CN102229610B - Method for synthesizing optical pure chiral 1,2,3,4-tetrahydropyrrole[1,2-a] pyrazine compound - Google Patents
Method for synthesizing optical pure chiral 1,2,3,4-tetrahydropyrrole[1,2-a] pyrazine compound Download PDFInfo
- Publication number
- CN102229610B CN102229610B CN201110102471.XA CN201110102471A CN102229610B CN 102229610 B CN102229610 B CN 102229610B CN 201110102471 A CN201110102471 A CN 201110102471A CN 102229610 B CN102229610 B CN 102229610B
- Authority
- CN
- China
- Prior art keywords
- pyrazine
- compound
- pyrrolidine
- nmr
- ppm
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- JIDRGEGDAHDJFW-UHFFFAOYSA-N Cc1ccc(C2NCC[n]3c2ccc3)cc1 Chemical compound Cc1ccc(C2NCC[n]3c2ccc3)cc1 JIDRGEGDAHDJFW-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a method for synthesizing an optical pure chiral 1,2,3,4-tetrahydropyrrole[1,2-a] pyrazine compound, comprising the following steps of: taking organic small molecular chiral phosphoric acid as a catalyst; and, under the condition of existing molecular sieve, performing an intramolecular asymmetric nitrogen miscellaneous Friedel-Crafts reaction of N-amine ethyl pyrrole and a relative carbonyl compound in field so as to synthesize the 1,2,3,4-tetrahydropyrrole[1,2-a] pyrazine compound in high stereoselectivity and high yield. The reaction process has the characteristics of being moderate in condition, simple for operation, high for yield, high for enantioselectivitiy and friendly in environment. Simultaneously, the reaction process has a wide substrate adaptive range and is applicable for various types of carbonyl compounds and pyrrole derivatives. The product has high enantioselectivitiy. A metal catalyst is unnecessary in the reaction process; and therefore, the compound is very applicable for synthesis and application of medicines or pharmaceutical intermediates.
Description
Technical field
The present invention relates to a kind of synthesizing optical homochiral 1,2,3,4-Pyrrolidine is the method for [1,2-a] pyrazine compound also.
Background technology
Organocatalysis has obtained very swift and violent development in the past ten years.Because organic micromolecule catalyst has stable, synthetic comparatively simple, cheap, reaction conditions is gentle, easily operation, and final product be there is no to many advantages such as problem of the heavy metal contamination that transition-metal catalyst causes, therefore there is very much prospects for commercial application [(a) Dalko, P.I., Ed.; Enantioselective Organocatalysis, Wiley-VCH:Weinheim, 2007. (b) Taylor, M.S.; Jacobsen, E.N.Asymmetric Catalysis by Chiral Hydrogen-Bond Donors.Angew.Chem.Int.Ed.2006,45 (10), 1520-1543. (c) asymmetric organocatalysis monograph: Chem.Rev.2007,107, issueNo.12.].From chirality phosphonic acids in 2004 be used to asymmetry catalysis synthetic since, organic chiral phosphonic acids be developed to into a kind of efficiently, extensively applicable organic catalyst is successfully applied to [(a) Akiyama in organic synthesis, T.Chem.Rev.2007,107,5744. (b) Doyle, A.G.; Jacobsen, E.N.Chem.Rev.2007,107,5713. (c) Terada, M.Chem.Commun.2008,4097. (d)].In molecule, asymmetric azepine Friedel-Crafts reaction is as a kind of important organic reaction of efficient structure nitrogen-containing heterocycle compound, synthetic at natural product, particularly in alkaloidal synthesizing, there is very important status and obtained application [(a) Pictet, A. very widely; Spengler, T.Ber.Dtsch.Chem.Ges.1911,44,2030-2036. (b) Tatsui, G.J.Pharm.Soc.Jpn.1928,48,92.For reviews:(c) Cox, E.D.; Cook, J.M.Chem.Rev., 1995,95,1797 – 1842. (b) Royer, J.; Bonin, M.; Micouin, L.Chem.Rev., 2004,104,2311 – 2352. (c) Bentley, KennethW.Nat.Prod.Rep., 2004,21,395-424.].For example, asymmetric Pictet-Spengler reaction as one of azepine Friedel-Crafts reaction in molecule, be in the news in recent years and can use chiral organic micromolecule as catalyzer, but successfully example is confined to tryptamines and derivative thereof at present substantially as reaction substrate [(a) Taylor, M.S.; Jacobsen, E.N.J.Am.Chem.Soc.2004,126,10558. (b) Raheem, I.T.; Thiara, P.S.; Peterson, E.A.; Jacobsen, E.N.J.Am.Chem.Soc.2007,129,13404. (c) Klausen, R.S.; Jacobsen, E.N.Org.Lett.2009,11,887. (d) Seayad, J.; Seayad, A.M.; List, B.J.Am.Chem.Soc.2006,128,1086. (e) Wanner, M.J.; Van der Haas, R.N.S.; De Cuba, K.R.; Van Maarseveen, J.H.; Hiemstra, H.Angew.Chem., Int.Ed.2007,46,7485. (f) Sewgobind, N.V.; Wanner, M.J.; Ingemann, S.; De Gelder, R.; Van Maarseveen, J.H.; Hiemstra, H.J.Org.Chem.2008,73,6405. (g) Muratore, M.E.; Holloway, C.A.; Pilling, A.W.; Storer, R.I.; Trevitt, G.; Dixon, D.J.J.Am.Chem.Soc.2009,131,10796. (h) Holloway, C.A.; Muratore, M.E.; Storer, R.l.; Dixon, D.J.Org.Lett., 2010,12,4720.].Through literature search, in hygron and derivative thereof the molecule as reaction substrate, asymmetric azepine Friedel-Crafts reaction only has example report [Raheem, an I.T. at present; Thiara, P.S.; Jacobsen, E.N.Org.Lett.2008,10,1577.].It is substrate that this report is used 3-amine N-ethyl pyrrole N-derivative, and using chirality thiocarbamide is catalyzer, utilizes the on-the-spot imide positive ion generating to obtain chirality pyrrolo-dihydropyridine product as reaction intermediate.1,2,3,4-Pyrrolidine also [1,2-a] pyrazine compound is the extremely important heterogeneous ring compound of a class, be in the news and there is anti-arrhythmia (antiarrhythmic), resist and forget (antiamnesic), anti-hypoxia (antihypoxic), psychiatric treatment (psychotropic), antianaphylaxis (antihypersensitive), aldose reductase inhibitor (aldose reductase inhibitor) active [(a) Likhosherstov, A.M.; Filippova, O.V.; Peresada, V.P.; Kryzhanovskii, S.A.; Vititnova, M.B.; Kaverina, N.V.; Reznikov, K.M.Pharm.Chem.J.2003,37,6. (b) Seredenin, S.B.; Voronina, T.A.; Beshimov, A.; Peresada, V.P.; Likhosherstov, A.M.RU2099055,1997. (c) Seredenin, S.B.; Voronina, T.A.; Likhosherstov, A.M.; Peresada, V.P.; Molodavkin, G.M.; Halikas, J.A.US5378846,1995,10pp. (d) Peresada, V.P.; Medvedev, O.S.; Likhosherstov, A.M.; Skoldinov, A.P.Khim.-Farm.Zh.1987,21,1054. (e) Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.; Suzuki, K.; Matsumoto, J.-i.J.Med.Chem.1998,41,4118.].In recent years, this compounds is also reported as potassium-channel part (potassium channel ligands), varies and noradrenaline reuptake inhibitor in blood (serotonin and noradrenaline reuptake inhibitor), antagonist (cannabinoid receptor agonists) [(a) Merla, B. with hemp chemical composition acceptor; Christoph, T.; Oberboersch, S.; Schiene, K.; Bahrenberg, G.; Frank, R.; Kuehnert, S.; Schroeder, W.WO2008046582,2008,93pp. (b) Finkenzeller, K.; Kluge, S.WO2008000424,2008. (c) Gahman, T.C.; Zhao, C.; Lang, H.; Massari, M.E.US20090062253,2009,66pp.].As far as we know, obtain optically pure 1,2,3,4-Pyrrolidine also [1,2-a] pyrazine compound need to pass through racemic 1,2,3,4-Pyrrolidine also [1,2-a] pyrazine compound splits (Jirkovsky, IvoL.US4188389,1980,8pp), at present not the method synthesizing optical by asymmetry catalysis pure 1,2,3,4-Pyrrolidine is the report of [1,2-a] pyrazine compound also.At this we invented a kind of efficiently, by asymmetry catalysis synthesis of chiral 1,2,3,4-Pyrrolidine is the method for [1,2-a] pyrazine compound also.
Summary of the invention
The object of this invention is to provide above-mentioned optical homochiral 1,2,3,4-Pyrrolidine is a kind of synthetic method of [1,2-a] pyrazine compound also.
The optical homochiral 1,2,3 that the present invention is synthetic, 4-Pyrrolidine is [1,2-a] pyrazine compound also, and its structural formula is as follows:
or
In structural formula: R
1, R
2or R
3be selected from the alkyl of H, F, Cl, Br, I, C1-C16, the-oxyl of C1-C16, C2-C16 thiazolinyl, C2-C16 alkynyl, C3-C16 cycloalkyl, C3-C16 cycloalkenyl group, C3-C16 cycloalkynyl radical, the carbonyl of C2-C16, benzyl, amino;
R
4or R
5be selected from the alkyl of H, C1-C16, the carbonyl of the-oxyl of C1-C16, C2-C16 thiazolinyl, C2-C16 alkynyl, C3-C16 cycloalkyl, C3-C16 cycloalkenyl group, C3-C16 cycloalkynyl radical, C1-C16, ketone carbonyl, ester group, benzyl, aromatic heterocycle,
the aryl replacing;
R
6, R
7or R
8be selected from the alkyl of C1-C16, the carbonyl of the-oxyl of C1-C16, C2-C16, benzyl, aromatic heterocycle,
the aryl, the carboxylic acid ester groups that replace;
R wherein
9, R
10, R
11, R
12or R
13be selected from the alkyl of H, F, Cl, Br, I, C1-C16, the carbonyl of the-oxyl of C1-C16, C2-C16 thiazolinyl, C2-C16 alkynyl, C3-C16 cycloalkyl, C3-C16 cycloalkenyl group, C3-C16 cycloalkynyl radical, C2-C16, benzyl, amino or conjugation aryl; Described conjugation aryl refers to naphthyl, anthryl or phenanthryl;
Described aryl is phenyl or naphthyl; Described aromatic heterocycle is nitrogenous, the sulphur of C5-C10, the heterocyclic group of oxygen;
Optical homochiral 1,2,3 of the present invention, 4-Pyrrolidine is the synthetic method of [1,2-a] pyrazine compound also, and comprising the steps: is having or is not having
or
under molecular sieve exists, temperature of reaction is in-85 ℃-100 ℃ and organic solvent, take N-amine N-ethyl pyrrole N-and aldehyde ketone carbonyl compound is raw material, there is asymmetric azepine Friedel-Crafts in molecule and react 5 minutes to 72 hours in the hand-type phosphonic acids of take, the separated pure products that obtains after catalyzer carries out condensation generation imines; The molar ratio of described N-amine N-ethyl pyrrole N-, aldehyde ketone carbonyl compound and chiral phosphine acid catalyst is: 1-10:1:0.001-1;
Described N-amine N-ethyl pyrrole N-structural formula is:
or
Described aldehyde ketone carbonyl compound structural formula is:
The structural formula of described chiral phosphine acid catalyst is: (R, or S)-
(R, or S)-
(R, or S)-
(R, or S)-
Wherein, R
14, R
15for being selected from arbitrarily the silica-based or thriaryl-silicon of alkyl, three (C1-C16 alkyl) of H, C1-C15; R
16for being selected from arbitrarily OH, NH
2, NHSO
2r
17, NHPO (R
17) or NHPO (OR
17) group; R
17for the alkyl of the C1-C16 that is selected from arbitrarily or perfluoroalkyl, the-oxyl of C1-C16, the carbonyl of C2-C16, benzyl, aromatic heterocycle,
the aryl replacing; Described aryl is phenyl or naphthyl; Described aromatic heterocycle is nitrogenous, the sulphur of C5-C10, the heterocyclic group of oxygen;
The groups such as abovementioned alkyl of the present invention,-oxyl, alkynyl, except particularly pointing out, generally recommending amount of carbon atom is the group of 1-16, wherein take amount of carbon atom as 1-10 is as good, especially recommended amount is 1-4.The amount of carbon atom of thiazolinyl and alkynyl is the group of 2-16, wherein take amount of carbon atom as 2-10 is as good, and especially recommended amount is 1-4.Cycloalkyl refers generally to the group that amount of carbon atom is 3-16, wherein take 3-10 as good, and especially recommended amount is 3-7.Aryl generally refers to phenyl and naphthyl, wherein take phenyl as best.It is the nitrogenous of 5-10 that heterocyclic group refers generally to carbon atoms quantity, oxygen, the heterocyclic group of sulphur.
Solvent used in synthetic method of the present invention can be polarity or non-polar solvent, comprises benzene, toluene, dimethylbenzene, methylene dichloride, trichloromethane, 1,2-ethylene dichloride, sherwood oil, ether, tetrahydrofuran (THF), normal hexane, hexanaphthene, Skellysolve A, normal heptane, dioxane, acetonitrile, dimethyl formamide etc.The water that used in addition refers to distilled water or deionized water.
The product separation method using in the present invention can be thin-layer chromatography, column chromatography, recrystallization, and the method such as underpressure distillation.If use thin-layer chromatography and column chromatography, developping agent used and eluent be polarity and non-polar solvent by a certain percentage mixed configuration form.The solvent system of recommendation can be ethyl acetate/petroleum ether, ethyl acetate/normal hexane, ethyl acetate/Virahol, ethyl acetate/dichloromethane, ethylacetate/ether, Virahol/sherwood oil, Virahol/normal hexane, methylene dichloride/sherwood oil, methylene dichloride/normal hexane, methylene chloride/methanol, the mixed solvent systems such as methylene dichloride/ethanol, its volume ratio can be respectively: polar solvent/non-polar solvent=1/0.5-600.
Compared with prior art, the present invention has following beneficial effect:
Using organic molecule chiral phosphoric acid as catalyzer, under the condition existing at molecular sieve, N-amine N-ethyl pyrrole N-and corresponding carbonyl compound are on-the-spot there is the interior asymmetric azepine Friedel-Crafts reaction of molecule with synthetic 1 of highly-solid selectively, high yield, 2,3,4-Pyrrolidine is [1,2-a] pyrazine compound also.Reaction has mild condition, and simple to operate, productive rate is high, and enantioselectivity is high, eco-friendly feature.There is substrate wide accommodation simultaneously, be applicable to various carbonyl compound and pyrrole derivative.Product has high enantioselectivity.In reaction process, without metal catalyst, be therefore very suitable for the synthetic and application of medicine or medicine intermediate.
Embodiment
Following case study on implementation contributes to the understanding of the present invention, but does not limit content of the present invention.
Embodiment 1: preparation N-amine N-ethyl pyrrole N-and derivative thereof
Pyrroles (10mmol) is dissolved in acetonitrile (30mL), then adds sodium hydroxide powder (2.0g, 50mmol) and 4-butyl ammonium hydrogen sulfate (0.17g, 50mmol).Stirring at room adds 2-chloroethyl amine hydrochloride (1.4g, 12mmol) after 30 minutes.The lower backflow of reactant stirring filters inorganic not tolerant after 24 hours, mother liquor is concentrated, and column chromatography (eluent is methylene chloride/methanol) purifying obtains pure products.
Pyrroles's product 1:N-amine N-ethyl pyrrole N-
1-(2-aminoethyl)pyrrole
0.94g (column chromatography methylene chloride/methanol=10/1), 86%yield, yellow oil,
1h NMR (300MHz CDCl
3) δ (ppm): 6.65 (t, J=3.0Hz, 2H), 6.14 (t, J=3.0Hz, 2H), 3.88 (t, J=6.0Hz, 2H), 2.97 (t, J=6.0Hz, 2H), 1.31 (s, 2H);
13c NMR (75MHzCDCl
3) δ (ppm): 121.0,108.6,52.9,43.5.
Pyrroles's product 2:1-(2-amine ethyl)-2-methylpyrrole
1-(2-aminoethyl)-2-methylpyrrole
1.1g, (column chromatography methylene chloride/methanol=10/1), 73%yield, yellow oil; The
1h NMR spectrum of the product matched the literature data
[10].
1h NMR (300MHz CDCl
3) δ (ppm): 6.56 (t, J=3.0Hz, 2H), 6.02 (t, J=3.0Hz, 1H), 5.85 (m, 1H), 3.82 (t, J=6.0Hz, 2H), 2.93 (t, J=6.0Hz, 2H), 2.21 (s, 3H), 1.19 (s, 2H);
13c NMR (75MHz CDCl
3) δ (ppm): 128.6,120.5,120.3,107.11,49.9,43.3,12.5.
Pyrroles's product 3:1-(2-amine ethyl)-2,4-dimethyl pyrrole
1-(2-aminoethyl)-2,4-dimethylpyrrole
0.60g (column chromatography methylene chloride/methanol=10/1), 50%yield, yellow oil,
1h NMR (300MHz CDCl
3) δ (ppm): 6.31 (s, 1H), 5.73 (s1H), 3.80 (t, J=6.0Hz, 2H), 2.97 (t, J=6.0Hz, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 1.42 (s, 2H);
13c NMR (75MHzCDCl
3) δ (ppm): 128.1,118.2,117.8,108.6,49.7,43.3,12.4,12.2; IR (KBr) υ: 3449,2918,1655,1638,1627,1561,1544,1476,1385,1107,708,562cm
-1; Mass spectrum high resolution (EI) m/z calculated value C
8h
14n
2([M
+]) 138.1152, measured value 138.1153.
Pyrroles's product 4:1-(2-amine ethyl)-3-N-ethyl pyrrole N-
1-(2-aminoethyl)-3-ethylpyrrole
0.96g (column chromatography methylene chloride/methanol=10/1), 70%yield, yellow oil,
1h NMR (300MHz CDCl
3) δ (ppm): 6.58 (t, J=3.0Hz, 1H), 6.46 (s, 1H), 6.02 (t, J=3.0Hz, 1H), 3.86 (t, J=6.0Hz, 2H), 3.00 (t, J=6.0Hz, 2H), 2.06 (q, J=6.0Hz, 2H), 1.32 (s, 2H), 1.21 (t, J=6.0Hz, 3H);
13c NMR (75MHz CDCl
3) δ (ppm): 120.8,117.7,108.2,126.7,50.0,43.7,20.5,15.7; IR (KBr) υ: 3448,1654,1647,1637,1073,602,581cm
-1; Mass spectrum high resolution (EI) m/z calculated value C
8h
14n
2([M
+]) 138.1152, measured value 138.1153.
Embodiment 2: chiral phosphine acid catalyzed N-amine N-ethyl pyrrole N-and aldehyde carry out condensation and generates and asymmetric azepine Friedel-Crafts reaction in molecule to occur after imines and prepare optical homochiral 1,2,3, and 4-Pyrrolidine is [1,2-a] pyrazine compound also
Toward adding high-temperature activation in dry reaction tubes
molecular sieve (50mg), anhydrous tetrahydro furan (1.0mL), carbonyl compound (0.1mmol) and catalyzer (0.01mmol).Under normal temperature (25 degrees Celsius) stirs, add N-amine N-ethyl pyrrole N-(0.1mmol), reaction detects to raw material and disappears with TLC.Column chromatography [eluent is a certain proportion of petrol ether/ethyl acetate (1/1-pure ethyl acetate)] separation obtains corresponding pure products.The present embodiment is used phosphonic acids catalyzer to be:
Chirality pyrazine product 1:1-phenyl-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
91%yield, 94%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=98/2,0.6mL/min), t
r-major26.9min, t
r-minor31.6min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.43-7.31 (m, 5H), 6.62 (t, J=2.1Hz, 1H), 6.13-6.12 (m, 1H), 5.58-5.57 (m, 1H), 5.10 (s, 1H) 4.15-3.97 (m, 2H), 3.42-3.24 (m, 2H), 1.96 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 143.1,130.8,128.6,128.5,127.9,119.3,107.9,105.1,59.5,45.8,43.5; IR (KBr) υ: 3230,3251,2928,1654,1631,1449,1381,1296,726,703cm
-1; High resolution mass spectrum (EI) m/z calculated value C
13h
14n
2([M
+]) 198.1152, measured value 198.1148.
Chirality pyrazine product 2:1-(4-fluorophenyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(4-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
94%yield, 91%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=98/2,0.6mL/min), t
r-major24.7min, t
r-minor35.0min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.42-7.36 (m, 2H), 7.07-7.00 (m, 2H), 6.62-6.61 (m, 1H), 6.13-6.11 (m, 1H), 5.55-5.43 (m, 1H), 5.08 (s, 1H), 4.14-3.96 (m, 2H), 3.41-3.23 (m, 2H), 1.89 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 162.5 (d, J=245.1Hz), 138.9,130.7,130.10 (d, J=7.1Hz, 2C), 119.4,115.3 (d, J=21.6Hz, 2C), 108.0,105.1,58.8,45.7,43.5; IR (KBr) υ: 3433,3251,3107,2922,2819,1603,1509,1297,1224,1084,840 .86,710cm
-1; High resolution mass spectrum (EI) m/z calculated value C
13h
12fN
2([M
+]) 216.1057, measured value 216.1060.
Chirality pyrazine product 3:1-(4-chloro-phenyl-)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(4-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
87%yield, 90%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=80/20,0.6mL/min), t
r-major10.4min, t
r-minor12.1min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.37-7.29 (m, 4H), 6.61 (s, 1H), 6.12 (t, J=2.7Hz, 1H), 5.54 (t, J=1.8Hz, 1H), 5.07 (s, 1H), 4.13-3.96 (m, 2H), 3.39-3.22 (m, 2H), 2.20 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 141.6,133.6,130.3,129.9 (2C), 128.7 (2C), 119.4,108.0,105.2,58.8,45.7,43.4; IR (KBr) υ: 3431,2955,2926,1634,1592,1486,1409,1091,731cm
-1; High resolution mass spectrum (EI) m/z calculated value C
13h
12clN
2([M
+]) 232.0762, measured value 232.0757.
Chirality pyrazine product 4:1-(4-bromophenyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
(1-(4-bromophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine)
77%yield, 94%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=80/20,0.6mL/min), t
r-major11.8min, t
r-minor14.0min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.48 (d, J=8.5Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 6.2 (t, J=1.8Hz, 1H), 6.14-6.12 (m, 1H), 5.56-5.54 (m, 1H), 5.06 (s, 1H), 4.14-3.96 (m, 2H), 3.39-3.21 (m, 2H), 2.07 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 142.1,131.7,130.3 (2C), 121.8,119.5,108.0,105.2,58.8,45.7,43.4; IR (KBr) υ: 3435,2947,2921,1636,1587,1483,1441,1329,1290,1100,1071,1011,708cm
-1; High resolution mass spectrum (EI) m/z calculated value C
13h
12brN
2([M
+]) 275.0178, measured value 276.0248.
Chirality pyrazine product 5:1-(4-aminomethyl phenyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-p-tolyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
84%yield, 90%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=98/2,0.6mL/min), t
r-major26.5min, t
r-minor34.3min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.32 (d, J=7.8Hz, 2H), 7.19 (d, J=7.8Hz, 2H), 6.65-6.64 (m, 1H), 6.17-6.15 (m, 1H), 5.60-5.59 (m, 1H), 5.09 (s, 1H), 4.16-3.98 (m, 2H), 3.43-3.25 (m, 2H), 2.41 (s, 3H), 2.01 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 140.1,137.6,131.1,129.3 (2C), 128.5 (2C), 119.1,107.9,105.0,59.2,45.8,43.6,21.6; IR (KBr) υ: 3430,2918,1647,1637,1437,1380,1271,1161,1110,1062,711,567cm
-1; High resolution mass spectrum (EI) m/z calculated value C
14h
15n
2([M
+]) 212.1308, measured value 212.1308.
Chirality pyrazine product 6:1-(4-aminomethyl phenyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
93%yield, 91%ee; HPLC analysis:Chiralcel AS-H (hexanes/iPrOH=98/2,0.6mL/min), t
r-minor24.7min, t
r-major28.6min.
1h NMR (300MHz, CDCl
3) δ (ppm) 7.36-7.28 (m, 1H), 7.22-7.13 (m, 2H), 7.04-6.97 (m, 1H), 6.62 (s, 1H), 6.15-6.13 (m, 1H), 5.60-5.59 (m, 1H), 5.11 (s, 1H), 4.14-3.97 (m, 2H), 3.40-3.22 (m, 2H), 2.10 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 163.0 (d, J=245.2), 145.6 (d, J=6.6), 130.1,130.0,124.2,119.4,115.4 (d, J=21.3), 114.9 (d, J=22.2), 108.0,105.2,58.8,45,7,43.3; IR (KBr) υ: 3248,3309,3087,2956,2918,2839,2807,1612,1588,1484,1499,1291,1263,1135,1079,752,727cm
-1; High resolution mass spectrum (EI) m/z calculated value C
13h
12fN
2([M
+]) 216.1057, measured value 216.1056.
Chirality pyrazine product 7:1-(2-fluorophenyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(2-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine,
92%yield, 91%ee; HPLC analysis:Chiralcel AS-H (hexanes/iPrOH=98/2,0.6mL/min), t
r-minor21.0min, t
r-major23.8min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.34-7.24 (m, 2H), 7.12-7.05 (m, 2H), 6.63-6.52 (m, 1H), 6.15 (dd, J=3.6,2.7,1H), 5.64-5.63 (m, 1H), 5.50 (s, 1H), 4.12-3.97 (m, 2H), 3.41-3.21 (m, 2H), 2.13 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 161.0 (d, J=246.3), 130.2,130.1 (d, J=18.7), 129.5 (d, J=8.3), 129.1,124.3,119.3,115.7 (d, J=21.7), 108.0,104.9,52.2,45.7,43.0; IR (KBr) υ: 3437,2916,1634,1486,1447,1438,1070,708,560cm
-1; High resolution mass spectrum (EI) m/z calculated value C
13h
12fN
2([M
+]) 216.1057, measured value 216.1053.
Chirality pyrazine product 8:1-(1-naphthyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(naphthalen-1-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine,
91%yield, 90%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=98/2,0.6mL/min), t
r-minor34.8min, t
r-major41.8min.
1h NMR (300MHz, CDCl
3) δ (ppm): 8.22 (d, J=9.1Hz, 1H), 7.92-7.89 (m, 1H), 7.83 (d, J=7.8,1H), 7.54-7.40 (m, 4H), 6.69-6.68 (m, 1H), 6.16-6.13 (m, 1H), 5.89 (s, 1H), 5.59-5.58 (m, 1H), 4.22-4.03 (m, 2H), 3.44-3.26 (m, 2H), 2.17 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 138.5,134.3,131.7,130.2,129.0,128.6,126.4,126.3,125.8,125.5,124.2,119.2,108.1,105.2,56.1,45.9,43.3; IR (KBr) υ: 3431,2916,1635,1384,1269,1107,1075,705,563cm
-1; High resolution mass spectrum (EI) m/z calculated value C
17h
15n
2([M
+]) 248.1308, measured value 248.1309.
Chirality pyrazine product 9:1-(4-isopropyl phenyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(4-isopropylphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
88%yield, 87%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=90/10,0.6mL/min), t
r-major16.0min, t
r-minor17.2min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.34 (d, J=8.1Hz, 2H), 7.22 (d, J=8.1Hz, 2H), 6.63 (t, J=2.1Hz, 1H), 6.15-6.13 (m, 1H), 5.62-5.50 (m, 1H), 5.09 (s, 1H), 4.15-3.97 (m, 2H), 3.49-3.23 (m, 2H), 2.99-2.96 (m, 1H), 1.94 (s, 1H), 1.29 (d, J=6.9Hz, 6H);
13c NMR (75MHz, CDCl
3) δ (ppm): 148.5,140.4,131.0,128.4 (2C), 126.6 (2C), 119.2,107.9,105.0,59.2,45.8,43.5,34.2,24.5 (2C); IR (KBr) υ: 3430,3255,3095,2955,2830,2818,1634,1508,1455,1369,1331,1297,1111,1078,1052,958,888,838,717cm
-1; High resolution mass spectrum (EI) m/z calculated value C
16h
19n
2([M
+]) 240.1621, measured value 240.1615.
Chirality pyrazine product 10:1-(4-p-methoxy-phenyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(4-methoxyphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine,
81%yield, 83%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=90/10,0.6mL/min), t
r-major20.2min, t
r-minor26.6min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.32 (d, J=8.7Hz, 2H), 6.87 (d, J=8.4Hz, 2H), 6.59 (s, 1H), 6.12-6.10 (m, 1H), 5.56-5.54 (m, 1H), 5.04 (s, 1H), 4.13-3.95 (m, 2H), 3.82 (s, 3H), 3.40-3.22 (m, 2H), 1.87 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 159.3,135.3,131.2,129.6 (2C), 119.2,114.0 (2C), 107.9,105.0,58.9,55.6,45.8,43.6; IR (KBr) υ: 3431,2916,1629,1448,1385,1159,1109,1071,876,711,562cm
-1; High resolution mass spectrum (EI) m/z calculated value C
14h
15n
2o ([M
+]) 228.1257, measured value 228.1252.
Chirality pyrazine product 11:1-(4-nitrophenyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine,
82%yield, 84%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=90/10,0.6mL/min), t
r-major33.7min, t
r-minor35.5min.
1h NMR (300MHz, CDCl
3) δ (ppm): 8.18 (d, J=9Hz, 2H), 7.59 (d, J=9Hz, 2H), 6.63-6.61 (m, 1H), 6.13-6.11 (m, 1H), 5.54-5.52 (m, 1H), 5.21 (s, 1H), 4.15-3.98 (m, 2H), 3.40-3.25 (m, 2H), 1.97 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 150.4,147.6,129.3 (2C), 129.1,123.8 (2C), 119.8,108.2,105.4,58.5,45.7,43.2; IR (KBr) υ: 3431,2953,2918,1635,1600,1516,1343,1285,1098,1075,717cm
-1; High resolution mass spectrum (EI) m/z calculated value C
13h
12n
3o
2([M
+]) 243.1002, measured value 243.1001.
Chirality pyrazine product 12:1-cyclohexyl-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-cyclohexyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine,
94%yield, 91%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=98/2,0.6mL/min), t
r-major12.6min, t
r-minor14.3min.
1h NMR (300MHz, CDCl
3) δ (ppm): 6.56-6.54 (m, 1H), 6.16 (t, J=3Hz, 1H), 5.88 (t, J=1.8Hz, 1H), 3.93-3.89 (m, 3H), 3.39-3.32 (m, 1H), 3.16-3.07 (m, 1H), 2.37 (s, 1H), 1.86-1.68 (m, 6H), 1.41-1.03 (m, 5H);
13c NMR (100MHz, CDCl
3) δ (ppm): 130.5,118.7,107.4,102.6,58.7,45.5,43.1,42.1,30.4,27.2,26.9,26.7,26.6.; IR (KBr) υ: 3430,2922,2852,1655,1633,1458,1443,1404,1383,1106,1075,705,563cm
-1; High resolution mass spectrum (EI) m/z calculated value C
13h
20n
2([M
+]) 204.1621, measured value 204.1622.
Chirality pyrazine product 13:6-methyl isophthalic acid-phenyl-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
6-methyl-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
93%yield, 86%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=98/2,0.6mL/min), t
r-major32.6min, t
r-minor43.5min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.42-7.33 (m, 5H), 5.82 (d, J=3.3Hz, 1H), 5.44 (d, J=3.3Hz, 1H), 5.07 (s, 1H), 3.88-3.84 (m, 2H), 3.46-3.39 (m, 1H), 3.33-3.24 (m, 1H), 2.36 (s, 1H), 2.23 (s, 3H);
13c NMR (75MHz, CDCl
3) δ (ppm): 143.1,130.1,128.5,127.9,127.2,105.6,104.2,59.7,43.1,30.1,12.0; IR (KBr) υ: 3411,2917,1637,1647,1421,1384,1110,1061,700,558cm
-1; High resolution mass spectrum (EI) m/z calculated value C
14h
16n
2212.1308, measured value 212.1310.
Chirality pyrazine product 14:6-methyl isophthalic acid-(4-chloro-phenyl-)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
1-(4-chlorophenyl)-6-methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
95%yield, 83%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=95/5,0.6mL/min), t
r-major17.9min, t
r-minor32.3min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.36 (d, J=8.5,2H), 7.31 (d, J=8.4,2H), 5.83 (d, J=2.8,1H), 5.43 (d, J=3.2,1H), 5.04 (s, 1H), 3.87-3.83 (m, 2H), 3.44-3.23 (m, 2H), 2.24 (s, 3H), 1.92 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 141.7,133.5,130.0 (2C), 129.7,128.7 (2C), 127.4,105.7,104.3,59.0,43.5,43.1,12.0; IR (KBr) υ: 3449,2916,1655,1637,1508,1459,1088,708,565cm
-1; High resolution mass spectrum (EI) m/z calculated value C
14h
15clN
2246.0918, measured value 246.0917.
Chirality pyrazine product 15:6,8-dimethyl-1-phenyl-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine also
6,8-dimethyl-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine,
92%yield, 85%ee; HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=95/5,0.6mL/min), t
r-major20.8min, t
r-minor30.4min.
1h NMR (300MHz, CDCl
3) δ (ppm): 7.31-7.26 (m, 1H), 5.73 (s, 1H), 5.13 (s, 1H), 3.84-3.70 (m, 2H), 3.24-3.07 (m, 2H), 2.22 (s, 3H), 1.57 (s, 3H), 1.27 (s, 1H);
13c NMR (75MHz, CDCl
3) δ (ppm): 143.3,128.5,127.5,126.3,123.8,113.3,107.6,57.2,43.2,41.1,11.9; IR (KBr) υ: 3450,2916,1654,1637,1509,1459,1384,1114,698,564cm
-1; High resolution mass spectrum (EI) m/z calculated value C
15h
17n
2198.1152, measured value 198.1148.
Chirality pyrazine product 15a and 15b:8-ethyl-1-phenyl-1,2,3,4-Pyrrolidine also [1,2-a] pyrazine (15a) and 7-ethyl-1-phenyl-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine (15b) (product is the two mixture, and ratio is about 1:1.2) also
8-ethyl-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine(15a),7-ethyl-1-phenyl-1,2,3,4-tetrah?ydropyrrolo[1,2-a]pyrazine(15b),
83% overall yield, 94%ee (15a), 94%ee (15b); HPLC analysis:Chiralcel AD-H (hexanes/iPrOH=95/5,0.6mL/min), 15bt
r-major15.0min, t
r-minor18.0min; 15at
r-major18.9min, t
r-minor24.0min.
1h NMR (15a) (300MHz, CDCl
3) δ (ppm): 7.42-7.23 (m, 5H), 6.60 (d, J=3Hz, 1H), 6.07 (d, J=3Hz, 1H), 5.18 (s, 1H), 4.04-3.88 (m, 2H), 3.40-3.05 (m, 2H), 2.12 (s, 1H), 2.07-1.88 (m, 2H), 0.93 (t, J=7.5Hz);
1h NMR (15b) (300MHz, CDCl
3) δ (ppm): 7.42-7.23 (m, 5H), 6.39 (s, 1H), 5.42 (s, 1H), 5.05 (s, 1H), 4.04-3.88 (m, 2H), 3.40-3.05 (m, 2H), 2.44 (q, J=7.5Hz, 2H), 2.12 (s, 1H), 1.15 (t, J=7.5Hz);
13c NMR (mixture of15a and15b) (75MHz, CDCl
3) δ (ppm): 143.5,143.1,133.6,130.8,130.2,128.5,127.9,127.6,126.1,124.19,121.1,118.6,118.4,115.9,107.6,107.5,104.9,103.8,59.3,57.2,57.1,46.0,43.2,41.0,30.1,20.5,19.4,15.1; IR (KBr) υ: 3433,2924,1654,1646,1509,1420,1386,700,571cm
-1; High resolution mass spectrum (EI) m/z calculated value C
15h
17n
2226.1465, measured value 226.1464.
Claims (3)
1. an optical homochiral 1,2,3,4-Pyrrolidine is the synthetic method of [1,2-a] pyrazine compound also, chirality 1,2,3, also [1,2-a] pyrazine compound structural formula is as follows for 4-Pyrrolidine:
It is characterized in that, synthetic method comprises the steps: having or do not having
or
under molecular sieve exists, temperature of reaction is in-85 ℃-100 ℃ and organic solvent, take N-amine N-ethyl pyrrole N-and aldehyde ketone carbonyl compound is raw material, there is asymmetric azepine Friedel-Crafts in molecule and react 5 minutes to 72 hours in the hand-type phosphonic acids of take, the separated pure products that obtains after catalyzer carries out condensation generation imines; The molar ratio of described N-amine N-ethyl pyrrole N-, aldehyde ketone carbonyl compound and chiral phosphine acid catalyst is: 1:1.2-2:0.02-0.2;
Described N-amine N-ethyl pyrrole N-structural formula is:
Described aldehyde ketone carbonyl compound structural formula is:
r wherein
4=H, R
5for
with
in a kind of;
The structural formula of described chiral phosphine acid catalyst is:
2. synthetic method as claimed in claim 1, it is characterized in that, described organic solvent is toluene, dimethylbenzene, benzene, methylene dichloride, 1,2-methylene dichloride, chloroform, tetracol phenixin, sherwood oil, normal hexane, tetrahydrofuran (THF), dimethyl formamide, ether, hexanaphthene, normal heptane, Skellysolve A, dioxane or acetonitrile.
3. synthetic method as claimed in claim 1, is characterized in that, the pure products of gained is in addition separated by recrystallization, thin-layer chromatography, column chromatography or underpressure distillation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110102471.XA CN102229610B (en) | 2011-04-22 | 2011-04-22 | Method for synthesizing optical pure chiral 1,2,3,4-tetrahydropyrrole[1,2-a] pyrazine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110102471.XA CN102229610B (en) | 2011-04-22 | 2011-04-22 | Method for synthesizing optical pure chiral 1,2,3,4-tetrahydropyrrole[1,2-a] pyrazine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102229610A CN102229610A (en) | 2011-11-02 |
| CN102229610B true CN102229610B (en) | 2014-10-29 |
Family
ID=44842225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110102471.XA Expired - Fee Related CN102229610B (en) | 2011-04-22 | 2011-04-22 | Method for synthesizing optical pure chiral 1,2,3,4-tetrahydropyrrole[1,2-a] pyrazine compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102229610B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102942431B (en) * | 2012-10-26 | 2014-07-23 | 青岛正大海尔制药有限公司 | Method for separating chiral compound by using molecular sieves |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009032754A2 (en) * | 2007-08-31 | 2009-03-12 | Kalypsys, Inc. | Heterocyclodiazepine cannabinoid receptor modulators for treatment of disease |
| WO2009090054A1 (en) * | 2008-01-17 | 2009-07-23 | Grünenthal GmbH | Substituted sulfonamide derivatives |
| CN101547925A (en) * | 2006-10-17 | 2009-09-30 | 格吕伦塔尔有限公司 | Substituted tetrahydropyrrolopyrazine compounds having affinity with the kcnq2/3 k+ channel and use thereof in medicaments |
-
2011
- 2011-04-22 CN CN201110102471.XA patent/CN102229610B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101547925A (en) * | 2006-10-17 | 2009-09-30 | 格吕伦塔尔有限公司 | Substituted tetrahydropyrrolopyrazine compounds having affinity with the kcnq2/3 k+ channel and use thereof in medicaments |
| WO2009032754A2 (en) * | 2007-08-31 | 2009-03-12 | Kalypsys, Inc. | Heterocyclodiazepine cannabinoid receptor modulators for treatment of disease |
| WO2009090054A1 (en) * | 2008-01-17 | 2009-07-23 | Grünenthal GmbH | Substituted sulfonamide derivatives |
Non-Patent Citations (1)
| Title |
|---|
| Jayasree Seayad，等.Catalytic Asymmetric Pictet-Spengler Reaction.《J.AM.CHEM.SOC》.2006,第128卷(第4期),第1086-1087页Table1和3. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102229610A (en) | 2011-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zheng et al. | Catalytic Kinetic Resolution by Enantioselective Aromatization: Conversion of Racemic Intermediates of the Barton–Zard Reaction into Enantioenriched 3‐Arylpyrroles | |
| Hu et al. | Enantioselective Synthesis of 2‐Oxindole Spirofused Lactones and Lactams by Heck/Carbonylative Cylization Sequences: Method Development and Applications | |
| Wang et al. | Enantioselective synthesis of nitrogen–nitrogen biaryl atropisomers via copper-catalyzed Friedel–Crafts alkylation reaction | |
| Wang et al. | Asymmetric Synthesis of Spirobenzazepinones with Atroposelectivity and Spiro‐1, 2‐Diazepinones by NHC‐Catalyzed [3+ 4] Annulation Reactions | |
| Liu et al. | Direct assembly of aldehydes, amino esters, and anilines into chiral imidazolidines via Brønsted acid catalyzed asymmetric 1, 3-dipolar cycloadditions | |
| Zhu et al. | Construction of the tetrahydroquinoline spiro skeleton via cascade [1, 5]-hydride transfer-involved C (sp 3)–H functionalization “on water” | |
| Guo et al. | N‐Heterocyclic Carbene Catalyzed Formal [3+ 2] Annulation Reaction of Enals: An Efficient Enantioselective Access to Spiro‐Heterocycles | |
| Ma et al. | Chiral bifunctional thiourea-catalyzed enantioselective Michael addition of ketones to nitrodienes | |
| Chen et al. | Brønsted Acid Catalyzed Dearomatization by Intramolecular Hydroalkoxylation/Claisen Rearrangement: Diastereo‐and Enantioselective Synthesis of Spirolactams | |
| He et al. | Chiral phosphoric acid catalyzed inverse-electron-demand aza-Diels–Alder reaction of isoeugenol derivatives | |
| Fan et al. | The Application of N‐Protected 3‐Vinylindoles in Chiral Phosphoric Acid‐Catalyzed [3+ 2] Cyclization with 3‐Indolylmethanols: Monoactivation of the Catalyst to Vinyliminium | |
| Xu et al. | Enantioselective Mannich‐Type Reactions to Construct Trifluoromethylthio‐Containing Tetrasubstituted Carbon Stereocenters via Asymmetric Dual‐Reagent Catalysis | |
| Madhusudhan Reddy et al. | Expanding the scope of primary amine catalysis: Stereoselective synthesis of indanedione-fused 2, 6-disubstituted trans-spirocyclohexanones | |
| Zhu et al. | Catalytic asymmetric homo-1, 3-dipolar cycloadditions of azomethine ylides: diastereo-and enantioselective synthesis of imidazolidines | |
| Quintavalla et al. | Organocatalytic conjugate addition of nitroalkanes to 3-ylidene oxindoles: a stereocontrolled diversity oriented route to oxindole derivatives | |
| Zhu et al. | α-Oxo-γ-butyrolactam, N-containing pronucleophile in organocatalytic one-pot assembly of butyrolactam-fused indoloquinolizidines | |
| Li et al. | Diastereodivergent Asymmetric Michael Addition of Cyclic Azomethine Ylides to Nitroalkenes: Direct Approach for the Synthesis of 1, 7‐Diazaspiro [4.4] nonane Diastereoisomers | |
| Bai et al. | Metal‐free asymmetric 1, 3‐dipolar cycloaddition of N‐arylmaleimides to azomethine ylides catalyzed by chiral tertiary amine thiourea | |
| Cheng et al. | N‐Heterocyclic Carbene Catalyzed Generation and [4+ 2] Annulation of Unsubstituted Dienolate–Enantioselective Synthesis of Spirocyclic Oxindolodihydropyranones | |
| Lin et al. | Organocatalytic Remote Asymmetric Inverse‐Electron‐Demand Oxa‐Diels‐Alder Reaction of Allyl Ketones with Isatin‐Derived Unsaturated Keto Esters | |
| Rodríguez‐Ferrer et al. | Synthesis of Enantioenriched 3‐Amino‐3‐Substituted Oxindoles by Stereoselective Mannich Reaction Catalyzed by Supported Bifunctional Thioureas. | |
| Zhang et al. | Direct construction of NOBINs via domino arylation and sigmatropic rearrangement reactions | |
| Jia et al. | Organocatalytic [4+ 2] cyclocondensation of α, β-unsaturated acyl chlorides with imines: highly enantioselective synthesis of dihydropyridinone and piperidine derivatives | |
| Shinde et al. | Highly Regio-and Diastereoselective Tethered Aza-Wacker Cyclizations of Alkenyl Phosphoramidates | |
| Yu et al. | Iodine-promoted formal [3+ 2] cycloaddition of enaminone: access to 2-hydroxy-1, 2-dihydro-pyrrol-3-ones with quaternary carbon center |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20141029 Termination date: 20170422 |