CN104788370B - A kind of method that configuration controllably synthesizes 2 (4 nitro) bytyry N-oxide compounds - Google Patents
A kind of method that configuration controllably synthesizes 2 (4 nitro) bytyry N-oxide compounds Download PDFInfo
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Abstract
The present invention relates to a kind of method that configuration controllably synthesizes 2 (4 nitro) bytyry N-oxide compounds, comprise the following steps：1) 2 enoyl- pyridine nitrogen oxygen class compounds and nitromethane or its analog are added separately in chiral copper complex catalyst system and catalyzing or the complex-catalyzed system of chiral scandium, reacted at room temperature；2) the solution separating-purifying after the completion of reaction is obtained into 2 opposite (4 nitro) bytyry N-oxide compounds of configuration.
Description
Technical field
The invention belongs to methodology of organic synthesis field, particularly relate to a kind of configuration and controllably synthesize 2- (4- nitros) butyryl
The method of yl pyridines nitrogen-oxygen compound.
Background technology
Asymmetric syntheses research is the key method and means that chiral material is created, and is chemical research the most active field
One of, its neck related to the chiral medicinal of human health, agricultural chemicals, spices, essence, food additives and a variety of functional materials etc.
Domain is closely related, with important theory significance and application prospect.
Michael additions in organic synthesis as a kind of effective ways of structure C-C keys, the spy with Atom economy
Point.2- enoyl-s pyridine nitrogen-oxygen compound, because lone pair electrons are present on its nitrogen-oxygen and ketonic oxygen, can be used as a kind of two tooth
The substrate of coordination is coordinated the product of synthesis enantioselectivity with chiral metal catalyst, receives significant attention in recent years
(Chem.Rev.2014,114,6081.).2- enoyl-s pyridine nitrogen-oxygen compound is used for asymmetric syntheses existing one as substrate
A little reports.For example,Group and Pedro groups use it for asymmetric Diels-Alder reactions
(J.Org.Chem.2007,72,240；Org.Lett.2007,9,1983.), Singh groups use it for asymmetric
Friedel-Crafts reacts (Org.Lett.2008,10,4121；Org.Lett.2010,12,80.), Pedro groups by its
For 1,3- dipole-diople interactions, the group such as Singh and Faita uses it for asymmetric Michael additions
(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 additions of 2- enoyl-s pyridine nitrogen-oxygen compound and nitromethane or its analog do not have also so far
Report.
The Michael additions of 2- enoyl-s pyridine nitrogen-oxygen compound and nitromethane or its analog can obtain 2- (4-
Nitro) bytyry pyridine nitrogen-oxygen compound, it can obtain biology in the presence of NH4Cl/Zn by simple reductive cyclization
The dihydro pyrrole derivates of activity, it is also the analog of natural products nicotine compound
(Annu.Rep.Med.Chem.1995,30,41；Eur.J.Pharmacol.2007,563,18；Pharmacol.Res.2014,
83,20)。
The content of the invention
The present invention has developed 2 kinds of catalyst system and catalyzing catalysis 2- enoyl-s pyridine nitrogen-oxygen class compounds and nitromethane or its class
Like the Michael additions of thing, be high enantioselectivity synthesize the side of various configuration 2- (4- nitros) bytyries pyridine nitrogen-oxygen
Method.
Specifically, the present invention includes following aspect：
The present invention provides a kind of method that configuration controllably synthesizes 2- (4- nitros) bytyries pyridine nitrogen-oxygen compound, institute
The method of stating comprises the following steps：
1) 2- enoyl-s pyridine nitrogen-oxygen class compound and nitromethane or its analog are separately added into chiral copper complex
In catalyst system and catalyzing or the complex-catalyzed system of chiral scandium, react at room temperature；
2) the solution separating-purifying after the completion of reaction is obtained into opposite 2- (4- nitros) bytyries pyridine nitrogen-oxygen of configuration.
In a preferred embodiment, the structural formula of the 2- enoyl-s pyridine nitrogen-oxygen class compound be (E)-
C5H4NO-C(O)-CH2=CH-R, wherein R are selected from the group being made up of the following：Phenyl, ethenylphenyl, 1- naphthyls, 2- thiophenes
Fen base, 2- furyls, 2- fluorophenyls, 2- chlorphenyls, 2- bromophenyls, 2- naphthyls, 3- aminomethyl phenyls, 3- methoxyphenyls, 3- nitre
Base phenyl, 3- fluorophenyls, 3- chlorphenyls, 3- bromophenyls, 4- trifluoromethyls, 4- nitrobenzophenones, 4- fluorophenyls, 4- chlorobenzenes
Base, 4- bromophenyls, n-propyl, normal-butyl, n-pentyl, n-hexyl, cyclopenta, cyclohexyl.
In a preferred embodiment, the 2- enoyl-s pyridine nitrogen-oxygen class compound can be selected from 2- cinnamoyls
Yl pyridines nitrogen-oxygen, (E) -2 (chlorphenyl between 3-) acryloyl group pyridine nitrogen-oxygen, (E) -2 (3- p-trifluoromethyl phenyls) acryloyl
Yl pyridines nitrogen-oxygen, (E) -2 (3- p-bromophenyls) acryloyl group pyridine nitrogen-oxygen, (E) -2 (3- m-methoxyphenyls) acryloyl group
Pyridine nitrogen-oxygen.
In a preferred embodiment, the nitromethane analog is selected from nitroethane, ethyl nitroacetate.
In a preferred embodiment, the chiral copper complex catalyst system and catalyzing is by mantoquita, alkali carbonate
With ligand L 1 with the mole ratio 1 of material:1:1 is stirred at room temperature reaction under nitrogen protection in a solvent is prepared from.
In a preferred embodiment, the mantoquita is selected from copper trifluoromethanesulfcomposite, copper bromide, copper acetate, is preferably
Copper trifluoromethanesulfcomposite；The alkali carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate；The part
L1 structural formulas are：
The solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE), preferably toluene.
In a preferred embodiment, the complex-catalyzed system of chiral scandium is by trifluoromethanesulfonic acid scandium, alkali gold
Belong to carbonate and ligand L 2 with the mole ratio 1 of material:1:1 is stirred at room temperature reaction and is prepared under nitrogen protection in a solvent.
In a preferred embodiment, the alkali carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate, preferably
For cesium carbonate；The structural formula of ligand L 2 is：
The solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE), preferably tetrahydrofuran.
In a preferred embodiment, the synthetic route of the ligand L 2 is as follows：
In a preferred embodiment, the 2- enoyl-s pyridine nitrogen-oxygen class compound and chiral copper complex or
The amount of the material of chiral scandium complex compares 10:1-20:1；The initial concentration of the 2- enoyl-s pyridine nitrogen-oxygen class compound is
0.2-0.3mol/L；The nitromethane is 1/3-1/5 with the solvent volume ratio in catalyst system and catalyzing.
In a preferred embodiment, the separating-purifying mode includes post layer chromatography, liquid chromatogram, distillation, again
Crystallization, preferably post layer chromatography.
In a preferred embodiment, the eluant, eluent of the post layer chromatography separation mixes for ethyl acetate/petroleum ether
Solvent.
The beneficial effects of the invention are as follows：
1. develop the asymmetric Michael reaction of 2- enoyl-s pyridine nitrogen-oxygen class compound and nitromethane.
Two kinds of tripe systems can be obtained 2. having developed two different catalyst system and catalyzings and being catalyzed the reaction high enantioselectivity
The product of type, 2- (4- nitros) bytyries pyridine nitrogen-oxygen compound is controllably synthesized so as to configuration.
3. obtained product 2- (4- nitros) bytyries pyridine nitrogen-oxygen class compound can be had by simple reduction
There is the pyrrolin compound of bioactivity.
Note：Abridge and compare in this specification：
-Cbz:Benzyloxycarbonyl group；NMM:N-methylmorpholine；HOBT:I-hydroxybenzotriazole；EDCI:1- (3- dimethylaminos third
Base) -3- ethyl-carbodiimide hydrochlorides；DMF:N,N-dimethylformamide；DCM:Dichloromethane.
Brief description of the drawings
Fig. 1, ligand L 21H NMR；
Fig. 2, ligand L 213C NMR；
Fig. 3, Examples 1 and 2 products therefrom1H NMR；
Fig. 4, Examples 1 and 2 products therefrom13C NMR；
Fig. 5, the products therefrom of embodiment 3 and 41H NMR；
Fig. 6, the products therefrom of embodiment 3 and 413C NMR；
Fig. 7, the products therefrom of embodiment 5 and 61H NMR；
Fig. 8, the products therefrom of embodiment 5 and 613C NMR；
Fig. 9, the products therefrom of embodiment 7 and 81H NMR；
Figure 10, the products therefrom of embodiment 7 and 813C NMR；
Figure 11, the products therefrom of embodiment 91H NMR；
Figure 12, the products therefrom of embodiment 913C NMR；
Figure 13, the X-ray diffraction mono-crystalline structures figure of the products therefrom of embodiment 9.
Embodiment
The X-ray diffraction of embodiments of the invention, the nuclear magnetic spectrogram of the embodiment and corresponding product is described below in detail
Mono-crystalline structures are shown in the drawings.
A kind of method that configuration controllably synthesizes 2- (4- nitros) bytyries pyridine nitrogen-oxygen, comprises the following steps：
1) chiral copper complex catalyst system and catalyzing and the complex-catalyzed system of chiral scandium are prepared.
The chiral copper complex catalyst system and catalyzing is that cesium carbonate and ligand L 1 are with the mole of material by copper trifluoromethanesulfcomposite
Than for 1:1:1 is stirred at room temperature reaction 2h in toluene under nitrogen protection is prepared from；Catalyst and reactant 2- enoyl- pyridines
The mole ratio of the material of nitrogen-oxygen is 1/10；The amount of toluene makes the initial dense of 2-enoyl- of reactant pyridine nitrogen-oxygen compound
Spend for 0.25mol/L.
The complex-catalyzed system of chiral scandium be by trifluoromethanesulfonic acid scandium, cesium carbonate and ligand L 2 using the amount ratio of material as
1:1:1 is stirred at room temperature reaction 2h in toluene under nitrogen protection is prepared from；Catalyst and reactant 2- enoyl-s pyridine nitrogen-oxygen
Material amount ratio be 1/10；The amount of toluene makes the initial concentration of reactant 2- enoyl-s pyridine nitrogen-oxygen for 0.25mol/L.
The ligand L 2 is to obtain compound 1 by N- benzyloxycarbonyl groups phenylalanine and the reaction of 1,3- diaminopropanes, then
Compound 1 is in Pd/C, H2The lower reaction of effect obtains compound 2, and then compound 2 and 2- hydroxyl -3- trifluoromethyl-benzaldehydes are anti-
Ligand L 2 should be obtained.
2) 2-enoyl- pyridine nitrogen-oxygen class compound and nitromethane or its analog are added separately to two kinds of catalyst
In, react at room temperature.
The structural formula of 2-enoyl- pyridine nitrogen-oxygen class compound is (E)-C5H4NO-C(O)-CH2=CH-R, wherein R
Selected from the group being made up of the following：Phenyl, ethenylphenyl, 1- naphthyls, 2- thienyls, 2- furyls, 2- fluorophenyls, 2- chlorine
Phenyl, 2- bromophenyls, 2- naphthyls, 3- aminomethyl phenyls, 3- methoxyphenyls, 3- nitrobenzophenones, 3- fluorophenyls, 3- chlorphenyls, 3-
Bromophenyl, 4- trifluoromethyls, 4- nitrobenzophenones, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, n-propyl, normal-butyl, just
Amyl group, n-hexyl, cyclopenta, cyclohexyl.
The nitromethane similar structures substrate includes nitroethane, ethyl nitroacetate.
2-enoyl- pyridine nitrogen-the initial concentration of oxygen in the solution is 0.25mol/L, nitromethane or its similar structures bottom
The volume ratio of thing and solvent in catalyst system and catalyzing is 1/3.
3) the solution separating-purifying after the completion of reaction is obtained into opposite 2- (4- nitros) bytyries pyridine nitrogen-oxygen of configuration.
Solution after the completion of reaction is spin-dried under vacuo, residue crosses post with silica gel, uses ethyl acetate/petroleum ether system
As eluant, eluent post is crossed from volume ratio 1/1-3/1；The eluant, eluent selected in this application is that ethyl acetate/petroleum ether mixing is molten
Agent, this is not to say that other eluant, eluent systems are not just the requirement of the application, can make as long as meeting the reagent of elution purpose
With.
Reaction equation is：
The application realizes nitromethane or its analog to the asymmetric of 2- enoyl-s pyridine nitrogen-oxygen compound first
Michael additions, and it was found that be catalyzed this respectively with chiral copper complex catalyst system and catalyzing and the chiral complex-catalyzed system of scandium
Reaction can obtain the product of 2 kinds of various configurations.Used catalyst is easily prepared, the method be high enantioselectivity synthesize not
The method of 2- (4- nitros) bytyries pyridine nitrogen-oxygen compound of isomorphism type.
Specific synthesis step and synthesis 2- (4- nitros) bytyries pyridine nitrogen-oxygen compound the following is the part of the application
Specific embodiment, all reagents used in embodiment are the AR directly bought, in addition to THF steams again,
It is other to be handled using preceding without other.Reagent source：All solvents, alkali metal salt and nitromethane are purchased from traditional Chinese medicines, fluoroform
Sulfonic acid copper and trifluoromethanesulfonic acid scandium etc. are purchased from splendid remote splendid remote scientific and technological (Shanghai) Co., Ltd. of chemistry.
Synthesis (the bibliography of ligand L 1:Chem.Eur.J.2011,17,1114.)
The synthesis of ligand L 2:
N- benzyloxycarbonyl groups phenylalanine (7.5mmol, 2.245g), DMF are added in 100mL round-bottomed flask
(50mL) is cooled to 0 DEG C, then sequentially adds NMM (24.0mmol, 2.7mL), HOBT (8.3mmol, 1.114g), EDCI thereto
(8.3mmol, 1.582g).After 30min, 1,3- diaminopropanes (3mmol) is added thereto in room temperature reaction 10h.Will reaction
Solution afterwards is poured into frozen water, has a large amount of white precipitates to separate out.Suction filtration obtains white solid precipitation, and 1M HCl are then used successively
(50mL), water (50mL), 1M NaOH (50mL), water (50mL), ethanol (5mL) washing of precooling obtains compound 1.
In 100mL round-bottomed flasks, addition compound 1 (2mmol), 10%Pd/C (0.2mmol), methanol (30mL),
1atm H2Middle reaction 24h, reacted mixture is filtered, filtrate is spin-dried for, and column chromatography for separation is carried out with silica gel
Compound 2.
In 50mL round-bottomed flasks, addition compound 2 (2mmol), 2- hydroxyl 3- trifluoromethylated benzaldehydes (4.4mmol),
After magnesium sulfate (2g), dichloromethane (20mL), reaction 24h, filter to get filtrate, be spin-dried for carrying out column chromatography for separation with silica gel being matched somebody with somebody
Body L2 (95% yield) (Fig. 1 and 2).1H NMR(400MHz,CDCl3)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)；13C NMR(100MHz,CDCl3)δ
170.7,166.7,159.1,136.7,135.6,130.3,130.2,130.2,129.6,128.5,126.9,124.8-122.1
(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 for C37H34F6N4O4[M+H]+713.2562,found 713.2561.
Embodiment 1：(S) synthesis of -2- (3- phenyl -4- nitros) bytyry pyridine nitrogen-oxygen compound
The addition copper trifluoromethanesulfcomposite (10.9mg, 0.03mmol) in a 10mL reaction tube, ligand L 1 (12.8mg,
0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL), are stirred at room temperature 2h under nitrogen protection.Then
2- cinnamoyls pyridine nitrogen-oxygen compound 1a (67.6mg, 0.3mmol) is added into reaction tube and nitromethane (0.3mL) exists
Stirring reaction at room temperature.After the completion of reaction (TLC tracing detections), obtained residue with Ethyl acetate/petroleum ether system is spin-dried for
Product (S) -2- (3- phenyl -4- nitros) bytyry pyridine nitrogen-oxidation conjunction that chromatographic column obtains yellow oily is crossed as eluant, eluent
Thing 3a (70.4mg, 89%yield, 95%ee).(Fig. 3, Fig. 4)
1H NMR(400MHz,CDCl3, ppm):δ 8.17-8.16 (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,CDCl3,
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/z calcd for C15H14N2O4[M+
Na]+309.0851,found 309.0851.
Embodiment 2：(R) synthesis of -2- (3- phenyl -4- nitros) bytyry pyridine nitrogen-oxygen compound is anti-in a 10mL
Ying Guanzhong addition trifluoromethanesulfonic acid scandiums (14.8mg, 0.03mmol), ligand L 2 (1.4mg, 0.03mmol), cesium carbonate (9.8mg,
0.03mmol) with solvent THF (1.2mL), 2h is stirred at room temperature under nitrogen protection.Then 2- cinnamoyls are added into reaction tube
Reaction is stirred at room temperature in pyridine nitrogen-oxygen compound 1a (67.6mg, 0.3mmol) and nitromethane (0.3mL).After the completion of reaction
(TLC tracing detections), the residue with Ethyl acetate/petroleum ether system for being spin-dried for obtaining crosses post as eluant, eluent and obtains yellow oily
Product (R) -2- (3- phenyl -4- nitros) bytyry pyridine nitrogen-oxygen compound 3a (76.4mg, 89%yield, 95%ee).
(Fig. 3, Fig. 4)
1H NMR(400MHz,CDCl3, ppm):δ 8.17-8.16 (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,CDCl3,
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/z calcd for C15H14N2O4[M+
Na]+309.0851,found 309.0851.
Embodiment 3：(S) synthesis of -2- (chlorphenyl -4- nitros between 3-) bytyry pyridine nitrogen-oxygen compound
The addition copper trifluoromethanesulfcomposite (10.9mg, 0.03mmol) in a 10mL reaction tube, ligand L 1 (12.8mg,
0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL), are stirred at room temperature 2h under nitrogen protection.Then
(E) -2 (chlorphenyl between 3-) acryloyl group pyridine nitrogen-oxygen compound 1f (77.9mg, 0.3mmol) and nitre are added into reaction tube
Reaction is stirred at room temperature in methylmethane (0.3mL).After the completion of reaction (TLC tracing detections), obtained residue acetic acid is spin-dried for
Ethyl ester/petroleum ether system obtains product (S) -2- (chlorphenyl -4- nitre between 3- of yellow oily as eluant, eluent rapid column chromatography
Base) bytyry pyridine nitrogen-oxygen compound 3f (60.6mg, 63%yield, 90%ee).(Fig. 5, Fig. 6)
1H NMR(400MHz,CDCl3, ppm):δ 8.20-8.18 (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,CDCl3,
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 C15H13ClN2O4[M+Na]+343.0462,found 343.0467.
Embodiment 4：(R) synthesis of -2- (chlorphenyl -4- nitros between 3-) bytyry pyridine nitrogen-oxygen compound
The addition trifluoromethanesulfonic acid scandium (14.8mg, 0.03mmol) in a 10mL reaction tube, ligand L 2 (21.4mg,
0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL), are stirred at room temperature 2h under nitrogen protection.Then
(E) -2 (chlorphenyl between 3-) acryloyl group pyridine nitrogen-oxygen compound 1f (77.9mg, 0.3mmol) and nitre are added into reaction tube
Reaction is stirred at room temperature in methylmethane (0.3mL).After the completion of reaction (TLC tracing detections), obtained residue acetic acid is spin-dried for
Ethyl ester/petroleum ether system obtains product (R) -2- (chlorphenyl -4- nitre between 3- of yellow oily as eluant, eluent rapid column chromatography
Base) bytyry pyridine nitrogen-oxygen compound 3f (69.3mg, 72%yield, 96%ee).(Fig. 5, Fig. 6)
1H NMR(400MHz,CDCl3, ppm):δ 8.20-8.18 (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,CDCl3,
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 C15H13ClN2O4[M+Na]+343.0462,found 343.0467.
Embodiment 5：(S) synthesis of -2- (3- p-trifluoromethyl phenyl -4- nitros) bytyry pyridine nitrogen-oxygen compound
The addition copper trifluoromethanesulfcomposite (10.9mg, 0.03mmol) in a 10mL reaction tube, ligand L 1 (12.8mg,
0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL), are stirred at room temperature 2h under nitrogen protection.Then
Added into reaction tube (E) -2 (3- p-trifluoromethyl phenyls) acryloyl group pyridine nitrogen-oxygen compound 1h (88.0mg,
Reaction 0.3mmol) is stirred at room temperature with nitromethane (0.3mL).After the completion of reaction (TLC tracing detections), it is spin-dried for what is obtained
Residue with Ethyl acetate/petroleum ether system obtains (3- couples of product (S) -2- of yellow oily as eluant, eluent rapid column chromatography
Trifluoromethyl -4- nitros) bytyry pyridine nitrogen-oxygen compound 3h (90.4mg, 85%yield, 93%ee).(Fig. 7, figure
8)
1H NMR(400MHz,CDCl3, ppm):δ 8.21-8.19 (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,CDCl3, ppm):δ 193.8,145.7,143.0,140.6,130.2-129.9 (q, J=32.5Hz), 128.5,
(d, J=2.0Hz), 128.1,127.2,125.9 125.9-125.8 (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 C16H13F3N2O4[M+Na]+377.0725,found377.0715.
Embodiment 6：(R) synthesis of -2- (3- p-trifluoromethyl phenyl -4- nitros) bytyry pyridine nitrogen-oxygen compound exists
Trifluoromethanesulfonic acid scandium (14.8mg, 0.03mmol), ligand L 2 (21.4mg, 0.03mmol), carbon are added in one 10mL reaction tube
Sour caesium (9.8mg, 0.03mmol) and solvent THF (1.2mL), are stirred at room temperature 2h under nitrogen protection.Then add into reaction tube
Enter (E) -2 (3- p-trifluoromethyl phenyls) acryloyl group pyridine nitrogen-oxygen compound 1h (88.0mg, 0.3mmol) and nitromethane
Reaction is stirred at room temperature in (0.3mL).After the completion of reaction (TLC tracing detections), obtained residue with Ethyl acetate/stone is spin-dried for
Oily ether system obtains product (R) -2- (3- p-trifluoromethyl phenyl -4- nitros) of yellow oily as eluant, eluent rapid column chromatography
Bytyry pyridine nitrogen-oxygen compound 3h (78.7mg, 74%yield, 92%ee).(Fig. 7, Fig. 8)
1H NMR(400MHz,CDCl3, ppm):δ 8.21-8.19 (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,CDCl3, ppm):δ 193.8,145.7,143.0,140.6,130.2-129.9 (q, J=32.5Hz), 128.5,
(d, J=2.0Hz), 128.1,127.2,125.9 125.9-125.8 (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 C16H13F3N2O4[M+Na]+377.0725,found377.0715.
Embodiment 7：(S) synthesis of -2- (3- p-bromophenyl -4- nitros) bytyry pyridine nitrogen-oxygen compound
The addition copper trifluoromethanesulfcomposite (10.9mg, 0.03mmol) in a 10mL reaction tube, ligand L 1 (12.8mg,
0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent Tol (1.2mL), are stirred at room temperature 2h under nitrogen protection.Then
(E) -2 (3- p-bromophenyls) acryloyl group pyridine nitrogen-oxygen compound 1j (91.2mg, 0.3mmol) and nitre are added into reaction tube
Reaction is stirred at room temperature in methylmethane (0.3mL).After the completion of reaction (TLC tracing detections), obtained residue acetic acid is spin-dried for
Ethyl ester/petroleum ether system obtains product (S) -2- (3- p-bromophenyl -4- nitre of yellow oily as eluant, eluent rapid column chromatography
Base) bytyry pyridine nitrogen-oxygen compound 3j (81.0mg, 74%yield, 91%ee).(Fig. 9, Figure 10)
1H NMR(400MHz,CDCl3, ppm):δ 8.18-8.16 (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,CDCl3,
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 for C15H13BrN2O4[M+Na]+
386.9956,found 386.9960.
Embodiment 8：(R) synthesis of -2- (3- p-bromophenyl -4- nitros) bytyry pyridine nitrogen-oxygen compound
The addition trifluoromethanesulfonic acid scandium (14.8mg, 0.03mmol) in a 10mL reaction tube, ligand L 2 (21.4mg,
0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL), are stirred at room temperature 2h under nitrogen protection.Then
(E) -2 (3- p-bromophenyls) acryloyl group pyridine nitrogen-oxygen compound 1j (91.2mg, 0.3mmol) and nitre are added into reaction tube
Reaction is stirred at room temperature in methylmethane (0.3mL).After the completion of reaction (TLC tracing detections), obtained residue acetic acid is spin-dried for
Ethyl ester/petroleum ether system crosses product (R) -2- (3- p-bromophenyl -4- nitros) butyryl that post obtains yellow oily as eluant, eluent
Yl pyridines nitrogen-oxygen compound 3j (75.6mg, 69%yield, 94%ee).(Fig. 9, Figure 10)
1H NMR(400MHz,CDCl3, ppm):δ 8.18-8.16 (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,CDCl3,
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 for C15H13BrN2O4[M+Na]+
386.9956,found 386.9960.
Embodiment 9：(R) synthesis of -2- (3- m-methoxyphenyl -4- nitros) bytyry pyridine nitrogen-oxygen compound
The addition trifluoromethanesulfonic acid scandium (14.8mg, 0.03mmol) in a 10mL reaction tube, ligand L 2 (21.4mg,
0.03mmol), cesium carbonate (9.8mg, 0.03mmol) and solvent THF (1.2mL), are stirred at room temperature 2h under nitrogen protection.Then
(E) -2 (3- m-methoxyphenyls) acryloyl group pyridine nitrogen-oxygen compound 1c (76.6mg, 0.3mmol) is added into reaction tube
Reaction is stirred at room temperature with nitromethane (0.3mL).After the completion of reaction (TLC tracing detections), the residue for being spin-dried for obtaining is used
Ethyl acetate/petroleum ether system obtains product (R) -2- (3- meta-methoxy benzene of yellow oily as eluant, eluent rapid column chromatography
Base -4- nitros) bytyry pyridine nitrogen-oxygen compound 3c (78.8mg, 83%yield, 92%ee).(Figure 11, Figure 12, Figure 13)
1H NMR(400MHz,CDCl3, ppm):δ 8.19-8.18 (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,CDCl3, 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 C16H16N2O5[M+Na]+399.0957,found399.0956.
In the other embodiments of the application, 2- enoyl-s pyridine nitrogen-oxygen compound and chiral copper complex or chiral scandium
The amount of the material of complex compares 10:1-20:The initial concentration of 1,2- enoyl- pyridine nitrogen-oxygen class compound is 0.1-0.5mol/
The volume ratio of L, nitromethane or its analog and solvent in catalyst system and catalyzing is 1/3-1/5.The application can not all implementations of limit
Example, is only capable of selecting representational limited embodiments doing the explanation of the application.
Although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of changes, modification can be carried out to these embodiments, replace without departing from the principles and spirit of the present invention by understanding
Or modification, the scope of the present invention is defined by the appended.
Claims (9)
1. a kind of method that configuration controllably synthesizes 2- (4- nitros) bytyries pyridine nitrogen-oxygen compound, methods described include with
Lower step：
1) 2- enoyl-s pyridine nitrogen-oxygen class compound and nitromethane or nitroethane are separately added into chiral copper complex catalysis
In system or the complex-catalyzed system of chiral scandium, react at room temperature；
2) solution after the completion of reaction is distinguished into separating-purifying, wherein obtaining (S) -2- (4- from chiral copper complex catalyst system and catalyzing
Nitro) bytyry pyridine nitrogen-oxygen compound, or obtain (R) -2- (4- nitros) bytyry pyrrole from the complex-catalyzed system of chiral scandium
Pyridine nitrogen-oxygen compound,
The structural formula of (S) -2- (4- nitros) bytyries pyridine nitrogen-oxygen compound is
The structural formula of (R) -2- (4- nitros) bytyries pyridine nitrogen-oxygen compound is
Wherein
R1Selected from the group being made up of the following：Phenyl, ethenylphenyl, 1- naphthyls, 2- thienyls, 2- furyls, 2- fluorobenzene
Base, 2- chlorphenyls, 2- bromophenyls, 2- naphthyls, 3- aminomethyl phenyls, 3- methoxyphenyls, 3- nitrobenzophenones, 3- fluorophenyls, 3- chlorine
Phenyl, 3- bromophenyls, 4- trifluoromethyls, 4- nitrobenzophenones, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, n-propyl, just
Butyl, n-pentyl, n-hexyl, cyclopenta, cyclohexyl,
R2It is H or CH3；
Wherein
The chiral copper complex catalyst system and catalyzing is with the mole ratio 1: 1 of material by mantoquita, alkali carbonate and ligand L 1:
1 is stirred at room temperature reaction under nitrogen protection in a solvent is prepared from, and the structural formula of ligand L 1 is：
The complex-catalyzed system of chiral scandium is with mole of material by trifluoromethanesulfonic acid scandium, alkali carbonate and ligand L 2
Amount is stirred at room temperature reaction and is prepared under nitrogen protection in a solvent than 1: 1: 1；
The structural formula of ligand L 2 is：
The structural formula of the 2- enoyl-s pyridine nitrogen-oxygen compound is
Wherein R is selected from the group being made up of the following：Phenyl, ethenylphenyl, 1- naphthyls, 2- thienyls, 2- furyls, 2- fluorine
Phenyl, 2- chlorphenyls, 2- bromophenyls, 2- naphthyls, 3- aminomethyl phenyls, 3- methoxyphenyls, 3- nitrobenzophenones, 3- fluorophenyls, 3-
Chlorphenyl, 3- bromophenyls, 4- trifluoromethyls, 4- nitrobenzophenones, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, n-propyl,
Normal-butyl, n-pentyl, n-hexyl, cyclopenta, cyclohexyl.
2. according to the method described in claim 1, wherein, for the chiral copper complex catalyst system and catalyzing, the mantoquita is selected from
Copper trifluoromethanesulfcomposite, copper bromide, copper acetate；The alkali carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate；The solvent
Selected from toluene, ethyl acetate, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE).
3. according to the method described in claim 1, wherein, for the chiral copper complex catalyst system and catalyzing, the mantoquita is three
Fluorine copper methane sulfonate, the alkali carbonate is cesium carbonate, and the solvent is toluene.
4. the method according to claim 1, wherein, the chiral complex-catalyzed system of scandium, the alkali carbonate choosing
From sodium carbonate, potassium carbonate and cesium carbonate；The solvent is selected from toluene, ethyl acetate, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE).
5. according to the method described in claim 1, wherein, for the chiral complex-catalyzed system of scandium, the alkali metal carbon
Hydrochlorate is cesium carbonate, and the solvent is tetrahydrofuran.
6. according to the method described in claim 1, wherein, the 2- enoyl-s pyridine nitrogen-oxygen class compound coordinates with chiral copper
The amount of the material of thing or chiral scandium complex is than 10: 1-20: 1；The initial concentration of the 2- enoyl-s pyridine nitrogen-oxygen class compound
For 0.2-0.3mol/L；The nitromethane or nitroethane are 1 with the solvent volume ratio in catalyst system and catalyzing：3-1：5.
7. according to the method described in claim 1, wherein, the separating-purifying mode include post layer chromatography, liquid chromatogram, steaming
Evaporate, recrystallize.
8. according to the method described in claim 1, the separating-purifying mode is post layer chromatography.
9. method according to claim 8, wherein, the eluant, eluent of the post layer chromatography separation is ethyl acetate/petroleum ether
Mixed solvent.
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