CN101723911B - Method for synthesizing N-aryl-1,3-oxazolin-2-one compounds - Google Patents
Method for synthesizing N-aryl-1,3-oxazolin-2-one compounds Download PDFInfo
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- CN101723911B CN101723911B CN2009101543663A CN200910154366A CN101723911B CN 101723911 B CN101723911 B CN 101723911B CN 2009101543663 A CN2009101543663 A CN 2009101543663A CN 200910154366 A CN200910154366 A CN 200910154366A CN 101723911 B CN101723911 B CN 101723911B
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- oxazolidine
- sulfonium salt
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- 238000000034 method Methods 0.000 title claims abstract description 43
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 239000003960 organic solvent Substances 0.000 claims abstract description 19
- 238000010523 cascade reaction Methods 0.000 claims abstract description 4
- 238000005580 one pot reaction Methods 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 52
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 48
- -1 thiazolinyl sulfonium salt Chemical class 0.000 claims description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 35
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- 239000003513 alkali Substances 0.000 claims description 28
- 238000005406 washing Methods 0.000 claims description 17
- 239000010410 layer Substances 0.000 claims description 16
- 238000001953 recrystallisation Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- 239000000758 substrate Substances 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims 6
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000001419 dependent effect Effects 0.000 abstract 1
- QDXBVEACAWKSFL-UHFFFAOYSA-N ethenethiol Chemical class SC=C QDXBVEACAWKSFL-UHFFFAOYSA-N 0.000 abstract 1
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- 239000000047 product Substances 0.000 description 28
- 238000012512 characterization method Methods 0.000 description 17
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 238000005303 weighing Methods 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 239000011593 sulfur Substances 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 4
- 239000004593 Epoxy Chemical class 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000005595 deprotonation Effects 0.000 description 4
- 238000010537 deprotonation reaction Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- BVCZEBOGSOYJJT-UHFFFAOYSA-N ammonium carbamate Chemical compound [NH4+].NC([O-])=O BVCZEBOGSOYJJT-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
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- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 2
- GEKLDGQKEZAPFZ-UHFFFAOYSA-N 2-(ethylamino)-1-(3-methylphenyl)propan-1-one Chemical compound CCNC(C)C(=O)C1=CC=CC(C)=C1 GEKLDGQKEZAPFZ-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- DRZYCRFOGWMEES-UHFFFAOYSA-N CC(C)(C)OC(Nc1ccncc1)=O Chemical compound CC(C)(C)OC(Nc1ccncc1)=O DRZYCRFOGWMEES-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
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- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
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- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to the synthesis of organic molecular compound, in particular to a new method for synthesizing N-aryl-1,3-oxazolin-2-one compounds. In the method, N-arylcarbamate and a vinyl sulfonium salt undergo a one-pot cascade reaction in an organic solvent under an alkalescent condition to obtain the N-aryl-1,3-oxazolin-2-one compounds directly. The method avoids the harsh conditions which the transitional synthesis method dependents on such as low temperature and high alkalinity, avoids the protection by an inter gas and is suitable to be used in laboratories or large-scale industrial production.
Description
Technical field
The invention belongs to the organic chemical industry field, relate to a kind of preparation of organic molecular compound, a kind of specifically novel N-aryl-1, the compound method of 3-oxazolidine-2-ketone compounds.
Background technology
N-aryl-1,3-oxazolidine-2-ketone compounds are numerous natural products and medical molecular structure fragment, have the important physical activity.Simultaneously also be the synthetic and organic synthesis intermediate of a kind of important medicine, be widely used in the synthetic of many medicines, material molecule.
Traditional N-aryl-1, the synthetic ring-closure reaction that basically all is based on N-arylamino acid esters and epoxy compounds or β-chloro-hydrin(e) of 3-oxazolidine-2-ketone compounds carries out.For example Brickners in 1996 etc. have been reported and have been utilized N-arylamino acid esters and the synthetic N-aryl-1 of epoxy compounds, and (nineteen ninety-five, D.K.WO 95/07271 for Brickner etc., international patent application book for the method for 3-oxazolidine-2-ketones derivant; Brickner etc., " pharmaceutical chemistry journal,, 39 volumes, 673 pages in 1996.) (Barbachyn, M.R.; Brickner, S.J.; Hutchingson, D.K.WO 95/07271 (1995) .Brickner, S.J.; Hutchinson, D.K.; Barbachyn, M.R.; Manninen, P.R.; Ulanowicz, D.A.; Garmon, S.A.; Grega, K.C.; Hendges, S.K.; Toops, D.S.; Ford, C.W.; Zurenko, G.E.J.Med.Chem.1996,39,673.), this method is unfavorable for preparation and industrialized production in the laboratory owing to need the loaded down with trivial details synthetic of epoxy raw material and use violent reaction conditions such as low temperature (78 ℃), highly basic (n-BuLi) etc. very much.Afterwards, the para top grade found to use β-chloro-hydrin(e) to replace epoxy substrate and N-arylamino acid esters to close ring (para top grade, international patent application book,, WO02/085849 in 2002; The para top grade, " organic process study and development ",, 7 volumes, 533-546 page or leaf in 2003.) (Perrault, W.R.; Pearlman, B.A.; Godrej, D.B.WO02/085849 (2002) .William R.Perrault, Bruce A.Pearlman, Delara B.Godrej; Azhwarsamy Jeganathan, Koji Yamagata, Jiong J.Chen, Cuong V.Lu; Paul M.Herrinton, Robert C.Gadwood, Lai Chan, Mark A.Lyster; Mark T.Maloney, Jeffery A.Moeslein, Meredith L.Greene, and Michael R.Barbachyn Organic Process Research & Development 2003; 7,533-546.), also can obtain 1; 3-oxazolidine-2-ketone compounds, but this reaction still needs could implement and the need highly basic equally use of (t-BuLi) at low temperatures.
Recently, Gao Xi etc. have reported a kind of based on transition metal-catalyzed linked reaction (Gao Xi etc., " organic chemistry journal,, 71 volumes, 1258-1261 page or leaf in 2006.) (Ghosh, A.; Sieser, J.E.; Caron, S.; Couturier, M.; Dupont-Gaudet, K.; Girardin, M.J.Org.Chem.2006,71; 1258-1261.), be used to prepare N-aryl-1,3-oxazolidine-2-ketone structural compounds; But this method needs to synthesize 1 in advance; 3-oxazolidine-2-ketone, and need to use be prone to pollute the metal remained catalyzer, limited should technology promotion and application.This shows, develop novel, easy, N-aryl-1 efficiently, it is very necessary and significant that 3-oxazolidine-2-ketone compound method just seems.
Summary of the invention
The objective of the invention is above-mentioned deficiency, a kind of simple and high-efficient N-aryl-1 is provided, the compound method of 3-oxazolidine-2-ketone compounds to existing compound method.This method has been broken away from conditions such as the low temperature that is relied in the prior synthesizing method, highly basic, is more convenient in laboratory and suitability for industrialized production, adopting.
The compound method that the present invention proposes is to adopt carbamate and thiazolinyl sulfonium salt under alkaline condition, in organic solvent, the one kettle way cascade reaction takes place, and obtains N-aryl 1,3-oxazolidine-2-ketone compounds.Its reaction equation is:
In the following formula, R
1NHCOOR
2Represent described N-aryl-carbamate; R
3R
4C=CR
5SR
6R
6A representes described thiazolinyl sulfonium salt, wherein, and R
1Represent 4-NO
2C
6H
4, 4-ClC
6H
4, 4-MeC
6H
4, 4-MeOC
6H
4, 3-NO
2C
6H
4, 3-MeC
6H
4, 2-MeOC
6H
4, 2-NO
2C
6H
4, 2-MeC
6H
4, a kind of aromatic ring or fragrant heterocycle such as 4-pyridyl or 3-pyridyl; R
2Represent a kind of alkyl or aryl such as t-Bu, Et, Me or Bz; R
3, R
4, R
5The three all can be a kind of alkyl or aryl such as H, Me, Ph; R
6Represent a kind of alkyl or aryl such as Ph, Me; A represents OTf, I, Br, CF
3A kind of in the negatively charged ion such as COO, OTs, OMs.
In compound method of the present invention, nitrogen-atoms is connecting a carbonyl and can be counted as an acid amides in the said carbamate, and normal temperature is met down and lost proton easily behind the alkali and become the acid amides negative ion.Said thiazolinyl sulfonium salt then has stronger close electroactive; The acid amides negative ion reaction that is easy to form with deprotonation generates the sulfur ylide midbody; Said sulfur ylide midbody have by an adjacent positive sulfonium ion stable carbanion structure; Carbanion is a strong nucleophile, in solvent, when said sulfur ylide midbody runs into the H that is caught by alkali
+Ion will combine to generate the sulfonium salt midbody with it, and the sulfonium salt midbody is because its unstable through further intramolecular nucleophilic substitution reaction taking place and taking off alkyl, generates N-aryl 1,3-oxazolidine-2-ketone compounds at last.
Draw through above analysis, through the synthetic N-aryl 1 of compound method disclosed by the invention, 3-oxazolidine-2-ketone compounds should possess following condition, and one, one of substrate should have-NH (CO) O-functional group; Two of substrate should have the sulfonium positive ion structure of alkenyl substituted.Two, should be under alkaline environment, to impel the carbamate deprotonation and to react with the thiazolinyl sulfonium salt.Hence one can see that, satisfying under the preceding topic of above-mentioned two conditions, as long as have time enough, carbamate and the thiazolinyl sulfonium salt that can adopt various different structures synthesize and have N-aryl 1, a compounds of 3-oxazolidine-2-ketone structure.
But from practicing thrift cost, cutting the waste and the preferred N-arylamino of said carbamate methyl-formiate, N-arylamino ethyl formate, N-arylamino t-butyl formate or N-arylamino benzyl formate are considered in aspect such as handled easily.The preferred trifluoromethanesulfonic acid of said thiazolinyl sulfonium salt-diphenylacetylene sulfonium salt or trifluoromethanesulfonic acid-dimethyl-vinyl sulfonium salt.
The main effect of said alkali in reaction is the deprotonation to N-H key in the carbamate, and therefore, the normal temperature pH value all can between 7 to 14 organic bases or mineral alkali under the unit concentration.Because the activity of N-H key is very high in the carbamate; Destroying this chemical bond need not special the employing as butyllithium etc. and has very strong and highly basic proton-binding energy power; Can use the weak base of the very little routine of corrodibility fully, as triethylamine, sodium hydride, DBU (1,8-diazacyclo [5; Hendecene-7) etc. 4,0] can realize bringing out the purpose of reaction.On the contrary, if adopt the strong highly basic of proton-binding energy power, its strong excessively destructive force makes metastable chemical bond disconnection in the substrate molecule structure easily, and then generates the outer product of purpose, has influenced degree of purity of production and productive rate on the contrary.
For the usage quantity aspect of alkali, owing in to carbamate, obtain H in the deprotonation process of N-H key
+The protonated of sulfur ylide midbody takes place again in alkali subsequently, and alkali is again by final release.So in the overall process of reaction, alkali is not consumed.Because the acid amides negative ion that generates is constantly consumed, impelled constantly moving of chemical reaction equilibrium again in reaction, so only need a spot of alkali that reaction is successfully carried out in the compound method of the present invention to the direction that generates product.
Can know that based on reaction principle the concentration of alkali has confidential relation to reaction rate in the reaction environment, the concentration of alkali is low, and reaction rate is then low, otherwise then high, but the unlimited concentration that increases alkali can't infinitely improve reaction rate, can cause waste on the contrary.Experiment showed, generally speaking every corresponding 1 mole carbamate, suitable adding 2～8 moles or above alkali.
Said organic solvent is used for solubilizing reaction substrate N-aryl-carbamate and thiazolinyl sulfonium salt, makes it thorough mixing, to reaction substrate an envrionment conditions that is in contact with one another and reacts is provided.This shows; In compound method of the present invention; Said organic solvent can be to make the consoluet various organic solvents of substrate at normal temperatures, and relatively commonly used generally speaking have methylene dichloride, trichloromethane, THF, 1,4-dioxane, an acetonitrile etc.
Experiment showed, N-aryl-1 of the present invention, in the compound method of 3-oxazolidine-2-ketone compounds, preferred 1 mole of the amount ratio of described carbamate, thiazolinyl sulfonium salt, alkali, four kinds of raw materials of organic solvent: 2～4 moles: 2～8 moles: 5～15 liters; The temperature of reaction condition is 25～80 ℃; Reaction times is 12～72 hours.
Wherein, corresponding 1 moles of ammonia carbamate uses 2～4 moles thiazolinyl sulfonium salt can guarantee that another reaction substrate carbamate contact with the thiazolinyl sulfonium salt of capacity fully and reacts in entire reaction course, to improve the yield that reacts; But, too much use the thiazolinyl sulfonium salt, obviously can cause waste, insignificant increase reaction cost.It is in order to guarantee to be reflected at reaction under certain alkaline condition, to reach the purpose that speed of response is accelerated that corresponding 1 moles of ammonia carbamate uses the alkali of 2～8 times of molar weights.From the consideration that reduces cost, reduces pollution, equally should not use the more alkali of volume yet.Volume of organic solvent be according to making substrate dissolve setting fully, crosses low and speed of response that cause is slow excessively for fear of reaction density simultaneously, and the consumption of organic solvent is unsuitable excessive.
Compared with prior art, the present invention has following advantage:
1) synthetic route is direct, and reaction yield is high.3 step reactions of traditional technology were foreshortened to for 1 step carry out, the experiment proof single step productive rate ratio of Theoretical Mass (the actual product quality that obtains with) basically all reaches more than 70% for various substitution reaction substrates.
2) reaction conditions is gentle.Weak basic condition with gentle gets final product realization response.Obviously be superior to the use of highly basic in the traditional method such as butyllithium, lithium alkoxide, adopt normal-temperature reaction to substitute the low-temp reaction technology of traditional method.
3) because each reactant that relates in the reaction process is all stable to empty G&W, do not need protection of inert gas in the entire reaction course, can directly in air, react.And solvent does not need promptly can carry out through drying especially.
4) operation is simple, and the product separation and purification is easy.Reaction can be carried out through simple one kettle way in air, and product purification only needs simple washing to increase the weight of the crystalline method just can obtain the product of purity more than 95%.
5) in this method, the range of choice of organic solvent and alkali is wide in range.Common organic solvent such as THF, second eyeball, methylene dichloride, chloroform, benzene, toluene etc. can react smoothly.Alternative alkali has conventional weak base such as triethylamine, also can be organic-inorganic alkali commonly used such as DBU or sodium hydrogen.
Description of drawings
Fig. 1 is a N-aryl-1 of the present invention, the reaction mechanism figure of the compound method of 3-oxazolidine-2-ketone compounds.
Embodiment
Below in conjunction with accompanying drawing, to N-aryl-1 of the present invention, the reaction principle of the compound method of 3-oxazolidine-2-ketone compounds further specifies.
With reference to Fig. 1, the thiazolinyl sulfonium salt in this example is an example with trifluoromethanesulfonic acid-thiazolinyl sulfonium salt, and one kettle way cascade reaction of the present invention specifically mainly comprises five steps.The first step, carbamate form acid amides negative ion I under the proton abstraction of alkali; In second step, acid amides negative ion I attack has the electroactive thiazolinyl sulfonium salt reagent of strong parent, generates the sulfur ylide intermediate II; In the 3rd step, the sulfur ylide intermediate II obtains the sulfonium salt intermediate III after protonated; In the 4th step, intramolecular nucleophilic substitution reaction takes place and generates the five-membered cyclic intermediate compound IV in the sulfonium salt intermediate III; In the 5th step, the five-membered cyclic intermediate compound IV is taken off the alkyl effect and is generated final product N-aryl-1,3-oxazolidine-2-ketone.
In order to confirm the most preferably reaction conditions of compound method of the present invention; We with the most frequently used N-phenyl-urethanum and phenylbenzene-vinyl sulfonium fluoroform sulphonate as reaction substrate in differential responses temperature, differential responses time, add Different Alkali or use under the situation such as different organic solvents and successively carried out 17 experiments; In the following experiment; The consumption of each raw material is respectively: N-phenyl-urethanum 1mmol; Phenylbenzene-vinyl sulfonium fluoroform sulphonate 2mmol, various alkali are 2mmol, solvent load is 5mL.
Record the experimental data tabulation at last as follows:
| Sequence number | Alkali | Organic solvent | Temperature of reaction (℃) | Duration of the reaction (h) | Yield (%) |
| 1 | Et 3N | DCM | 0 | 24 | 23 |
| 2 | Et 3N | DCM | 10 | 24 | 38 |
| 3 | Et 3N | DCM | 25 | 24 | 61 |
| 4 | Et 3N | DCM | 35 | 24 | 71 |
| 5 | Et 3N | DCM | 45 | 24 | 70 |
| 6 | Et 3N | DCM | 60 | 24 | 73 |
| 7 | Et 3N | DCM | 80 | 24 | 72 |
| 8 | NaH | DCM | 35 | 24 | 54 |
| 9 | DBU | DCM | 35 | 24 | 59 |
| 10 | Et 3N | THF | 35 | 24 | 41 |
| 11 | Et 3N | CH 3Cl | 35 | 24 | 37 |
| 12 | Et 3N | MeCN | 35 | 24 | 51 |
| 13 | Et 3N | DCM | 35 | 6 | 38 |
| 14 | Et 3N | DCM | 35 | 12 | 65 |
| 15 | Et 3N | DCM | 35 | 48 | 72 |
| 16 | Et 3N | DCM | 35 | 72 | 74 |
| 17 | Et 3N | DCM | 35 | 96 | 74 |
Can know that based on above experimental result under the lower situation of reaction temperature, reaction yield is very low.Along with the raising of temperature of reaction, productive rate obviously promotes, when temperature of reaction is brought up to 25 ℃; Productive rate can reach more than 60%, continues to improve temperature, and the amplitude that productive rate promotes eases up; After temperature of reaction surpassed 60 ℃, it is stable that productive rate has kept basically, promotes no longer to some extent.According to the analysis of reaction principle, compound method of the present invention does not have particular requirement to alkali and organic solvent, and common organic solvent and conventional weak base all can use, and this point can obtain proof through the experimental result of experiment 8-12 basically.The experimental result of experiment 4,13-16 has embodied the relation between reaction times and the productive rate.We are not difficult to find out that in preceding 24 hours of reaction, along with the prolongation of time, product is in quick increase.After surpassing 24 hours, productive rate amplification reduces.Reach more than 72 hours, productive rate is constant basically.This shows that the best reaction times is probably between 24-72 hour.
Following examples are used to understand the present invention and prove beneficial effect of the present invention, but are not to qualification of the present invention.
Embodiment 1
Take by weighing 1mmolN-phenyl-urethanum, 2mmol trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt in the little flask of 25mL, add 2mmol triethylamine and 5mL methylene dichloride, stirred 24 hours down at 35 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer merges organic layer after 10mL ETHYLE ACETATE washing 2 times, dry back solvent evaporated; ETHYLE ACETATE and sherwood oil recrystallization obtain product N-phenyl-1,3-oxazolidine-2-ketone 116mg.Calculating this reaction yield with the ratio of theoretical yield 163mg is 71%.Reaction equation is shown in the following figure:
Product is tested through nucleus magnetic resonance, obtains its nuclear magnetic resonance data and is:
1H NMR (400MHz, CDCl
3, TMS) δ 7.51 (d, J=8.0Hz, 2H), 7.36 (t, J=8.0Hz, 2H), 7.12 (t, J=7.4Hz, 1H), 4.42 (t, J=8.0Hz, 2H), 3.99 (t, J=8.0Hz, 2H);
13C NMR (100MHz, CDCl
3) δ 155.3,138.3,129.1,124.1,118.2,61.3, the 45.2. product is tested through high resolution mass spectrum, obtains its mass-spectrometric data and is: HRMS (EI) Calcd for C
9H
9NO
2: [M]
+163.0633; Found, 163.0627.
Embodiment 2
Take by weighing 1mmolN-p-nitrophenyl-Urethylane, 2mmol trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt in the little flask of 25mL, add 2mmol triethylamine and 5mL methylene dichloride, stirred 12 hours down at 25 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer merges organic layer after 10mL ETHYLE ACETATE washing 2 times, dry back solvent evaporated; ETHYLE ACETATE and sherwood oil recrystallization obtain product N-p-nitrophenyl-1; 3-oxazolidine-2-ketone 154mg, theoretical yield 208mg, calculating productive rate is 74%.Reaction equation is shown in the following figure:
The product nuclear magnetic resonance data is:
1H NMR (400MHz, CDCl
3, TMS) δ 8.26 (d, J=9.2Hz, 2H), 7.74 (d, J=9.2Hz, 2H), 4.57 (t, J=7.8Hz, 2H), 4.16 (t, J=8.0Hz, 2H);
13C NMR (100MHz, CDCl
3) δ 154.6,143.8,143.3,125.0,117.4,61.4,44.9. high resolution mass spectrum characterization data is: HRMS (EI) Calcd forC
9H
8N
2O
4: [M]
+208.0484; Found, 208.0477.
Embodiment 3
Take by weighing 1mmolN-rubigan-t-butyl carbamate, 3mmol trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt in the little flask of 25mL, add sodium hydride 144mg and 10mL methylene dichloride, stirred 12 hours down at 45 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer is after 10mL ETHYLE ACETATE washing 2 times; Merge organic layer, dry back solvent evaporated, ETHYLE ACETATE and sherwood oil recrystallization obtain product N-rubigan-1; 3-oxazolidine-2-ketone 167mg calculates productive rate 85% according to theoretical yield 197mg.Reaction equation such as figure below:
Product nucleus magnetic resonance characterization data is:
1H NMR (400MHz, CDCl
3, TMS) δ 7.49 (d, J=9.6Hz, 2H), 7.33 (d, J=9.2Hz, 2H), 4.48 (t, J=8.0Hz, 2H), 4.03 (t, J=7.8Hz, 2H);
13C NMR (100MHz, CDCl
3) δ 155.1,136.9,129.3,129.1,119.4,61.3. high resolution mass spectrum characterization data is: HRMS (EI) Calcd forC
9H
8ClNO
2: [M]
+197.0244; Found, 197.0242.
Embodiment 4
Take by weighing 1mmolN-p-methoxyphenyl-urethanum, 3mmol trifluoromethanesulfonic acid-dimethyl-vinyl sulfonium salt in the little flask of 25mL, add triethylamine 6mmol and 10mL THF, stirred 60 hours down at 45 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer is after 10mL ETHYLE ACETATE washing 2 times; Merge organic layer, dry back solvent evaporated, ETHYLE ACETATE and sherwood oil recrystallization obtain product N-p-methoxyphenyl-1; 3-oxazolidine-2-ketone 101mg calculates productive rate 52% according to theoretical yield 193mg.Reaction equation such as figure below:
Product nucleus magnetic resonance characterization data is:
1H NMR (400MHz, CDCl
3, TMS) δ 7.43 (d, J=9.6Hz, 2H), 6.91 (d, J=9.6Hz, 2H), 4.50 (t, J=8.0Hz, 2H), 4.01 (t, J=7.8Hz, 2H), 3.79 (s, 3H);
13C NMR (100MHz, CDCl
3) δ 156.4,156.6,131.5,120.3,114.3,61.4,55.5,45.7. high resolution mass spectrum characterization data is: HRMS (EI) Calcd for C
10H
11NO
3: [M]
+193.0739; Found, 193.0736.
Embodiment 5
Take by weighing 1mmolN-m-nitro base-benzyl carbamate, 3mmol trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt in the little flask of 25mL, add sodium hydrogen 144mg and 15mL dioxane, stirred 12 hours down at 80 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer is after 10mL ETHYLE ACETATE washing 2 times; Merge organic layer, dry back solvent evaporated, ETHYLE ACETATE and sherwood oil recrystallization obtain product N-m-nitro base-1; 3-oxazolidine-2-ketone 172mg, calculating productive rate according to theoretical yield 208mg is 83%.Reaction equation such as figure below:
Product nucleus magnetic resonance characterization data is:
1H NMR (400MHz, CDCl
3, TMS) δ 8.24 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.99 (d, J=8.0Hz, 1H), 7.56 (t, J=8.2Hz, 1H), 4.56 (t, J=8.0Hz, 2H), 4.15 (t, J=8.0Hz, 2H);
13C NMR (100MHz, CDCl
3) δ 154.9,148.6,139.5,130.0,123.9,118.6,112.3,61.4,45.0. high resolution mass spectrum characterization data is: HRMS (EI) Calcd for C
9H
8N
2O
4: [M]
+208.0484; Found, 208.0477.
Embodiment 6
Take by weighing aminomethyl phenyl-urethanum between 1mmolN-, 4mmol trifluoromethanesulfonic acid-dimethyl-vinyl sulfonium salt in the little flask of 25mL, add triethylamine 8mmol and 15mL trichloromethane, stirred 72 hours down at 60 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer is after 10mL ETHYLE ACETATE washing 2 times; Merge organic layer, dry back solvent evaporated, ETHYLE ACETATE and sherwood oil recrystallization obtain aminomethyl phenyl between product N--1; 3-oxazolidine-2-ketone 82mg, calculating productive rate according to theoretical yield 177mg is 46%.Reaction equation is as scheming:
Product nucleus magnetic resonance characterization data is:
1H NMR (400MHz, CDCl
3, TMS) δ 7.37 (s, 1H), 7.30 (d, J=9.2Hz, 1H), 7.25 (t, J=7.8Hz, 1H), 6.95 (d, J=7.6Hz, 1H), 4.43 (t, J=8.0Hz, 2H), 4.01 (t, J=8.0Hz, 2H), 2.36 (s, 3H);
13C NMR (100MHz, CDCl
3) δ 155.4,139.0,138.2,128.9,124.9,119.0,115.4,61.4,45.3,21.7. high resolution mass spectrum characterization data is: HRMS (EI) Calcd for C
10H
11NO
2: [M]
+177.0790; Found, 177.0786.
Embodiment 7
Take by weighing 1mmolN-ortho-nitrophenyl base-benzyl carbamate, 2mmol trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt in the little flask of 25mL, add triethylamine 2mmol and 5mL methylene dichloride, stirred 24 hours down at 35 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer is after 10mL ETHYLE ACETATE washing 2 times; Merge organic layer, dry back solvent evaporated, ETHYLE ACETATE and sherwood oil recrystallization obtain product N-ortho-nitrophenyl base-1; 3-oxazolidine-2-ketone 131mg calculates productive rate 63% according to theoretical yield 208mg.Reaction equation is as scheming:
Product nucleus magnetic resonance characterization data is:
1H NMR (400MHz, CDCl
3, TMS) δ 8.02 (dd, J=8.0Hz, 1H), 7.67 (t, J=7.6Hz, 1H), 7.46 (m, 2H), 4.59 (t, J=8.0Hz, 2H), 4.10 (t, J=7.8Hz, 2H);
13C NMR (100MHz, CDCl
3) δ 156.2,145.6,133.9,131.4,128.1,125.9,62.9,47.4. high resolution mass spectrum characterization data is: HRMS (EI) Calcd for C
9H
8N
2O
4: [M]
+208.0484; Found, 208.0477.
Embodiment 8
Take by weighing 1mmolN-o-methoxyphenyl-urethanum, 4mmol trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt in the little flask of 25mL, add DBU8mmol and 15mL methylene dichloride, stirred 72 hours down at 45 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer is after 10mL ETHYLE ACETATE washing 2 times; Merge organic layer, dry back solvent evaporated, ETHYLE ACETATE and sherwood oil recrystallization obtain product N-o-methoxyphenyl-1; 3-oxazolidine-2-ketone 87mg calculates productive rate 45% according to theoretical yield 193mg.Reaction equation is:
The nucleus magnetic resonance characterization data is:
1H NMR (400MHz, CDCl
3, TMS) δ 7.36 (dd, J=8.0Hz, 1H), 7.29 (t, J=9.2Hz, 1H), 6.98 (m, 2H), 4.49 (t, J=8.2Hz, 2H), 3.99 (t, J=8.2Hz, 2H), 3.87 (s, 3H);
13CNMR (100MHz, CDCl
3) δ 157.4,154.9,128.9,128.4,126.1,121.0,112.0,62.5,55.7,47.0. high resolution mass spectrum characterization data is: HRMS (EI) Calcd for C
10H
11NO
3: [M]
+193.0739; Found, 193.0736.
Embodiment 9
Take by weighing 1mmolN-4-pyridyl-t-butyl carbamate, 2mmol trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt in the little flask of 25mL, add triethylamine 2mmol and 5mL acetonitrile, stirred 24 hours down at 80 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer is after 10mL ETHYLE ACETATE washing 2 times; Merge organic layer, dry back solvent evaporated, ETHYLE ACETATE and sherwood oil recrystallization obtain product N-(4-pyridyl)-1; 3-oxazolidine-2-ketone 146mg, calculating its productive rate according to theoretical yield 164mg is 89%.Reaction formula is as scheming:
Product nucleus magnetic resonance characterization data is:
1H NMR (400MHz, CDCl
3, TMS) δ 8.55 (d, J=5.6Hz, 2H), 7.49 (d, J=6.0Hz, 2H), 4.55 (t, J=7.8Hz, 2H), 4.07 (t, J=8.2Hz, 2H);
13C NMR (100MHz, CDCl
3) δ 154.5,150.6,145.0,111.7,61.6,44.0. high resolution mass spectrum characterization data is: HRMS (EI) Calcd forC
8H
8N
2O
2: [M]
+164.0586; Found, 164.0580.
Embodiment 10
Take by weighing 1mmolN-3-pyridyl-urethanum, 2mmol trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt in the little flask of 25mL, add triethylamine 4mmol and 5mL methylene dichloride, stirred 24 hours down at 45 ℃.Reaction is revolved dried solvent after finishing, and adds entry 10mL and ETHYLE ACETATE 10mL, separates organic layer; Water layer is after 10mL ETHYLE ACETATE washing 2 times; Merge organic layer, dry back solvent evaporated, ETHYLE ACETATE and sherwood oil recrystallization obtain product N-(3-pyridyl)-1; 3-oxazolidine-2-ketone 69mg, calculating its productive rate according to theoretical yield 171mg is 40%.Reaction formula is following:
Product nucleus magnetic resonance characterization data is:
1H NMR (400MHz, CDCl
3, TMS) δ 6.03 (d, J=1.2Hz, 1H), 5.64 (d, J=0.8Hz, 1H), 4.41 (t, J=7.8Hz, 2H), 3.88 (t, J=8.0Hz, 2H), 3.80 (s, 3H);
13C NMR (100MHz, CDCl
3) δ 163.6,156.1,134.7,117.7,62.4,52.7,45.8. high resolution mass spectrum characterization data is: HRMS (EI) Calcd for C
7H
9NO
4: [M]
+171.0532; Found, 171.0535.
Through above experiment, proved the feasibility and the eurytropy of compound method of the present invention.The present invention all can be suitable for for substituted carbamate of all kinds and thiazolinyl sulfonium salt, through the reaction of gentleness and easily purifying just obtain the good yield and the title product of purity, shown good application potential and value.
Claims (10)
1. N-aryl-1, the compound method of 3-oxazolidine-2-ketone compounds is characterized in that; Adopt N-aryl-carbamate and thiazolinyl sulfonium salt under alkaline condition; One pot of cascade reaction takes place in organic solvent, obtains N-aryl 1,3-oxazolidine-2-ketone compounds.
2. a kind of N-aryl-1 according to claim 1; The compound method of 3-oxazolidine-2-ketone compounds; It is characterized in that described N-aryl-carbamate, thiazolinyl sulfonium salt, alkali, the amount ratio of four kinds of raw materials of organic solvent in reaction are 1 mole: 2～4 moles: 2～8 moles: 5～15 liters; The temperature of reaction condition is 25～80 ℃; Reaction times is 12～72 hours.
3. a kind of N-aryl-1 according to claim 1; The compound method of 3-oxazolidine-2-ketone compounds; It is characterized in that described N-aryl-carbamate is N-arylamino methyl-formiate, N-arylamino ethyl formate, N-arylamino t-butyl formate or N-arylamino benzyl formate; Described thiazolinyl sulfonium salt is trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt or trifluoromethanesulfonic acid-dimethyl-vinyl sulfonium salt; Described alkali be under the unit concentration normal temperature pH value between 7 to 14 organic bases or mineral alkali; Said organic solvent is for can make the consoluet various organic solvents of substrate at normal temperatures.
4. a kind of N-aryl-1 according to claim 3; The compound method of 3-oxazolidine-2-ketone compounds; It is characterized in that; Described alkali is a kind of in triethylamine, DBU and the sodium hydride, and organic solvent is methylene dichloride, trichloromethane, THF, 1, one or both mixing in 4-dioxane, the acetonitrile.
5. N-phenyl-1; The compound method of 3-oxazolidine-2-ketone; It is characterized in that; With amount ratio is 1 mole: 2 moles: 2 moles: N-phenyl-urethanum of 5 liters, trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt, triethylamine, methylene dichloride place reactor drum, stir 24 hours down at 35 ℃; Reaction is revolved dried solvent after finishing, and adds entry and ETHYLE ACETATE, separates organic layer, and water layer merges organic layer after ETHYLE ACETATE washing 2 times, and dry back solvent evaporated obtains product with ETHYLE ACETATE and sherwood oil recrystallization.
6. N-p-nitrophenyl-1; The compound method of 3-oxazolidine-2-ketone; It is characterized in that; With amount ratio is 1 mole: 2 moles: 2 moles: N-p-nitrophenyl-Urethylane of 5 liters, trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt, triethylamine, methylene dichloride place reactor drum, stir 12 hours down at 25 ℃; Reaction is revolved dried solvent after finishing, and adds entry and ETHYLE ACETATE, separates organic layer, and water layer merges organic layer after ETHYLE ACETATE washing 2 times, and dry back solvent evaporated obtains product with ETHYLE ACETATE and sherwood oil recrystallization.
7. N-rubigan-1; The compound method of 3-oxazolidine-2-ketone; It is characterized in that; With amount ratio is 1 mole: 3 moles: 144 grams: N-rubigan-t-butyl carbamate of 10 liters, trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt, sodium hydride, methylene dichloride place reactor drum, stir 12 hours down at 45 ℃; Reaction is revolved dried solvent after finishing, and adds entry and ETHYLE ACETATE, separates organic layer, and water layer merges organic layer after ETHYLE ACETATE washing 2 times, dry back solvent evaporated, and ETHYLE ACETATE and sherwood oil recrystallization obtain product.
8. N-p-methoxyphenyl-1; The compound method of 3-oxazolidine-2-ketone; It is characterized in that; With amount ratio is 1 mole: 3 moles: 6 moles: N-p-methoxyphenyl-urethanum of 10 liters, trifluoromethanesulfonic acid-dimethyl-vinyl sulfonium salt, triethylamine, THF place reactor drum, stir 60 hours down at 45 ℃; Reaction is revolved dried solvent after finishing, and adds entry and ETHYLE ACETATE, separates organic layer, and water layer merges organic layer after ETHYLE ACETATE washing 2 times, dry back solvent evaporated, and ETHYLE ACETATE and sherwood oil recrystallization obtain product.
9. N-m-nitro base-1; The compound method of 3-oxazolidine-2-ketone; It is characterized in that; With amount ratio is 1 mole: 3 moles: 144 grams: N-m-nitro base-benzyl carbamate of 15 liters, trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt, sodium hydrogen, dioxane place reactor drum, stir 12 hours down at 80 ℃; Reaction is revolved dried solvent after finishing, and adds entry and ETHYLE ACETATE, separates organic layer, and water layer merges organic layer after ETHYLE ACETATE washing 2 times, dry back solvent evaporated, and ETHYLE ACETATE and sherwood oil recrystallization obtain product.
10. a N-(4-pyridyl)-1; The compound method of 3-oxazolidine-2-ketone; It is characterized in that; With amount ratio is 1 mole: 2 moles: 2 moles: 5 liters N-(4-pyridyl)-t-butyl carbamate, trifluoromethanesulfonic acid-diphenylacetylene sulfonium salt, triethylamine, acetonitrile place reactor drum, stir 24 hours down at 80 ℃; Reaction is revolved dried solvent after finishing, and adds entry and ETHYLE ACETATE, separates organic layer, and water layer merges organic layer after ETHYLE ACETATE washing 2 times, dry back solvent evaporated, and ETHYLE ACETATE and sherwood oil recrystallization obtain product.
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