CN108084079A - Novel chiral nitrogen oxygen ligand and its synthetic method - Google Patents

Novel chiral nitrogen oxygen ligand and its synthetic method Download PDF

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CN108084079A
CN108084079A CN201711405733.3A CN201711405733A CN108084079A CN 108084079 A CN108084079 A CN 108084079A CN 201711405733 A CN201711405733 A CN 201711405733A CN 108084079 A CN108084079 A CN 108084079A
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冯小明
陈龙
刘小华
林丽丽
周鹏飞
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
    • B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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Abstract

The invention discloses Novel series chiral nitrogen oxygen ligand and its synthetic methods, with simple amino acid and amino acid derivativges proline, thunder rice acid, nipecotic acid and the different quinoline acid of tetrahydrochysene are raw material, pass through a series of critical process processes, finally synthesize 4 carbon, 6 carbon, 7 carbon and 8 carbon novel chiral nitrogen oxygen, 23, A propane carbon, 2, 2 two 3, B propane carbon, 1, 1 pair of methyl cyclopropane, 3 carbon, 1, 1 pair of methyl cyclobutane, 3 carbon, 1, 1 pair of methyl cyclopentane, 3 carbon and 1, 1 pair of hexahydrotoluene, 3 carbon novel chiral nitrogen oxygen, paraxylene, meta-xylene and ortho-xylene novel chiral nitrogen oxygen, p-Diethylbenzene, the synthetic method of the novel chirals nitrogen oxygen ligand such as NSC 62102 and adjacent diethylbenzene.Above-mentioned novel chiral nitrogen oxygen molecule can realize high enantioselectivity in a variety of asymmetric reactions and with high reactivity, solve existing nitrogen oxygen cannot catalytic reaction, be of great significance.

Description

Novel chiral nitrogen oxygen ligand and its synthetic method
Technical field
The present invention relates to chiral nitrogen oxygen ligand for being used as catalyst in asymmetric catalysis and preparation method thereof, especially It is with simple amino acid and amino acid derivativges proline, thunder rice acid, nipecotic acid and tetrahydroisoquinoline acid are raw material, pass through one Serial critical process process finally synthesizes 4 carbon novel chiral nitrogen oxygen, 6 carbon novel chiral nitrogen oxygen, 7 carbon novel chirals Nitrogen oxygen, 8 carbon novel chiral nitrogen oxygen, 3 carbon novel chiral nitrogen oxygen of 2-A- propane, 2,2- bis- 3, B- propane carbon novel chiral nitrogen Oxygen, 1,1- double -3 carbon novel chiral nitrogen oxygen of methyl cyclopropane, 1,1- double -3 carbon novel chiral nitrogen oxygen of methyl cyclobutane, 1, 1- pairs -3 carbon novel chiral nitrogen oxygen of methyl cyclopentane, 1,1- double -3 carbon novel chiral nitrogen oxygen of hexahydrotoluene, paraxylene, Meta-xylene and ortho-xylene and aryl substitution novel chiral nitrogen oxygen, p-Diethylbenzene, NSC 62102 and adjacent diethylbenzene and virtue Base substitution etc. novel chirals nitrogen oxygen ligand and its synthetic method.
(A=methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, phenyl, benzyl.)
(B=methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, phenyl, benzyl.)
Background technology
Asymmetry catalysis and the hot spot that synthesis is current organic chemistry filed.2001, the William of Monsanto Chemicals S. Knowles (William S.Knowles), the Ryoji Noyori (Ryoji Noyori) of Japan Nagoya university and this gram of the U.S. The Nobel chemistry Prize for obtaining 2001 of Sharp Leix (K.Barry Sharpless) three of Li Pusi research institutes, with table The evident outstanding contributions that they obtain in asymmetric catalysis research field, it is important with synthesizing that this embodies asymmetry catalysis Property, wherein three Nobel Laureate all design and develop excellent chiral ligand (Chem.Comm., 1968,1445； Acc.Chem. Res.1990,23,345-350；J.Org.Chem.,Vol.43,No.12,1978).Therefore, design and develop Go out novel chiral ligands and and catalyst system it is most important for different asymmetric catalysis.At present in asymmetric field In, the BINAP ligands of Ryoji Noyori et al. development；Weicheng Zhang and Xumu Zhang et al. development DuPhos ligands；Ham-Ulrich Blaser,Benoit Pugin,Felix Spindler,Esteban Mejia,and The Josiphos ligands of Antonio Togni et al. development；Shou-Fei Zhu and Qi-Lin Zhou et al. development Spiro ligands；The BOX ligands of Levi M.Stanley and Mukund P.Sibl et al. development；Cory C.Bausch and The PHOX ligands of Andreas Pfaltz et al. development；Wen-Zhen Zhang and Xiao-Bing Lu et al. development Chiral Salen Comlexes；Masakatsu Shibasaki and Shigeki Matsunaga et al. development BINOL ligands, here are the simple structure signals of various ligands.
Any of the above ligand can obtain good enantioselectivity in a series of asymmetric catalysis, but therefrom As can be seen that advantage chiral ligand and catalyst that they are developed all are rigid backbones, traditional concept thinks, chiral ligand is only Can have rigid backbone that could realize high enantioselectivity and high reactivity in asymmetric catalysis.Until 2011 Year, Feng little Ming seminars report the summary of 3 carbon chiral nitrogen oxygen ligands of the soft skeleton of first case in ACS Accounts, It is catalyzed asymmetry Een and aza-Een Reaction, F-C Reaction, Roskamp Reaction, Sulfa- Outstanding result is achieved in the series reactions such as Michael Reaction, Michael Reaction (Acc.Chem.Res.,2011,44(8), pp 574–587).Here is 3 carbon chiral nitrogen oxygen and simple synthetic reaction Flow.
Later and in 2011, Feng little Ming seminars report 2 carbon chiral nitrogen oxygen ligands (Org. Lett., 2011,13(15),pp 3814–3817)；Afterwards in 2016, Feng little Ming seminars report 5 carbon chiral nitrogen oxygen ligands again (ACS Catal.,2016,6(4),pp 2482–2486).Here is 2 carbon and 5 carbon chiral nitrogen oxygen and simple synthesis Reaction process.
In conclusion on the basis of existing chiral nitrogen oxygen, it has been found that chiral nitrogen oxygen ligand can be used for Een and aza- Een Reaction、F-C Reaction、Roskamp Reaction、Sulfa-Michael Reaction、Michael Reaction、 Oxa-Michael Reaction、Herero-DA Reaction、Haloamination、Henry and aza-Henry Reaction、Hydroxymethylation、Cyanation Reaction、Mannich Reaction、 Aldol Reaction、 Allylation Reaction、Amination Reaction、α-ChlorinationyAnd light is urged Change reaction etc., therefore Development of Novel hand-type nitrogen oxygen ligand, for asymmetric catalysis and synthesis, solving existing nitrogen oxygen cannot Catalytic reaction is of great significance.
The content of the invention
The object of the present invention is to provide have soft skeleton, intermediate chain in a kind of molecular structure with 4 carbon, 6 carbon, 7 The chiral nitrogen oxygen ligand of a carbon and 8 carbon.
The object of the present invention is achieved like this：
By the chiral nitrogen oxygen ligand of following various expression：
L4- PrR, L4- RaR, L4- PiR, L4- PqR, L6- PrR, L6- RaR, L6- PiR, L6- PqR, L7- PrR, L7- RaR, L7- PiR, L7- PqR, L8- PrR, L8- RaR, L8- PiR, L8- PqR, LA- PrR, LA- RaR, LA- PiR, LA- PqR, LB- PrR, LB- RaR, LB- PiR, LB- PqR, Lc- PrR, Lc- RaR, Lc- PiR, Lc- PqR, Lcb- PrR, Lcb- RaR, Lcb- PiR, Lcb- PqR, Lcp- PrR, Lcp- RaR, Lcp- PiR, Lcp- PqR, Lch- PrR, Lch- RaR, Lch- PiR, Lch- PqR, Lpx- PrR, Lpx- RaR, Lpx- PiR, Lpx- PqR, Lmx- PrR, Lmx- RaR, Lmx- PiR, Lmx- PqR, Lox- PrR, Lox- RaR, Lox- PiR, Lox- PqR, Lpd- PrR, Lpd- RaR, Lpd- PiR, Lpd- PqR, Lmd- PrR, Lmd- RaR, Lmd- PiR, Lmd- PqR, Lod- PrR, Lod- RaR, Lod- PiR, Lod-PqR structures are as follows：
A=methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, phenyl, benzyl.
B=methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, phenyl, benzyl.
All of above novel chiral nitrogen oxygen
R=2,6-iPr2C6H3,2,4,6-iPr3C6H2,2,6-Et2C6H3,2,6-Me2C6H3,2,4,6-Me3C6H2,Ph, CH2C6H5,2,6-Et2 -4-MeC6H2,tBu,cyclohexyl,cyclopentyl,C6H5(CH2)2,3- anthracenylmethyl,4-BrC6H4,1-adama ntyl,2,6-Me2-4-tBuC6H2,3,5-tBu2C6H3,3,5- Me2C6H3,Ph2CH,(S)-C6H5CHCH3,2,6-bis(trifluoromet hyl)phenyl,2,4,6-tris (trifluoromethyl) phenyl, 3,5-tris (trifluoromethyl) phenyl etc..2,6- in above formulaiPr2C6H3 In represent 2,6- diisopropyl phenyls；2,4,6-iPr3C6H2Represent 2,4,6- triisopropyl phenyl； 2,6-Et2C6H3Represent 2, 6- diethyl phenyls 2,6-Me2C6H3Represent 2,6- 3,5-dimethylphenyls；2,4,6-Me3C6H2Represent 2,4,6- trimethylphenyls；Ph Represent phenyl；CH2C6H5Represent benzyl；2,6-Et2-4-MeC6H2Represent -4 aminomethyl phenyl of 2,6- diethyl；TBu represents tertiary fourth Base；Cyclohexyl represents cyclohexyl；Cyclopentyl represents cyclopenta；C6H5(CH2)2Represent phenethyl；3- Anthracenylmethyl represents 3- anthracene methyl；4-BrC6H4Represent 4- bromophenyls；1-adamantyl represents 1- adamantyls； 2,6-Me2-4-tBuC6H2Represent 2,6- dimethyl -4- tert-butyl-phenyls；3,5-tBu2C6H3Represent 3,5- di-tert-butyl-phenyls；3, 5-Me2C6H3Represent 3,5- 3,5-dimethylphenyls；Ph2CH represents benzhydryl；(S)-C6H5CHCH3Represent (S) -1- phenylethyls； 2,6-bis (trifluoromethyl) phenyl represents 2,6- bis- (trifluoromethyl) phenyl；2,4,6-tris (trifluoromethyl) phenyl represents 2,4,6- tri- (trifluoromethyl) phenyl； 3,5-tris(trifluoromethyl) Phenyl represents 3,5- bis- (trifluoromethyl) phenyl.
The problem to be solved in the present invention is design synthesis various new chiral nitrogen oxygen, it has been found that previous chiral nitrogen oxygen is matched somebody with somebody Chain length only has 2 carbon, 3 carbon and 5 carbon among body, therefore we devise 4 carbon chiral nitrogen oxygen ligands, 6 carbon chiral nitrogens Oxygen ligand, 7 carbon chiral nitrogen oxygen ligands and 8 carbon chiral nitrogen oxygen ligands, in addition, it has been found that, previous chiral nitrogen oxygen Ligand intermediate chain is simple straight chain, therefore we devise 3 carbon chiral nitrogen oxygen ligands of 2-A- propane, 2,2- bis- B- propane 3 A carbon novel chiral nitrogen oxygen, 1,1- double -3 carbon chiral nitrogen oxygen ligands of methyl cyclopropane, 1,1- double -3 carbon hands of methyl cyclobutane Property nitrogen oxygen ligand, 1,1- it is double -3 carbon chiral nitrogen oxygen ligands of methyl cyclopentane, 1,1- be double -3 carbon chiral nitrogen oxygen of hexahydrotoluene Ligand, paraxylene, meta-xylene and ortho-xylene and aryl substituted chiral nitrogen oxygen ligand, p-Diethylbenzene, NSC 62102 and By changing the structure of chain length and chain, new chiral nitrogen is explored with this for adjacent diethylbenzene and aryl substituted chiral nitrogen oxygen ligand Oxygen ligand carrys out catalytic asymmetric reaction.
It is a further object of the present invention to provide the synthetic methods of above-mentioned ligand：This method is mainly proline, thunder rice, piperidines The different coupling methods of synthesis and various amides with Tetrahydroisoquinoli- morpholine amide.
It is another object of the present invention to what is be achieved in that：A kind of synthetic method of chiral nitrogen oxygen ligand, wherein L4- PrR, L4- RaR, L4- PiR, L4- PqR is synthesized in two steps, and the first step is aldehyde source as coupling agent with 2,5- dimethoxy-tetrahydrofurans, with Sodium triacetoxy borohydride is reducing agent, with 1,2- dichloroethanes for solvent, amide and aldehyde molar ratio 0.5:1, reaction temperature 0 It DEG C -50 DEG C, reaction time 4-72h, carries out in next step after column chromatography；Second step using m-CPBA as oxidant, using dichloromethane as Solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20- 300min obtains product after column chromatography；
Wherein L6- PrR, L6- RaR, L6- PiR, L6- PqR is synthesized in two steps, and the first step adds sodium acid carbonate oxygen with sodium metaperiodate It is aldehyde source as coupling agent that 1,2- cyclohexanediols are oxidized to hexandial by change system, using sodium triacetoxy borohydride to reduce Agent, with 1,2- dichloroethanes for solvent, sodium metaperiodate, sodium acid carbonate and 1,2- cyclohexanediol molar ratio are 1:1:1-2:2.1:1, Amide and aldehyde molar ratio 0.5:1,0 DEG C -50 DEG C, reaction time 4-72h of reaction temperature is carried out in next step after column chromatography；Second step Using m-CPBA as oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction 0 DEG C of temperature -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein L7- PrR, L7- RaR, L7- PiR, L7- PqR is synthesized in two steps, and the first step is with 1,7- dibromo-heptanes as coupling Agent, it is amide, 1,7- dibromo-heptanes, two different using acetonitrile as solvent using sodium iodide as catalyst using diisopropyl ethyl amine as alkali Ethylamine and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, reaction time 8- 36 it is small when, carry out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, obtained by the first step Product and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min, after column chromatography To product；
Wherein L8- PrR, L8- RaR, L8- PiR, L8- PqR is synthesized in two steps, and the first step is with 1,8-, bis- bromooctanes as coupling Agent, it is amide, 1,8-, bis- bromooctanes, two different using acetonitrile as solvent using sodium iodide as catalyst using diisopropyl ethyl amine as alkali Ethylamine and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, reaction time 8- 36 it is small when, carry out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, obtained by the first step Product and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min, after column chromatography To product；
Wherein LA- PrR, LA- RaR, LA- PiR, LA- PqR is synthesized in two steps, and the first step is with 2-A-1,3-propanediol, tetrabromo Change carbon, triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide to urge Agent, using acetonitrile as solvent, amide, 2-A-1,3- dibromopropanes, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2: 0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is with m- CPBA is oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction temperature 0 DEG C -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；(A=methyl, ethyl, propyl, isopropyl, fourth Base, isobutyl group, tertiary butyl, phenyl, benzyl.)
Wherein LB- PrR, LB- RaR, LB- PiR, LB- PqR is synthesized in two steps, the first step with 2,2-, bis- B-1,3-propanediol, Carbon tetrabromide, triphenyl phosphorus and dichloromethane system for two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, with sodium iodide For catalyst, using acetonitrile as solvent, amide, 2,2-, bis- B-1,3- dibromopropanes, potassium carbonate and sodium iodide molar ratio 1:0.5:2: 0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step Using m-CPBA as oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction 0 DEG C of temperature -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；(B=methyl, ethyl, propyl, isopropyl, Butyl, isobutyl group, tertiary butyl, phenyl, benzyl.)
Wherein Lc- PrR, Lc- RaR, Lc- PiR, Lc- PqR is synthesized in two steps, and the first step is with 1,1- pairs-bromomethyl cyclopropane As coupling agent, using potassium carbonate as alkali, using sodium iodide as catalyst, using acetonitrile as solvent, amide, 1,1- be double-bromomethyl ring third Alkane, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, reaction time 8- 36 it is small when, carry out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, obtained by the first step Product and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min, after column chromatography To product；
Wherein Lcb- PrR, Lcb- RaR, Lcb- PiR, Lcb- PqR is synthesized in two steps, and the first step is with 1,1- pairs-bromomethyl ring fourth Alkane is as coupling agent, and using potassium carbonate as alkali, using sodium iodide as catalyst, using acetonitrile as solvent, amide, 1,1- be double-bromomethyl ring Butane, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, the reaction time When 8-36 is small, carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step institute Obtain product and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min, after column chromatography Obtain product；
Wherein Lcp- PrR, Lcp- RaR, Lcp- PiR, Lcp- PqR is synthesized in two steps, and the first step is with 1,1- pairs-bromomethyl ring penta Alkane is as coupling agent, and using potassium carbonate as alkali, using sodium iodide as catalyst, using acetonitrile as solvent, amide, 1,1- be double-bromomethyl ring Pentane, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, the reaction time When 8-36 is small, carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step institute Obtain product and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min, after column chromatography Obtain product；
Wherein Lch- PrR, Lch- RaR, Lch- PiR, Lch- PqR is synthesized in two steps, and the first step is with 1,1- pairs-bromomethyl hexamethylene Alkane is as coupling agent, and using potassium carbonate as alkali, using sodium iodide as catalyst, using acetonitrile as solvent, amide, 1,1- be double-bromomethyl ring Hexane, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, the reaction time When 8-36 is small, carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step institute Obtain product and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min, after column chromatography Obtain product；
Wherein Lpx- PrR, Lpx- RaR, Lpx- PiR, Lpx- PqR is synthesized in two steps, and the first step is using terephthalaldehyde as coupling Agent, using sodium triacetoxy borohydride as reducing agent, with 1,2- dichloroethanes for solvent, amide and aldehyde molar ratio 0.5:1, reaction 0 DEG C -50 DEG C, reaction time 4-72h of temperature is carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, with dichloromethane Alkane is solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20- 300min obtains product after column chromatography；
Wherein Lmx- PrR, Lmx- RaR, Lmx- PiR, Lmx- PqR is synthesized in two steps, and the first step is using m-terephthal aldehyde as coupling Agent, using sodium triacetoxy borohydride as reducing agent, with 1,2- dichloroethanes for solvent, amide and aldehyde molar ratio 0.5:1, reaction 0 DEG C -50 DEG C, reaction time 4-72h of temperature, column layer.It is carried out in next step after analysis；Second step is using m-CPBA as oxidant, with dichloro Methane is solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, the reaction time 20-300min obtains product after column chromatography；
Wherein Lox- PrR, Lox- RaR, Lox- PiR, Lox- PqR is synthesized in two steps, and the first step is using o-phthalaldehyde as coupling Agent, using sodium triacetoxy borohydride as reducing agent, with 1,2- dichloroethanes for solvent, amide and aldehyde molar ratio 0.5:1, reaction 0 DEG C -50 DEG C, reaction time 4-72h of temperature is carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, with dichloromethane Alkane is solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20- 300min obtains product after column chromatography；
Wherein Lpd- PrR, Lpd- RaR, Lpd- PiR, Lpd- PqR is synthesized in two steps, and the first step is with Isosorbide-5-Nitrae-benzoglycols, tetrabromo Change carbon, triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide to urge Agent, using acetonitrile as solvent, amide, Isosorbide-5-Nitrae-bis- -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2: 0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is with m- CPBA is oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction temperature 0 DEG C -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein Lmd- PrR, Lmd-RaR,Lmd- PiR, Lmd- PqR is synthesized in two steps, and the first step is with 1,3- benzoglycols, tetrabromo Change carbon, triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide to urge Agent, using acetonitrile as solvent, amide, 1,3- pairs -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2: 0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is with m- CPBA is oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction temperature 0 DEG C -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein Lod- PrR, Lod- RaR, Lod- PiR, Lod- PqR is synthesized in two steps, and the first step is with 1,2- benzoglycols, tetrabromo Change carbon, triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide to urge Agent, using acetonitrile as solvent, amide, 1,2- pairs -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2: 0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is with m- CPBA is oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction temperature 0 DEG C -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein each amide synthesis and its structure are as follows：
Compared with prior art, the beneficial effects of the invention are as follows：The present invention provides 4 carbon, 6 carbon, 7 carbon and 8 carbon Molecular structure for 3 carbon of simple straight chain and 2-A- propane, 2,2- bis- 3, B propane carbon, 1,1- double -3 carbon of methyl cyclopropane, 1,1- double -3 carbon novel chiral nitrogen oxygen of methyl cyclobutane, 1,1- double -3 carbon novel chiral nitrogen oxygen of methyl cyclopentane, 1,1- pair - 3 carbon novel chiral nitrogen oxygen of hexahydrotoluene, paraxylene, meta-xylene and ortho-xylene and aryl substitution, p-Diethylbenzene, NSC 62102 and adjacent diethylbenzene and the molecular structure of aryl substitution are non-simple straight chain, have soft skeleton in molecular structure, The above-mentioned novel chiral nitrogen oxygen of the present invention realizes high enantioselectivity and high reactivity with physical efficiency in asymmetric reaction, Synthetic method is simple, step is few and raw material is cheap and easily-available.
In conclusion on the basis of existing chiral nitrogen oxygen, it has been found that chiral nitrogen oxygen ligand can be used for Een and aza- Een Reaction、F-C Reaction、Roskamp Reaction、Sulfa-Michael Reaction、Michael Reaction、 Oxa-Michael Reaction、Herero-DA Reaction、Haloamination、Henry and aza-Henry Reaction、Hydroxymethylation、Cyanation Reaction、Mannich Reaction、 Aldol Reaction, Allylation Reaction, Amination Reaction, α-Chlorinationy and light Catalytic reaction etc., therefore Development of Novel hand-type nitrogen oxygen ligand solves existing nitrogen oxygen not for asymmetric catalysis and synthesis The catalytic reaction of energy, is of great significance.
Specific embodiment
Amide synthetic method each first can use following simple reaction process to represent:
Since amide is more, we are using R group as 2,6-iPr2C6H3(work as R=2,4,6- for example continuation is set forth belowiPr3C6H2,2,6-Et2C6H3,2,6-Me2C6H3,2,4,6-Me3C6H2,Ph,CH2C6H5,2,6-Et2-4-MeC6H2,tBu,cy clohexyl,cyclopentyl,C6H5(CH2)2,3-anthracenylmethyl,4-BrC6H4,1-adamantyl,2,6- Me2-4- tBuC6H2,3,5-tBu2C6H3,3,5-Me2C6H3,Ph2CH,(S)-C6H5CHCH3,2,6-bis (trifluoromethyl)phenyl,2, 4,6-tris(trifluoromethyl)phenyl,3,5-tris (trifluoromethyl) phenyl etc. is also this method)
When n is respectively 0 and 1, R 2,6-iPr2C6H3It is that can obtain：
Boc represents tertbutyloxycarbonyl in formula, and TFA represents trifluoroacetic acid,iPr represents isopropyl.
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
Prolinamide 1a is prepared from boc-protected proline：
First boc-protected proline is dissolved in organic solvent, acid anhydrides can be formed under triethylamine, isobutyl chlorocarbonate, It can be reacted afterwards with 2,6-DIPA and generate boc-protected prolinamide, it, can after column chromatography for separation purifies It is dissolved in after organic solvent and adds in trifluoroacetic acid and slough Boc blocking groups, using obtaining 1a after column chromatography for separation.Wherein, Boc is protected The proline of shield, triethylamine, the molar ratio of isobutyl chlorocarbonate and 2,6-DIPA are 1:1:1:1-1:1.2:1.2: 1.5；Boc-protected prolinamide, the molar ratio of trifluoroacetic acid are 1:1-1:1.2.First step charging sequence is protected for Boc Proline, triethylamine, be added dropwise under zero degree under isobutyl chlorocarbonate after 20-30 minutes, again zero degree 2,6- isopropyl anilines be added dropwise, Reaction temperature is room temperature, when the reaction time is 12-72 small.Second step reaction be boc-protected prolinamide is dissolved in it is organic After solvent, trifluoroacetic acid is added dropwise under zero degree, is neutralized afterwards with sodium hydrate aqueous solution, extract, column chromatography obtains 1a.
2a, 3a, 4a. can be obtained with identical method
Since novel nitrogen oxygen is too many, we are to synthesize various L-RaR as example, wherein when R is 2,6-iPr2C6H3Shi Jixu It is set forth below.
After compound 2a is obtained, compound L4- RaR synthetic reaction flows are as follows：
M-CPBA represents metachloroperbenzoic acid in formula, and DCM represents dichloromethane.
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
Butanedial is obtained under dilute hydrochloric acid hydrolysis with 2,5- dimethoxy-tetrahydrofurans first, it afterwards will reaction gained fourth two Aldehyde and 2a are in organic solvent 1, and 2- dichloroethanes mixes after stirring 15-30 minute, addition sodium triacetoxy borohydride, Product 2b, 2b be can obtain after column chromatography for separation purifies, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand L4-RaR.Wherein butanedial is recommended as 0.5 with 2a molar ratios:1,2b and m-CPBA molar ratios It is recommended as 1:2-1:2.2.First step reaction temperature is recommended as 0 DEG C -50 DEG C, when the reaction time is 4-72h small；Second step reacts Temperature is recommended as 0 DEG C -- and 30 DEG C, reaction time 20-300 is minute.
After compound 2a is obtained, compound L6- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
Add sodium acid carbonate oxidation system that 1,2- cyclohexanediols are oxidized to hexandial with sodium metaperiodate first, wherein reaction is high Sodium iodate, sodium acid carbonate and 1,2- cyclohexanediols molar ratio are 1:1:1-2:2.1:1, reaction temperature is room temperature, and the reaction time is When 24-48 is small.Gained hexandial is dissolved in 2a in organic solvent afterwards and being stirred, adds sodium triacetoxy borohydride, i.e., Product 2c can be obtained, wherein reaction hexandial is recommended as 0.5 with 2a molar ratios:1, reaction temperature is 0 DEG C -50 DEG C, reaction time 4- 72 it is small when.2c is after column chromatography for separation purifies, with m-CPBA under dichloromethane, it is possible to obtain final product --- and it is new Chiral nitrogen oxygen ligand L6- RaR, wherein reaction 2c is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- 30 DEG C, reaction time 20-300 is minute.
After compound 2a is obtained, compound L7- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
First by 2a and 1,7- dibromo-heptanes are dissolved in organic solvent acetonitrile, add in diisopropyl ethyl amine and sodium iodide, Reaction can obtain 2d, and product 2d is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand L7- RaR, the wherein first step reaction 2a, 1,7- dibromo-heptanes, diisopropyl ethyl amine and iodine Change sodium molar ratio and be recommended as 1:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time recommends For 8-36 it is small when.Second step reacts 2d and is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
After compound 2a is obtained, compound L8- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
First by 2a and 1, bis- bromooctanes of 8- are dissolved in organic solvent acetonitrile, add in diisopropyl ethyl amine and sodium iodide, Reaction can obtain 2e, and product 2e is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand L8- RaR, the wherein first step reaction 2a, 1,8-, bis- bromooctanes, diisopropyl ethyl and iodate Sodium molar ratio is recommended as 1:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as When 8-36 is small.Second step reacts 2e and is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
Due to LA- RaR is more, we are using A=methyl as example (A=ethyls, propyl, isopropyl, butyl, isobutyl group, uncle Butyl, phenyl, benzyl are also this method), after compound 2a is obtained, compound LA- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
First by 2- methyl-1s, 3-propanediol is dissolved in organic solvent dichloromethane, is added in carbon tetrabromide, is added under zero degree Triphenyl phosphorus can obtain 2- methyl-1s, 3- dibromopropanes, wherein reaction 2- methyl-1s, 3-propanediol, tetrabormated after reaction Carbon and triphenyl phosphorus molar ratio are recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, and the reaction time is recommended as 12- 48 it is small when.Afterwards by 2- methyl-1s, 3- dibromopropanes and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, instead Should be that can obtain product 2f, product 2f is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final Product --- novel chiral nitrogen oxygen ligand LA- RaR (R=2,6-iPr2C6H3, A=methyl) wherein react 2a, 2- methyl-1,3- bis- N-Propyl Bromide, potassium carbonate and sodium iodide molar ratio are recommended as 1:0.5:2:0.1-2:0.5:8:0.4, reaction temperature be recommended as 60 DEG C- 120 DEG C, the reaction time be recommended as 8-36 it is small when.Final step is reacted, and 2f is recommended as 1 with m-CPBA molar ratios:2-1:2.2, instead Temperature is answered to be recommended as 0 DEG C -- 30 DEG C.
Due to LB- RaR is more, we using B=methyl as example (B=, ethyl, propyl, isopropyl, butyl, isobutyl group, Tertiary butyl, phenyl, benzyl are also this method), after compound 2a is obtained, compound LB- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
2,2-dimethyl-1,3-propanediol is dissolved in organic solvent dichloromethane first, addition carbon tetrabromide, under zero degree Triphenyl phosphorus is added in, i.e. available 2,2- dimethyl -1,3- dibromopropanes after reaction, wherein 2 are reacted, 2- dimethyl -1,3- Propylene glycol, carbon tetrabromide and triphenyl phosphorus molar ratio are recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, reaction Time be recommended as 12-48 it is small when.2,2- dimethyl -1,3- dibromopropane and 2a are dissolved in organic solvent acetonitrile afterwards, added in Potassium carbonate and sodium iodide, reaction can obtain product 2g, and product 2g is after column chromatography for separation, with m-CPBA in dichloromethane Under, it is possible to obtain final product --- novel chiral nitrogen oxygen ligand LB- RaR (R=2,6-iPr2C6H3, A=methyl) it is wherein anti- 2a, 2,2- dimethyl -1,3- dibromopropanes, potassium carbonate and sodium iodide molar ratio is answered to be recommended as 1:0.5:2:0.1-2:0.5:8: 0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when.Final step is reacted, and 2g rubs with m-CPBA You are recommended as 1 by ratio:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
After compound 2a is obtained, compound Lc- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,1- first pairs-bromomethyl cyclopropane and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction Product 2h is can obtain, product 2h is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand Lc-RaR.Wherein reaction 2a, 1,1- pairs-bromomethyl cyclopropane, potassium carbonate and sodium iodide rubs You are recommended as 1 by ratio:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as 8-36 Hour.Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
After compound 2a is obtained, compound Lcb- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,1- first pairs-Bromomethylcyclobutane and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction It can obtain product 2h1, product 2h1After column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand Lcb-RaR.Wherein reaction 2a, 1,1- pairs-Bromomethylcyclobutane, potassium carbonate and sodium iodide rubs You are recommended as 1 by ratio:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as 8-36 Hour.Final step is reacted, 2h1It is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
After compound 2a is obtained, compound Lcp- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,1- first pairs-bromomethyl pentamethylene and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction It can obtain product 2h2, product 2h2After column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand Lcp-RaR.Wherein reaction 2a, 1,1- pairs-bromomethyl pentamethylene, potassium carbonate and sodium iodide rubs You are recommended as 1 by ratio:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as 8-36 Hour.Final step is reacted, 2h2It is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
After compound 2a is obtained, compound Lch- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,1- first pairs-bromomethylcyclohexane and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction It can obtain product 2h3, product 2h3After column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand Lch-RaR.Wherein reaction 2a, 1,1- pairs-bromomethylcyclohexane, potassium carbonate and sodium iodide rubs You are recommended as 1 by ratio:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as 8-36 Hour.Final step is reacted, 2h3It is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
After compound 2a is obtained, compound Lpx- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
2a and terephthalaldehyde are dissolved in organic solvent 1 first, in 2- dichloroethanes, glacial acetic acid is added in, adds three second Triacetoxyborohydride, you can obtain product 2i, product 2i is after column chromatography for separation, with m-CPBA under dichloromethane, so that it may To obtain final product --- novel chiral nitrogen oxygen ligand Lpx-RaR.Wherein react 2a, terephthalaldehyde, glacial acetic acid and triacetyl Oxygroup sodium borohydride molar ratio is recommended as 1:0.5:1:1-1:0.2:2:2.Reaction temperature is recommended as 0 DEG C -50 DEG C, and the reaction time pushes away Recommend for 4-72 it is small when.Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C --30℃。
After compound 2a is obtained, compound Lmx- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
2a and m-terephthal aldehyde are dissolved in organic solvent 1 first, in 2- dichloroethanes, glacial acetic acid is added in, adds three second Triacetoxyborohydride, you can obtain product 2j, product 2j is after column chromatography for separation, with m-CPBA under dichloromethane, so that it may To obtain final product --- novel chiral nitrogen oxygen ligand Lmx-RaR.Wherein react 2a, m-terephthal aldehyde, glacial acetic acid and triacetyl Oxygroup sodium borohydride molar ratio is recommended as 1:0.5:1:1-1:0.2:2:2.Reaction temperature is recommended as 0 DEG C -50 DEG C, and the reaction time pushes away Recommend for 4-72 it is small when.Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C --30℃。
After compound 2a is obtained, compound Lox- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
2a and o-phthalaldehyde are dissolved in organic solvent 1 first, in 2- dichloroethanes, glacial acetic acid is added in, adds three second Triacetoxyborohydride, you can obtain product 2k, product 2k is after column chromatography for separation, with m-CPBA under dichloromethane, so that it may To obtain final product --- novel chiral nitrogen oxygen ligand Lmx-RaR.Wherein react 2a, o-phthalaldehyde, glacial acetic acid and triacetyl Oxygroup sodium borohydride molar ratio is recommended as 1:0.5:1:1-1:0.2:2:2.Reaction temperature is recommended as 0 DEG C -50 DEG C, and the reaction time pushes away Recommend for 4-72 it is small when.Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C --30℃。
After compound 2a is obtained, compound Lpd- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
Isosorbide-5-Nitrae-benzoglycols is dissolved in organic solvent dichloromethane first, carbon tetrabromide is added in, triphen is added under zero degree Base phosphorus can obtain Isosorbide-5-Nitrae-bis- -2 bromoethyl benzene after reaction, wherein reaction Isosorbide-5-Nitrae-benzoglycols, carbon tetrabromide and triphenyl Phosphorus molar ratio is recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, the reaction time be recommended as 12-48 it is small when.Afterwards Isosorbide-5-Nitrae-bis- -2- bromo ethyl phenenyls and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction can be produced Object 2l, product 2l are after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- and it is new Chiral nitrogen oxygen ligand Lpd- RaR wherein react 2a, 1,4- it is double -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio be recommended as 1: 0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when.Last Step reaction, 2l are recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
After compound 2a is obtained, compound Lmd- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,3- benzoglycols is dissolved in organic solvent dichloromethane first, carbon tetrabromide is added in, triphen is added under zero degree Base phosphorus, i.e. available 1,3- pairs -2 bromoethyl benzene after reaction, wherein 1 is reacted, 3- benzoglycols, carbon tetrabromide and triphenyl Phosphorus molar ratio is recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, the reaction time be recommended as 12-48 it is small when.Afterwards Double -2- the bromo ethyl phenenyls of 1,3- and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction can be produced Object 2m, product 2m are after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- and it is new Chiral nitrogen oxygen ligand Lmd- RaR wherein react 2a, 1,3- it is double -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio be recommended as 1: 0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when.Last Step reaction, 2l are recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
After compound 2a is obtained, compound Lod- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,2- benzoglycols is dissolved in organic solvent dichloromethane first, carbon tetrabromide is added in, triphen is added under zero degree Base phosphorus, i.e. available 1,2- pairs -2 bromoethyl benzene after reaction, wherein 1 is reacted, 2- benzoglycols, carbon tetrabromide and triphenyl Phosphorus molar ratio is recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, the reaction time be recommended as 12-48 it is small when.Afterwards Double -2- the bromo ethyl phenenyls of 1,2- and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction can be produced Object 2n, product 2n are after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- and it is new Chiral nitrogen oxygen ligand Lod- RaR wherein react 2a, 1,2- it is double -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio be recommended as 1: 0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when.Last Step reaction, 2n are recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
The present invention is to synthesize various L-RaR, R group 2,6-iPr2C6H3Exemplified by, it provides various new chiral nitrogen oxygen and matches somebody with somebody Body and its synthetic method, the synthetic method of ligand is simple, and step is few, and is all from cheap raw material.Prepared by the present invention Ligand can all use asymmetric catalysis.
It will be helpful to further understand the present invention by following embodiments.
Embodiment 1：Compound L is synthesized from compound 2a4-RaR
2,5- dimethoxy-tetrahydrofurans (1eq) are added in reaction vessel, add in a small amount of dilute hydrochloric acid, raise temperature, it will It is hydrolyzed to butanedial.Butanedial obtained by front is dissolved in 1,2- dichloroethanes, adds compound 2a (2eq) afterwards, is mixed After 15min, sodium triacetoxy borohydride (2.4eq) is continuously added, 12h is stirred at room temperature, is slowly added to saturated sodium bicarbonate extremely Bubble-free generates, and after dichloromethane extract and separate, vacuum distillation column chromatography purifying obtains white solid product afterwards by 2b Dichloromethane is dissolved in, is cooled to -20 DEG C, adds in metachloroperbenzoic acid (2.2eq), after stirring 30min, room temperature is warming up to, adds Enter saturated sodium bicarbonate, stir 5 minutes, add in dichloromethane extract and separate, be evaporated under reduced pressure column chromatography (ethyl acetate:Petroleum ether =1:1) final white solid product L, is obtained4-RaR。
Embodiment 2：Compound L is synthesized from compound 2a6-RaR
1,2- cyclohexanediols (1eq) are added in reaction vessel, add in solvent 1,2- dichloroethanes cools down 0 DEG C, slowly adds Enter sodium metaperiodate (2eq) and sodium acid carbonate (2.1eq), be stirred at room temperature for 24 hours, filtering is washed with a small amount of solvent, gained filtrate is added It is young to enter stirring, adds in compound 2a (2eq) afterwards, after stirring 15min, continuously adds sodium triacetoxy borohydride (2.4eq), 12h is stirred at room temperature, is slowly added to saturated sodium bicarbonate to bubble-free and generates, after dichloromethane extract and separate, be evaporated under reduced pressure column Chromatographic purifying obtains white solid product 2c.Subsequent operation is referring to embodiment 1.
Embodiment 3：Compound L is synthesized from compound 2a7-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in solvent acetonitrile dissolving, adds in 1,7- dibromo-heptanes (1eq), Diisopropyl ethyl amine (4eq) and sodium iodide (0.2eq) are added in, is heated to 100 DEG C of reflux 12h, cooling room temperature filters, by gained Filtrate decompression distills column chromatography (ethyl acetate:Petroleum ether=1:1) white solid product 2d, is obtained.Subsequent operation is referring to embodiment 1.
Embodiment 4：Compound L is synthesized from compound 2a8-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in solvent acetonitrile dissolving, adds in 1,8-, bis- bromooctanes (1eq), Diisopropyl ethyl amine (4eq) and sodium iodide (0.2eq) are added in, is heated to 100 DEG C of reflux 12h, cooling room temperature filters, by gained Filtrate decompression distills column chromatography (ethyl acetate:Petroleum ether=1:1) white solid product 2e, is obtained.Subsequent operation is referring to embodiment 1.
Embodiment 5：Compound L is synthesized from compound 2aA- RaR is (with R=2,6-iPr2C6H3, exemplified by A=methyl)
2- methyl-1s are added in reaction vessel, 3-propanediol (10eq) after being dissolved with anhydrous methylene chloride, adds in tetrabormated Carbon (22eq) treats that solution clarifies postcooling to 0 DEG C, is slowly added to triphenyl phosphorus (22eq), is stirred at room temperature for 24 hours, after vacuum distillation A large amount of anhydrous ethers are added in, solid analysis is treated after rolling, filters, washed with anhydrous ether, gained filtrate decompression is distilled into column chromatography (ethyl acetate:Petroleum ether=1:5) light yellow liquid 2- methyl-1s, 3- dibromopropanes are obtained.Compound 2a is added in reaction vessel (2eq) after adding in solvent acetonitrile dissolving, takes 2- methyl-1s prepared before 1eq, and 3- dibromopropanes add in potassium carbonate (4eq) With sodium iodide (0.2eq), 100 DEG C of reflux 12h are heated to, cooling room temperature filters, and gained filtrate decompression is distilled column chromatography (acetic acid Ethyl ester:Petroleum ether=1:1) white solid product 2f, is obtained.Subsequent operation is referring to embodiment 1.
Embodiment 6：Compound L is synthesized from compound 2aB- RaR is (with R=2,6-iPr2C6H3, exemplified by B=methyl)
2,2-dimethyl-1,3-propanediol (10eq) is added in reaction vessel, after being dissolved with anhydrous methylene chloride, adds in four Bromination carbon (22eq) treats that solution clarifies postcooling to 0 DEG C, is slowly added to triphenyl phosphorus (22eq), is stirred at room temperature for 24 hours, decompression is steamed A large amount of anhydrous ethers are added in after evaporating, solid analysis is treated after rolling, filters, washed with anhydrous ether, by gained filtrate decompression distillation column Chromatograph (ethyl acetate:Petroleum ether=1:5) light yellow liquid 2,2- dimethyl -1,3- dibromopropanes are obtained.It is added in reaction vessel Compound 2a (2eq) after adding in solvent acetonitrile dissolving, takes 2,2- dimethyl -1,3- dibromopropanes prepared before 1eq, adds Enter potassium carbonate (4eq) and sodium iodide (0.2eq), be heated to 100 DEG C of reflux 12h, cooling room temperature filters, gained filtrate decompression is steamed Fractional distillation column chromatographs (ethyl acetate:Petroleum ether=1:1) white solid product 2g, is obtained.Subsequent operation is referring to embodiment 1.
Embodiment 7：Compound L is synthesized from compound 2ac-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in solvent acetonitrile dissolving, adds in 1,1- pairs-bromomethyl ring third Alkane (1eq) adds in potassium carbonate (4eq) and sodium iodide (0.2eq), is heated to 100 DEG C of reflux 48h, cooling room temperature filters, by institute Obtain filtrate decompression distillation column chromatography (ethyl acetate:Petroleum ether=1:1) white solid product 2h, is obtained.Subsequent operation is referring to implementation Example 1.
Embodiment 8：Compound L is synthesized from compound 2acb-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in solvent acetonitrile dissolving, adds in 1,1- pairs-bromomethyl ring fourth Alkane (1eq) adds in potassium carbonate (4eq) and sodium iodide (0.2eq), is heated to 100 DEG C of reflux 48h, cooling room temperature filters, by institute Obtain filtrate decompression distillation column chromatography (ethyl acetate:Petroleum ether=1:1) white solid product 2h, is obtained1.Subsequent operation is referring to implementation Example 1.
Embodiment 9：Compound L is synthesized from compound 2acp-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in solvent acetonitrile dissolving, adds in 1,1- pairs-bromomethyl ring penta Alkane (1eq) adds in potassium carbonate (4eq) and sodium iodide (0.2eq), is heated to 100 DEG C of reflux 48h, cooling room temperature filters, by institute Obtain filtrate decompression distillation column chromatography (ethyl acetate:Petroleum ether=1:1) white solid product 2h, is obtained2.Subsequent operation is referring to implementation Example 1.
Embodiment 10：Compound L is synthesized from compound 2ach-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in solvent acetonitrile dissolving, adds in 1,1- pairs-bromomethyl hexamethylene Alkane (1eq) adds in potassium carbonate (4eq) and sodium iodide (0.2eq), is heated to 100 DEG C of reflux 48h, cooling room temperature filters, by institute Obtain filtrate decompression distillation column chromatography (ethyl acetate:Petroleum ether=1:1) white solid product 2h, is obtained3.Subsequent operation is referring to implementation Example 1.
Embodiment 11：Compound L is synthesized from compound 2apx-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in the dissolving of 1,2- dichloroethanes, adds in terephthalaldehyde (1eq) adds in glacial acetic acid (4eq), adds sodium triacetoxy borohydride (4eq), and room temperature reaction for 24 hours, is slowly added to saturation Sodium acid carbonate to bubble-free generates, and after dichloromethane extract and separate, vacuum distillation column chromatography purifying obtains white solid product 2i.Subsequent operation is referring to embodiment 1.
Embodiment 12：Compound L is synthesized from compound 2amx-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in the dissolving of 1,2- dichloroethanes, adds in m-terephthal aldehyde (1eq) adds in glacial acetic acid (4eq), adds sodium triacetoxy borohydride (4eq), and room temperature reaction for 24 hours, is slowly added to saturation Sodium acid carbonate to bubble-free generates, and after dichloromethane extract and separate, vacuum distillation column chromatography purifying obtains white solid product 2j.Subsequent operation is referring to embodiment 1.
Embodiment 13：Compound L is synthesized from compound 2aox-RaR
Compound 2a (2eq) is added in reaction vessel, after adding in the dissolving of 1,2- dichloroethanes, adds in o-phthalaldehyde (1eq) adds in glacial acetic acid (4eq), adds sodium triacetoxy borohydride (4eq), and room temperature reaction for 24 hours, is slowly added to saturation Sodium acid carbonate to bubble-free generates, and after dichloromethane extract and separate, vacuum distillation column chromatography purifying obtains white solid product 2k.Subsequent operation is referring to embodiment 1.
Embodiment 14：Compound L is synthesized from compound 2apd-RaR
Isosorbide-5-Nitrae-benzoglycols (10eq) is added in reaction vessel, after being dissolved with anhydrous methylene chloride, adds in carbon tetrabromide (22eq) treats that solution clarifies postcooling to 0 DEG C, is slowly added to triphenyl phosphorus (22eq), is stirred at room temperature for 24 hours, add after vacuum distillation Enter a large amount of anhydrous ethers, treat solid analysis after rolling, filter, washed with anhydrous ether, gained filtrate decompression is distilled into column chromatography (second Acetoacetic ester:Petroleum ether=1:5) 1,4- pairs -2 bromoethyl benzene of light yellow liquid is obtained.Compound 2a (2eq) is added in reaction vessel, After adding in solvent acetonitrile dissolving, Isosorbide-5-Nitrae-bis- -2 bromoethyl benzene prepared before 1eq is taken, adds in potassium carbonate (4eq) and sodium iodide (0.2eq) is heated to 100 DEG C of reflux 12h, and cooling room temperature filters, and gained filtrate decompression is distilled column chromatography (ethyl acetate:Stone Oily ether=1:1) white solid product 2l, is obtained.Subsequent operation is referring to embodiment 1.
Embodiment 15：Compound L is synthesized from compound 2amd-RaR
1,3- benzoglycols (10eq) is added in reaction vessel, after being dissolved with anhydrous methylene chloride, adds in carbon tetrabromide (22eq) treats that solution clarifies postcooling to 0 DEG C, is slowly added to triphenyl phosphorus (22eq), is stirred at room temperature for 24 hours, add after vacuum distillation Enter a large amount of anhydrous ethers, treat solid analysis after rolling, filter, washed with anhydrous ether, gained filtrate decompression is distilled into column chromatography (second Acetoacetic ester:Petroleum ether=1:5) 1,3- pairs -2 bromoethyl benzene of light yellow liquid is obtained.Compound 2a (2eq) is added in reaction vessel, After adding in solvent acetonitrile dissolving, 1,3- prepared before 1eq pairs -2 bromoethyl benzene is taken, adds in potassium carbonate (4eq) and sodium iodide (0.2eq) is heated to 100 DEG C of reflux 12h, and cooling room temperature filters, and gained filtrate decompression is distilled column chromatography (ethyl acetate:Stone Oily ether=1:1) white solid product 2l, is obtained.Subsequent operation is referring to embodiment 1.
Embodiment 16：Compound L is synthesized from compound 2aod-RaR
1,2- benzoglycols (10eq) is added in reaction vessel, after being dissolved with anhydrous methylene chloride, adds in carbon tetrabromide (22eq) treats that solution clarifies postcooling to 0 DEG C, is slowly added to triphenyl phosphorus (22eq), is stirred at room temperature for 24 hours, add after vacuum distillation Enter a large amount of anhydrous ethers, treat solid analysis after rolling, filter, washed with anhydrous ether, gained filtrate decompression is distilled into column chromatography (second Acetoacetic ester:Petroleum ether=1:5) 1,2- pairs -2 bromoethyl benzene of light yellow liquid is obtained.Compound 2a (2eq) is added in reaction vessel, After adding in solvent acetonitrile dissolving, 1,2- prepared before 1eq pairs -2 bromoethyl benzene is taken, adds in potassium carbonate (4eq) and sodium iodide (0.2eq) is heated to 100 DEG C of reflux 12h, and cooling room temperature filters, and gained filtrate decompression is distilled column chromatography (ethyl acetate:Stone Oily ether=1:1) white solid product 2n, is obtained.Subsequent operation is referring to embodiment 1.

Claims (4)

1. by the chiral nitrogen oxygen ligand of following various expression：
L4- PrR, L4- RaR, L4- PiR, L4- PqR, L6- PrR, L6- RaR, L6- PiR, L6- PqR, L7- PrR, L7- RaR, L7- PiR, L7- PqR, L8- PrR, L8- RaR, L8- PiR, L8- PqR, LA- PrR, LA- RaR, LA- PiR, LA- PqR, LB- PrR, LB- RaR, LB- PiR, LB- PqR, Lc- PrR, Lc- RaR, Lc- PiR, Lc- PqR, Lcb- PrR, Lcb- RaR, Lcb- PiR, Lcb- PqR, Lcp- PrR, Lcp- RaR, Lcp- PiR, Lcp- PqR, Lch- PrR, Lch- RaR, Lch- PiR, Lch- PqR, Lpx- PrR, Lpx- RaR, Lpx- PiR, Lpx- PqR, Lmx- PrR, Lmx- RaR, Lmx- PiR, Lmx- PqR, Lox- PrR, Lox- RaR, Lox- PiR, Lox- PqR, Lpd- PrR, Lpd- RaR, Lpd- PiR, Lpd- PqR, Lmd- PrR, Lmd- RaR, Lmd- PiR, Lmd- PqR, Lod- PrR, Lod- RaR, Lod- PiR, Lod- PqR structures are such as Under：
All of above novel chiral nitrogen oxygen
R=2,6-iPr2C6H3,2,4,6-iPr3C6H2,2,6-Et2C6H3,2,6-Me2C6H3,2,4,6-Me3C6H2,Ph,CH2C6H5, 2,6-Et2-4-MeC6H2,tBu,cyclohexyl,cyclopentyl,C6H5(CH2)2,3-anthracenylmethyl,4- BrC6H4,1-adama ntyl,2,6-Me2-4-tBuC6H2,3,5-tBu2C6H3,3,5-Me2C6H3,Ph2CH,(S)- C6H5CHCH3,2,6-bis(trifluorome thyl)phenyl,2,4,6-tris(trifluoromethyl)phenyl,3, 5-tris (trifluoromethyl) phenyl etc.；2,6- in above formulaiPr2C6H3In represent 2,6- diisopropyl phenyls；2, 4,6-iPr3C6H2Represent 2,4,6- triisopropyl phenyl；2,6-Et2C6H3Represent 2,6- diethyl phenyls 2,6-Me2C6H3It represents 2,6- 3,5-dimethylphenyls；2,4,6-Me3C6H2Represent 2,4,6- trimethylphenyls；Ph represents phenyl；CH2C6H5Represent benzyl；2, 6-Et2-4-MeC6H2Represent -4 aminomethyl phenyl of 2,6- diethyl；TBu represents tertiary butyl；Cyclohexyl represents cyclohexyl； Cyclopentyl represents cyclopenta；C6H5(CH2)2Represent phenethyl；3-anthracenylmethyl represents 3- anthracene methyl；4- BrC6H4Represent 4- bromophenyls；1-adamantyl represents 1- adamantyls；2,6-Me2-4-tBuC6H2Represent 2,6- dimethyl -4- Tert-butyl-phenyl；3,5-tBu2C6H3Represent 3,5- di-tert-butyl-phenyls；3,5-Me2C6H3Represent 3,5- 3,5-dimethylphenyls；Ph2CH Represent benzhydryl；(S)-C6H5CHCH3Represent (S) -1- phenylethyls；2,6-bis (trifluoromethyl) phenyl generations Table 2,6- bis- (trifluoromethyl) phenyl；
2,4,6-tris (trifluoromethyl) phenyl represents 2,4,6- tri- (trifluoromethyl) phenyl；
3,5-tris (trifluoromethyl) phenyl represents 3,5- bis- (trifluoromethyl) phenyl.
2. a kind of synthetic method of chiral nitrogen oxygen ligand as described in claim 1, which is characterized in that
Wherein L4- PrR, L4- RaR, L4- PiR, L4- PqR is synthesized in two steps, and the first step is with 2,5- dimethoxy-tetrahydrofurans for aldehyde Source is as coupling agent, using sodium triacetoxy borohydride as reducing agent, with 1,2- dichloroethanes for solvent, and amide and aldehyde mole Than 0.5:1,0 DEG C -50 DEG C, reaction time 4-72h of reaction temperature is carried out in next step after column chromatography；Second step is using m-CPBA as oxygen Agent, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein L6- PrR, L6- RaR, L6- PiR, L6- PqR is synthesized in two steps, and the first step adds sodium acid carbonate oxysome with sodium metaperiodate It is aldehyde source as coupling agent that 1,2- cyclohexanediols are oxidized to hexandial by system, using sodium triacetoxy borohydride as reducing agent, With 1,2- dichloroethanes for solvent, sodium metaperiodate, sodium acid carbonate and 1,2- cyclohexanediol molar ratio are 1:1:1-2:2.1:1, acyl Amine and aldehyde molar ratio 0.5:1,0 DEG C -50 DEG C, reaction time 4-72h of reaction temperature is carried out in next step after column chromatography；Second step with M-CPBA is oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction temperature 0 DEG C of degree -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein L7- PrR, L7- RaR, L7- PiR, L7- PqR is synthesized in two steps, the first step with 1,7- dibromo-heptanes as coupling agent, with Diisopropyl ethyl amine is alkali, using sodium iodide as catalyst, using acetonitrile as solvent, and amide, 1,7- dibromo-heptanes, diisopropyl second Base amine and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, the reaction time, 8-36 was small When, it carries out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step products therefrom With m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min is produced after column chromatography Object；
Wherein L8- PrR, L8- RaR, L8- PiR, L8- PqR is synthesized in two steps, the first step with 1,8-, bis- bromooctanes as coupling agent, with Diisopropyl ethyl amine is alkali, using sodium iodide as catalyst, using acetonitrile as solvent, and amide, 1,8-, bis- bromooctanes, diisopropyl second Base amine and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, the reaction time, 8-36 was small When, it carries out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step products therefrom With m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min is produced after column chromatography Object；
Wherein Lm- PrR, Lm- RaR, Lm- PiR, Lm- PqR is synthesized in two steps, and the first step is with 2- methyl-1s, 3-propanediol, tetrabormated Carbon, triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide to be catalyzed Agent, using acetonitrile as solvent, amide, 2- methyl-1s, 3- dibromopropanes, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2: 0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is with m- CPBA is oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction temperature 0 DEG C -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein LA- PrR, LA- RaR, LA- PiR, LA- PqR is synthesized in two steps, the first step with 2-A-1,3-propanediol, carbon tetrabromide, Triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide as catalyst, Using acetonitrile as solvent, amide, 2-A-1,3- dibromopropanes, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8: 0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is using m-CPBA as oxygen Agent, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；(A=methyl, ethyl, propyl, isopropyl, butyl, isobutyl Base, tertiary butyl, phenyl, benzyl；)
Wherein LB- PrR, LB- RaR, LB- PiR, LB- PqR is synthesized in two steps, and the first step is with 2,2-, bis- B-1,3-propanediol, tetrabormated Carbon, triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide to be catalyzed Agent, using acetonitrile as solvent, amide, 2,2-, bis- B-1,3- dibromopropanes, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2: 0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is with m- CPBA is oxidant, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2, reaction temperature 0 DEG C -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；(B=methyl, ethyl, propyl, isopropyl, butyl, Isobutyl group, tertiary butyl, phenyl, benzyl；)
Wherein Lc- PrR, Lc- RaR, Lc- PiR, Lc- PqR is synthesized in two steps, and the first step is with 1,1- pairs-bromomethyl cyclopropane as even Join agent, using potassium carbonate as alkali, using sodium iodide as catalyst, using acetonitrile as solvent, amide, 1,1- pairs-bromomethyl cyclopropane, carbonic acid Potassium and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, when reaction time 8-36 is small, It is carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step products therefrom and m- CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein Lcb- PrR, Lcb- RaR, Lcb- PiR, Lcb- PqR is synthesized in two steps, and the first step is made with 1,1- pairs-Bromomethylcyclobutane For coupling agent, using potassium carbonate as alkali, using sodium iodide as catalyst, using acetonitrile as solvent, amide, 1,1- be double-Bromomethylcyclobutane, Potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, the reaction time, 8-36 was small When, it carries out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step products therefrom With m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min is produced after column chromatography Object；
Wherein Lcp- PrR, Lcp- RaR, Lcp- PiR, Lcp- PqR is synthesized in two steps, and the first step is made with 1,1- pairs-bromomethyl pentamethylene For coupling agent, using potassium carbonate as alkali, using sodium iodide as catalyst, using acetonitrile as solvent, amide, 1,1- be double-bromomethyl pentamethylene, Potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, the reaction time, 8-36 was small When, it carries out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step products therefrom With m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min is produced after column chromatography Object；
Wherein Lch- PrR, Lch- RaR, Lch- PiR, Lch- PqR is synthesized in two steps, and the first step is made with 1,1- pairs-bromomethylcyclohexane For coupling agent, using potassium carbonate as alkali, using sodium iodide as catalyst, using acetonitrile as solvent, amide, 1,1- be double-bromomethylcyclohexane, Potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8:0.4,60 DEG C -120 DEG C of reaction temperature, the reaction time, 8-36 was small When, it carries out in next step after column chromatography；Second step is using m-CPBA as oxidant, using dichloromethane as solvent, first step products therefrom With m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min is produced after column chromatography Object；
Wherein Lpx- PrR, Lpx- RaR, Lpx- PiR, Lpx- PqR synthesize in two steps, the first step using terephthalaldehyde as coupling agent, Using sodium triacetoxy borohydride as reducing agent, with 1,2- dichloroethanes for solvent, amide and aldehyde molar ratio 0.5:1, reaction temperature 0 DEG C -50 DEG C, reaction time 4-72h are spent, is carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, with dichloromethane For solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20- 300min obtains product after column chromatography；
Wherein Lmx- PrR, Lmx- RaR, Lmx- PiR, Lmx- PqR synthesize in two steps, the first step using m-terephthal aldehyde as coupling agent, Using sodium triacetoxy borohydride as reducing agent, with 1,2- dichloroethanes for solvent, amide and aldehyde molar ratio 0.5:1, reaction temperature 0 DEG C -50 DEG C, reaction time 4-72h are spent, is carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, with dichloromethane For solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20- 300min obtains product after column chromatography；
Wherein Lox- PrR, Lox- RaR, Lox- PiR, Lox- PqR synthesize in two steps, the first step using o-phthalaldehyde as coupling agent, Using sodium triacetoxy borohydride as reducing agent, with 1,2- dichloroethanes for solvent, amide and aldehyde molar ratio 0.5:1, reaction temperature 0 DEG C -50 DEG C, reaction time 4-72h are spent, is carried out in next step after column chromatography；Second step is using m-CPBA as oxidant, with dichloromethane For solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20- 300min obtains product after column chromatography；
Wherein Lpd- PrR, Lpd- RaR, Lpd- PiR, Lpd- PqR synthesize in two steps, the first step with Isosorbide-5-Nitrae-benzoglycols, carbon tetrabromide, Triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide as catalyst, Using acetonitrile as solvent, amide, Isosorbide-5-Nitrae-bis- -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8: 0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is using m-CPBA as oxygen Agent, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein Lmd- PrR, Lmd-RaR,Lmd- PiR, Lmd- PqR synthesize in two steps, the first step with 1,3- benzoglycols, carbon tetrabromide, Triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide as catalyst, Using acetonitrile as solvent, amide, 1,3- pairs -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8: 0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is using m-CPBA as oxygen Agent, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein Lod- PrR, Lod- RaR, Lod- PiR, Lod- PqR synthesize in two steps, the first step with 1,2- benzoglycols, carbon tetrabromide, Triphenyl phosphorus and dichloromethane system are two bromo-derivative sources as coupling agent, using potassium carbonate as alkali, using sodium iodide as catalyst, Using acetonitrile as solvent, amide, 1,2- pairs -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio 1:0.5:2:0.1-2:0.5:8: 0.4,60 DEG C -120 DEG C of reaction temperature when reaction time 8-36 is small, carries out in next step after column chromatography；Second step is using m-CPBA as oxygen Agent, using dichloromethane as solvent, first step products therefrom and m-CPBA molar ratios 1:2-1:2.2,0 DEG C of reaction temperature -- 30 DEG C, reaction time 20-300min obtains product after column chromatography；
Wherein each amide synthesis and its structure are as follows：
3. the synthetic method of chiral nitrogen oxygen ligand according to claim 2, it is characterized in that, in the amide molecule structural formula When n is respectively 0 and 1, using R as 2,6-iPr2C6H3For example, can obtain：
(R=2,4,6-iPr3C6H2,2,6-Et2C6H3,2,6-Me2C6H3,2,4,6-Me3C6H2,Ph,CH2C6H5,2,6-Et2-4- MeC6H2,tBu,cyclohexyl,cyclopentyl,C6H5(CH2)2,3-anthracenylmethyl,4-BrC6H4,1- adamantyl,2,6-Me2-4-tBuC6H2,3,5-tBu2C6H3,3,5-Me2C6H3,Ph2CH,(S)-C6H5CHCH3,2,6-bis (trifluoromethyl)phenyl,2,4,6-tris(trifluoromethyl)phenyl,3,5-tris (trifluoromethyl) phenyl etc. is also this method)
Boc represents tertbutyloxycarbonyl in formula, and TFA represents trifluoroacetic acid；iPr represents isopropyl；
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
Prolinamide 1a is prepared from boc-protected proline：
First boc-protected proline is dissolved in organic solvent, acid anhydrides can be formed under triethylamine, isobutyl chlorocarbonate, afterwards It can be reacted with 2,6-DIPA and generate boc-protected prolinamide, after column chromatography for separation purifies, dissolved in Trifluoroacetic acid is added in after organic solvent and sloughs Boc blocking groups, using obtaining 1a after column chromatography for separation；Wherein, it is boc-protected Proline, triethylamine, the molar ratio of isobutyl chlorocarbonate and 2,6-DIPA are 1:1:1:1-1:1.2:1.2:1.5； Boc-protected prolinamide, the molar ratio of trifluoroacetic acid are 1:1-1:1.2；First step charging sequence is boc-protected dried meat ammonia It is added dropwise under acid, triethylamine, zero degree under isobutyl chlorocarbonate after 20-30 minute, again zero degree and 2,6- isopropyl anilines is added dropwise, reaction is warm Spend for room temperature, the reaction time for 12-72 it is small when；Second step reaction is after boc-protected prolinamide is dissolved in organic solvent, Trifluoroacetic acid is added dropwise under zero degree, is neutralized afterwards with sodium hydrate aqueous solution, extracts, column chromatography obtains 1a；
2a, 3a, 4a. can be obtained with identical method
Since novel nitrogen oxygen is too many, we are to synthesize various L-RaR as example, wherein when R is 2,6-iPr2C6H3Below Shi Jixu Statement；
After compound 2a is obtained, compound L4- RaR synthetic reaction flows are as follows：
M-CPBA represents metachloroperbenzoic acid in formula, and DCM represents dichloromethane；
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
First with 2,5- dimethoxy-tetrahydrofurans dilute hydrochloric acid hydrolysis under obtain butanedial, afterwards will reaction gained butanedial with 2a in organic solvent 1,2- dichloroethanes mix stirring 15-30 minute after, add in sodium triacetoxy borohydride, you can must To product 2b, 2b is after column chromatography for separation purifies, with m-CPBA under dichloromethane, it is possible to obtain final product --- and it is new Chiral nitrogen oxygen ligand L4-RaR；Wherein butanedial is recommended as 0.5 with 2a molar ratios:1,2b is recommended as 1 with m-CPBA molar ratios:2- 1:2.2；First step reaction temperature is recommended as 0 DEG C -50 DEG C, when the reaction time is 4-72h small；Second step reaction temperature is recommended as 0 DEG C -- 30 DEG C, reaction time 20-300 is minute；
After compound 2a is obtained, compound L6- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
Add sodium acid carbonate oxidation system that 1,2- cyclohexanediols are oxidized to hexandial with sodium metaperiodate first, wherein reacting periodic acid Sodium, sodium acid carbonate and 1,2- cyclohexanediols molar ratio are 1:1:1-2:2.1:1, reaction temperature is room temperature, reaction time 24-48 Hour；Gained hexandial is dissolved in 2a in organic solvent afterwards and being stirred, adds sodium triacetoxy borohydride, you can must be produced Object 2c, wherein reaction hexandial is recommended as 0.5 with 2a molar ratios:1, reaction temperature is 0 DEG C -50 DEG C, when reaction time 4-72 is small； 2c is after column chromatography for separation purifies, with m-CPBA under dichloromethane, it is possible to obtain final product --- novel chiral nitrogen oxygen Ligand L6- RaR, wherein reaction 2c is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C, instead 20-300 is minute between seasonable；
After compound 2a is obtained, compound L7- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
First by 2a and 1,7- dibromo-heptanes are dissolved in organic solvent acetonitrile, add in diisopropyl ethyl amine and sodium iodide, reaction 2d is can obtain, product 2d is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- Novel chiral nitrogen oxygen ligand L7- RaR, the wherein first step reaction 2a, 1,7- dibromo-heptanes, diisopropyl ethyl amine and sodium iodide rub You are recommended as 1 by ratio:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as 8-36 Hour；Second step reacts 2d and is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C；
After compound 2a is obtained, compound L8- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
First by 2a and 1, bis- bromooctanes of 8- are dissolved in organic solvent acetonitrile, add in diisopropyl ethyl amine and sodium iodide, reaction 2e is can obtain, product 2e is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- Novel chiral nitrogen oxygen ligand L8- RaR, the wherein first step reaction 2a, 1,8-, bis- bromooctanes, diisopropyl ethyl and sodium iodide mole Than being recommended as 1:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and it is small that the reaction time is recommended as 8-36 When；Second step reacts 2e and is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C；
Due to LA- RaR is more, we are with A=methyl (methyl) for example (A=ethyls, propyl, isopropyl, butyl, isobutyl Base, tertiary butyl, phenyl, benzyl are also this method), after compound 2a is obtained, compound LA- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
First by 2- methyl-1s, 3-propanediol is dissolved in organic solvent dichloromethane, adds in carbon tetrabromide, triphen is added under zero degree Base phosphorus can obtain 2- methyl-1s after reaction, 3- dibromopropanes, wherein reaction 2- methyl-1s, 3-propanediol, carbon tetrabromide and Triphenyl phosphorus molar ratio is recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, and it is small that the reaction time is recommended as 12-48 When；Afterwards by 2- methyl-1s, 3- dibromopropanes and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction are Product 2f is can obtain, product 2f is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand LA- RaR (R=2,6-iPr2C6H3, A=methyl) wherein react 2a, 2- methyl-1,3- dibromos Propane, potassium carbonate and sodium iodide molar ratio are recommended as 1:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when；Final step is reacted, and 2f is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature Degree is recommended as 0 DEG C -- and 30 DEG C；
Due to LB- RaR is more, we using B=methyl as example (B=ethyls, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, Phenyl, benzyl are also this method), after compound 2a is obtained, compound LB- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
2,2-dimethyl-1,3-propanediol is dissolved in organic solvent dichloromethane first, carbon tetrabromide is added in, is added under zero degree Triphenyl phosphorus, i.e. available 2,2- dimethyl -1,3- dibromopropanes after reaction, wherein react 2,2- dimethyl -1,3- the third two Alcohol, carbon tetrabromide and triphenyl phosphorus molar ratio are recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, reaction time Be recommended as 12-48 it is small when；2,2- dimethyl -1,3- dibromopropane and 2a are dissolved in organic solvent acetonitrile afterwards, add in carbonic acid Potassium and sodium iodide, reaction can obtain product 2g, and product 2g is after column chromatography for separation, with m-CPBA under dichloromethane, just It can obtain final product --- novel chiral nitrogen oxygen ligand LB- RaR (R=2,6-iPr2C6H3, A=methyl) wherein react 2a, 2,2- dimethyl -1,3- dibromopropanes, potassium carbonate and sodium iodide molar ratio are recommended as 1:0.5:2:0.1-2:0.5:8:0.4, Reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when；Final step is reacted, 2g and m-CPBA molar ratios It is recommended as 1:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C；
After compound 2a is obtained, compound Lc- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,1- first pairs-bromomethyl cyclopropane and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction Product 2h is obtained, product 2h is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- Novel chiral nitrogen oxygen ligand Lc-RaR；Wherein reaction 2a, 1,1- pairs-bromomethyl cyclopropane, potassium carbonate and sodium iodide molar ratio pushes away It recommends as 1:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when； Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C；
After compound 2a is obtained, compound Lcb- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,1- first pairs-Bromomethylcyclobutane and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction Obtain product 2h1, product 2h1After column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand Lcb-RaR；Wherein reaction 2a, 1,1- pairs-Bromomethylcyclobutane, potassium carbonate and sodium iodide rubs You are recommended as 1 by ratio:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as 8-36 Hour；Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C；
After compound 2a is obtained, compound Lcp- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,1- first pairs-bromomethyl pentamethylene and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction Obtain product 2h2, product 2h2After column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand Lcp-RaR；Wherein reaction 2a, 1,1- pairs-bromomethyl pentamethylene, potassium carbonate and sodium iodide rubs You are recommended as 1 by ratio:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as 8-36 Hour；Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C；
After compound 2a is obtained, compound Lch- RaR synthetic reaction flows are as follows：
The synthetic method of the compound of above-mentioned reaction process can specifically be recommended as follows：
1,1- first pairs-bromomethylcyclohexane and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, reaction Obtain product 2h3, product 2h3After column chromatography for separation, with m-CPBA under dichloromethane, it is possible to finally be produced Object --- novel chiral nitrogen oxygen ligand Lch-RaR；Wherein reaction 2a, 1,1- pairs-bromomethylcyclohexane, potassium carbonate and sodium iodide rubs You are recommended as 1 by ratio:0.5:2:0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, and the reaction time is recommended as 8-36 Hour；Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C； After obtaining compound 2a, compound Lpx- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
2a and terephthalaldehyde are dissolved in organic solvent 1 first, in 2- dichloroethanes, glacial acetic acid is added in, adds triacetyl oxygen Base sodium borohydride, you can obtain product 2i, product 2i is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to To final product --- novel chiral nitrogen oxygen ligand Lpx-RaR；Wherein react 2a, terephthalaldehyde, glacial acetic acid and triacetoxyl group Sodium borohydride molar ratio is recommended as 1:0.5:1:1-1:0.2:2:2；Reaction temperature is recommended as 0 DEG C -50 DEG C, and the reaction time is recommended as When 4-72 is small；Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 ℃；
After compound 2a is obtained, compound Lmx- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
2a and m-terephthal aldehyde are dissolved in organic solvent 1 first, in 2- dichloroethanes, glacial acetic acid is added in, adds triacetyl oxygen Base sodium borohydride, you can obtain product 2j, product 2j is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to To final product --- novel chiral nitrogen oxygen ligand Lmx-RaR；Wherein react 2a, m-terephthal aldehyde, glacial acetic acid and triacetoxyl group Sodium borohydride molar ratio is recommended as 1:0.5:1:1-1:0.2:2:2；Reaction temperature is recommended as 0 DEG C -50 DEG C, and the reaction time is recommended as When 4-72 is small；Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 ℃；
After compound 2a is obtained, compound Lox- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
2a and o-phthalaldehyde are dissolved in organic solvent 1 first, in 2- dichloroethanes, glacial acetic acid is added in, adds triacetyl oxygen Base sodium borohydride, you can obtain product 2k, product 2k is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to To final product --- novel chiral nitrogen oxygen ligand Lmx-RaR；Wherein react 2a, terephthalaldehyde, glacial acetic acid and triacetoxyl group Sodium borohydride molar ratio is recommended as 1:0.5:1:1-1:0.2:2:2；Reaction temperature is recommended as 0 DEG C -50 DEG C, and the reaction time is recommended as When 4-72 is small；Final step is reacted, and 2h is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 ℃；
After compound 2a is obtained, compound Lpd- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
Isosorbide-5-Nitrae-benzoglycols is dissolved in organic solvent dichloromethane first, carbon tetrabromide is added in, triphenyl phosphorus is added under zero degree, Isosorbide-5-Nitrae-bis- -2 bromoethyl benzene is can obtain after reaction, wherein reaction Isosorbide-5-Nitrae-benzoglycols, carbon tetrabromide and triphenyl phosphorus mole Than being recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, the reaction time be recommended as 12-48 it is small when；Afterwards by 1,4- Double -2 bromoethyl benzene and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, and reaction can obtain product 2l, produce Object 2l is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- novel chiral nitrogen oxygen Ligand Lpd-RaR；Wherein reaction 2a, 1,4- pairs -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio is recommended as 1:0.5:2: 0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when；Final step is reacted, 2l is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C；
After compound 2a is obtained, compound Lmd- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
1,3- benzoglycols is dissolved in organic solvent dichloromethane first, carbon tetrabromide is added in, triphenyl phosphorus is added under zero degree, I.e. available 1,3- pairs -2 bromoethyl benzene after reaction, wherein 1 is reacted, 3- benzoglycols, carbon tetrabromide and triphenyl phosphorus mole Than being recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, the reaction time be recommended as 12-48 it is small when；Afterwards by 1,3- Double -2 bromoethyl benzene and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, and reaction can obtain product 2m, produce Object 2m is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- novel chiral nitrogen oxygen Ligand Lmd-RaR；Wherein reaction 2a, 1,3- pairs -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio is recommended as 1:0.5:2: 0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when；Final step is reacted, 2l is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C；
After compound 2a is obtained, compound Lod- RaR synthetic reaction flows are as follows：
It is as follows to the synthetic method of the compound of above-mentioned reaction process：
1,2- benzoglycols is dissolved in organic solvent dichloromethane first, carbon tetrabromide is added in, triphenyl phosphorus is added under zero degree, I.e. available 1,2- pairs -2 bromoethyl benzene after reaction, wherein 1 is reacted, 2- benzoglycols, carbon tetrabromide and triphenyl phosphorus mole Than being recommended as 1:2:2-1:2.2:2.2, reaction temperature is recommended as room temperature, the reaction time be recommended as 12-48 it is small when；Afterwards by 1,2- Double -2 bromoethyl benzene and 2a are dissolved in organic solvent acetonitrile, add in potassium carbonate and sodium iodide, and reaction can obtain product 2n, produce Object 2n is after column chromatography for separation, with m-CPBA under dichloromethane, it is possible to obtain final product --- novel chiral nitrogen oxygen Ligand Lod-RaR；Wherein reaction 2a, 1,2- pairs -2 bromoethyl benzene, potassium carbonate and sodium iodide molar ratio is recommended as 1:0.5:2: 0.1-2:0.5:8:0.4, reaction temperature is recommended as 60 DEG C -120 DEG C, the reaction time be recommended as 8-36 it is small when；Final step is reacted, 2n is recommended as 1 with m-CPBA molar ratios:2-1:2.2, reaction temperature is recommended as 0 DEG C -- and 30 DEG C.
4. a kind of chiral nitrogen oxygen ligand as described in claim 1 is used as the application of catalyst in asymmetric catalysis.
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