CN104788370A - Configuration-controllable method for synthesizing 2-(4-nitryl) butyryl pyridine nitrogen-oxygen compounds - Google Patents
Configuration-controllable method for synthesizing 2-(4-nitryl) butyryl pyridine nitrogen-oxygen compounds Download PDFInfo
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Abstract
The invention relates to a configuration-controllable method for synthesizing a 2-(4-nitryl) butyryl pyridine nitrogen-oxygen compounds. The method comprises the following steps of (1), respectively adding a 2-enoyl pyridine nitrogen-oxygen compound and nitromethane or analogues thereof into a chiral copper complex catalytic system or a chiral scandium complex catalytic system, and reacting at room temperature; and (2), separating and purifying reacted solution so as to obtain the 2-(4-nitryl) butyryl pyridine nitrogen-oxygen compounds with contrary configurations.
Description
Technical field
The invention belongs to methodology of organic synthesis field, refer to that a kind of configuration controllably synthesizes the method for 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen compound especially.
Background technology
Asymmetric synthesis research is key method and the means of chiral material creation, it is one of chemical research field of enlivening the most, the chiral medicinal of it and human health, agricultural chemicals, spices, essence, the association area such as foodstuff additive and several functions material are closely related, have important theory significance and application prospect.
Michael addition as a kind of effective ways building C-C key, has the feature of Atom economy in organic synthesis.2-enoyl-pyridine nitrogen-oxygen compound; because lone-pair electron on its nitrogen-oxygen and ketonic oxygen exist, the product of enantioselectivity can be synthesized as a kind of substrate of bidentate coordination and chiral metal catalyst coordination, be subject to extensive concern (Chem.Rev.2014 in recent years; 114,6081.).2-enoyl-pyridine nitrogen-oxygen compound is used for asymmetric synthesis as substrate, and there are reports.Such as,
group and Pedro group use it for asymmetric Diels-Alder and react (J.Org.Chem.2007,72,240; Org.Lett.2007,9,1983.), Singh group uses it for asymmetric Friedel-Crafts and reacts (Org.Lett.2008,10,4121; Org.Lett.2010,12,80.), Pedro group uses it for 1,3-dipole-diople interaction, and the groups such as Singh and Faita use it for asymmetric Michael addition (Org.Lett.2011,13,5812; Chem.Eur.J.2012,18,11662; J.Org.Chem.2012,77,8802; Adv.Synth.Catal.2013,355,383; Org.Biomol.Chem.2013,11,2412; Chem.Rev.2014,114,6081).But the Michael addition of 2-enoyl-pyridine nitrogen-oxygen compound and Nitromethane 99Min. or its analogue is not also reported so far.
The Michael addition of 2-enoyl-pyridine nitrogen-oxygen compound and Nitromethane 99Min. or its analogue can obtain 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen compound, it can obtain bioactive dihydro pyrrole derivates through simple reductive cyclization under NH4Cl/Zn exists, it is also the analogue (Annu.Rep.Med.Chem.1995 of natural product nicotine compound, 30,41; Eur.J.Pharmacol.2007,563,18; Pharmacol.Res.2014,83,20).
Summary of the invention
The present invention has developed the Michael addition of 2 kinds of catalyst system catalysis 2-enoyl-pyridine nitrogen-oxygen compounds and Nitromethane 99Min. or its analogue, be high enantioselectivity synthesize the method for different configuration 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen.
Particularly, the present invention includes following aspect:
The invention provides a kind of method that configuration controllably synthesizes 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen compound, said method comprising the steps of:
1) 2-enoyl-pyridine nitrogen-oxygen compounds and Nitromethane 99Min. or its analogue are added in chiral copper complex catalyst system or the complex-catalyzed system of chirality scandium respectively, at room temperature react;
2) solution separating after having reacted is purified obtain contrary 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen of configuration.
In a preferred embodiment, the structural formula of described 2-enoyl-pyridine nitrogen-oxygen compounds is (E)-C
5h
4nO-C (O)-CH
2=CH-R, wherein R is selected from the group be made up of the following: phenyl, ethenylphenyl, 1-naphthyl, 2-thienyl, 2-furyl, 2-fluorophenyl, 2-chloro-phenyl-, 2-bromophenyl, 2-naphthyl, 3-aminomethyl phenyl, 3-p-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chloro-phenyl-, 3-bromophenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, cyclopentyl, cyclohexyl.
In a preferred embodiment; described 2-enoyl-pyridine nitrogen-oxygen compounds can be selected from 2-cinnamoyl pyridine nitrogen-oxygen; (E)-2 (between 3-chloro-phenyl-) acryl pyridine nitrogen-oxygen; (E)-2 (3-p-trifluoromethyl phenyl) acryl pyridine nitrogen-oxygen; (E)-2 (3-is to bromophenyl) acryl pyridine nitrogen-oxygen, (E)-2 (3-m-methoxyphenyl) acryl pyridine nitrogen-oxygen.
In a preferred embodiment, described Nitromethane 99Min. analogue is selected from nitroethane, ethyl nitroacetate.
In a preferred embodiment, described chiral copper complex catalyst system be by mantoquita, alkaline carbonate and ligand L 1 with the molar weight of material than 1:1:1 in a solvent under nitrogen protection stirring at room temperature react be prepared from.
In a preferred embodiment, described mantoquita is selected from copper trifluoromethanesulfcomposite, cupric bromide, neutralized verdigris, is preferably copper trifluoromethanesulfcomposite; Described alkaline carbonate is selected from sodium carbonate, salt of wormwood and cesium carbonate, is preferably cesium carbonate; Described ligand L 1 structural formula is:
Described solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, is preferably toluene.
In a preferred embodiment, the complex-catalyzed system of described chirality scandium is prepared from than stirring at room temperature reaction under 1:1:1 in a solvent nitrogen protection with the molar weight of material by trifluoromethanesulfonic acid scandium, alkaline carbonate and ligand L 2.
In a preferred embodiment, described alkaline carbonate is selected from sodium carbonate, salt of wormwood and cesium carbonate, is preferably cesium carbonate; Described ligand L 2 structural formula is:
Described solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, is preferably tetrahydrofuran (THF).
In a preferred embodiment, the synthetic route of described ligand L 2 is as follows:
In a preferred embodiment, described 2-enoyl-pyridine nitrogen-oxygen compounds compares 10:1-20:1 with the amount of substance of chiral copper complex or chirality scandium title complex; The initial concentration of described 2-enoyl-pyridine nitrogen-oxygen compounds is 0.2-0.3mol/L; Described Nitromethane 99Min. and the solvent volume in catalyst system are than being 1/3-1/5.
In a preferred embodiment, described separating-purifying mode comprises post layer chromatography, liquid chromatography, distillation, recrystallization, preferred post layer chromatography.
In a preferred embodiment, the eluent that described post layer chromatography is separated is ethyl acetate/petroleum ether mixed solvent.
The invention has the beneficial effects as follows:
1. developed the asymmetric Michael reaction of 2-enoyl-pyridine nitrogen-oxygen compounds and Nitromethane 99Min..
2. develop the product that two different these reactions of catalyst system catalysis can obtain two kinds of different configurations high enantioselectivity, thus can controllably synthesize 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen compound by configuration.
3. product 2-(4-nitro) the butyryl radicals pyridine nitrogen obtained-oxygen compounds can obtain having bioactive pyrrolin compound through simple reduction.
Note: abbreviation contrast in the application's book:
-Cbz: carbobenzoxy-(Cbz); NMM:N-methylmorpholine; HOBT:1-hydroxybenzotriazole; EDCI:1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride; DMF:N, dinethylformamide; DCM: methylene dichloride.
Accompanying drawing explanation
Fig. 1, ligand L 2
1h NMR;
Fig. 2, ligand L 2
13c NMR;
Fig. 3, embodiment 1 and 2 products therefrom
1h NMR;
Fig. 4, embodiment 1 and 2 products therefrom
13c NMR;
Fig. 5, embodiment 3 and 4 products therefrom
1h NMR;
Fig. 6, embodiment 3 and 4 products therefrom
13c NMR;
Fig. 7, embodiment 5 and 6 products therefrom
1h NMR;
Fig. 8, embodiment 5 and 6 products therefrom
13c NMR;
Fig. 9, embodiment 7 and 8 products therefrom
1h NMR;
Figure 10, embodiment 7 and 8 products therefrom
13c NMR;
Figure 11, embodiment 9 products therefrom
1h NMR;
Figure 12, embodiment 9 products therefrom
13c NMR;
Figure 13, the X-ray diffraction single crystal structure figure of embodiment 9 products therefrom.
Embodiment
Embodiments of the invention are described below in detail, the nuclear magnetic spectrogram of described embodiment and the X-ray diffraction single crystal structure of corresponding product shown in the drawings.
A kind of configuration controllably synthesizes the method for 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen, comprises the following steps:
1) chiral copper complex catalyst system and the complex-catalyzed system of chirality scandium is prepared.
Described chiral copper complex catalyst system is by copper trifluoromethanesulfcomposite, cesium carbonate and ligand L 1 with the molar weight of material than for 1:1:1 in toluene under nitrogen protection stirring at room temperature reaction 2h be prepared from; Catalyzer is 1/10 with the molar weight ratio of the material of reactant 2-enoyl-pyridine nitrogen-oxygen; The amount of toluene is 0.25mol/L making the starting point concentration of reactant 2 – enoyl-Bi Ding Dan – oxygen compound.
The complex-catalyzed system of described chirality scandium is by trifluoromethanesulfonic acid scandium, cesium carbonate and ligand L 2 with amount of substance than for 1:1:1 in toluene under nitrogen protection stirring at room temperature reaction 2h be prepared from; Catalyzer is 1/10 with the amount of substance ratio of reactant 2-enoyl-pyridine nitrogen-oxygen; The amount of toluene is 0.25mol/L making the starting point concentration of reactant 2-enoyl-pyridine nitrogen-oxygen.
Described ligand L 2 is obtained by reacting compound 1 by N-carbobenzoxy-(Cbz) phenylalanine and 1,3-diaminopropanes, and then compound 1 is at Pd/C, H
2be obtained by reacting compound 2 under effect, then compound 2 and 2-hydroxyl-3-trifluoromethyl-benzaldehyde are obtained by reacting ligand L 2.
2) 2 – enoyl-Bi Ding Dan – oxygen compounds and Nitromethane 99Min. or its analogue are joined in two kinds of catalyzer respectively, at room temperature react.
The structural formula of described 2 – enoyl-Bi Ding Dan – oxygen compounds is (E)-C
5h
4nO-C (O)-CH
2=CH-R, wherein R is selected from the group be made up of the following: phenyl, ethenylphenyl, 1-naphthyl, 2-thienyl, 2-furyl, 2-fluorophenyl, 2-chloro-phenyl-, 2-bromophenyl, 2-naphthyl, 3-aminomethyl phenyl, 3-p-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chloro-phenyl-, 3-bromophenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, cyclopentyl, cyclohexyl.
Described Nitromethane 99Min. similar structures substrate comprises nitroethane, ethyl nitroacetate.
2 – enoyl-Bi Ding Dan – oxygen starting point concentration is in the solution 0.25mol/L, and in Nitromethane 99Min. or its similar structures substrate and catalyst system, the volume ratio of solvent is 1/3.
3) solution separating after having reacted is purified obtain contrary 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen of configuration.
Be spin-dried under vacuo by solution after having reacted, post crossed by residue silica gel, crosses post by ethyl acetate/petroleum ether system as eluent from volume ratio 1/1-3/1; The eluent selected in this application is ethyl acetate/petroleum ether mixed solvent, and this is not the requirement of other eluent system with regard to not being the application, as long as the reagent meeting wash-out object all can use.
Reaction equation is:
The application achieves Nitromethane 99Min. or its analogue first to the asymmetric Michael reaction of 2-enoyl-pyridine nitrogen-oxygen compound, and discovery chiral copper complex catalyst system and the complex-catalyzed system of chirality scandium respectively this reaction of catalysis can obtain the product of 2 kinds of different configurations.Used catalyst is easy to preparation, this method be high enantioselectivity synthesize the method for 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen compound of different configuration.
Below the concrete synthesis step of the part of the application and the specific embodiment of synthesis 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen compound; all reagent used in an embodiment are the analytical reagent directly bought; except THF heavily steams, other processes without other before using.Reagent source: all solvents, an alkali metal salt and Nitromethane 99Min. are all purchased from traditional Chinese medicines, copper trifluoromethanesulfcomposite and trifluoromethanesulfonic acid scandium etc. are purchased from splendid splendid scientific and technological (Shanghai) Co., Ltd. of chemistry far away far away.
The synthesis (reference: Chem.Eur.J.2011,17,1114.) of ligand L 1
The synthesis of ligand L 2:
N-carbobenzoxy-(Cbz) phenylalanine (7.5mmol is added in the round-bottomed flask of a 100mL, 2.245g), DMF (50mL) is cooled to 0 DEG C, add NMM (24.0mmol successively wherein again, 2.7mL), HOBT (8.3mmol, 1.114g), EDCI (8.3mmol, 1.582g).After 30min, add 1,3-diaminopropanes (3mmol) wherein at room temperature reaction 10h.Reacted solution is poured in frozen water, has a large amount of white precipitate to separate out.Suction filtration obtains white solid precipitation, then uses 1M HCl (50mL) successively, water (50mL), 1M NaOH (50mL), water (50mL), and ethanol (5mL) washing of precooling obtains compound 1.
In 100mL round-bottomed flask, add compound 1 (2mmol), 10%Pd/C (0.2mmol), methyl alcohol (30mL), at the H of 1atm
2middle reaction 24h, filters reacted mixture, filtrate is spin-dried for, and carries out column chromatography for separation obtain compound 2 with silica gel.
In 50mL round-bottomed flask, add compound 2 (2mmol), 2-hydroxyl 3-trifluoromethylated benzaldehyde (4.4mmol), magnesium sulfate (2g), methylene dichloride (20mL), after reaction 24h, filter to get filtrate, be spin-dried for and carry out column chromatography for separation with silica gel and obtain ligand L 2 (productive rate of 95%) (Fig. 1 and 2).
1H NMR(400MHz,CDCl
3)δ13.49(s,2H),7.96(s,2H),7.63-7.61(d,2H),7.30-7.12(m,12H),6.94-6.90(m,2H),6.76(d,2H),4.08-4.05(q,2H),3.44-3.39(m,2H),3.02-3.18(d,4H),3.08-3.03(q,2H),1.60-1.59(m,2H)；
13CNMR(100MHz,CDCl
3)δ170.7,166.7,159.1,136.7,135.6,130.3,130.2,130.2,129.6,128.5,126.9,124.8-122.1(q,J＝270.6Hz),119.1,118.1,117.9,75.3,40.7,35.7,29.3；IR(film,ν/cm
-1):3894,3796,3667,3642,3061,2924,1859,1666,1535,1450,1331,1121,876,843,752；HRMS(ESI)m/z calcd forC
37H
34F
6N
4O
4[M+H]
+713.2562,found 713.2561.
Embodiment 1:(S) synthesis of-2-(3-phenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound
Copper trifluoromethanesulfcomposite (10.9mg, 0.03mmol) is added, ligand L 1 (12.8mg in a 10mL reaction tubes; 0.03mmol); cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add 2-cinnamoyl pyridine nitrogen-oxygen compound 1a (67.6mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained and cross as eluent product (S)-2-(3-phenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3a (70.4mg that chromatographic column obtains yellow oily; 89%yield, 95%ee).(Fig. 3, Fig. 4)
1H NMR(400MHz,CDCl
3，ppm):δ8.17-8.16(d,J＝6.4Hz,1H),7.51-7.49(dd,J＝7.8Hz,1.8Hz,1H),7.37-7.21(m,7H),4.80-4.75(dd,J＝12.6Hz,6.6Hz,1H),4.70-4.65(dd,J＝12.6Hz,8.6Hz,1H),4.26-4.20(m,1H),3.72-3.70(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ194.5,145.9,140.4,138.7,128.8,128.2,127.7,127.4,126.8,125.7,79.5,45.8,39.4；IR(film,ν/cm
-1):3850,3813,3732,3626,3586,3360,3030,2922,2297,1940,1842,1682,1549,1429,1296,1179,1030,854,766,669；HRMS(ESI)m/zcalcd for C
15H
14N
2O
4[M+Na]
+309.0851,found 309.0851.
Embodiment 2:(R) synthesis of-2-(3-phenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound adds trifluoromethanesulfonic acid scandium (14.8mg in a 10mL reaction tubes; 0.03mmol); ligand L 2 (1.4mg; 0.03mmol); cesium carbonate (9.8mg; 0.03mmol) with solvent THF (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add 2-cinnamoyl pyridine nitrogen-oxygen compound 1a (67.6mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained and cross as eluent product (R)-2-(3-phenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3a (76.4mg that post obtains yellow oily; 89%yield, 95%ee).(Fig. 3, Fig. 4)
1H NMR(400MHz,CDCl
3，ppm):δ8.17-8.16(d,J＝6.4Hz,1H),7.51-7.49(dd,J＝7.8Hz,1.8Hz,1H),7.37-7.21(m,7H),4.80-4.75(dd,J＝12.6Hz,6.6Hz,1H),4.70-4.65(dd,J＝12.6Hz,8.6Hz,1H),4.26-4.20(m,1H),3.72-3.70(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ194.5,145.9,140.4,138.7,128.8,128.2,127.7,127.4,126.8,125.7,79.5,45.8,39.4；IR(film,ν/cm
-1):3850,3813,3732,3626,3586,3360,3030,2922,2297,1940,1842,1682,1549,1429,1296,1179,1030,854,766,669；HRMS(ESI)m/zcalcd for C
15H
14N
2O
4[M+Na]
+309.0851,found 309.0851.
Embodiment 3:(S) synthesis of-2-(between 3-chloro-phenyl--4-nitro) butyryl radicals pyridine nitrogen-oxygen compound
Copper trifluoromethanesulfcomposite (10.9mg, 0.03mmol) is added, ligand L 1 (12.8mg in a 10mL reaction tubes; 0.03mmol); cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add (E)-2 (between 3-chloro-phenyl-) acryl pyridine nitrogen-oxygen compound 1f (77.9mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained obtains yellow oily product (S)-2-(between 3-chloro-phenyl--4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3f (60.6mg as eluent rapid column chromatography; 63%yield, 90%ee).(Fig. 5, Fig. 6)
1H NMR(400MHz,CDCl
3，ppm):δ8.20-8.18(d,J＝6.4Hz,1H),7.60-7.58(dd,J＝7.8Hz,1.6Hz,1H),7.41-7.17(m,6H),4.80-4.75(dd,J＝12.8Hz,6.3Hz,1H),4.69-4.64(dd,J＝12.7Hz,8.7Hz,1H),4.25-4.18(m,1H),3.72-3.67(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ194.0,145.8,140.9,140.6,134.7,130.2,128.4,128.0,127.8,127.1,125.8,125.8,79.2,45.8,39.1；IR(film,ν/cm
-1):3792,3684,2920,1692,1599,1551,1431,1254；HRMS(ESI)m/z calcd for C
15H
13ClN
2O
4[M+Na]
+343.0462,found 343.0467.
Embodiment 4:(R) synthesis of-2-(between 3-chloro-phenyl--4-nitro) butyryl radicals pyridine nitrogen-oxygen compound
Trifluoromethanesulfonic acid scandium (14.8mg, 0.03mmol) is added, ligand L 2 (21.4mg in a 10mL reaction tubes; 0.03mmol); cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add (E)-2 (between 3-chloro-phenyl-) acryl pyridine nitrogen-oxygen compound 1f (77.9mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained obtains yellow oily product (R)-2-(between 3-chloro-phenyl--4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3f (69.3mg as eluent rapid column chromatography; 72%yield, 96%ee).(Fig. 5, Fig. 6)
1H NMR(400MHz,CDCl
3，ppm):δ8.20-8.18(d,J＝6.4Hz,1H),7.60-7.58(dd,J＝7.8Hz,1.6Hz,1H),7.41-7.17(m,6H),4.80-4.75(dd,J＝12.8Hz,6.3Hz,1H),4.69-4.64(dd,J＝12.7Hz,8.7Hz,1H),4.25-4.18(m,1H),3.72-3.67(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ194.0,145.8,140.9,140.6,134.7,130.2,128.4,128.0,127.8,127.1,125.8,125.8,79.2,45.8,39.1；IR(film,ν/cm
-1):3792,3684,2920,1692,1599,1551,1431,1254；HRMS(ESI)m/z calcd for C
15H
13ClN
2O
4[M+Na]
+343.0462,found 343.0467.
Embodiment 5:(S) synthesis of-2-(3-p-trifluoromethyl phenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound
Copper trifluoromethanesulfcomposite (10.9mg, 0.03mmol) is added, ligand L 1 (12.8mg in a 10mL reaction tubes; 0.03mmol); cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add (E)-2 (3-p-trifluoromethyl phenyl) acryl pyridine nitrogen-oxygen compound 1h (88.0mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained obtains yellow oily product (S)-2-(3-p-trifluoromethyl phenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3h (90.4mg as eluent rapid column chromatography; 85%yield, 93%ee).(Fig. 7, Fig. 8)
1H NMR(400MHz,CDCl
3，ppm):δ8.21-8.19(d,J＝6.4Hz,1H),7.62-7.59(dd,J＝7.9Hz,2.1Hz,1H),7.57-7.55(d,2H),7.44-7.28(m,4H),4.84-4.79(dd,J＝12.9Hz,6.2Hz,1H),4.73-4.68(dd,J＝12.9Hz,8.8Hz,1H),4.34-4.28(m,1H),3.82-3.69(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ193.8,145.7,143.0,140.6,130.2-129.9(q,J＝32.5Hz),128.5,128.1,127.2,125.9(d,J＝2.0Hz),125.9-125.8(d,J＝3.7Hz),125.2-122.5(q,J＝270.5Hz),79.1,45.8,39.2；IR(film,ν/cm
-1):3850,3813,3732,3645,3564,3501,3053,2920,2515,1940,1798,1730,1682,1566,1557,1433,1327,1117,1069,843,768,610；HRMS(ESI)m/z calcd for C
16H
13F
3N
2O
4[M+Na]
+377.0725,found377.0715.
Embodiment 6:(R) synthesis of-2-(3-p-trifluoromethyl phenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound adds trifluoromethanesulfonic acid scandium (14.8mg in a 10mL reaction tubes; 0.03mmol); ligand L 2 (21.4mg; 0.03mmol); cesium carbonate (9.8mg; 0.03mmol) with solvent THF (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add (E)-2 (3-p-trifluoromethyl phenyl) acryl pyridine nitrogen-oxygen compound 1h (88.0mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained obtains yellow oily product (R)-2-(3-p-trifluoromethyl phenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3h (78.7mg as eluent rapid column chromatography; 74%yield, 92%ee).(Fig. 7, Fig. 8)
1H NMR(400MHz,CDCl
3，ppm):δ8.21-8.19(d,J＝6.4Hz,1H),7.62-7.59(dd,J＝7.9Hz,2.1Hz,1H),7.57-7.55(d,2H),7.44-7.28(m,4H),4.84-4.79(dd,J＝12.9Hz,6.2Hz,1H),4.73-4.68(dd,J＝12.9Hz,8.8Hz,1H),4.34-4.28(m,1H),3.82-3.69(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ193.8,145.7,143.0,140.6,130.2-129.9(q,J＝32.5Hz),128.5,128.1,127.2,125.9(d,J＝2.0Hz),125.9-125.8(d,J＝3.7Hz),125.2-122.5(q,J＝270.5Hz),79.1,45.8,39.2；IR(film,ν/cm
-1):3850,3813,3732,3645,3564,3501,3053,2920,2515,1940,1798,1730,1682,1566,1557,1433,1327,1117,1069,843,768,610；HRMS(ESI)m/z calcd for C
16H
13F
3N
2O
4[M+Na]
+377.0725,found377.0715.
Embodiment 7:(S) synthesis of-2-(3-is to bromophenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound
Copper trifluoromethanesulfcomposite (10.9mg, 0.03mmol) is added, ligand L 1 (12.8mg in a 10mL reaction tubes; 0.03mmol); cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add (E)-2 (3-is to bromophenyl) acryl pyridine nitrogen-oxygen compound 1j (91.2mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained obtains yellow oily product (S)-2-(3-is to bromophenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3j (81.0mg as eluent rapid column chromatography; 74%yield, 91%ee).(Fig. 9, Figure 10)
1H NMR(400MHz,CDCl
3，ppm):δ8.18-8.16(d,J＝6.4Hz,1H),7.58-7.55(dd,J＝7.9Hz,2.0Hz,1H),7.43-7.15(m,6H),4.79-4.74(dd,J＝12.7Hz,6.3Hz,1H),4.68-4.62(dd,J＝12.7Hz,8.8Hz,1H),4.24-4.16(m,1H),3.76-3.64(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ194.0,145.7,140.5,137.9,131.9,129.2,128.4,127.0,125.7,121.6,79.2,45.7,38.8；IR(film,ν/cm
-1):3850,3813,3732,3645,3586,3499,3063,2920,1865,1730,1682,1634,1551,1429,1296,1011,827,768；HRMS(ESI)m/z calcd forC
15H
13BrN
2O
4[M+Na]
+386.9956,found 386.9960.
Embodiment 8:(R) synthesis of-2-(3-is to bromophenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound
Trifluoromethanesulfonic acid scandium (14.8mg, 0.03mmol) is added, ligand L 2 (21.4mg in a 10mL reaction tubes; 0.03mmol); cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add (E)-2 (3-is to bromophenyl) acryl pyridine nitrogen-oxygen compound 1j (91.2mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained and cross as eluent product (R)-2-(3-is to bromophenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3j (75.6mg that post obtains yellow oily; 69%yield, 94%ee).(Fig. 9, Figure 10)
1H NMR(400MHz,CDCl
3，ppm):δ8.18-8.16(d,J＝6.4Hz,1H),7.58-7.55(dd,J＝7.9Hz,2.0Hz,1H),7.43-7.15(m,6H),4.79-4.74(dd,J＝12.7Hz,6.3Hz,1H),4.68-4.62(dd,J＝12.7Hz,8.8Hz,1H),4.24-4.16(m,1H),3.76-3.64(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ194.0,145.7,140.5,137.9,131.9,129.2,128.4,127.0,125.7,121.6,79.2,45.7,38.8；IR(film,ν/cm
-1):3850,3813,3732,3645,3586,3499,3063,2920,1865,1730,1682,1634,1551,1429,1296,1011,827,768；HRMS(ESI)m/z calcd forC
15H
13BrN
2O
4[M+Na]
+386.9956,found 386.9960.
Embodiment 9:(R) synthesis of-2-(3-m-methoxyphenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound
Trifluoromethanesulfonic acid scandium (14.8mg, 0.03mmol) is added, ligand L 2 (21.4mg in a 10mL reaction tubes; 0.03mmol); cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL), stirring at room temperature 2h under nitrogen protection.Then in reaction tubes, add (E)-2 (3-m-methoxyphenyl) acryl pyridine nitrogen-oxygen compound 1c (76.6mg, 0.3mmol) and Nitromethane 99Min. (0.3mL) at room temperature stirring reaction.After having reacted (TLC tracing detection); be spin-dried for the residue with Ethyl acetate/petroleum ether system obtained obtains yellow oily product (R)-2-(3-m-methoxyphenyl-4-nitro) butyryl radicals pyridine nitrogen-oxygen compound 3c (78.8mg as eluent rapid column chromatography; 83%yield, 92%ee).(Figure 11, Figure 12, Figure 13)
1H NMR(400MHz,CDCl
3，ppm):δ8.19-8.18(d,J＝6.4Hz,1H),7.56-7.54(dd,J＝7.8Hz,1.6Hz,1H),7.38-7.19(m,3H),6.85-6.76(m,3H),4.78-4.73(dd,J＝12.6Hz,6.7Hz,1H),4.69-4.64(dd,J＝12.6Hz,8.4Hz,1H),4.22-4.19(m,1H),3.78(s,3H),3.73-3.70(m,2H)；
13C NMR(100MHz,CDCl
3，ppm):δ194.4,159.9,146.1,140.6,140.4,130.0,128.2,127.0,125.7,119.6,113.5,113.1,79.6,55.2,45.9,39.5；IR(film,ν/cm
-1):3850,3813,3732,3645,3586,3501,3053,2922,1682,1549,1429,1258,1152,1042,853,768,565；HRMS(ESI)m/z calcd for C
16H
16N
2O
5[M+Na]
+399.0957,found399.0956.
In other embodiment of the application; 2-enoyl-pyridine nitrogen-oxygen compound compares 10:1-20:1 with the amount of substance of chiral copper complex or chirality scandium title complex; the initial concentration of 2-enoyl-pyridine nitrogen-oxygen compounds is 0.1-0.5mol/L, and in Nitromethane 99Min. or its analogue and catalyst system, the volume ratio of solvent is 1/3-1/5.The application cannot all embodiments of limit, and representational limited embodiments only can be selected to do the explanation of the application.
Although illustrate and describe embodiments of the invention, for the ordinary skill in the art, be appreciated that and can carry out multiple change, amendment, replacement or modification to these embodiments without departing from the principles and spirit of the present invention, scope of the present invention is by claims and equivalents thereof.
Claims (10)
1. configuration controllably synthesizes a method for 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen compound, said method comprising the steps of:
1) 2-enoyl-pyridine nitrogen-oxygen compounds and Nitromethane 99Min. or its analogue are added in chiral copper complex catalyst system or the complex-catalyzed system of chirality scandium respectively, at room temperature react;
2) solution separating after having reacted is purified obtain contrary 2-(4-nitro) butyryl radicals pyridine nitrogen-oxygen of configuration.
2. method according to claim 1, the structural formula of wherein said 2-enoyl-pyridine nitrogen-oxygen compounds is (E)-C
5h
4nO-C (O)-CH
2=CH-R,
Wherein R is selected from the group be made up of the following: phenyl, ethenylphenyl, 1-naphthyl, 2-thienyl, 2-furyl, 2-fluorophenyl, 2-chloro-phenyl-, 2-bromophenyl, 2-naphthyl, 3-aminomethyl phenyl, 3-p-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chloro-phenyl-, 3-bromophenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, cyclopentyl, cyclohexyl.
3. method according to claim 1, wherein said Nitromethane 99Min. analogue is selected from nitroethane, ethyl nitroacetate.
4. method according to claim 1; wherein; described chiral copper complex catalyst system be by mantoquita, alkaline carbonate and ligand L 1 with the molar weight of material than 1:1:1 in a solvent under nitrogen protection stirring at room temperature react be prepared from, described ligand L 1 structural formula is:
5. method according to claim 4, wherein said mantoquita is selected from copper trifluoromethanesulfcomposite, cupric bromide, neutralized verdigris, is preferably copper trifluoromethanesulfcomposite; Described alkaline carbonate is selected from sodium carbonate, salt of wormwood and cesium carbonate, is preferably cesium carbonate; Described solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, is preferably toluene.
6. method according to claim 1, wherein, the complex-catalyzed system of described chirality scandium is prepared from than stirring at room temperature reaction under 1:1:1 in a solvent nitrogen protection with the molar weight of material by trifluoromethanesulfonic acid scandium, alkaline carbonate and ligand L 2;
Described ligand L 2 structural formula is:
7. according to the method described in claim 6, wherein, described alkaline carbonate is selected from sodium carbonate, salt of wormwood and cesium carbonate, is preferably cesium carbonate; Described solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, is preferably tetrahydrofuran (THF).
8. method according to claim 1, wherein, described 2-enoyl-pyridine nitrogen-oxygen compounds compares 10:1-20:1 with the amount of substance of chiral copper complex or chirality scandium title complex; The initial concentration of described 2-enoyl-pyridine nitrogen-oxygen compounds is 0.2-0.3mol/L; Described Nitromethane 99Min. and the solvent volume in catalyst system are than being 1/3-1/5.
9. method according to claim 1, wherein, described separating-purifying mode comprises post layer chromatography, liquid chromatography, distillation, recrystallization, is preferably post layer chromatography.
10. method according to claim 1, wherein, the eluent that described post layer chromatography is separated is ethyl acetate/petroleum ether mixed solvent.
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