catalyst, such as stannous chloride or cuprous bromide.Preferably, the copper catalyst is stannous chloride or protobromide Copper.
The alkali includes common weak base and highly basic, such as cesium fluoride, sodium carbonate, cesium carbonate, sodium tert-butoxide or 1,8- bis- 11 carbon -7- alkene (DBU) of azabicyclic etc..Preferably, the alkali is cesium carbonate, sodium tert-butoxide or DBU.It is it is highly preferred that described Alkali is DBU.
The trifluoromethyl reagent be Togni ' s reagents or Umemoto (Umemoto ' s reagent) reagent, such as Generation Togni ' s reagents (Togni ' s reagent I) or two generation Togni ' s (Togni ' s reagent II) reagent.Preferably, The trifluoromethyl reagent is two generation Tognis reagents.
The solvent is any organic solvent that can dissolve contained substance in reaction system, including intensive polar solvent and weak Polar solvent, such as 1,2- dichloroethanes, dichloromethane, tetrahydrofuran, methanol, n,N-Dimethylformamide, acetonitrile etc..It is preferred that Ground, the solvent are n,N-Dimethylformamide or acetonitrile.
The molar ratio of substrate and catalyst is 20:1~5:1, preferably 10:1；The molar ratio of substrate and alkali is 1:1~1:3, preferably 1:2；The molar ratio of substrate and trifluoromethyl reagent is 1:1~1:2, preferably 1:1.1.On It is that inventor obtains, in the case where ensureing synthetic yield, making material on the basis of lot of experiments to state amount ratio Amount ratio obtains optimal control as far as possible.
The method of the present invention reaction condition is mild, and reaction temperature, pressure are not required particularly.Preferably, present invention side Method at 25 degrees c with carried out under 1atm reaction pressures.
In the method for the present invention preferred embodiment, R in 1 compound represented of formula3For benzyl, particular compound can be with Including following compound：
There are during substituent group on substrate medium vinyl aromatic ring, the substrate of methoxyl group or phenoxy group substitution is all can be fine Compatible.For the cyclosubstituted allylamine derivatives of naphthalene, reaction can also be carried out successfully, but steric hindrance it is larger substrate it is opposite The small substrate of steric hindrance, reactivity worth is a bit weaker, and raw material fails to convert completely.In addition, the substrate of hetero-aromatic ring is with preferable yield Target product is obtained, the product without monitoring aromatic ring trifluoromethylation, it is shown that the selectivity of reaction.
For it is other substitution types allylamine derivatives, such as nitrogen α positions there are methyl substrate in optimal conditions Show good reactivity.Further, cyclenes propylamine analog derivative has also obtained corresponding loop coil product with higher yields, And detected by subsequent analysis, it is found that product has very high diastereoselectivity.In addition, esters of acrylic acid spreads out Biology can also efficiently be reacted.
Embodiment
The invention will be further elaborated with reference to embodiments.Embodiment is merely to illustrate the present invention, and cannot manage It solves as limitation of the present invention.
Laboratory apparatus and reagent：
Nuclear-magnetism (1H NMR, 13C NMR)：Bruker Advance-400 Nuclear Magnetic Resonance (0.5%TMS is internal standard)
Gas-mass spectrometer (GC-MS)：SHIMADZU GCMS-QP2010SE
Electrospray ionization mass spectrum (ESI-MS)：Bruker Daltonics Micro TOF-Q
Column chromatography silica gel (200-300 mesh)：Haiyang Chemical Plant, Qingdao, it is unactivated.
Agents useful for same and drug are that analysis is pure or chemical pure, in addition to especially indicating, not after further treatment.Anhydrous reagent It is all from laboratory solvent processing system or purchased from Reagent Companies such as lark prestige, Yi Nuokai.Other source chemicals are bought from hundred Clever prestige, Yi Nuokai, Rui Ouke, Ke Longdeng Reagent Company.
The synthesis of propylamine compounds substrate (hereinafter referred to as substrate)：
1. the synthesis of substrate 1a
Sequentially add 18.7g N- bromo-succinimides (NBS) in round-bottomed flasks of the 500mL with magneton, 1.72g pairs Then toluenesulfonic acid adds in 300mL THF, is eventually adding 13mL α-methylstyrenes, is vigorously stirred down and is warming up to reflux state (100 DEG C) react 4h.TLC is monitored to raw material disappear substantially after, be spin-dried for solvent, wet method crosses column (PE:EA=20:1) 15g A, are obtained Crude product, yellow oil.
Compound A 7.5g is taken to be dissolved in 300mL acetonitriles, 5.25g potassium carbonate is then sequentially added under stirring condition, 12.4mL benzylamines are heated to reflux, react 12h.TLC is monitored to raw material disappear substantially after, be extracted with ethyl acetate three times, Merge organic phase, add in Na2SO4It is dry, it filters, revolving, dry method loading crosses column (PE:EA=1:1), separating-purifying obtains pale yellow Color oily liquids 7.0g.
1H NMR(400MHz,CDCl3)δ7.47–7.39(m,2H),7.37–7.19(m,8H),5.46–5.39(m,1H), 5.26 (d, J=1.3Hz, 1H), 3.80 (s, 2H), 3.67 (d, J=0.6Hz, 2H)
2. the synthesis of substrate 1s
21.97g methyltriphenylphosphonium bromides and 6.90g potassium tert-butoxides are added in round-bottomed flasks of the 250mL with magneton, is used The super dry THF dissolvings of 150mL, are stirred at room temperature after about 0.5h, 6.15g 3- methoxyacetophenones are slowly added dropwise and are dissolved in 30mL The solution that super dry THF is formed, stirs 12h at room temperature.TLC is monitored after raw material disappears substantially, water quenching is added to go out, liquid separation obtains organic It is mutually extracted with ethyl acetate again 3 times with water phase, water phase, merges organic phase, organic phase saturated common salt water washing, liquid separation adds in Na2SO4It is dry, it filters, revolving, wet method loading crosses column (PE:EA=20:1), separating-purifying obtains colourless oil liquid 4.15g, Yield 68%.
In N2Under atmosphere, 4.15g compounds B is dissolved in the in the mixed solvent of the super dry THF of the super dry DCM and 17mL of 68mL, according to Secondary addition l26 μ L trim,ethylchlorosilanes, 5.99g N- bromo-succinimides and 174mg trifluoromethayl sulfonic acid ytterbiums, are stirred at room temperature 1h is mixed, whole process is in N2It is completed under atmosphere.TLC is monitored to raw material disappear substantially after, be spin-dried for solvent, dry method mixes sample and crosses column (PE: EA=20:1) crude product 3.41g, is detached to obtain.
Compound C 3.41g is taken to be dissolved in 60mL acetonitriles, 2.07g potassium carbonate is then sequentially added under stirring condition, 4.92mL benzylamines are heated to reflux, react 12h.TLC is monitored to raw material disappear substantially after, be extracted with ethyl acetate three times, Merge organic phase, add in Na2SO4It is dry, it filters, revolving, dry method loading crosses column (PE:EA=1:1), separating-purifying obtains pale yellow Color oily liquids 1.98g.
1H NMR(400MHz,CDCl3)δ7.35–7.28(m,4H),7.28–7.21(m,2H),7.05–6.97(m,2H), 6.84 (ddd, J=8.2,2.6,0.8Hz, 1H), 5.43 (d, J=1.2Hz, 1H), 5.26 (d, J=1.3Hz, 1H), 3.81 (d, J=5.5Hz, 5H), 3.65 (d, J=0.6Hz, 2H)
3. the synthesis of substrate 1q
Operating procedure refers to substrate 1z, isolates and purifies to obtain product 528mg.
1H NMR(400MHz,CDCl3)δ7.43–7.38(m,2H),7.37–7.29(m,6H),7.27–7.22(m,1H), 7.14-7.08 (m, 1H), 7.05-6.94 (m, 4H), 5.41-5.38 (m, 1H), 5.23 (d, J=1.3Hz, 1H), 3.81 (s, 2H), 3.66 (d, J=0.6Hz, 2H)
4. the synthesis of substrate 1x
Operating procedure refers to substrate 1b, and separating-purifying obtains final product 3.4g.
5. the synthesis of substrate 1y
Operating procedure refers to 1b, and separating-purifying obtains final product 5.4g.
1H NMR(400MHz,CDCl3) δ 8.12-7.99 (m, 1H), 7.83 (dd, J=6.0,3.5Hz, 1H), 7.76 (d, J =8.2Hz, 1H), 7.51-7.38 (m, 3H), 7.36-7.15 (m, 6H), 5.61 (s, 1H), 5.25 (s, 1H), 3.83 (s, 2H), 3.65 (d, J=0.4Hz, 2H), 1.50 (s, 1H)
6. the synthesis of substrate 1z
10.40g 6- bromoquinolines, 449mg palladiums, 1.65g are sequentially added in drying Shrek bottles of the 250mL with magneton 1,3- bis- (diphenylphosphine) propane (DPPP) are then taken out displacement N2 three times on biexhaust pipe, are then sequentially added under n 2 atmosphere 100mL DMF, 17mL allyl alcohols and 11.12mL triethylamines, add rear tube sealing, react 30h under the conditions of 125 DEG C.Reaction terminates Afterwards, it is cooled to room temperature, contact plate monitoring response situation is spin-dried for mixing sample and crosses column (PE:EA=3:1) brown-red solid, is isolated and purified to obtain 2.12g。
2g compounds D is taken to be dissolved in the super dry DCM of 18mL, 1.80mL triethylamines are added under stirring condition, is then divided at 0 DEG C It criticizes and adds in 2.47g paratoluensulfonyl chlorides, stir 2h after adding at room temperature.After contact plate detection raw material disappears, gone out instead with 15mL water quenchings Should, with DCM extractions three times, merge organic phase, add in Na2SO4It is dry, it filters, revolving, dry method loading crosses column (PE:EA=30： 1), separating-purifying obtains pale yellowish oil liquid 1.01g.
1g compound E and 408mg potassium carbonate is added in 20mL acetonitriles, 966 μ L benzylamines is added with stirring, is stirred at reflux React 12h.After contact plate detection raw material disappears, it is extracted with ethyl acetate three times, merges organic phase, add in Na2SO4It is dry, filtering, Revolving, dry method loading cross column (PE:EA=1：1), separating-purifying obtains product 516mg (pale yellowish oil liquid).
1H NMR(400MHz,CDCl3) δ 8.86 (dd, J=4.2,1.7Hz, 1H), 8.13-7.99 (m, 2H), 7.87- 7.76 (m, 2H), 7.38-7.28 (m, 5H), 7.25 (td, J=4.8,2.6Hz, 1H), 5.59 (s, 1H), 5.40 (d, J= 1.0Hz,1H),3.83(s,2H),3.76(s,2H).
7. the synthesis of substrate 1aa
It weighs 3.79g compounds F to be dissolved in 250mL THF, 7.38g triphenylphosphines is sequentially added at 0 DEG C, 4.14g is adjacent Phthalimide, 5.70mL diethyl azodiformates (DEAD), is then stirred at room temperature 20h.TLC monitors raw material base After this disappearance, solvent is spin-dried for, adds in the 1 of ether and petroleum ether:1 mixed solvent 500mL makes triphenylphosphine oxide precipitate, pad Suction filtered through kieselguhr collects filtrate, is spin-dried for mixing sample and crosses column (PE:EA=30:1) white solid 3.60g, is isolated and purified to obtain.
3.60g compounds G is taken to be dissolved in 100mL absolute ethyl alcohols, 4.74mL hydrazine hydrates (80%) are then added dropwise into system, After dripping, it is stirred at reflux reaction 3h.After contact plate monitoring reaction disappears to raw material, precipitation is generated in system, pads suction filtered through kieselguhr, The punching of filter cake ether is washed 3 times, collects filtrate, is spin-dried for mixing sample and is crossed column (PE:EA=10:1, DCM:MeOH=30:1) it, isolates and purifies Obtain white solid H 1.36g.
469mg benzaldehydes are added in 50mL eggplant type bottles, is dissolved with 15mL ethyl alcohol, then added under agitation 500mg compound H, temperature rising reflux reaction 4h.Contact plate is monitored to raw material disappear substantially after, be cooled to 0 DEG C, 386mg be added portionwise Sodium borohydride is stirred to react 4h at room temperature after adding.Contact plate monitoring is slowly added to saturation after the reaction was complete under stirring condition NaHCO3Solution to system is clarified, and is extracted with ethyl acetate 3 times, merges organic phase, adds in Na2SO4It is dry, it filters, rotates, do Method loading crosses column (PE:EA=10:1), separating-purifying obtains pale yellowish oil liquid 367mg.
1H NMR(400MHz,CDCl3) δ 7.32-7.14 (m, 10H), 5.23 (dd, J=4.2,1.1Hz, 2H), 3.79 (d, J=13.0Hz, 1H), 3.70-3.62 (m, 2H), 1.15 (d, J=6.6Hz, 3H)
8. the synthesis of substrate 1ae
Operating procedure refers to the building-up process of substrate 1b, and separating-purifying obtains final product 4.4g.
1H NMR(400MHz,CDCl3) δ 7.37-7.30 (m, 4H), 7.26 (dd, J=7.4,2.3Hz, 2H), 7.21- 7.12 (m, 3H), 6.04 (t, J=4.4Hz, 1H), 3.85 (s, 2H), 3.63 (s, 2H), 2.76 (t, J=8.0Hz, 2H), 2.29 (dd, J=12.4,8.0Hz, 2H), 1.63 (s, 1H)
9. the synthesis of substrate 1af
Operating procedure refers to the building-up process of substrate 1f, and separating-purifying obtains final product 2.4g.
1H NMR(400MHz,CDCl3) δ 7.33 (d, J=4.5Hz, 5H), 6.19-6.18 (m, 1H), 5.67 (dd, J= 2.9,1.5Hz,1H),3.78(s,2H),3.45(s,2H),1.76(s,1H),1.50(s,9H).
1 3- benzyl -5- phenyl -5- (2,2,2- trifluoroethyls) of embodiment -2-oxazolidinone (3-benzyl-5- Phenyl-5- (2,2,2-trifluoroethyl) oxazolidin-2-one) (hereinafter referred to as compound 2a) preparation
Table 1:The optimum choice of reaction condition
[a]：Listed yield is target GC yields in being made with n-dodecane in table, is separation yield in bracket；[b]：Alkali Dosage 0.6mmol；[c]：25 degrees Celsius；[d]：Use generation Togni reagents；[e]：Use Umemoto reagents；N.D.=is not Detection；[f]：80 degrees Celsius；[g]0.1atm；[h]20atm.
According to the condition shown in table 1 using 1a as substrate prepare compound 2a, concrete operations are as follows：In 25mL with magneton 0.04mmol catalyst, 0.44mmol bis- generations Tognis reagents (139mg) are sequentially added in Schlenk pipes, more than operation in hand It is completed in casing, reaction tube is then taken out into glove box, use CO2Gas takes out displacement three times, then in CO2Syringe is used under atmosphere Sequentially add 0.40mmol allylamine derivatives 1a, 4mL solvent, 0.80mmol alkali.Then, in the CO of an atmospheric pressure2Atmosphere Under tighten reaction tube, be stirred to react 16h at room temperature.After having reacted, reaction solution is spin-dried for, dry method loading crosses column (PE:EA 10:1~ 5:1), separating-purifying obtains target product.
Rf(pentane/EtOAc 5:1):0.35
1H NMR(400MHz,CDCl3) δ 7.42-7.27 (m, 8H), 7.19 (dd, J=7.3,1.8Hz, 2H), 4.43 (dd, J=47.4,14.9Hz, 2H), 3.68 (dd, J=62.1,9.2Hz, 2H), 2.89-2.70 (m, 2H)；13C NMR(101MHz, CDCl3) δ 156.40,140.89,135.06,128.93,128.91,128.67,128.17,128.08,124.46 (q J= 278.6Hz), 124.29,78.11 (q, J=2.2Hz), 55.13,48.26.44.35 (q, J=27.7Hz)；19F NMR (376MHz,CDCl3)δ-60.54；HRMS(ESI+):calcd for C18H17F3NO2 +[M+H]+336.1206,found 336.1212。
Embodiment 2 to 32 2-oxazolidinone class compound 2aa, 2ab, 2ac, 2ad, 2ae, 2af, 2b-2z of embodiment system It is standby
Explanation：2-oxazolidinone class compound 2aa represents that the compound is prepared by substrate 1aa, other 2- oxazolines The naming rule of ketone compounds is herewith.
According to the condition shown in table 2 and table 3 prepare 2-oxazolidinone class compound 2aa, 2ab, 2ac, 2ad, 2ae, 2af, 2b-2z, concrete operations are as follows：0.04mmol tetrem cyanogen copper hexafluorophosphoric acids are sequentially added in Schlenk pipes of the 25mL with magneton Salt (14.9mg), 0.44mmol bis- generations Tognis reagents (139mg), 0.40mmol allylamine derivatives are (if substrate is solid If), more than operate and completed in glove box, reaction tube is then taken out into glove box, uses CO2Gas takes out displacement three times, then In CO2Under atmosphere 0.40mmol allylamine derivatives (if substrate is liquid), the anhydrous second of 4mL are sequentially added with syringe Nitrile, 11 carbon -7- alkene (DBU) of 0.80mmol (120 μ L) 1,8- diazabicyclos [5.4.0].Then, in atmospheric pressure CO2Reaction tube is tightened under atmosphere, (25 DEG C) are stirred to react 16h at room temperature.After having reacted, reaction solution is spin-dried for, dry method loading crosses column (PE:EA 10:1~5:1), separating-purifying obtains target product.
Table 2
In table 2, " 1a, 81% " represents that with substrate 1a when being reacted by reaction equation in table, the yield of products therefrom is 81%；It is similar in table to mark meaning herewith." 1d, R=Ph, trace " represent that substrate is named as 1d, and R substituent Ph presses When reaction equation is reacted in table, trace product is obtained." 1e, R=Ts, N.D " represent that substrate is named as 1e, R substituent For Ts, when being reacted by reaction equation in table, product production is not detected；It is similar in table to mark meaning herewith.
Table 3
[b]：Reaction time 30h；[c]：Diastereoisomer is not detected；[d]：D.r. ＞ 16:1.
3- butyl -5- phenyl -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2b)
In table 3, " 2i：F, 79% " means when R substituent is F, yield 79%,
Remaining similar mark herewith understands.
3-butyl-5-phenyl-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
98mg, yield 82%, colorless oil；Rf(pentane/EtOAc 3:1):0.3；
1H NMR(400MHz,CDCl3) δ 7.48-7.32 (m, 5H), 3.85 (dd, J=88.8,9.1Hz, 2H), 3.36- 3.17 (m, 2H), 2.86 (q, J=10.2Hz, 2H), 1.55-1.45 (m, 2H), 1.35-1.21 (m, 2H), 0.90 (t, J= 7.3Hz,3H)；13C NMR(101MHz,CDCl3) δ 156.31,141.24,128.88,128.58,124.59 (q, J= 278.4Hz), 124.23,77.78 (q, J=2.2Hz), 55.74 (d, J=1.4Hz), 44.33 (q, J=27.6Hz), 43.79, 29.18,19.71,13.61；19F NMR(376MHz,CDCl3)δ-60.58；HRMS(ESI+):calcd for C15H19F3NO2 + [M+H]+302.1362,found 302.1371。
3- (1- phenethyls) -5- phenyl -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2c)
5-phenyl-3-(1-phenylethyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
45mg, yield 32%yield, white solid；Rf(pentane/EtOAc 5:1):0.4；
1H NMR(400MHz,CDCl3) δ 7.48-7.28 (m, 10H), 5.23 (q, J=7.1Hz, 1H), 3.55 (dd, J= 79.4,9.1Hz, 2H), 2.84-2.57 (m, 2H), 1.47 (d, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ 155.80,140.94,138.92,128.91,128.86,128.62,128.19,127.10 124.35 (q, J=278.5Hz), 124.28,78.11 (q, J=2.0Hz), 51.73 (d, J=1.2Hz), 51.64,44.20 (q, J=27.7Hz), 15.99；19F NMR(376MHz,CDCl3)δ-60.45；HRMS(ESI+):calcd for C19H19F3NO2 +[M+H]+350.1362,found 350.1357。
3- (1- phenethyls) -5- phenyl -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2c ')
5-phenyl-3-(1-phenylethyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
40mg, yield 29%, white solid；Rf(pentane/EtOAc 5:1):0.35；
1H NMR(400MHz,CDCl3) δ 7.41-7.22 (m, 8H), 7.21-7.13 (m, 2H), 5.25 (q, J=7.1Hz, 1H), 3.62 (dd, J=204.0,9.1Hz, 2H), 2.94-2.74 (m, 2H), 1.64 (d, J=7.1Hz, 3H)；13C NMR (101MHz,CDCl3)δ155.86,140.86,138.83,128.83,128.70,128.60,127.89,126.82,124.55 (d, J=278.3Hz), 124.29,78.22 (q, J=2.1Hz), 51.41,51.04 (d, J=1.6Hz), 44.33 (q, J= 27.7Hz),16.34；19F NMR(376MHz,CDCl3)δ-60.52；HRMS(ESI+):calcd for C19H19F3NO2 +[M+ H]+350.1362,found 350.1361。
3- benzyls -5- (4- fluorophenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2i)
3-benzyl-5-(4-fluorophenyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
112mg, yield 79%, white solid；Rf(pentane/EtOAc 3:1):0.40；
1H NMR(400MHz,CDCl3)δ7.40–7.26(m,5H),7.24–7.15(m,2H),7.11–7.01(m,2H), 4.43 (q, J=15.0Hz, 2H), 3.67 (dd, J=68.6,9.2Hz, 2H), 2.80 (q, J=10.1Hz, 2H)；13C NMR (101MHz,CDCl3) δ 162.59 (d, J=248.1Hz), 156.24,136.58 (d, J=3.2Hz), 135.00,128.96, 128.22,128.03,126.37 (d, J=8.4Hz), 124.41 (q, J=278.4Hz), 115.85 (d, J=21.8Hz), 77.84 (q, J=2.1Hz), 55.33,48.21,44.29 (q, J=27.7Hz)；19F NMR(376MHz,CDCl3)δ- 60.48,-112.95；HRMS(ESI+):calcd for C18H16F4NO2 +[M+H]+354.1112,found 354.1100。
3- benzyls -5- (4- chlorphenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2j)
3-benzyl-5-(4-chlorophenyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
125mg, yield 84%, colorless oil；Rf(pentane/EtOAc 4:1):0.35；
1H NMR(400MHz,CDCl3) δ 7.38-7.27 (m, 7H), 7.22-7.15 (m, 2H), 4.42 (dd, J=34.4, 15.0Hz, 2H), 3.65 (dd, J=72.5,9.2Hz, 2H), 2.79 (q, J=10.0Hz, 2H)；13C NMR(101MHz, CDCl3)δ156.14,139.27,134.93,134.67,129.09,128.98,128.26,128.04,125.91,124.35 (q, J=278.4Hz), 77.75 (q, J=2.2Hz), 55.24 (d, J=1.4Hz), 48.24,44.17 (q, J=27.8Hz)；19F NMR(376MHz,CDCl3)δ-60.41；HRMS(ESI+):calcd for C18H15ClF3NNaO2 +[M+Na]+ 392.0636,found 392.0627。
3- benzyls -5- (4- bromophenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2k)
3-benzyl-5-(4-bromophenyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
126mg, yield 76%, yellow oil；Rf(pentane/EtOAc 4:1):0.35；
1H NMR(400MHz,CDCl3)δ7.54–7.48(m,2H),7.35–7.27(m,3H),7.27–7.15(m,4H), 4.42 (q, J=36.7,14.9Hz, 2H), 3.65 (dd, J=73.2,9.2Hz, 2H), 2.79 (q, J=10.0Hz, 2H)；13C NMR(101MHz,CDCl3)δ156.13,139.80,134.90,132.06,129.00,128.28,128.06,126.20, 124.33 (q, J=278.4Hz), 122.82,77.79 (q, J=2.2Hz), 55.19 (d, J=1.3Hz), 48.24,44.12 (q, J=27.8Hz)；19F NMR(376MHz,CDCl3)δ-60.39；HRMS(ESI+):calcd for C18H15BrF3NNaO2 + [M+Na]+436.0130,found 436.0122。
3- benzyls -5- (4- aminomethyl phenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2l)
3-benzyl-5-(p-tolyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
105mg, yield 75%, white solid；Rf(pentane/EtOAc 3:1):0.44；
1H NMR(400MHz,CDCl3) δ 7.34-7.26 (m, 3H), 7.26-7.14 (m, 6H), 4.42 (dd, J=46.4, 15.0Hz, 2H), 3.66 (dd, J=61.0,9.1Hz, 2H), 2.77 (q, J=10.4Hz, 2H), 2.34 (s, 3H)；13C NMR (101MHz,CDCl3)δ156.50,138.54,137.96,135.14,129.53,128.92,128.14,128.09,124.53 (q, J=278.5Hz), 124.22,78.15 (q, J=2.1Hz), 55.19,48.25,44.33 (q, J=27.5Hz), 21.07 ；19F NMR(376MHz,CDCl3)δ-60.49；HRMS(ESI+):calcd for C19H18F3NNaO2 +[M+Na]+372.1182, found 372.1172。
3- benzyls -5- (4- trifluoromethyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2m)
3-benzyl-5-(2,2,2-trifluoroethyl)-5-(4-(trifluoromethyl)phenyl) oxazolidin-2-one
125mg, yield 77%, white solid；Rf(pentane/EtOAc 5:1):0.25；
1H NMR(400MHz,CDCl3) δ 7.65 (d, J=8.3Hz, 2H), 7.51 (d, J=8.2Hz, 2H), 7.36-7.25 (m, 3H), 7.24-7.15 (m, 2H), 4.43 (dd, J=35.7,14.9Hz, 2H), 3.69 (dd, J=84.4,9.3Hz, 2H), 2.85 (q, J=10.0Hz, 2H)；13C NMR(101MHz,CDCl3) δ 156.03,144.68,134.83,130.92 (q, J= 32.8Hz), 128.98,128.29,128.03,125.93 (q, J=3.7Hz), 124.99,124.31 (q, J=278.4Hz), 123.76 (q, J=272.3Hz), 77.77 (q, J=2.1Hz), 55.30,48.23,44.03 (q, J=28.0Hz)；19F NMR (376MHz,CDCl3)δ-60.44,-62.76；HRMS(ESI+):calcd for C19H15F6NNaO2 +[M+Na]+426.0899, found 426.0893。
3- benzyls -5- (4- nitrobenzophenones) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2n)
3-benzyl-5-(4-nitrophenyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
130mg, yield 85%, light yellow solid；Rf(pentane/EtOAc 3:1):0.10；
1H NMR(400MHz,CDCl3) δ 8.25 (d, J=8.9Hz, 2H), 7.59 (d, J=8.9Hz, 2H), 7.38-7.28 (m, 3H), 7.24-7.16 (m, 2H), 4.45 (dd, J=40.2,14.9Hz, 2H), 3.71 (dd, J=82.3,9.3Hz, 2H), 2.88 (q, J=9.8Hz, 2H)；13C NMR(101MHz,CDCl3)δ155.75,147.92,147.40,134.66,129.06, (128.41,128.09,125.79,124.16,124.15 q, J=278.5Hz), 77.61 (q, J=2.2Hz), 55.32 (d, J =0.9Hz), 48.30,44.08 (q, J=28.2Hz)；19F NMR(376MHz,CDCl3)δ-60.31；HRMS(ESI+): calcd for C18H15F3N2NaO4 +[M+Na]+403.0876,found 403.0860。
3- benzyls -5- (4 benzoic acid tert-butyl ester base phenyl) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2o)
tert-butyl-4-(3-benzyl-2-oxo-5-(2,2,2-trifluoroethyl)oxazolidin-5-yl) benzoate
122mg, yield 70%, white foam solid；Rf(pentane/EtOAc 3:1):0.27；
1H NMR(400MHz,CDCl3) δ 8.01 (d, J=8.5Hz, 2H), 7.43 (d, J=8.6Hz, 2H), 7.35-7.27 (m, 3H), 7.24-7.11 (m, 2H), 4.44 (dd, J=41.3,14.9Hz, 2H), 3.68 (dd, J=73.8,9.2Hz, 2H), 2.83 (q, J=10.0Hz, 2H), 1.60 (s, 9H)；13C NMR(101MHz,CDCl3)δ164.95,156.13,144.90, (134.89,132.40,130.00,128.97,128.24,128.04,124.32 q, J=278.4Hz), 124.31,81.51, 77.94 (q, J=2.2Hz), 55.27,48.27,44.16 (q, J=27.9Hz), 28.14；19F NMR(376MHz,CDCl3)δ- 60.41；HRMS(ESI+):calcd for C23H25F3NO4 +[M+H]+436.1730,found 436.1735。
3- benzyls -5- (4- Trifluoromethoxyphen-ls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2p)
3-benzyl-5-(2,2,2-trifluoroethyl)-5-(4-(trifluoromethoxy)phenyl) oxazolidin-2-one
139mg, yield 83%, white solid；Rf(pentane/EtOAc 3:1):0.3；
1H NMR(400MHz,CDCl3) δ 7.41 (d, J=8.8Hz, 2H), 7.35-7.28 (m, 3H), 7.27-7.16 (m, 4H), 4.44 (dd, J=33.2,14.9Hz, 2H), 3.68 (dd, J=74.9,9.2Hz, 2H), 2.81 (q, J=10.0Hz, 2H)；13C NMR(101MHz,CDCl3) δ 156.09,149.23 (d, J=1.7Hz), 139.38,134.88,128.96, (128.27,128.04,126.14,120.37 q, J=257.8Hz), 121.29,120.37 (q, J=257.8Hz), 77.71 (q, J=2.1Hz), 55.19 (d, J=1.1Hz), 48.22,44.21 (q, J=27.9Hz)；19F NMR(376MHz,CDCl3) δ-57.92,-60.52；HRMS(ESI+):calcd for C19H15F6NNaO3 +[M+Na]+442.0848,found 442.0832。
3- benzyls -5- (4- Phenoxyphenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2q)
3-benzyl-5-(4-phenoxyphenyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
134mg, yield 78%, white solid；Rf(pentane/EtOAc 3:1):0.3；
1H NMR(400MHz,CDCl3) δ 7.40-7.26 (m, 7H), 7.21 (dd, J=8.7,6.8Hz, 2H), 7.13 (t, J =7.4Hz, 1H), 7.07-6.92 (m, 4H), 4.43 (dd, J=35.4,14.9Hz, 2H), 3.67 (dd, J=54.3,9.2Hz, 2H),2.97–2.66(m,2H)；13C NMR(101MHz,CDCl3)δ157.72,156.49,156.34,135.20,135.09, (129.94,128.94,128.20,128.11,125.99,124.45 q, J=278.4Hz), 123.90,119.32,118.68, 77.99 (q, J=2.2Hz), 55.11,48.28,44.41 (q, J=27.6Hz)；19F NMR(376MHz,CDCl3)δ- 60.48.HRMS(ESI+):calcd for C24H21F3NO2 +[M+H]+428.1468,found 428.1475。
3- benzyls -5- (3- aminomethyl phenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2r)
3-benzyl-5-(m-tolyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
126mg, yield 90%, light yellow solid；Rf(pentane/EtOAc 3:1):0.25；
1H NMR(400MHz,CDCl3) δ 7.21-7.06 (m, 7H), 7.05-6.98 (m, 2H), 4.30 (dd, J=50.6, 15.0Hz, 2H), 3.56 (dd, J=69.3,9.2Hz, 2H), 2.67 (q, J=10.2Hz, 2H), 2.22 (s, 3H)；13C NMR (101MHz,CDCl3)δ156.53,141.03,138.75,135.15,129.37,128.93,128.81,128.16, (128.11,124.87,124.61 q, J=278.8Hz), 121.29,78.16 (q, J=2.1Hz), 55.25,48.20,44.21 (q, J=27.6Hz), 21.51；19F NMR(376MHz,CDCl3)δ-60.45；HRMS(ESI+):calcd for C19H19F3NO2 +[M+H]+350.1362,found 350.1367。
3- benzyls -5- (3- methoxyphenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2s)
3-benzyl-5-(3-methoxyphenyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
112mg, yield 77%, white solid；Rf(pentane/EtOAc 3:1):0.28；
1H NMR(400MHz,CDCl3) δ 7.26-7.14 (m, 4H), 7.13-7.03 (m, 2H), 6.85 (t, J=2.0Hz, 1H), 6.77 (d, J=8.5Hz, 2H), 4.33 (dd, J=49.5,14.9Hz, 2H), 3.69 (s, 3H), 3.58 (dd, J= 62.1,9.2Hz,2H),2.69(m,2H)；13C NMR(101MHz,CDCl3)δ159.96,156.36,142.66,135.07, (130.07,128.92,128.16,128.09,124.50 q, J=278.5Hz), 116.35,113.93,110.23,78.00 (q, J=4.2,2.0Hz), 55.37,55.16,48.25,44.25 (q, J=27.7Hz)；19F NMR(376MHz,CDCl3)δ- 60.53；HRMS(ESI+):calcd for C19H19F3NO3 +[M+H]+366.1312,found 366.1309。
3- benzyls -5- (3- (2,2,2- trimethyl-acetyls) phenyl) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2t)
N-(3-(3-benzyl-2-oxo-5-(2,2,2-trifluoroethyl)oxazolidin-5-yl)phenyl) pivalamide
142mg, yield 82%, white foam solid；Rf(pentane/EtOAc 3:1):0.15；
1H NMR(400MHz,CDCl3) δ 7.63 (t, J=1.9Hz, 1H), 7.53 (dd, J=8.1,1.3Hz, 1H), 7.48 (s, 1H), 7.38-7.27 (m, 4H), 7.20 (dd, J=7.4,1.8Hz, 1H), 7.10 (d, J=7.9Hz, 1H), 4.42 (dd, J =90.1,14.9Hz, 2H), 3.67 (dd, J=56.6,9.2Hz, 2H), 2.77 (q, J=10.0Hz, 2H), 1.32 (s, 9H)；13C NMR(101MHz,CDCl3)δ177.35,156.42,141.91,139.03,134.91,129.42,128.92,124.46 (q, J=278.5Hz), 128.18,128.04,120.12,119.51,115.78,78.07 (q, J=2.1Hz), 55.25, 48.19,44.07 (q, J=27.7Hz), 39.71,27.49；19F NMR(376MHz,CDCl3)δ-60.52；HRMS(ESI+): calcd for C23H26F3N2O3 +[M+H]+435.1890,found 435.1869。
3- benzyls -5- (3- (2,2,2- trimethylace tonitrics) phenyl) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2u)
3-(3-benzyl-2-oxo-5-(2,2,2-trifluoroethyl)oxazolidin-5-yl) phenylpivalate
136mg, yield 78%, white solid；Rf(pentane/EtOAc 3:1):0.20；
1H NMR(400MHz,CDCl3) δ 7.41 (t, J=8.0Hz, 1H), 7.37-7.28 (m, 3H), 7.27-7.12 (m, 4H), 7.08 (d, J=8.0Hz, 1H), 4.45 (dd, J=75.5,14.9Hz, 2H), 3.69 (dd, J=64.6,9.2Hz, 2H), 2.88–2.71(m,2H),1.37(s,9H)；13C NMR(101MHz,CDCl3)δ176.87,156.17,151.49,142.68, (134.94,129.96,128.96,128.21,128.09,124.39 q, J=278.5Hz), 121.98,121.37,117.88, 77.69 (d, J=2.1Hz), 55.04 (d, J=0.9Hz), 48.27,44.26 (q, J=27.8Hz), 39.11,27.11；19F NMR(376MHz,CDCl3)δ-60.52；HRMS(ESI+):calcdfor C23H25F3NO4 +[M+H]+436.1730,found 436.1730。
3- benzyls -5- (2- aminomethyl phenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2v)
3-benzyl-5-(o-tolyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
104mg, yield 74%, white solid；Rf(pentane/EtOAc 3:1):0.45；
1H NMR(400MHz,CDCl3) δ 7.68-7.53 (m, 1H), 7.43-7.07 (m, 9H), 4.44 (dd, J=82.2, 15.0Hz, 2H), 3.75 (dd, J=107.3,9.1Hz, 2H), 2.81 (q, J=10.2Hz, 2H), 2.26 (s, 3H)13C NMR (101MHz,CDCl3)δ156.00,139.07,135.09,132.55,132.33,128.94,128.74,128.17, (128.09,126.52,125.23,124.66 q, J=278.6Hz), 78.56 (q, J=2.1Hz), 54.64,48.25,42.88 (q, J=27.6Hz), 20.79；19F NMR(376MHz,CDCl3)δ-61.09；HRMS(ESI+):calcd for C19H19F3NO2 +[M+H]+350.1362,found 350.1347。
3- benzyls -5- (2- chlorphenyls) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2w)
3-benzyl-5-(2-chlorophenyl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
110mg, yield 74%, white solid；Rf(pentane/EtOAc 3:1):0.40；
1H NMR(400MHz,CDCl3) δ 7.83 (dd, J=7.6,1.8Hz, 1H), 7.41-7.27 (m, 6H), 7.26- 7.20 (m, 2H), 4.44 (dd, J=101.4,15.0Hz, 2H), 3.81 (dd, J=88.2,9.8Hz, 2H), 3.14-2.87 (m, 2H)；13C NMR(101MHz,CDCl3)δ155.65,138.15,135.04,130.87,130.22,129.53,128.96, (128.19,128.08,127.61,127.39,124.62 q, J=278.6Hz), 77.71 (q, J=2.1Hz), 54.81 (d, J =0.7Hz), 48.20,41.75 (q, J=27.9Hz)；19F NMR(376MHz,CDCl3)δ-61.02；HRMS(ESI+): calcd for C18H15ClF3NNaO2 +[M+Na]+392.0636,found 392.0619。
3- benzyls -5- (2- naphthalenes) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2x)
3-benzyl-5-(naphthalen-2-yl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
116mg, yield 75%, white solid；Rf(pentane/EtOAc 4:1):0.35；
1H NMR(400MHz,CDCl3) δ 7.92 (d, J=1.6Hz, 1H), 7.87-7.78 (m, 3H), 7.49 (dd, J= 6.3,3.2Hz, 2H), 7.34-7.16 (m, 6H), 4.42 (dd, J=55.9,15.0Hz, 2H), 3.74 (dd, J=54.0, 9.2Hz, 2H), 2.87 (q, J=10.1Hz, 2H)；13C NMR(101MHz,CDCl3)δ156.50,137.98,135.07, 132.99,132.90,129.11,128.96,128.41,128.20,128.10,127.71,126.95,126.95,124.57 (q, J=278.6Hz), 78.28 (q, J=2Hz), 55.19,48.29,44.17 (q, J=27.7Hz)；19F NMR(376MHz, CDCl3)δ-60.39；HRMS(ESI+):calcd for C22H19F3NO2 +[M+H]+386.1362,found 386.1350。
3- benzyls -5- (1- naphthalenes) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2y)
3-benzyl-5-(naphthalen-1-yl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
101mg, yield 65%, white solid；Rf(pentane/EtOAc 3:1):0.30；
1H NMR(400MHz,CDCl3) δ 7.92 (t, J=6.3Hz, 2H), 7.86 (d, J=8.2Hz, 1H), 7.56-7.45 (m, 4H), 7.36-7.20 (m, 5H), 4.44 (dd, J=144.2,15.1Hz, 2H), 4.02 (dd, J=147.3,9.2Hz, 2H),3.22–2.89(m,2H)；13C NMR(101MHz,CDCl3)δ155.82,136.73,135.07,134.58,130.20, 129.98,128.93,128.16,128.07,127.89,126.96,125.77,125.40 124.87 (q, J=278.7Hz), 123.43,122.70,78.46 (d, J=1.9Hz), 54.47 (d, J=0.9Hz), 48.29,43.59 (q, J=27.6 Hz)；19F NMR(376MHz,CDCl3)δ-60.87；HRMS(ESI+):calcd for C22H19F3NO2 +[M+H]+386.1362, found 386.1370。
3- benzyls -5- (6- quinoline) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2z)
3-benzyl-5-(quinolin-6-yl)-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
90mg, yield 58%, light yellow solid；Rf(pentane/EtOAc 1:3):0.4；
1H NMR(400MHz,CDCl3) δ 8.98 (d, J=2.9Hz, 1H), 8.20 (d, J=8.0Hz, 1H), 8.15 (d, J =8.9Hz, 1H), 7.99 (d, J=1.8Hz, 1H), 7.54 (dd, J=8.9,2.0Hz, 1H), 7.48 (dd, J=8.3, 4.2Hz, 1H), 7.35-7.29 (m, 3H), 7.24-7.15 (m, 2H), 4.47 (dd, J=52.0,14.9Hz, 2H), 3.78 (dd, J=56.5,9.2Hz, 2H), 2.93 (q, J=10.0Hz, 2H)；13C NMR(101MHz,CDCl3)δ156.20,151.42, 147.85,138.57,136.54,134.88,130.63,128.96,128.24,128.06,127.82,125.30,124.36 (q, J=278.5Hz), 123.82,122.07,77.99 (q, J=2.1Hz), 55.14 (d, J=1.4Hz), 48.32,44.17 (q, J=27.9Hz)；19F NMR(376MHz,CDCl3)δ-60.45；HRMS(ESI+):calcd for C21H17F3N2NaO2 +[M +Na]+409.1134,found 409.1141。
3- benzyls -4- methyl -5- phenyl -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2aa)
3-benzyl-4-methyl-5-phenyl-5-(2,2,2-trifluoroethyl)oxazolidin-2-one
110mg, yield 78%, white solid；Rf(pentane/EtOAc 3:1):0.20；
1H NMR(400MHz,CDCl3)δ7.42–7.30(m,5H),7.23–7.13(m,3H),7.03–6.93(m,2H), 4.41 (dd, J=287.7,15.5Hz, 2H), 3.63 (q, J=6.6Hz, 1H), 2.95-2.71 (m, 2H), 1.29 (d, J= 6.6Hz,3H)；13C NMR(101MHz,CDCl3)δ156.37,140.29,135.29,128.74,128.74,128.45, (127.85,127.54,124.92 q, J=278.5Hz), 124.33,81.12 (dd, J=3.9,1.8Hz), 61.66,45.71, 38.95 (q, J=28.2Hz), 13.29；19F NMR(376MHz,CDCl3)δ-59.01；HRMS(ESI+):calcd for C19H19F3NO2 +[M+H]+350.1362,found 350.1371。
3- benzyl -5- phenyl -5- (1- trifluoromethyls ethyl) -2-oxazolidinone (2ab)
3-benzyl-5-phenyl-5-(1,1,1-trifluoropropan-2-yl)oxazolidin-2-one
99mg, yield 71%yield, light yellow solid (racemic mixture Z:E=1.14:1)；105mg, yield 75%, white solid (starting material is Z configurations)；
Rf(pentane/EtOAc 5:1):0.30；
1H NMR(400MHz,CDCl3)δ7.43–7.32(m,5H),7.31–7.24(m,3H),7.20–7.12(m,2H), 4.41 (q, J=14.9Hz, 2H), 3.94 (d, J=9.4Hz, 1H), 3.58 (d, J=9.3Hz, 1H), 2.76 (qd, J=8.5, 1.2Hz, 1H), 1.08 (d, J=7.1Hz, 3H)；13C NMR(101MHz,CDCl3)δ156.44,141.46,135.07, (128.82,128.81,128.51,128.07,126.59 q, J=281.6Hz), 124.69,80.95,53.70 (q, J= 2.4Hz), 48.24,46.63 (q, J=24.9Hz), 9.77 (q, J=2.9Hz)；19F NMR(376MHz,CDCl3)δ-65.66； HRMS(ESI+):calcd for C19H19F3NO2 +[M+H]+350.1362,found 350.1368。
3- benzyl -5- phenyl -5- (tri- fluoro- 2- methyl-propyls of 1,1,1-) -2-oxazolidinone (2ac)
3-benzyl-5-phenyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)oxazolidin- 2-one
50mg, yield 34%, white solid；Rf(pentane/EtOAc 3:1):0.50；
1H NMR(400MHz,CDCl3)δ7.47–7.39(m,2H),7.38–7.31(m,3H),7.30–7.23(m,3H), 7.14-7.06 (m, 2H), 4.39 (dd, J=55.7,15.1Hz, 2H), 3.84 (dd, J=111.4,9.6Hz, 2H), 1.20 (d, J=22.1Hz, 6H)；13C NMR(101MHz,CDCl3)δ156.36,139.67,135.09,128.83,128.59,128.03, (127.84,127.83,127.81 q, J=284.5Hz), 126.99,83.52,52.88 (q, J=2.9Hz), 48.10,47.89 (q, J=22.8Hz), 18.25 (q, J=2.3Hz), 17.99 (q, J=2.3Hz)；19F NMR(376MHz,CDCl3)δ- 70.02；HRMS(ESI+):calcd for C20H20F3NNaO2 +[M+Na]+386.1338,found 386.1324。
3- benzyls -6- Trifluoromethyl-1s-oxa- -3- azaspiros [4.5] decyl- 2- ketone (2ad)
3-benzyl-6-(trifluoromethyl)-1-oxa-3-azaspiro[4.5]decan-2-one
70mg, yield 56%, white solid；Rf(pentane/EtOAc 5:1):0.40；
1H NMR(400MHz,CDCl3) δ 7.42-7.21 (m, 5H), 4.44 (q, J=14.9Hz, 2H), 3.32 (dd, J= 187.3,9.3Hz,2H),2.54–2.38(m,1H),2.08–1.97(m,1H),1.92–1.66(m,4H),1.42–1.16(m, 3H)；13C NMR(101MHz,CDCl3) δ 156.62,135.40,128.83,128.15,128.03,126.33 (q, J= 281.6Hz), 77.85 (d, J=0.5Hz), 49.47 (d, J=1.7Hz), 48.33,47.67 (q, J=24.6Hz), 38.36, 23.10,23.07,21.94；19F NMR(376MHz,CDCl3)δ-65.67；HRMS(ESI+):calcd for C16H18F3NNaO2 +[M+Na]+336.1182,found 336.1169。
3'- benzyls -2- trifluoromethyl -3,4- dihydro -2H- spiral shells [naphthalene -1,5'- oxazolines] -2'- ketone (2ae)
3'-benzyl-2-(trifluoromethyl)-3,4-dihydro-2H-spiro[naphthalene-1,
5'-oxazolidin]-2'-one
113mg, yield 78%, white solid；Rf(pentane/EtOAc 3:1):0.40；
1H NMR(400MHz,CDCl3) δ 7.33-7.09 (m, 8H), 7.03-6.94 (m, 1H), 4.40 (dd, J=38.2, 14.8Hz, 2H), 3.75 (d, J=9.8Hz, 1H), 3.22 (d, J=9.8Hz, 1H), 2.94-2.59 (m, 3H), 2.26-2.02 (m,1H),1.78–1.54(m,1H)；13C NMR(101MHz,CDCl3)δ157.05,138.61,135.20,134.63, (128.85,128.74,128.64,128.34,128.16,127.51,126.50 q, J=281.1Hz), 125.27,77.73, 53.40 (d, J=1.9Hz), 48.41,46.36 (q, J=25.4Hz), 27.61,20.10 (d, J=2.4Hz)；19F NMR (376MHz,CDCl3)δ-66.39；HRMS(ESI+):calcd for C20H19F3NO2 +[M+H]+362.1362,found 362.1358。
3- benzyl -5- t-butyl formate bases -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2af)
tert-butyl-3-benzyl-2-oxo-5-(2,2,2-trifluoroethyl)oxazolidine-5- carboxylate
99mg, yield 69%, white solid；Rf(pentane/EtOAc 3:1):0.4；
1H NMR(400MHz,CDCl3) δ 7.39-7.29 (m, 3H), 7.26 (d, J=7.5Hz, 2H), 4.44 (dd, J= 82.8,15.0Hz 2H), 3.53 (dd, J=96.5,9.6Hz, 2H), 2.96-2.69 (m, 2H), 1.45 (s, 9H)；13C NMR (101MHz, CDCl3) δ 167.38,155.82,134.97,128.96,128.24,128.00,124.33 (q, J= 278.0Hz), 84.56,75.89 (q, J=2.3Hz), 51.56,48.06,39.92 (q, J=29.3Hz), 27.55；19F NMR (376MHz,CDCl3)δ-60.94；HRMS(ESI+):calcd for C17H20F3NNaO4 +[M+Na]+382.1237,found 382.1221。
3- benzyls -5- (tri- fluoro- 1- butylene of 4,4,4-) -5- (2,2,2- trifluoroethyls) -2-oxazolidinone (2ag)
(E)-3-benzyl-5-(4,4,4-trifluorobut-1-en-1-yl)-5-(2,2,2- trifluoroethyl)oxazolidin-2-one
32mg, yield 23%, light yellow solid；Rf(pentane/EtOAc 5:1)=0.16；
1H NMR(400MHz,CDCl3) δ 7.41-7.29 (m, 3H), 7.25-7.17 (m, 2H), 5.92 (dt, J=15.4, 7.0Hz, 1H), 5.76 (d, J=15.7Hz, 1H), 4.43 (dd, J=75.7,15.0Hz, 2H), 3.38 (dd, J=52.2, 9.3Hz,2H),2.96–2.77(m,2H),2.73–2.50(m,2H)；13C NMR(101MHz,CDCl3)δ156.04,134.99, (134.97,128.98,128.24,127.94,125.34 dd, J=553.5,276.7Hz), 124.41 (q, J=277.7Hz), 120.45 (q, J=3.5Hz), 75.80 (q, J=2.3Hz), 53.47 (d, J=1.7Hz), 48.15,42.93 (q, J= 28.0Hz), 36.68 (q, J=30.3Hz)；19F NMR(376MHz,CDCl3)δ-60.59,-66.10.HRMS(ESI+): calcd for C16H16F6NO2 +[M+H]+368.1080,found 368.1091。
Embodiment 33 to 35 compound 2a of embodiment application
Compound 3,4 and 5 can be obtained with high yield by compound 2a.Specific preparation method is as described below.
N- benzyls-N- (4,4,4,-three fluoro- 2- hydroxyls -2- phenyl butyls) -3- alkene butyramide (compound 3)
N-benzyl-N-(4,4,4-trifluoro-2-hydroxy-2-phenylbutyl)but-3-enamide
0.6mmol is added dropwise into THF (1mL) solution of 0.2mmol (67mg, 1.0equiv) compounds 2a at -78 DEG C The allylic bromination magnesium of (3.0equiv).It keeps after reacting 3 hours at the temperature disclosed above, adds in 1mL saturated ammonium chloride solutions, treat When reaction system is warmed to room temperature, 3 times (3 × 5mL) are extracted with ether, are then spin-dried for, carry out column chromatography (PE:EA=5:1) it detaches Purification obtains target compound 3 (72mg), for colourless oil liquid, yield 96%.
Rf(pentane/EtOAc 5:1)=0.5；1H NMR(400MHz,CDCl3)δ7.57–7.44(m,2H),7.44– 7.37 (m, 2H), 7.37-7.26 (m, 4H), 6.95 (d, J=6.9Hz, 2H), 5.87 (ddt, J=16.8,10.2,6.4Hz, 1H), 5.70 (s, 1H), 5.10 (dddd, J=46.1,17.2,2.8,1.4Hz, 2H), 4.36 (dd, J=33.6,15.9Hz, 2H), 3.36 (dd, J=154.9,15.9Hz, 2H), 3.14-3.00 (m, 2H), 2.84-2.59 (m, 2H)；13C NMR (101MHz,CDCl3)δ174.64,141.78,134.42,129.50,128.08,127.36,126.89,126.56, 125.03,124.72 (q, J=278.7Hz), 124.40,117.44,74.63 (d, J=1.9Hz), 56.84 (d, J= 1.7Hz), 52.00,42.61 (q, J=26.1Hz), 37.43；19F NMR(376MHz,CDCl3)δ-58.68.HRMS(ESI+): calcd for C21H22F3NNaO2 +[M+Na]+400.1495,found 400.1500。
Three fluoro- 2- phenyl butyl- 2- alcohol (compound 4) of 1- (methylbenzylamide) -4,4,4-
1-(benzyl(methyl)amino)-4,4,4-trifluoro-2-phenylbutan-2-ol
1.0mmol lithium aluminium hydride reductions (38mg, 5.0equiv), 4mL are sequentially added into 25mL Schlenk pipes at room temperature THF (4mL) solution of THF, 0.2mmol compound 2a (67mg, 1.0equiv).Then reaction 1 hour is maintained the reflux for, is then added Enter 2mL sodium hydrate aqueous solutions (2M) and reaction is quenched.Diatomite filters, and is spin-dried for solvent, column chromatography (PE:EA=10:1) separation carries Pure acquisition target compound 4 (62mg), white solid, yield 96%.
Rf(pentane/EtOAc 5:1)=0.6；1H NMR(400MHz,CDCl3)δ7.50–7.34(m,2H),7.31– 7.02 (m, 8H), 4.66 (s, 1H), 3.33 (dd, J=31.1,13.0Hz, 2H), 2.97-2.77 (m, 2H), 2.60-2.38 (m, 2H),1.92(s,3H)；13C NMR(101MHz,CDCl3)δ144.72,138.12,129.05,128.46,128.29, (127.48,127.11,125.64 q, J=278.6Hz), 125.22,71.23 (q, J=1.9Hz), 67.12 (d, J= 1.1Hz), 63.57,44.89 (q, J=26.1Hz), 43.79；19F NMR(376MHz,CDCl3)δ-59.15；HRMS(ESI+): calcd for C18H21F3NO+[M+H]+324.1570,found 324.1574。
The preparation of compound 5 and 5 '
10.4mmol hydroxides are added in into methanol (4mL) solution of 0.4mmol compounds 2a (134mg, 1.0equiv) Sodium (416mg, 26.0equiv), is then stirred to react 2 hours under the conditions of 65 DEG C, after reaction system is cooled to room temperature, adds in 1N hydrochloric acid neutralizes, and when neutrality is adjusted to, 3 times (3 × 10mL) are extracted with dichloromethane, and anhydrous sodium sulfate drying is spin-dried for, column chromatography (PE:EA=10:1) separating-purifying obtains target compound 5 and 5 ', pale yellowish oil empty (95.6mg, yield 82%).
Wherein, (Z)-N- benzyls -4,4, tri- fluoro- 2- phenyl but-2-ene -1- amine (compound 5) of 4- be 57.8mg, yield 50%；Rf(pentane/EtOAc 5:1)=0.6；1H NMR(400MHz,CDCl3)δ7.52–7.26(m,5H),7.25–7.05 (m, 5H), 5.84 (q, J=8.6Hz, 1H), 3.79 (d, J=0.9Hz, 2H), 3.64 (s, 2H)；13C NMR(101MHz, CDCl3) δ 150.82 (q, J=5.3Hz), 138.66,137.50,128.21,127.79,127.33,127.14,126.05, 125.79,122.23 (q, J=271.3Hz), 116.98 (q, J=34.1Hz), 52.10,46.44；19F NMR(376MHz, CDCl3)δ-55.87.HRMS(ESI+):calcd for C17H17F3N+[M+H]+292.1308,found 292.1308。
(E)-N- benzyls -4,4, tri- fluoro- 2- phenyl but-2-ene -1- amine (5 ') of 4- be 37.8mg, yield 32%；Rf (pentane/EtOAc 5:1)=0.5；1H NMR(400MHz,CDCl3)δ7.41–7.23(m,8H),7.23–7.15(m,2H), 6.00 (qt, J=8.2,1.6Hz, 1H), 3.81 (s, 2H), 3.56-3.47 (m, 2H)；13C NMR(101MHz,CDCl3)δ 150.82 (q, J=5.3Hz), 138.60,135.96,127.49,127.25,127.16,127.08,126.33 (d, J= 1.7Hz), 126.19,122.13 (d, J=270.8Hz), 114.36 (q, J=33.7Hz), 54.51,51.83；19F NMR (376MHz,CDCl3)δ-55.90.HRMS(ESI+):calcd for C17H17F3N+[M+H]+292.1308,found 292.1309。

Claims (17)

  1. A kind of 1. method of 2-oxazolidinone class compound prepared containing trifluoromethyl, which is characterized in that the method includes with Propylamine compound shown in formula 1 is as substrate and CO2In molten in the presence of copper catalyst, alkali and trifluoromethyl reagent In agent, the step of reacting in the environment of 0~80 degree, 1~20atm；
    Wherein, the 2-oxazolidinone class compound containing trifluoromethyl is as shown in Equation 2；
    Wherein, R1、R2、R4And R5It is each independently including H, halogen, cyano, alkyl, carbonyl, ester group, aryl and heteroaryl exist Interior one kind；Further R4Or R5Optionally with R1Cyclization, the alkyl, carbonyl, ester group, aryl and heteroaryl can be optional Ground is by a kind of substitution including halogen, alkyl；R3It is one kind including H, halogen, alkyl, aryl；
    The trifluoromethyl reagent is Togni ' s reagents or Umemoto reagents；Togni ' the s reagents include a generation or two For one kind in Togni ' s reagents.
  2. 2. according to the method described in claim 1, it is characterized in that, the alkyl is the straight chain alkane with 1-20 carbon atom Base, branched alkyl or cycloalkyl.
  3. 3. according to the method described in claim 1, it is characterized in that, the aryl is the aryl with 6-20 carbon atom.
  4. 4. according to the method described in claim 1, it is characterized in that, the heteroaryl is the heteroaryl with 6-20 carbon atom Base.
  5. 5. according to Claims 1 to 4 any one of them method, which is characterized in that the copper catalyst includes organic copper catalysis At least one of agent and inorganic copper catalyst.
  6. 6. according to the method described in claim 5, it is characterized in that, organic copper catalyst is cupric acetylacetonate or tetrem Cyanogen copper hexafluorophosphate；The inorganic copper catalyst is stannous chloride or cuprous bromide.
  7. 7. according to Claims 1 to 4 any one of them method, which is characterized in that the alkali is selected from cesium fluoride, sodium carbonate, carbon It is one or more in 11 carbon -7- alkene (DBU) of sour caesium, sodium tert-butoxide or 1,8- diazabicylos.
  8. 8. the method according to the description of claim 7 is characterized in that the alkali is cesium carbonate, sodium tert-butoxide or DBU.
  9. 9. according to the method described in claim 8, it is characterized in that, the alkali is DBU.
  10. 10. according to Claims 1 to 4 any one of them method, which is characterized in that the trifluoromethyl reagent was two generations Togni ' s reagents.
  11. 11. according to Claims 1 to 4 any one of them method, which is characterized in that the solvent be selected from 1,2- dichloroethanes, It is one or more in dichloromethane, tetrahydrofuran, methanol, N,N-dimethylformamide, acetonitrile.
  12. 12. according to the method for claim 11, which is characterized in that the solvent is n,N-Dimethylformamide or acetonitrile.
  13. 13. according to Claims 1 to 4 any one of them method, which is characterized in that the substrate and catalyst feed intake mole Than being 20:1~5:1；The molar ratio of substrate and alkali is 1:1~1:3；The molar ratio of substrate and trifluoromethyl reagent It is 1:1~1:2.
  14. 14. according to the method for claim 13, which is characterized in that the molar ratio of the substrate and catalyst is 10: 1。
  15. 15. according to the method for claim 13, which is characterized in that the molar ratio of substrate and alkali is 1:2.
  16. 16. according to the method for claim 13, which is characterized in that the molar ratio of substrate and trifluoromethyl reagent is 1:1.1。
  17. 17. according to the method described in claim 1, it is characterized in that, the reaction is under 25 degrees Celsius and 1atm reaction pressures Lower progress.
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