CN104710377A - Method for synthesizing chiral amine through biomimetic asymmetric hydrogenation - Google Patents

Method for synthesizing chiral amine through biomimetic asymmetric hydrogenation Download PDF

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CN104710377A
CN104710377A CN201310690964.9A CN201310690964A CN104710377A CN 104710377 A CN104710377 A CN 104710377A CN 201310690964 A CN201310690964 A CN 201310690964A CN 104710377 A CN104710377 A CN 104710377A
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chiral
quinoxaline
compound
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imines
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周永贵
陈章培
陈木旺
郭冉柠
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Dalian Institute of Chemical Physics of CAS
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
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    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
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    • B01J2540/00—Compositional aspects of coordination complexes or ligands in catalyst systems
    • B01J2540/50—Non-coordinating groups comprising phosphorus
    • B01J2540/52—Phosphorus acid or phosphorus acid ester groups
    • B01J2540/522—Phosphorus acid or phosphorus acid ester groups being phosphoric acid mono-, di- or triester groups ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
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Abstract

The invention relates to a method for synthesizing chiral amine through biomimetic asymmetric hydrogenation. According to the present invention, a transition metal [Ru(II)] is adopted as a hydrogenation catalyst to achieve in-situ regeneration of a dihydropyrrolo[1,2-a]quinoxaline compound, the in-situ regenerated dihydropyrrolo[1,2-a]quinoxaline compound is adopted as a hydrogen source so as to be applied in asymmetric transfer hydrogenation of unsaturated imine, and only a catalytic amount of pyrrolo[1,2-a]quinoxaline is added so as to carry out high-enantioselectivity chiral amine synthesis; and the method has characteristics of simple and practical operation, high diastereoselectivity/enantioselectivity and high yield, and the reaction has characteristics of green atom economy and environment-protection.

Description

A kind of method of bionical asymmetric hydrogenation synthesis of chiral amine
Technical field
The present invention relates to a kind of method being carried out synthesis of chiral nitrogenous compound by bionical asymmetric hydrogenation imines.
Background technology
Chirality nitrogenous compound is the key intermediate of many natural products and drug molecule, is widely used in the synthesis of materials chemistry, agricultural chemicals and medicine intermediate [1], therefore obtain the extensive concern of many scientists.Up to the present, develop serial of methods and carry out synthesis of chiral nitrogenous compound.The advantages such as bionical asymmetric hydrogenation [2] has that Atom economy is good, the activity of catalyzer is high, speed of response is fast, the convenient separation of product, side reaction are few.In view of the significance of chirality nitrogenous compound in synthetic chemistry, develop a kind of high yield, the bionical asymmetric hydrogenation method synthesis of chiral imines of highly-solid selectively is the focus and difficult point studied at present.
Reference:
1.(a)Ouellet,S.G.;Walji,A.M.;MacMillan,D.W.C.Acc.Chem.Res.2007,40,1327.(b)You,S.-L.
Chem.Asian J.2007,2,820.(c)Connon,S.B.J.Org.Biomol.Chem.2007,5,3407.(d)Rueping,M.;
Dufour,J.;Schoepke,F.R.Green Chem.2011,13,1084.(e)Vries,J.G.; N.Catal.Sci.Technol.
2011,1,727.(f)Zheng,C.;You,S.-L.Chem.Soc.Rev.2012,41,2498.(g)McSkimming,A.;Colbran,S.
B.Chem.Soc.Rev.2013,42,5439.
2.(a)Chen,Q.-A.;Chen,M.-W.;Yu,C.-B.;Shi,L.;Wang,D.-S.;Yang,Y.;Zhou,Y.-G.J.Am.Chem.Soc.
2011,133,16432.;(b)Chen,Q.-A.;Gao,K.;Duan,Y.;Ye,Z.-S.;Shi,L.;Yang,Y.;Zhou,Y.-G.J.Am.
Chem.Soc.2012,134,2442.
Summary of the invention
The object of this invention is to provide a kind of method of bionical asymmetric hydrogenation synthesis of chiral amine.The present invention's practicality easy and simple to handle, raw material is easy to get, and stereoselectivity is high, and productive rate is good, and reaction has green Atom economy, advantages of environment protection.
For achieving the above object, the present invention is using chiral phosphoric acid (CPA) as chiral catalyst, the pyrrolin [1 of in-situ regeneration, 2-a] and quinoxaline compound as hydrogen source capable of circulation, transition metal [Ru (II)] complex compound, as regenerated catalyst, achieves the asymmetric hydrogenation of a series of imines.
Technical scheme of the present invention is as follows:
The present invention is to provide a kind of method of bionical asymmetric hydrogenation synthesis of chiral amine, its catalyst system is that chiral phosphoric acid (CPA) makes chiral catalyst, the pyrrolin [1 of in-situ regeneration, 2-a] and quinoxaline compound as hydrogen source capable of circulation, complex compound is as regenerated catalyst for transition metal [Ru (II)], and its synthetic route is as follows:
Described R 1, R 2for the alkyl of C1-C10; Phenyl and containing substituent phenyl ring, substituting group is a kind of substituting group in F, Cl, Br, Me, MeO or two kinds of substituting groups;
Described R 3for phenyl and containing substituent phenyl ring;
Described R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11be respectively the substituted aryl of hydrogen, C1-C6 alkyl, aryl or C7-C12, substituting group is CF 3, a kind of substituting group in Cl, Br, Me, MeO or two kinds of substituting groups.
Described CPA is the chiral phosphoric acid of octahydro dinaphthol skeleton or dinaphthol skeleton, and Ar is 1-position naphthyl, benzene and containing substituent phenyl ring, and substituting group is F, Cl, CF 3, a kind of substituting group in Me, MeO or two kinds of substituting groups.
The reactions steps of synthesis of chiral amine is:
Imines substrate A being dissolved in concentration is in the organic solvent of 0.01-1.0mol/L, and to this system by imines: the mol ratio 1:0.001-1:0.1 of metal catalyst adds metal catalyst, metal catalyst is the metal complex of Ru (II); By imines: the mol ratio 1:0.001-1:0.1 of chiral phosphoric acid adds chiral phosphoric acid CPA catalyzer; By imines: pyrroles [1,2-a] the mol ratio 1:0.001-1:0.2 of quinoxaline adds hydrogen source precursor 1 capable of circulation; After stirring, reaction system to be transferred in autoclave and to pour hydrogen, hydrogen pressure 1-100atm; After 0-100 DEG C of stirring reaction 6-48h, carefully discharge remaining hydrogen, column chromatography or recrystallization obtain Chiral Amine.
Transition metal [Ru (II)] complex compound as regenerated catalyst, catalytic hydrogenation pyrroles [1,2-a] quinoxaline compound.
Described catalyzer is chiral phosphoric acid, is by chirality BINOL or H 8-BINOL is by after 3,3 ' position iodate and corresponding substituted benzene boric acid ArB (OH) 2through Suzuki coupling preparation, in reaction, the usage quantity of chiral phosphoric acid catalyzer and the mol ratio of imines A are 0.01:1-0.075:1.
Described pyrrolin [1,2-a] and quinoxaline compound as hydrogen source capable of circulation, use pyrroles [1,2-a] in reaction and quinoxaline compound is hydrogen source precursor capable of circulation, its consumption is for press imines: pyrroles [1,2-a] the mol ratio 1:0.001-1:0.2 of quinoxaline.
The organic solvent reacting used is one or more in tetrahydrofuran (THF), methylene dichloride, toluene, Isosorbide-5-Nitrae-dioxane, benzene.
Step temperature of reaction used is 0-100oC.
7, the method for claim 1, it is characterized in that: described reaction formula is to 3-aryl-2H-benzene [b] [1,4] Bing oxazine quinoline compounds and 1-alkyl-3-aryl quinoxaline-2 (1H)-one compound asymmetric hydrogenation result the best, enantiomeric excess can reach 92%.
The present invention has the following advantages:
1. raw material is simple and easy to get.
2. reaction conditions is gentle, and reactive behavior is high, and feedstock conversion is complete, and convenient separation, can obtain highly purified product.
3. present method is by pyrrolin [1,2-a] and the in-situ regeneration of quinoxaline is applied in the asymmetric transfer hydrogenation of imines, only need add the pyrrolin [1,2-a] of catalytic amount and quinoxaline can high enantioselective synthesis Chiral Amine.
Accompanying drawing explanation
Fig. 1 is asymmetric transfer hydrogenation synthesis of chiral 1-alkyl-3-aryl-3,4-dihydro-quinoxalin-2 (1H)-one compound 6
Embodiment
Below by embodiment in detail the present invention is described in detail, but the present invention is not limited to following embodiment.
Embodiment 1: the optimization of condition
In glove box, to being added with 3-phenyl-2H-benzene [b] [Isosorbide-5-Nitrae] Bing oxazine (3a), pyrroles [1,2-a] quinoxaline (1,0.1eq.) and in the ampere bottle of chiral phosphoric acid ((S)-5,1mol%) add 2 milliliters of solvents (benzene: tetrahydrofuran (THF)=2:1).Load autoclave, be filled with 40psi hydrogen, under 25oC after stirring reaction 15-24h, direct column chromatography (volume ratio of eluent sherwood oil and ethyl acetate is 20:1) obtains pure product, and reaction formula is as follows:
Transformation efficiency is slightly composed by nuclear-magnetism and is determined, the enantiomeric excess Chiral liquid chromatography of product measures, in table 1.
The optimization of table 1. bionical asymmetric hydrogenation synthesis of chiral amine condition
anot hydrogenation source precursor. b40℃。
Embodiment 2: asymmetric transfer hydrogenation synthesis of chiral 3-aryl-3,4-dihydro-2H-benzene [b] [Isosorbide-5-Nitrae] Bing oxazine quinoline compound 4
In glove box, to being added with 3-aryl-2H-benzene [b] [Isosorbide-5-Nitrae] Bing oxazine (3), pyrroles [1,2-a] quinoxaline (1,0.1eq.) and in the ampere bottle pipe of chiral phosphoric acid ((S)-5,1mol%) add 2 milliliters of solvents (benzene: tetrahydrofuran (THF)=2:1).Load autoclave, be filled with 40psi hydrogen, at 40 DEG C after stirring reaction 15-24h, direct column chromatography (volume ratio of eluent sherwood oil and ethyl acetate is 20:1) obtains pure product, and reaction formula is as follows:
Productive rate is separation yield, and the enantiomeric excess Chiral liquid chromatography of product measures, in table 2.
Table 2. asymmetric transfer hydrogenation synthesis of chiral 3-aryl-3,4-dihydro-2H-benzene [b] [Isosorbide-5-Nitrae] Bing oxazine quinoline compound 4
The present invention is to 3-aryl-2H-benzene [b] [1, the asymmetric bionical hydrogenation of 4] Bing oxazines (3) obtains corresponding chiral 3-aryl-3,4-dihydro-2H-benzene [b] [Isosorbide-5-Nitrae] Bing oxazine quinoline compound 4, its productive rate can reach 96%, and enantiomeric excess can reach 89%.The present invention's practicality easy and simple to handle, enantioselectivity is high, and productive rate is good, and reaction has Atom economy, environmentally friendly.
Embodiment 3: asymmetric transfer hydrogenation synthesis of chiral 1-alkyl-3-aryl-3,4-dihydro-quinoxalin-2 (1H)-one compound 5
In glove box, to being added with 1-alkyl-3-aryl quinoxaline-2 (1H)-one compound (5), pyrroles [1,2-a] and quinoxaline (1,0.1eq.) and in the ampere bottle of chiral phosphoric acid ((S)-5,1mol%) add 2 milliliters of solvents (benzene: methylene dichloride=1:2).Load autoclave, be filled with 500psi hydrogen, under 40oC after stirring reaction 15-24h, direct column chromatography (volume ratio of eluent sherwood oil and methylene dichloride is 1:1) obtains pure product, and reaction formula is as follows:
Productive rate is separation yield, and the enantiomeric excess Chiral liquid chromatography of product measures, and sees Fig. 1
Fig. 1. asymmetric transfer hydrogenation synthesis of chiral 1-alkyl-3-aryl-3,4-dihydro-quinoxalin-2 (1H)-one compound 6
(R)-3-Phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine(4a).Yield92%,92%ee,[α] 20 D=-135.5(c0.60,CHCl 3)[lit.:[α] RT D=+102.0(c1.08,CHCl 3)for88%ee]; 1H NMR(400MHz,CDCl 3)δ7.40–7.33(m,5H),6.88–6.82(m,2H),6.68–6.65(m,2H),4.50(dd,J=8.6,2.8Hz,1H),4.28(dd,J=10.6,2.8Hz,1H),4.00–3.96(m,2H); 13C NMR(100MHz,CDCl 3)δ143.7,139.3,134.1,129.0,128.5,127.4,121.7,119.1,116.8,115.5,71.1,54.4;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=11.5min(maj),t 2=15.2min.
(R)-3-p-Tolyl-3,4-dihydro-2H-benzo[b][1,4]oxazine(4b).Yield93%,85%ee,[α] 20 D=-158.0(c1.0,CHCl 3)[lit.:[α] 17D=-119.2(c0.88,CHCl 3)for86%ee]; 1H NMR(400MHz,CDCl 3)δ7.27(d,J=8.0Hz,2H),7.18(d,J=7.9Hz,2H),6.90–6.74(m,2H),6.74–6.57(m,2H),4.44(dd,J=8.6,2.8Hz,1H),4.24(dd,J=10.6,3.0Hz,1H),3.96(m,2H),2.35(s,3H); 13C NMR(100MHz,CDCl 3)δ143.7,138.3,136.3,134.2, 129.7,127.2,121.6,119.0,116.7,115.5,71.2,54.1,21.3;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=9.8min(maj),t 2=17.5min.
(R)-3-(Biphenyl-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(4c).Yield88%,88%ee,[α] 20D=-128.4(c0.5,CHCl 3)[lit.:[α] RT D=-93.1(c1.16,CHCl 3)for88%ee]; 1H NMR(400MHz,CDCl 3)δ7.59(t,J=8.2Hz,4H),7.50–7.39(m,4H),7.35(t,J=7.3Hz,1H),6.91–6.77(m,2H),6.70–6.65(m,2H),4.54(dd,J=8.4,2.7Hz,1H),4.31(dd,J=10.6,2.8Hz,1H),4.03–4.00(m,2H); 13C NMR(100MHz,CDCl 3)δ143.7,141.5,140.7,138.3,134.0,129.0,127.8,127.7,127.6,127.3,121.7,119.1,116.8,115.6,71.1,54.1;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=19.6min(maj),t 2=24.5min.
(R)-3-(4-Chlorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(4d).Yield92%,87%ee,[α] 20 D=-140.2(c1.0,CHCl 3)[lit.:[α] 17 D=-113.4(c0.96,CHCl 3)for88%ee]; 1H NMR(400MHz,CDCl 3)δ7.43–7.28(m,4H),6.85–6.80(m,2H),6.79–6.65(m,2H),4.48(dd,J=8.3,2.8Hz,1H),4.24(dd,J=10.7,2.8Hz,1H),3.97–3.92(m,2H); 13C NMR(100MHz,CDCl 3)δ143.7,137.9,134.5,133.8,129.2,128.7,121.8,119.3,116.8,115.6,70.9,53.8;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=13.0min(maj),t 2=22.1min.
(R)-3-(4-Bromophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(4e).Yield95%,88%ee,[α] 20 D=-126.6.0(c1.0,CHCl 3)[lit.:[α] 17 D=-101.6(c1.14,CHCl 3)for91%ee]; 1H NMR(400MHz,CDCl 3)δ7.50(d,J=8.1Hz,2H),7.26(d,J=7.6Hz,2H),6.85–6.78(m,2H),6.72–6.65(m,2H),4.46(d,J=7.7Hz,1H),4.24(d,J=10.6Hz,1H),4.11–3.80(m,2H); 13C NMR(100MHz,CDCl 3)δ143.6,138.4,133.7,132.1,129.0,122.3,121.8,119.3,116.8,115.6,70.8,53.8;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=13.9min(maj),t 2=23.7min;
(R)-3-(4-Fluorophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(4f).Yield95%,87%ee,[α] 20 D=-159.2(c0.5,CHCl 3)[lit.:[α] 17 D=-124.4(c0.9,CHCl 3)for88%ee]; 1H NMR(400MHz,CDCl 3)δ7.41–7.10(m,2H),7.10–7.06(m,2H),6.87–6.80(m,2H),6.74–6.67(m,2H),4.51(d,J=8.3Hz,1H),4.26(d,J=10.7Hz,1H),4.06–3.86(m,2H); 13C NMR(100MHz,CDCl 3)δ162.8(d, 1J C-F=246.7Hz),143.7,135.1(d, 4J C-F=3.0Hz),133.9,129.0(d, 3J C-F=8.1Hz),121.7,119.3,116.8,116.0,115.7(d, 2J C-F=19.5Hz),71.1(d, 5J C-F=1.4Hz),53.7; 19F NMR(377MHz,CDCl 3)δ-113.8(s,1F);HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=11.1min(maj),t 2=16.6min;
(R)-3-(3-Methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(4g).Yield89%,88%ee,[α] 20 D=-140.8(c0.6,CHCl 3)[lit.:[α] 17 D=+84.6(c0.87,CHCl 3)for87%ee]; 1H NMR(400MHz,CDCl 3)δ7.31–7.25(m,1H),7.01–6.94(m,2H),6.88–6.79(m,3H),6.73–6.64(m,2H),4.49(dd,J=8.5,2.6Hz,1H),4.29(dd,J=10.6,2.9Hz,1H),3.99(dd,J=10.4,8.8Hz,2H),3.81(s,3H); 13C NMR(100MHz,CDCl 3)δ160.2,143.7,141.0,134.0,130.0,121.7,119.6,119.1,116.8,115.6,113.9,112.9,71.1,55.5,54.3;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=17.9min(maj),t 2=20.0min.
(R)-3-(3-Bromophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(4h).Yield90%,92%ee,[α] 20 D=-143.6(c1.0,CHCl 3)[lit.:[α] RT D=-118.1(c1.16,CHCl 3)for92%ee]; 1H NMR(400MHz,CDCl 3)δ7.58(s,1H),7.48(d,J=7.9Hz,1H),7.34(d,J=7.7Hz,1H),7.28–7.24(m,1H),6.85(dd,J=15.5,8.1Hz,2H),6.77–6.63(m,2H),4.57–4.40(m,1H),4.28(d,J=10.4Hz,1H),4.00–3.95(m,2H); 13C NMR(100MHz,CDCl 3)δ143.6,141.8,133.6,131.6,130.5,130.4,126.0,123.1,121.8,119.4,116.8,115.7,70.8,53.9;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=13.6min(maj),t 2=18.3min.
(R)-3-(Naphthalen-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(4i).Yield87%,84%ee,[α] 20 D=-150.2(c0.6,CHCl 3)[lit.:[α] 17 D=-134.4(c1.04,CHCl 3)for87%ee]; 1H NMR(400MHz,CDCl 3)δ7.89–7.85(m,4H),7.54–7.50(m,3H),6.94–6.82(m,2H),6.76–6.72(m,2H),4.69(d,J=8.2Hz,1H),4.38(dd,J=10.7,2.7Hz,1H),4.12–4.07(m,2H); 13C NMR(100MHz,CDCl 3)δ143.8,136.7,134.1,133.5,133.5,128.8,128.1,127.9,126.6,126.4,126.3,125.1,121.7,119.2,116.8,115.6,71.1,54.5;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=18.1min(maj),t 2=31.5min.
(R)-6-Chloro-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine(4j).Yield96%,87%ee,[α] 20 D=-111.2(c1.0,CHCl 3)[lit.:[α] 25 D=+52.6(c1.0,CHCl 3)for91%ee]; 1H NMR(400MHz,CDCl 3)δ7.43–7.27(m,5H),6.78–6.77(m,1H),6.69–6.61(m,2H),4.50(d,J=7.7Hz,1H),4.28(d,J=10.5Hz,1H),4.08(bs,1H),3.97(dd,J=9.5Hz,J=8.4Hz,1H); 13C NMR(100MHz,CDCl 3)δ142.2,138.8,135.0,129.1,128.7,127.3,126.3,118.5,117.6,114.9,71.0,54.1;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=11.2min(maj),t 2=13.4min.
(R)-6-Chloro-3-(3-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(4k).White solid,mp137-139℃,yield94%,90%ee,[α] 20 D=-146.3(c1.0,CHCl 3); 1H NMR(400MHz,CDCl 3)δ7.33–7.26(m,1H),6.97–6.88(m,3H),6.77–6.74(m,1H),6.70–6.58(m,2H),4.48–4.45(m,1H),4.34–4.21(m,1H),4.07(bs,1H),3.96(dd,J=10.6,8.5Hz,1H),3.82(s,3H); 13C NMR(100MHz,CDCl 3)δ160.3,142.2,140.5,134.9,130.1,126.3,119.5,118.6,117.6,114.9,114.0,112.9,71.0,55.5,54.1;HPLC(OD-H,elute:Hexanes/i-PrOH=70/30,detector:230nm,flow rate:0.7mL/min),t 1=20.0min,t 2=26.2min(maj);HRMS Calculated For C 15H 15ClNO 2[M-H]-276.0791,found:276.0786.
(R)-N-(2,2-Difluoro-1-phenylethyl)-4-methoxyaniline(6a).85%ee,[α] 20 D=-135.1(c1.0,CHCl 3)[lit.:[α] 20 D=+153.0(c0.4,CHCl 3)for92%ee]; 1H NMR(400MHz,CDCl 3)δ7.38(d,J=7.1Hz,2H),7.35–7.27(m,3H),6.95(dd,J=7.2,4.5Hz,2H),6.88(d,J=7.1Hz,1H),6.75(d,J=7.5Hz,1H),5.07(s,1H),4.35(brs,1H),3.40(s,3H); 13C NMR(100MHz,CDCl 3)δ166.2,139.3,134.7,128.9,128.5,128.5,127.3,123.9,119.7,115.0,114.1,61.0,29.4;HPLC(AD-H,elute:Hexanes/i-PrOH=80/20,detector:254nm,flow rate:1.0mL/min),t 1=10.8min,t 2=13.7min(maj).
(R)-N-(2,2,3,3,4,4,4-Heptafluoro-1-phenylbutyl)-4-methoxyaniline(6b).84%ee,[α] 20 D=-93.2(c0.4,CHCl 3)[lit.:[α] 20 D=+106.2(c0.4,CHCl 3)for89%ee]; 1H NMR(400MHz,CDCl 3)δ7.34–7.18(m,2H),7.12(d,J=8.0Hz,2H),6.98–6.90(m,2H),6.87–6.79(m,1H),6.77–6.67(m,1H),5.02(s,1H),4.31(brs,1H),3.39(s,3H),2.31(s,3H); 13C NMR(100MHz,CDCl 3)δ166.4,138.2,136.3,134.7,129.6,128.6,127.2,123.9,119.7,114.9,114.1,60.8,29.4,21.3;HPLC(AD-H,elute:Hexanes/i-PrOH=80/20,detector:220nm,flow rate:1.0mL/min),t 1=11.0min,t 2=14.7min(maj).
(R)-N-(2,2-difluoro-1-phenylbutyl)-4-methoxyaniline(6c).86%ee,[α] 20 D=-66.8(c0.4,CHCl 3)[lit.:[α] 20 D=+74.2(c0.4,CHCl 3)for91%ee]; 1H NMR(400MHz,CDCl 3)δ7.40(d,J=6.2Hz,2H),7.33(d,J=6.9Hz,3H),7.24(d,J=8.0Hz,1H),6.99(dd,J=9.9,5.1Hz,1H),6.87(dd,J=10.3,5.0Hz,1H),6.76(d,J=7.7Hz,1H),5.43(d,J=10.6Hz,1H),5.30(d,J=10.6Hz,1H),5.05(s,1H),4.36(brs,1H),3.34(s,3H); 13C NMR(100MHz,CDCl 3)δ167.4,138.7,134.7,129.0,128.6,127.5,127.3,124.6,120.1,116.2,114.5,74.0,61.0,56.6;HPLC(AD-H,elute:Hexanes/i-PrOH=80/20,detector:220nm,flow rate:1.0mL/min),t 1=9.6min,t 2=12.6min(maj).
(R)-4-Methoxy-N-(2,2,3,3,3-pentafluoro-1-phenylpropyl)aniline(6d).89%ee,[α] 20 D=-77.5(c0.2,CHCl 3)[lit.:[α] 20 D=+79.0(c0.2,CHCl 3)for91%ee]; 1H NMR(400MHz,CDCl 3)δ7.43(d,J=6.5Hz,2H),7.36–7.30(m,3H),7.26–7.19(m,3H),7.15(d,J=7.3Hz,2H),6.90(t,J=7.6Hz,1H),6.82(d,J=8.0Hz,1H),6.78–6.65(m,2H),5.29(d,J=16.1Hz,1H),5.17(s,1H),5.08(d,J=16.1Hz,1H),4.42(brs,1H); 13C NMR(100MHz,CDCl 3)δ166.3,139.1,136.8,134.8,129.0,128.9,128.5,127.7,127.3,127.3,126.6,124.0,119.8,115.8,114.4,61.0,46.0;HPLC(AD-H,elute:Hexanes/i-PrOH=80/20,detector:220nm,flow rate:1.0mL/min),t 1=18.9min,t 2=20.7min(maj).
The present invention is to 1-alkyl-3-aryl-3, the asymmetric bionical hydrogenation of 4-dihydro-quinoxalin-2 (1H)-one compound (5) obtains corresponding chirality 1-alkyl-3-aryl-3,4-dihydro-quinoxalin-2 (1H)-one compound 6, its transformation efficiency can reach 98%, and enantiomeric excess can reach 89%.The present invention's practicality easy and simple to handle, enantioselectivity is high, and productive rate is good, and reaction has Atom economy, environmentally friendly.

Claims (7)

1. the method for a bionical asymmetric hydrogenation synthesis of chiral amine, it is characterized in that: its catalyst system is that chiral phosphoric acid (CPA) makes chiral catalyst, the pyrrolin [1 of in-situ regeneration, 2-a] and quinoxaline compound as hydrogen source capable of circulation, complex compound is as regenerated catalyst for transition metal [Ru (II)], and reaction formula is as follows:
Described R 1, R 2for the alkyl of C1-C10; Phenyl and containing substituent phenyl ring, substituting group is a kind of substituting group in F, Cl, Br, Me, MeO or two kinds of substituting groups;
Described R 3for phenyl and containing substituent phenyl ring;
Described R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11be respectively the substituted aryl of hydrogen, C1-C6 alkyl, aryl or C7-C12, substituting group is CF 3, a kind of substituting group in Cl, Br, Me, MeO or two kinds of substituting groups;
Described CPA is the chiral phosphoric acid of octahydro dinaphthol skeleton or dinaphthol skeleton, and Ar is 1-position naphthyl, benzene and containing substituent phenyl ring, and substituting group is F, Cl, CF 3, a kind of substituting group in Me, MeO or two kinds of substituting groups;
The reactions steps of synthesis of chiral amine is:
Imines substrate A being dissolved in concentration is in the organic solvent of 0.01-1.0mol/L, and to this system by imines: the mol ratio 1:0.001-1:0.1 of metal catalyst adds metal catalyst, metal catalyst is the metal complex of Ru (II); By imines: the mol ratio 1:0.001-1:0.1 of chiral phosphoric acid adds chiral phosphoric acid CPA catalyzer; By imines: pyrroles [1,2-a] the mol ratio 1:0.001-1:0.2 of quinoxaline adds hydrogen source precursor 1 capable of circulation; After stirring, reaction system to be transferred in autoclave and to pour hydrogen, hydrogen pressure 1-100atm; After 0-100oC stirring reaction 6-48h, carefully discharge remaining hydrogen, column chromatography or recrystallization obtain Chiral Amine.
2. the method for claim 1, is characterized in that: transition metal [Ru (II)] complex compound as regenerated catalyst, catalytic hydrogenation pyrroles [1,2-a] quinoxaline compound.
3. the method for claim 1, is characterized in that: described catalyzer is chiral phosphoric acid, is by chirality BINOL or H 8-BINOL is by after 3,3 ' position iodate and corresponding substituted benzene boric acid ArB (OH) 2through Suzuki coupling preparation, in reaction, the usage quantity of chiral phosphoric acid catalyzer and the mol ratio of imines A are 0.01:1-0.075:1.
4. the method for claim 1, it is characterized in that: described pyrrolin [1,2-a] and quinoxaline compound as hydrogen source capable of circulation, pyrroles [1 is used in reaction, 2-a] and quinoxaline compound is hydrogen source precursor capable of circulation, its consumption is for press imines: pyrroles [1,2-a] the mol ratio 1:0.001-1:0.2 of quinoxaline.
5. the method for claim 1, is characterized in that: the organic solvent reacting used is one or more in tetrahydrofuran (THF), methylene dichloride, toluene, Isosorbide-5-Nitrae-dioxane, benzene.
6. the method for claim 1, is characterized in that: temperature of reaction used is 0-100 DEG C.
7. the method for claim 1, it is characterized in that: described reaction formula is to 3-aryl-2H-benzene [b] [1,4] Bing oxazine quinoline compounds and 1-alkyl-3-aryl quinoxaline-2 (1H)-one compound asymmetric hydrogenation result the best, enantiomeric excess can reach 92%.
CN201310690964.9A 2013-12-13 2013-12-13 Method for synthesizing chiral amine through biomimetic asymmetric hydrogenation Pending CN104710377A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108117569A (en) * 2016-11-29 2018-06-05 中国科学院大连化学物理研究所 A kind of method of organic catalysis Friedel-Crafts reaction synthesis of chiral amine group phosphonate
CN110194735A (en) * 2018-02-27 2019-09-03 河南大学 A kind of chirality 3-(2- pyridine) -3- aryl substitutional amine-group compound visible light asymmetry catalysis synthetic method
CN111170949A (en) * 2018-11-09 2020-05-19 中国科学院大连化学物理研究所 Method for synthesizing 3, 4-dihydropyrimidinone compound by asymmetric transfer hydrogenation

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108117569A (en) * 2016-11-29 2018-06-05 中国科学院大连化学物理研究所 A kind of method of organic catalysis Friedel-Crafts reaction synthesis of chiral amine group phosphonate
CN110194735A (en) * 2018-02-27 2019-09-03 河南大学 A kind of chirality 3-(2- pyridine) -3- aryl substitutional amine-group compound visible light asymmetry catalysis synthetic method
CN110194735B (en) * 2018-02-27 2022-02-22 河南大学 Visible light asymmetric catalytic synthesis method of chiral 3- (2-pyridine) -3-aryl substituted amine compound
CN111170949A (en) * 2018-11-09 2020-05-19 中国科学院大连化学物理研究所 Method for synthesizing 3, 4-dihydropyrimidinone compound by asymmetric transfer hydrogenation
CN111170949B (en) * 2018-11-09 2021-07-27 中国科学院大连化学物理研究所 Method for synthesizing 3, 4-dihydropyrimidinone compound by asymmetric transfer hydrogenation

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