CN106632511A - Chiral tridentate phosphonic amine ligand and application thereof in asymmetric catalytic reaction - Google Patents

Chiral tridentate phosphonic amine ligand and application thereof in asymmetric catalytic reaction Download PDF

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CN106632511A
CN106632511A CN201611088720.3A CN201611088720A CN106632511A CN 106632511 A CN106632511 A CN 106632511A CN 201611088720 A CN201611088720 A CN 201611088720A CN 106632511 A CN106632511 A CN 106632511A
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reaction
asymmetric
hydrogenation
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ligand
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张绪穆
余建飞
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WUHAN KAITE LISI TECHNOLOGY Co Ltd
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
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    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • C07C29/145—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones with hydrogen or hydrogen-containing gases
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
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    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
    • B01J2531/0244—Pincer-type complexes, i.e. consisting of a tridentate skeleton bound to a metal, e.g. by one to three metal-carbon sigma-bonds
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    • C07B2200/07—Optical isomers

Abstract

The invention relates to a chiral tridentate phosphonic amine ligand and application thereof in an asymmetric catalytic reaction. The novel chiral tridentate phosphonic amine ligand disclosed by the invention is a first case of tridentate phosphonic amine ligand containing ferrocenyl chiral phosphine at present and is successfully applied to high-efficiency and high-selectivity asymmetric hydrogenation and similar reaction thereof for simple aromatic ketone and aliphatic ketone. The type of ligand has the advantages of simple synthetic route, low cost, easiness in large-scale synthesis and stable air; the chiral tridentate phosphonic amine ligand shows high activity and high selectivity for asymmetric hydrogenation reaction of carbon-oxygen double bond, and has a broad industrial application prospect.

Description

A kind of chiral tridentate phosphine amino acid part and its application in asymmetric catalysis
Technical field
The present invention relates to a kind of chiral tridentate phosphine amino acid part and its answering in asymmetric hydrogenation and similar reaction With belonging to asymmetric catalysis field.
Background technology
It is not right as people increasingly increase the demand of optically active medicine, agricultural chemicals, spices and other fine chemicals Catalysis technique is claimed to obtain significant progress.The asymmetry catalysis hydrogen of the unsaturated compounds such as prochiral alkene, ketone and imines Change reaction, due to having the advantages that efficient, high selectivity, high atom economy, always the research heat of asymmetric catalysis field Point[1].The central factor for affecting asymmetric catalytic hydrogenation efficiency is catalyst, and catalyst is made up of metal center and part, due to The restriction of the periodic table of elements, alternative kinds of transition metals is limited, therefore the exploitation of novel chiral ligands effectively becomes The most basic research theme in asymmetric hydrogenation field, through whole asymmetric hydrogenation history.
Wilkinson teaches the hydrogenation that first case homogeneous catalysis is reported in nineteen sixty-five[2].Subsequently in nineteen sixty-eight Professor Knowles reports the asymmetric hydrogenation of first case homogeneous catalysis[3].Due to efficient, high selectivity, plateau The advantages of subeconomy, catalysis asymmetry hydrogenation reaction has been widely used in the example of industrialized production.Some are important not Asymmetric hydrogenation reaction realizes that industrialized example is as follows：1) synthesis (dehydroamino acid of the L-DOPA of Monsanto companies Asymmetric hydrogenation, 94%ee, with Rh-DIPAMP catalyst system and catalyzings obtain 2,000 turn over number)[4], 2) Takasago is public The synthesis of department L-Menthol is to obtain 98%ee and up to 300,000 turn over number with Rh-BINAP catalyst system and catalyzings[5], 3) The synthesis of (S)-Metolachlor of Norvatis companies is catalyzed with Ir-ferrocenyl phosphine catalyst system and catalyzings The asymmetric hydrogenation of imines, obtains 80%ee and 1,000,000 turn over number[6-7].Especially in 2012, BASF AG's success 10,000 tonnes of synthesis of L-Menthol are realized using asymmetric hydrogenation.
In asymmetric hydrogenation, the structure of chiral ligand has important shadow to the activity and stereoselectivity of reaction Ring, therefore chemists can pass through rational part electrically and the finely regulating to reacting is realized in sterically hindered design.But Not a kind of part can solve the problem that all of problem, thus develop efficient, high selectivity, the chirality of wide application range of substrates and match somebody with somebody Body and asymmetry catalysis system will be eternal themes.
Since the BINAP parts of DIPAMP parts and Noyori professors from Knowles professors are reported, asymmetric hydrogenation is matched somebody with somebody The research of body is concentrated mainly in the research of the bidentate phosphine ligandses of both types, and professor Xu Mu is made that in this respect outstanding Contribution, has developed a series of bidentate phosphine ligandses that efficient phosphines are chiral and skeleton is chiral, establish one it is highly useful not right Claim hydrogenation chiral ligand tool box[8].Relative to bidentate ligand, chiral tridentate part is used for the research of asymmetric hydrogenation then It is relatively fewer.In theory, the difunctionality dough mechanism for being proposed according to Noyori, bidentate phosphine amine (providing NH) part is capable of achieving double Sense dough mechanism, chiral spiro phosphine amine ligand (SpiroAP) of Zhou Qilin professors confirms this point[9].But with bidentate ligand Compare, tridentate ligand typically can provide around transition metal centre deeper into, preferably " chiral pocket ", so as to show more Good stereoselectivity.In addition tridentate ligand skeleton is generally more consolidated and is unlikely to deform, higher with the adhesion of metal, is made corresponding Catalyst show higher activity.Early in 1998, professor Xu Mu just design synthesized a class containing double oxazole woods rings and The tridentate ligand (ph-ambox) of NH functional groups, and it is anti-to be successfully applied to the highly-solid selectively asymmetric transfer hydrogenation of aromatic ketone Should[10].Later his seminar designed and had synthesized the indan-ambox that steric hindrance is more increased again on the basis of above, and successfully For the asymmetric hydrogenation of simple ketone[11].2011, Zhou Qilin taught the base in chiral spiro phosphine amine ligand SpiroAP The SpiroPAP parts that one extra pyridine coordination group of increase is obtained on plinth are showed the asymmetric hydrogenation of simple ketone Go out super-active[12], but the part synthesis is complicated, and it is expensive.Recently, open Xu Mu professors to be based in military big seminar Ambox ligand designs have synthesized chiral tridentate PNN parts (f-amphox) of a class novel ferrocene base, and the part is in aromatic ketone Asymmetric hydrogenation in show super-active and stereoselectivity[13]。
Several representational asymmetric hydrogenation tridentate ligands are as follows：
Compared to existing tridentate ligand, the present invention proposes a raw material and is easy to get, and synthetic route is simple, high income, easily In extensive preparation, structure and electrical property are easy to the new tridentate chiral ligand for adjusting, and the part is in catalysis asymmetric hydrogenation Super-active and stereoselectivity are shown in reaction, with wide prospects for commercial application.
Bibliography：
[1]Book,Ojima,I.,Ed.Catalytic Asymmetric Synthesis,VCH,New York, 1993and Noyori,R.Asymmetric Catalysis In Organic Synthesis,John Wiley&Sons, Inc.,New York,1994.
[2]J.A.Osborn,G.Wilkinson,J.F.Young.Chem.Commun.1965,17.
[3]W.S.Knowles and M.J.Sabacky.Chem.Commun.1968,1445.
[4]Knowles,W.S.J.Chem.Educ.1986,63,222.
[5]Noyori,R.；Takaya,H.Acc.Chem.Res.1990,23,345.
[6]Spindler,F.；Pugin,B.；Jalett,H.-P.,Buser,H.-P.；Pittelknow,U.； Blaser,H,-U.,Altanta,1996；Chem.Ind.(Dekker),1996,63.
[7]Tongni,A.Angew.Chem.Int.Ed.1996,35,1475.
[8]W.Zhang,Y.Chi,X.Zhang,Acc.Chem.Res.2007,40,1278.
[9]J.Xie,Q.Zhou,J.Am.Chem.Soc.2010,132,4538.
[10]Y.Jiang,Q.Jiang,X.Zhang,J.Am.Chem.Soc.1998,120,3817.
[11]W.Li,G.Hou,C.Wang,Y.Jiang,X.Zhang,Chem.Commun.2010,46,3979.
[12]J.Xie,X.Liu,Q.Zhou,Angew.Chem.Int.Ed.2011,50,7329.
[13]W.Wu,S.Liu,X.-Q.Dong,X.Zhang,Org.Lett.2016,18,2938.
The content of the invention
The technical problem to be solved is to provide a kind of raw material to be easy to get, convieniently synthesized, it is easy to industrialized production Chiral tridentate part and its purposes on catalysis asymmetry hydrogenation reaction and its similar reaction.The chiral tridentate part is in sky Stable in gas atmosphere, catalysis activity is high, and stereoselectivity is high, it is easy to accomplish industrialized production.In order to realize above-mentioned target, this Three tooth chiral ligands of bright proposition have the structure of below general formula (1)：
In formula (1)：R1、R2Stand alone as alkyl, alkoxyl, aryl or aryloxy group, R1And R2It is cyclic or not cyclic；R3、R4 Stand alone as alkyl, aryl or hydrogen atom.
The present invention provide catalysis asymmetry hydrogenation reaction catalyst, by the invention described above provide new tridentate ligand with Transition metal precursors complexing is formed.
The concept being introduced for using concerted catalysis of NH functional groups in part, strengthens substrate and urges by hydrogen bond action Molecular recognition between agent, so as to greatly improve the activity and stereoselectivity of catalyst, this effect is commonly referred to as " NH effects Should ".Chiral amino acid as a kind of wide material sources, electrically and the interval big, raw material that is stably easy to get of steric hindrance otherness span, little Journal of Molecular Catalysis field is widely studied and uses.Chiral phosphine ligand as a kind of advantage part, in known asymmetric catalysis In occupy half of the country.Chiral amino acid is combined with chiral phosphine, the chiral phosphine amino acid part of gained is that a class has NH The novel chiral ligands of functional group, have been applied successfully to the efficient high selectivity asymmetric hydrogenation of simple ketone.In addition, It is due to having amino acid backbone and Phosphine ligands skeleton simultaneously, it will accomplish something in some special catalytic reactions, such as double Metal concerted catalysis, organic-metal concerted catalysis etc..Thus the part is a kind of potential efficiently advantage part, with important Potential using value.
The Novel Ligands being related in the present invention can be used for the asymmetric catalysis of number of different types, such as：It is not right Claim hydrogenation, asymmetric transfer hydrogenation reaction, Asymmetric hydrosilylation, asymmetric hydroboration, asymmetric hydrogen formyl Change reaction, allylation reaction, olefin metathesis reaction, isomerization reaction, Diels-Alder reactions, asymmetric coupling reacts, Aldol reacts, Michael addition reactions, asymmetric epoxidation reaction, Kinetic Resolution and [m+n] cyclization etc..The present invention The phosphorus atoms of middle part can be with phosphine oxygen, in the form of phosphine sulphur or borine protection.
Preferred tridentate ligand example (L1-L16) in part of the invention is following present, each part two kinds of mapping of correspondence Isomers, is also present disclosure, specific as follows：
The present invention also provides the preparation method of the tridentate ligand：
By initiation material (S)-Ugi-amine cheap and easy to get, through the step successive reaction system of simple one kettle way three Chiral amino phosphine is obtained, then amino phosphine heating response in anhydrous aceticanhydride is obtained for a period of time intermediate acetate.Finally, vinegar Acid esters obtains final product corresponding chiral phosphine histidine ligand under triethylamine existence condition with the reaction of corresponding amino acid condensation.Concrete operations Referring to embodiment 1-4.
Present invention also offers the preparation method of catalyst：The tridentate ligand of the present invention is with transition metal precursors suitable The complex reaction some time in solvent.Additionally provide application case of the catalyst in the asymmetric hydrogenation of simple ketone simultaneously Example.
Suitable transition metal has Ru, Rh, Ir, Fe, Co, Ni, Mn, Cu, Ag, Pd.
Suitable transition metals precursor includes [Rh (NBD)2]+BF4 -；[Rh(NBD)Cl]2；[Rh(COD)Cl]2；[Rh (COD)2]+X-；Rh(acac)(CO)2；Rh(ethylene)2(acac)；[Rh(ethylene)2Cl]2；RhCl(PPh3)3；Rh (CO)2Cl2；Ru(aryl group)X2；RuHX(L)2(diphosphine)；RuX2(L)2(diphosphine)；Ru(arene) X2(diphosphine)；Ru(RCOO)2(diphosphine)；Ru(methallyl)2(diphosphine)；Ru(aryl group)X2(PPh3)3；Ru(COD)(COT)；Ru(COD)(COT)X；RuX2(cymene)；Ru(COD)n；RuCl2(=CHR) (PR′3)2；Ru(aryl group)X2(diphosphine)；RuCl2(COD)；(Ru(COD)2)X；RuX2(diphosphine)； Ru(ArH)Cl2；Ru(COD)(methallyl)2；[Ir(NBD)Cl]2；[Ir(NBD)2]X；(Ir(COD)Cl)2；[Ir(COD)2] X；(Ni(allyl)X)2；Ni(acac)2；Ni(COD)2；NiX2；MnX2；Mn(acac)2；CoX2；FeX2；CuX；CuX2；AgX； [Pd(allyl)Cl]2；PdCl2；Pd(OAc)2；Pd(CF3COO)2。
In above transition metal precursors, R and R ' can be respectively alkyl, alkoxyl or replace alkyl, and aryl is aryl, and X is Negative anion, such as Cl-, Br-, BF4 -, ClO4 -, SbF6 -, PF6 -, CF3SO3 -, RCOO-, B (Ar)4 -, wherein Ar can be 3,5- bis- or three Methyl fluoride benzene or fluorobenzene.L is solvent molecule, such as CH3CN etc..
The tridentate ligand that the present invention is provided, relative to ambox class parts, the coordinating phosphorus atoms in the present invention have higher To electrical, and electrically can easily be accommodated, this causes the negative hydrogen species of metal to have higher nucleophilicity, and catalyst activity is significantly carried It is high.Relative to SpiroPAP and f-amphox class parts, the part in the present invention can be by Ugi-amine and chirality cheap and easy to get Amino acid is quickly obtained through simple three-step reaction, and the part air is sufficiently stable, it is easy to purified, generally applicable simple Fragment regulation and control part it is sterically hindered and electrical, be very suitable on a large scale synthetically prepared, potential industrial application value is bigger.
Part and metal are the cores of catalytic reaction, and great shadow can be produced to reaction by the fine setting to ligand environment Ring, therefore the adjustability of part determines to a great extent the substrate scope of application of catalyst, different substrates may need Different steric hindrances and electrical part realize high response and high selectivity to be catalyzed.No matter the part of the present invention is gone back sterically hindered It is all to be highly susceptible to regulation and control on electrical, it is thus possible to the extensive substrate scope of application.
Specific embodiment
The present invention is illustrated below by embodiment, but the present invention is not limited in following examples.
Embodiment 1：The synthesis of ligand L 1：
(S)-Ugi-amine 1 (2.57g, 10mmol) is dissolved in 20mL absolute ethers, N2Protection, under the conditions of -78 DEG C, uncle Butyl lithium (6.9mL, 1.6M pentane solution) is dropwise instilled, and after dripping, is stirred half an hour at -78 DEG C, then by room temperature Lithiumation 1h.Diphenylphosphine chlorine (4.41g, 20mmol) is slowly dropped at 0 DEG C.After completion of dropping, back flow reaction 2h.Ice-water bath Under, saturated sodium bicarbonate solution is quenched reaction, and ether aqueous phase extracted merges organic phase, and washing, anhydrous sodium sulfate drying is concentrated, Column chromatography, ethyl alcohol recrystallization obtains 2.92g orange solids, yield 66%.
N2Under atmosphere, 2 (2.2g, 5mmol) and 3.2mL anhydrous acetic acid acid anhydrides, back flow reaction at 100 DEG C are added in reaction tube 2h.After being cooled to room temperature, high vacuum backspin removes unnecessary aceticanhydride, toluene band twice after, add 1mL isopropanols ultrasound to have yellow Solid is separated out, and the crude product that the dry isopropanol of pump is obtained can be directly used for next step reaction, be not required to be further purified.
In 20mL reaction tubes, 0.1825g (0.4mmol) acetate 3 and 0.1049g (0.8mmol) S-Leucine are added, Displacement N2Afterwards, anhydrous triethylamine 0.17mL (1.2mmol, 3equiv), absolute methanol 2mL are sequentially added, after 2h is stirred at room temperature, plus Overnight, concentrated by rotary evaporation, column chromatography obtains faint yellow solid 0.103g, yield 49% to hot back flow reaction.
1HNMR(400MHz,CDCl3)δ7.57-7.49(m,2H),7.45-7.36(m,3H),7.32-7.23(m,3H), 7.21-7.12(m,2H),4.54(s,1H),4.45-4.40(m,1H),4.25-4.15(m,1H),4.00(s,5H),3.91(s, 1H), 2.92 (s, 1H), 1.49 (d, J=6.8Hz, 3H), 0.67 (s, 9H)；31P NMR(162MHz,CDCl3)δ-26.81(s).
Embodiment 2：The synthesis of ligand L 2：
N2Under atmosphere, (S)-Ugi-amine 1 (2.57g, 10mmol) is dissolved in 20mL absolute ethers, and system is cooled to 0 DEG C, tert-butyl lithium (6.9mL, 1.6M pentane solution) is added dropwise, after dripping, system is warmed to room temperature after reaction 1.5h, cooling To -78 DEG C, PCl is slowly added to3Diethyl ether solution (1mLin 10mL Et2O), refrigeration is closed, warms naturally to room temperature, reacted Night.System is cooled to -78 DEG C again, and p-methylphenyl bromide solution is dropwise added dropwise, and (30mmol is to methyl bromobenzene and 0.8g Mg It is prepared by the reaction in THF), after dripping, warm naturally to room temperature, reaction overnight.Saturated ammonium chloride solution is quenched reaction, ether Aqueous phase extracted, merges organic phase, and anhydrous sodium sulfate drying, concentrated by rotary evaporation, column chromatography obtains orange/yellow solid 2.0g, yield 43%.
N2Under atmosphere, 2 (0.47g, 1mmol) and 1.5mL anhydrous acetic acid acid anhydrides, back flow reaction at 90 DEG C are added in reaction tube 2h.After being cooled to room temperature, high vacuum backspin removes unnecessary aceticanhydride, and twice the rear dry crude product for obtaining of pump can be directly used for toluene band Next step is reacted, and is not required to be further purified.
In 20mL reaction tubes, 1mmol acetates 3 and 0.26g (2mmol) S-Leucine are added, replace N2Afterwards, add successively Enter anhydrous triethylamine 0.42mL (3mmol, 3equiv), absolute methanol 2mL, after 2h is stirred at room temperature, heating reflux reaction overnight, revolves Inspissation contracts, and column chromatography obtains faint yellow solid 0.298g, yield 54%.
1H NMR(400MHz,CDCl3) δ 7.40 (t, J=8.0Hz, 2H), 7.20 (d, J=7.6Hz, 2H), 7.13-7.01 (m,4H),4.53(s,1H),4.40(s,1H),4.25-4.16(m,1H),4.02(s,5H),3.88(s,1H),2.91(s, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 1.49 (d, J=6.4Hz, 3H), 0.66 (s, 9H)；31P NMR(162MHz,CDCl3) δ-28.87(s)；13C NMR(101MHz,CDCl3)δ139.62,138.60,135.22,135.01,132.40,132.23, 129.64 (d, J=6.1Hz), 129.09 (d, J=8.3Hz), 71.99 (d, J=4.0Hz), 70.15,70.02,69.83, 69.60 (d, J=4.4Hz), 53.03 (d, J=8.3Hz), 33.54,26.56,21.45,21.20,17.83.
Embodiment 3：The synthesis of ligand L 3：
N2Under atmosphere, (S)-Ugi-amine1 (2.57g, 10mmol) is dissolved in 20mL absolute ethers, and system is cooled to 0 DEG C, tert-butyl lithium (6.9mL, 1.6M pentane solution) is added dropwise, after dripping, system is warmed to room temperature after reaction 1.5h, be cooled to- 78 DEG C, it is slowly added to PCl3Diethyl ether solution (1mL in 10mL Et2O), refrigeration is closed, warms naturally to room temperature, reacted Night.System is cooled to -78 DEG C again, and 3,5- 3,5-dimethylphenyl bromide solutions (30mmol 3,5- dimethyl bromobenzene is dropwise added dropwise Preparation is reacted in THF with 0.8g Mg), after dripping, warm naturally to room temperature, reaction overnight.Saturated ammonium chloride solution is quenched Reaction, ether aqueous phase extracted merges organic phase, and anhydrous sodium sulfate drying, concentrated by rotary evaporation, column chromatography obtains orange/yellow solid 2.1g, Yield 42%.
N2Under atmosphere, 2 (0.25g, 0.5mmol) and 1mL anhydrous acetic acid acid anhydrides, back flow reaction at 90 DEG C are added in reaction tube 2h.After being cooled to room temperature, high vacuum backspin removes unnecessary aceticanhydride, can be directly used for next step reaction, is not required to be further purified.
In 20mL reaction tubes, 0.26g (0.5mmol) acetate 3 and 0.13g (1mmol) S-Leucine are added, replace N2 Afterwards, anhydrous triethylamine 0.21mL (1.5mmol, 3equiv), absolute methanol 2mL are sequentially added, after 2h is stirred at room temperature, is heated to reflux Overnight, concentrated by rotary evaporation, column chromatography obtains faint yellow solid 0.105g, yield 36% for reaction.
1H NMR(400MHz,CDCl3) δ 7.14 (d, J=8.4Hz, 2H), 7.06 (s, 1H), 6.89 (s, 1H), 6.74 (d, J=7.2Hz, 2H), 4.56 (s, 1H), 4.45-4.40 (m, 1H), 4.33-4.24 (m, 1H), 4.02 (s, 5H), 3.92 (s, 1H), 3.03 (s, 1H), 2.33 (s, 6H), 2.21 (s, 6H), 1.58 (d, J=6.4Hz, 3H), 0.65 (s, 9H)；31P NMR (162MHz,CDCl3)δ-27.49(s)；13C NMR(101MHz,CDCl3) δ 138.47 (d, J=6.3Hz), 137.68 (d, J= 8.7Hz),133.01,132.80,131.38,130.50,130.03,129.85,70.40,70.27,69.90,69.68(d,J =5.9Hz), 33.36,26.40,21.37 (d, J=3.8Hz), 17.24.
Embodiment 4：The synthesis of ligand L 4：
N2Under atmosphere, (S)-Ugi-amine1 (3.86g, 15mmol) is dissolved in 30mL absolute ethers, and system is cooled to 0 DEG C, tert-butyl lithium is added dropwise, and ((10.3mL, 1.6M pentane solution), after dripping, system is warmed to room temperature after reaction 1.5h, cooling To -78 DEG C, PCl is slowly added to3Diethyl ether solution (1.5mL in 10mL Et2O), refrigeration is closed, warms naturally to room temperature, instead Should overnight.System is cooled to -78 DEG C again, and 3, the 5- di-tert-butyl-phenyl bromide solutions (uncle of 45mmol 3,5- bis- is dropwise added dropwise Butyl bromobenzene reacts preparation with 1.2g Mg in THF), after dripping, warm naturally to room temperature, reaction overnight.Saturated ammonium chloride Solution is quenched reaction, ether aqueous phase extracted, merges organic phase, anhydrous sodium sulfate drying, and concentrated by rotary evaporation, column chromatography obtains orange-yellow solid Body 5.8g, yield 58%.
N2Under atmosphere, 2 (0.27g, 0.4mmol) and 1mL anhydrous acetic acid acid anhydrides, back flow reaction at 90 DEG C are added in reaction tube 2h.After being cooled to room temperature, high vacuum backspin remove unnecessary aceticanhydride, the crude product for obtaining be directly used in next step reaction, be not required into One step is purified.
In 20mL reaction tubes, 0.27g (0.4mmol) acetate 3 and 0.10g (0.8mmol) S-Leucine, displacement are added N2Afterwards, anhydrous triethylamine 0.17mL (1.2mmol, 3equiv), absolute methanol 2mL are sequentially added, after 2h is stirred at room temperature, at 60 DEG C Overnight, concentrated by rotary evaporation, column chromatography obtains faint yellow solid 0.177g, yield 59% for reaction.
1H NMR(400MHz,CDCl3) δ 7.42-7.38 (m, 1H), 7.30 (t, J=1.6Hz, 1H), 7.24 (d, J= 2.0Hz, 1H), 7.22 (d, J=2.0Hz, 1H), 7.05 (d, J=2.0Hz, 1H), 7.03 (d, J=2.0Hz, 1H), 4.55- 4.50 (m, 1H), 4.38 (t, J=2.4Hz, 1H), 4.29-4.19 (m, 1H), 4.06 (s, 5H), 3.71-3.68 (m, 1H), 2.90 (s, 1H), 1.49 (d, J=6.8Hz, 3H), 1.27 (s, 18H), 1.20 (s, 18H), 0.61 (s, 9H)；31P NMR (162MHz,CDCl3)δ-26.58(s)；13C NMR(101MHz,CDCl3) δ 173.12,151.04 (d, J=6.0Hz), 150.17 (d, J=7.7Hz), 138.10 (d, J=6.7Hz), 134.93 (d, J=6.3Hz), 129.41,129.20, (d, J=3.9Hz), 127.19,127.01,123.11,122.73,71.81 69.76,69.71,69.36 (d, J=3.7Hz), 52.67 (d, J=7.7Hz), 34.87,33.64,31.40 (d, J=6.4Hz), 31.01,26.73 (d, J=1.6Hz), 17.68.
Embodiment 5：Ligand L 1 and [Ir (COD) Cl]2The asymmetric hydrogenation of situ catalytic acetophenone 4a：
In the glove box of argon atmosphere, ligand L 1 (7.9mg, 0.0105mmol) and [Ir (COD) Cl]2(3.4mg, 0.005mmol) add in 2.5mL bottles, with room temperature complexing 1h after iPrOH (1.0mL) dissolvings catalyst solution is obtained.Take catalyst Solution (20uL, 0.0002mmol) is added in the hydrogenation bottle of 5mL, then sequentially adds 1.6mg tBuOLi (0.02mmol), Substrate acetophenone 4a (0.23mL, 2mmol), 2mL isopropanol solvents.Hydrogenation bottle is put into hydrogenation reaction cauldron, hydrogen exchange 20atm H are filled with after three times2, 6h is reacted at room temperature.Reaction is finished after release hydrogen, and reactant mixture crosses a short silica gel Post.NMR determine conversion ratio (>99%) enantioselectivity ee values (96%) of reaction, is determined with high performance liquid chromatography (HPLC).
Embodiment 6：Ligand L 2 and [Ir (COD) Cl]2The asymmetric hydrogenation of situ catalytic acetophenone 4a：
In the glove box of argon atmosphere, ligand L 2 (7.9mg, 0.0105mmol) and [Ir (COD) Cl]2(3.4mg, 0.005mmol) add in 2.5mL bottles, with room temperature complexing 1h after iPrOH (1.0mL) dissolvings catalyst solution is obtained.Take catalyst Solution (20uL, 0.0002mmol) is added in the hydrogenation bottle of 5mL, then sequentially adds 1.6mg tBuOLi (0.02mmol), Substrate acetophenone 4a (0.23mL, 2mmol), 2mL isopropanol solvents.Hydrogenation bottle is put into hydrogenation reaction cauldron, hydrogen exchange 20atm H are filled with after three times2, 6h is reacted at room temperature.Reaction is finished after release hydrogen, and reactant mixture crosses a short silica gel Post.NMR determine conversion ratio (>99%) enantioselectivity ee values (96%) of reaction, is determined with high performance liquid chromatography (HPLC).
Embodiment 7：Ligand L 3 and [Ir (COD) Cl]2The asymmetric hydrogenation of situ catalytic acetophenone 4a：
In the glove box of argon atmosphere, ligand L 3 (7.9mg, 0.0105mmol) and [Ir (COD) Cl]2(3.4mg, 0.005mmol) add in 2.5mL bottles, with room temperature complexing 1h after iPrOH (1.0mL) dissolvings catalyst solution is obtained.Take catalyst Solution (20uL, 0.0002mmol) is added in the hydrogenation bottle of 5mL, then sequentially adds 1.6mg tBuOLi (0.02mmol), Substrate acetophenone 4a (0.23mL, 2mmol), 2mL isopropanol solvents.Hydrogenation bottle is put into hydrogenation reaction cauldron, hydrogen exchange 20atm H are filled with after three times2, 6h is reacted at room temperature.Reaction is finished after release hydrogen, and reactant mixture crosses a short silica gel Post.NMR determine conversion ratio (>99%) enantioselectivity ee values (98%) of reaction, is determined with high performance liquid chromatography (HPLC).
Embodiment 8：Ligand L 4 and [Ir (COD) Cl]2The asymmetric hydrogenation of situ catalytic acetophenone 4a：
In the glove box of argon atmosphere, ligand L 4 (7.9mg, 0.0105mmol) and [Ir (COD) Cl]2(3.4mg, 0.005mmol) add in 2.5mL bottles, with room temperature complexing 1h after iPrOH (1.0mL) dissolvings catalyst solution is obtained.Take catalyst Solution (20uL, 0.0002mmol) is added in the hydrogenation bottle of 5mL, then sequentially adds 1.6mg tBuOLi (0.02mmol), Substrate acetophenone 4a (0.23mL, 2mmol), 2mL isopropanol solvents.Hydrogenation bottle is put into hydrogenation reaction cauldron, hydrogen exchange 20atm H are filled with after three times2, 6h is reacted at room temperature.Reaction is finished after release hydrogen, and reactant mixture crosses a short silica gel Post.NMR determine conversion ratio (>99%), with high performance liquid chromatography (HPLC) determine reaction enantioselectivity ee values (>99%).
Embodiment 9：Ligand L 4 and [Ir (COD) Cl]2Situ catalytic simple ketone 4b-4m asymmetric hydrogenations：
In the glove box of argon atmosphere, ligand L 4 (7.9mg, 0.0105mmol) and [Ir (COD) Cl]2(3.4mg, 0.005mmol) add in 2.5mL bottles, with room temperature complexing 1h after iPrOH (1.0mL) dissolvings catalyst solution is obtained.Take catalyst Solution (20uL, 0.0002mmol) is added in the hydrogenation bottle of 5mL, then sequentially adds 1.6mg tBuOLi (0.02mmol), Substrate ketone 4b-4m (product 5b-5m in correspondence figure below) (0.23mL, 2mmol), 2mL isopropanol solvents.Hydrogenation bottle is put into hydrogen In changing reactor, after hydrogen exchange three times 20atm H are filled with2, 6h is reacted at room temperature.Reaction is finished after release hydrogen, reaction Mixture crosses a short silicagel column.NMR determines conversion ratio, determines with high performance liquid chromatography (HPLC) or gas-chromatography (GC) The enantioselectivity ee values of reaction.

Claims (5)

1. a kind of chiral phosphine amino acid tridentate ligand, it is characterised in that the structure with formula (1)：
In formula (1)：
R1、R2Stand alone as alkyl, alkoxyl, aryl, aryloxy group or hydrogen atom, R1And R2It is cyclic or not cyclic；
R3、R4Stand alone as alkyl, aryl or hydrogen atom.
2. a kind of catalyst, is obtained by the chiral phosphine amino acid tridentate ligand and transition metal precursors complexing described in claim 1 Complex.
3. catalyst according to claim 2, it is characterised in that described transition metal be Ru, Rh, Ir, Fe, Co, Ni, Mn, Cu, Ag or Pd.
4. application of the catalyst described in Claims 2 or 3 in catalytic asymmetric reaction, the asymmetric reaction includes hydrogenation Reaction, hydroformylation reaction, silicon hydrogenation, hydroboration, hydrogen hydroxylating, hydrogen aminating reaction, the cyanalation reaction of hydrogen, Isomerization formyl reaction, hydroaminomethylation, transfer hydrogenation, allylation reaction, olefin metathesis reaction, ring Isomerization reaction, Diels-Alder reactions, asymmetric coupling reaction, Aldol reactions, Michael addition reactions, asymmetric ring Oxidation reaction, Kinetic Resolution and [m+n] cyclization.
5. application of the catalyst described in Claims 2 or 3 in catalysis aromatic ketone or aliphatic ketone asymmetric hydrogenation.
CN201611088720.3A 2016-12-01 2016-12-01 Chiral tridentate phosphonic amine ligand and application thereof in asymmetric catalytic reaction Pending CN106632511A (en)

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CN113004341A (en) * 2021-03-08 2021-06-22 洛阳师范学院 PNO ligand containing chiral ferrocene and axial chiral biphenol and application thereof
CN114478372A (en) * 2020-10-27 2022-05-13 凯特立斯（深圳）科技有限公司 Asymmetric preparation method of pyridinol nitrogen oxide
CN114478362A (en) * 2020-10-27 2022-05-13 凯特立斯（深圳）科技有限公司 Preparation method of chiral pyridinol derivative
WO2023206665A1 (en) * 2022-04-26 2023-11-02 凯特立斯（深圳）科技有限公司 Process for unprotected asymmetric preparation of nicotine
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US11831995B2 (en) 2019-01-30 2023-11-28 Ricoh Company, Ltd. Image capturing apparatus, image capturing method, and carrier means
CN112390738A (en) * 2019-08-16 2021-02-23 凯特立斯（深圳）科技有限公司 Ezetimibe intermediate compound and synthetic method of ezetimibe
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CN114478362A (en) * 2020-10-27 2022-05-13 凯特立斯（深圳）科技有限公司 Preparation method of chiral pyridinol derivative
CN113004341A (en) * 2021-03-08 2021-06-22 洛阳师范学院 PNO ligand containing chiral ferrocene and axial chiral biphenol and application thereof
CN113004341B (en) * 2021-03-08 2023-08-01 洛阳师范学院 PNO ligand containing facial chiral ferrocene and axial chiral diphenol and application thereof
WO2023206665A1 (en) * 2022-04-26 2023-11-02 凯特立斯（深圳）科技有限公司 Process for unprotected asymmetric preparation of nicotine

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