CN117362358A - Planar chiral iodo-metallocene, preparation method thereof and method for preparing polysubstituted planar chiral metallocene compound - Google Patents

Planar chiral iodo-metallocene, preparation method thereof and method for preparing polysubstituted planar chiral metallocene compound Download PDF

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CN117362358A
CN117362358A CN202311218119.1A CN202311218119A CN117362358A CN 117362358 A CN117362358 A CN 117362358A CN 202311218119 A CN202311218119 A CN 202311218119A CN 117362358 A CN117362358 A CN 117362358A
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chiral
metallocene
alkyl
aryl
planar
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程鸿刚
周强辉
周兰
侯靖
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SUZHOU Institute OF WUHAN UNIVERSITY
Wuhan University WHU
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SUZHOU Institute OF WUHAN UNIVERSITY
Wuhan University WHU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table

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Abstract

The invention discloses a planar chiral iodo-metallocene, a preparation method thereof and a method for preparing a polysubstituted planar chiral metallocene compound. The method takes simple N, N-dialkyl amino methyl metallocene (ferrocene, ruthenium dichloride) as an initial raw material, and under the action of a palladium catalyst, chiral amino acid, o-trifluoro acetyl iodobenzene derivative and alkali, stirring and reacting in an organic solvent at a certain temperature to obtain the 1, 2-disubstituted plane chiral iodo metallocene compound. The method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, good universality of substrates, high yield and simple preparation process. The prepared 1, 2-disubstituted planar chiral iodo-metallocene can be used for further synthesizing other functionalized polysubstituted planar chiral metallocene compounds.

Description

Planar chiral iodo-metallocene, preparation method thereof and method for preparing polysubstituted planar chiral metallocene compound
Technical Field
The invention relates to a planar chiral iodo-metallocene, a preparation method thereof and a method for preparing a polysubstituted planar chiral metallocene compound, belonging to the field of organic synthesis.
Background
The planar chiral ferrocene compound has important application in the fields of catalysis, materials, biomedicine and the like, and particularly can be widely applied to asymmetric catalytic reactions as efficient chiral ligands or catalysts (1 Fu, G.C.Acc.Chem.Res.2000,33,412; 2 Dai, L. -X.; tu, T.; young, S. -L.; deng, W. -P.; hou, X. -L.Acc.Chem.Res.2003,36,659; 3 Atkinson, R.C.J.; gibson, V.C.; long, N.J.Chem.Soc.Rev.2004,33,313; 4 Array's, R. -G.; adrio, J..C.Angew.Chem.2006, L..D. 2006, 52, U.C..Chem.62, U.G..G..35, N.C.Chem., C.Chen.G., 62, L..G. 62, U.G.; cherj..G. 6, J..R.E.G. 35, J..G. X.11, U.G. 6, U.C. 62, L..G. 6, U.C. 62).
The planar chiral ferrocene compound has remarkable advantages and large development space in the directions of asymmetric catalysis, industrial application and the like, and the design, development and synthesis of the ferrocene compound also become important research directions in the field. To date, chemists have developed methods and strategies for synthesizing planar chiral ferrocene compounds. The traditional strategies mainly comprise the following four types: (1) Chiral prosthetic group-induced diastereoselective orthometalation ([ 1)]Battelle,L.F.；Bau,R.；Gokel,G.W.；Oyakawa,R.T.；Ugi,I.K.J.Am.Chem.Soc.1973,95,482；[2]Rebière,F.；Riant,O.；Ricard,L.；Kagan,H.B.Angew.Chem.Int.Ed.1993,32,568；[3]Enders,D.；Peters,R.；Lochtman,R.；Raabe,G.Angew.Chem.Int.Ed.1999,38,2421；[4]Bolm,C.；Kesselgruber,M.；K.; rabe, g.organometallics 2000,19,1648); (2) Enantioselective orthometalation using an equivalent amount of an added chiral base or chiral ligand ([ 1]]Tsukazaki,M.；Tinkl,M.；Roglans,A.；Chapell,B.J.；Taylor,N.J.；Snieckus,V.J.Am.Chem.Soc.1996,118,685；[2]Laufer,R.S.；Veith,U.；Taylor,N.J.；Snieckus,V.Org.Lett.2000,2,629；[3]Genet, c.; canipa, S.J.; o' Brein, p.; taylor, s.j.am.chem.soc.2006,128, 9336); (3) Antisymmetric strategy ([ 1]]Yamazaki,Y.；Hosono,K.Agric.Biomol.Chem.1990,54,2183；[2]Mercier, a; yeo, W.C.; chou, j.; chaudhuri, p.d.; bernard-inelli, G.; kundig, e.p. chem. Commun.2009, 5227.); (4) Chiral resolution of racemates ([ 1)]Alba,A.-N.；Rios,R.Molecules 2009,14,4747；[2]Ogasawara,M.；Arae,S.；Watanabe,S.；Nakajima,K.；Takahashi,T.ACS Catal.2016,6,1308.[3]Ogasawara,M.；Watanabe,S.；Nakajima,K.；Takahashi,T.J.Am.Chem.Soc.2010,132,2136.[4]Liu, c. -x; zhao, f.; feng, z.; wang, q.; gu, q.; you, s. -l.nat.synth.2023,2,49.). However, these methods often have limitations such as poor functional group tolerance and low atomic economy. In recent years, transition metal catalyzed ferrocene ortho-asymmetric C-H functionalization has been rapidly developed and has become an important strategy for constructing planar chiral ferrocenes ([ 1)]Zhu,D.-Y.；Chen,P.；Xia,J.-B.ChemCatChem2016,8,68；[2]Gao,D.-W.；Gu,Q.；Zheng,C.；You,S.-L.Acc.Chem.Res.2017,50,351；[3]Huang,J.-P.；Gu,Q.；You,S.-L.Chin.J.Org.Chem.2018,38,51；[4]Liu,C.-X.；Gu,Q.；You,S.-L.Trends Chem.2020,2,737；[5]Zhang,Z.-Z.；Huang,D.-Y.；Shi,B.-F.Org.Biomol.Chem.2022,20,4061；[6]Mou,Q.；Zhao,R.；Sun,B.Chem.Asian.J.2022,e202200818.[7]Zhou, l.; cheng, h. -g; li, L.; wu, k; hou, j.; jiao, c.; deng, s.; liu, z; yu, j. -q; zhou, q.nat.chem.2023,15,815.). Unfortunately, this method requires a specific substrate and can introduce only a single functional group, and the types of functional groups that can be constructed at present are limited, especially the construction of ferrocene ortho-carbon-heteroatom bonds is rarely reported. Therefore, developing a general and efficient synthesis strategy to realize the introduction of a series of different functional groups ortho to ferrocene has important significance for the construction of planar chiral ferrocene.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a planar chiral iodo-metallocene, a preparation method thereof and a method for preparing a polysubstituted planar chiral metallocene compound. The method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, good universality of substrates, high yield and simple preparation process.
The technical scheme provided by the invention is as follows:
in a first aspect, the present invention provides a method of synthesizing a planar chiral iodo-metallocene comprising the steps of:
a method for synthesizing planar chiral iodo-metallocene, comprising the steps of:
under the protection of inert gas, taking N, N-dialkylaminomethyl ferrocene or ruthenium dioxide A as a starting raw material, stirring in an organic solvent F under the action of an iodination reagent B, a palladium catalyst C, chiral amino acid D and alkali E until the reaction is finished, extracting, concentrating and purifying a reaction mixture by column chromatography to obtain a 1, 2-disubstituted plane chiral iodinated metallocene compound G in a reaction formula;
wherein, the structure of A is:
R 1 ，R 2 is two independent groups or is mutually connected to form a group; if it is an independent group, R 1 ，R 2 Selected from C1-C6 alkyl; if R is 1 ，R 2 A group is connected, and then the group is C1-C6 cycloalkyl, C1-C6 epoxyalkyl;
m is iron or ruthenium;
R 3 selected from hydrogen, C6-C12 aryl, N, S substituted C5-C12 heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, C1-C6 aldehyde, C2-C7 epoxy, C2-C11 ester, carboxyl, amide, -TMS or
The structure of B is as follows:
R 4 any one or more selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy and halogen. Preferably, R 4 The substitution position of (2) is position 3, position 4 or position 5.
The structure of G is:
further, R 3 Including hydrogen; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; a C6-C12 aryl group; C2-C11 ester groupIs- (CH) 2 ) x -COOR ', x is an integer from 0 to 4, R' is a C1-C6 alkyl group; n, S substituted C5-C12 heteroaryl groups includeHalogen; cyano group; a C1-C6 aldehyde group; the acetal comprises->-TMS；/>
Further, R 3 Wherein halogen is fluorine, chlorine, bromine or iodine.
Further, the palladium catalyst C is selected from Pd (OAc) 2 、Pd(PPh 3 ) 2 (OAc) 2 、Pd(TFA) 2 、Pd(acac) 2 、Pd(OPiv) 2 、Pd(PhCN) 2 Cl 2 、Pd(MeCN) 2 Cl 2 、Pd(PPh 3 ) 2 Cl 2 、PdCl 2 、PdI 2 、[Pd(allyl)Cl] 2 Any one or more of the following.
Further, the structural formula of the chiral amino acid D is as follows:
wherein:
i)R 5 any one selected from benzoyl, acetyl, carbobenzoxy, t-butyloxycarbonyl, ester group, C1-C6 alkyl and benzyl;
ii)R 6 is selected from any one of C6-C12 aryl or C1-C6 alkyl.
Further, in the chiral amino acid D, R 5 Wherein the ester group is-COOR ', and R' is C1-C6 alkyl or C6-C12 aryl; r is R 6 The C6-C12 aryl group in (C1-C12) is- (CH) 2 ) y -Ph, y is an integer from 0 to 4.
Further, the alkali E is selected from any one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, tripotassium phosphate, potassium formate, sodium hydroxide and sodium tert-butoxide.
Further, the solvent F is selected from any one or more of methanol, ethanol, isopropanol, tertiary butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethylethylene glycol ether, methyl tertiary butyl ether, 1, 4-dioxane, 1, 3-dioxane, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, saturated alkane of C4-12, fluorinated or chlorinated alkane of C3-12, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile and saturated alkyl nitrile of C3-12.
Further, the reaction temperature is 25 to 120 ℃.
Further, the amount of N, N-dialkylaminomethyl ferrocene/ruthenium-bis-a is 1.0 molar equivalent, the amount of iodinated reagent B is 2.0-4.0 molar equivalent, the amount of palladium catalyst C is 0.05-0.2 molar equivalent, the amount of chiral amino acid D is 0.1-0.5 molar equivalent and the amount of base E is 1.0-3.0 molar equivalent.
Further, the inert gas includes one of nitrogen and argon.
The invention takes easily available N, N-dialkyl amino methyl ferrocene/ruthenium as an initial raw material, and reacts with an iodination reagent in an organic solvent under the action of a palladium catalyst, chiral amino acid and alkali at 25 ℃ to 120 ℃ under stirring, thus obtaining the 1, 2-disubstituted plane chiral iodination metallocene. The method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, good universality of substrates, high yield and simple preparation process.
The reaction path of the invention is as follows:
in a second aspect, the present invention provides a planar chiral iodo-metallocene prepared by the method of the first aspect.
In a third aspect, the present invention provides the use of a planar chiral iodo-metallocene prepared by the method of the first aspect in the synthesis of other functional group di-or tri-substituted planar chiral metallocene compounds.
1. The preparation method of the 1, 2-disubstituted plane chiral metallocene compound and the 1,2, 3-trisubstituted plane chiral metallocene compound comprises the following steps:
(1) The preparation of the 1, 2-disubstituted planar chiral metallocene compound comprises the following steps:
under the protection of inert gas, taking iodized ferrocene or ruthenium G as a starting material, stirring in an organic solvent F until the reaction is finished under the action of an electrophile H and alkali E, extracting, concentrating and purifying a reaction mixture by column chromatography to obtain the 1, 2-disubstituted planar chiral metallocene compound shown as the reaction formula I;
the reaction formula is as follows:
wherein:
h and corresponding radicals R 7 Expressed as H/R 7 Selected from: trialkylchlorosilanes/trialkylsilyl groups, diaryl phosphine chlorides/diaryl phosphines, aryl formyl chlorides/aryl formyl groups, diaryl methanones/diaryl hydroxymethyl groups, alkyl chloroformates/alkoxy acyl groups, diaryl chlorophosphates/diaryloxyphosphonyl groups, diaryl sulfides/diaryl sulfides groups; the alkyl is C1-C6 alkyl, and the aryl is C6-C12 aryl.
Further, the reaction temperature is 25-120 ℃, and the reaction time is 1-72h.
Further, the shielding gas is argon or nitrogen.
(2) The preparation method of the 1,2, 3-trisubstituted plane chiral metallocene compound comprises the following steps:
under the protection of inert gas, 1, 2-disubstituted ferrocene or ruthenium I is used as a starting material, under the action of electrophile H and alkali E, stirring is carried out in organic solvent F until the reaction is finished, and the reaction mixture is extracted, concentrated and purified by column chromatography to obtain the 1,2, 3-trisubstituted plane chiral metallocene compound shown as the reaction formula J.
The reaction formula is as follows:
wherein:
h and corresponding radicals R 8 Expressed as H/R 8 Selected from: trialkylchlorosilanes/trialkylsilyl groups, diaryl phosphine chlorides/diaryl phosphines, aryl formyl chlorides/aryl formyl groups, diaryl methanones/diaryl hydroxymethyl groups, alkyl chloroformates/alkoxy acyl groups, diaryl chlorophosphates/diaryloxyphosphonyl groups, diaryl sulfides/diaryl sulfides groups; the alkyl is C1-C6 alkyl, and the aryl is C6-C12 aryl.
Further, the reaction temperature is 25-120 ℃, and the reaction time is 1-72h.
Further, the shielding gas is argon or nitrogen.
2. A process for preparing a 1,2, 4-trisubstituted planar chiral metallocene comprising the steps of:
under the protection of inert gas, taking iodized ferrocene or ruthenium dichloride G and aryl halide K as starting materials, stirring and reacting in an organic solvent F under the action of a palladium catalyst C, chiral amino acid D, norbornene derivatives L and alkali E until the reaction is finished, filtering, concentrating and purifying a reaction mixture by column chromatography to obtain the 1,2, 4-trisubstituted plane chiral metallocene compound shown as the formula M;
the reaction formula is as follows:
wherein:
R 9 one or more selected from C6-C12 aryl, N, S substituted C5-C12 heteroaryl, C1-C6 alkyl, aldehyde, hydroxyl, amino, cyano, nitro, amido, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl and halogen;
x is bromine or iodine;
m meterR is shown 9 M is more than or equal to 0 and less than or equal to 3; when m=2 or 3, the substituent groups may be the same or different;
Ar 1 C6-C12 aromatic hydrocarbon and N, S substituted C5-C12 heterocyclic aromatic hydrocarbon;
the norbornene derivative L has the structural formula:
wherein:
i)R 10 n represents the number of substituents, and n is more than or equal to 0 and less than or equal to 8; r is R 11 P represents the number of substituents, p is more than or equal to 0 and less than or equal to 2;
ii)R 10 ，R 11 any one or more of C6-C12 aryl, N, S substituted C5-C12 heterocyclic aryl, C1-C6 alkyl, aldehyde group, carboxyl, hydroxyl, amino, cyano, nitro, amido, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl or halogen;
iii) When the number of substituents on the five-membered ring on the left side is 2 or more, the substituents may be the same or different; when the number of substituents on the double bond is 2, the substituents may be the same or different;
iv)R 10 and R is 11 The substituents may be the same or different.
Preferably, the norbornene derivative L has the structural formula
Further, the reaction temperature is 25-120 ℃, and the reaction time is 1-72h.
Further, the shielding gas is argon or nitrogen.
The beneficial effects of the invention are as follows:
1. the main raw material N, N-alkyl amino methyl ferrocene/ruthenium is a commercial raw material (the derivative thereof only needs to be quickly synthesized by simple commercial raw material ferrocene/ruthenium in one to two steps);
2. the iodinated reagent related to the invention only needs one-step rapid synthesis;
3. the method has very good enantioselectivity, and the ee value of the obtained product is up to 99%;
4. the catalyst used in the reaction related to the method is cheaper metal palladium salt, and compared with equivalent organic metal reagents used in other synthesis methods, the catalyst is an important improvement and supplement;
5. the planar chiral iodo-metallocene prepared by the invention can be used for further synthesizing other functional group di-substituted or tri-substituted planar chiral metallocene compounds.
Detailed Description
The present invention will be further illustrated by the following specific examples, and it should be noted that the present invention is not limited to the following examples.
Example 1: preparation of Compound G-1
A stirrer of appropriate size was placed in a dry 10mL Schlenk flask, followed by palladium acetate (2.2 mg,0.01mmol,0.1 equiv.) N- (t-butoxycarbonyl) -L-valine(6.5 mg,0.03mmol,0.3 equiv), potassium carbonate (27.6 mg,0.2mmol,2.0 equiv), and after three argon substitutions through the double drain, dry N, N-dimethylformamide DMF (0.9 mL), dry dimethyl sulfoxide (0.1 mL), N-dimethylaminomethyl ferrocene (24.3 mg,0.1mmol,1.0 equiv), 2-trifluoromethyl-1- (2-iodo-3-methyl) phenylethanone were added(94.2 mg,0.3mmol,3.0 equiv) then the reaction system was stirred at 80℃for 18 hours, cooled to room temperature after the completion of the reaction, quenched by adding a saturated sodium carbonate solution to the reaction system, extracted three times with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic phase was driedDrying sodium sulfate, filtering, removing solvent under reduced pressure, and separating by column chromatography to obtain the product G-1 (red oily liquid, yield 68%). 1 H NMR(600MHz,CDCl 3 ):δ4.31(dd,J＝2.4,1.4Hz,1H),4.20(dd,J＝2.7,1.4Hz,1H),4.16(t,J＝2.5Hz,1H),3.98(t,J＝2.0Hz,2H),3.94(dt,J＝6.2,1.7Hz,2H),3.34(d,J＝13.0Hz,1H),3.30(d,J＝13.0Hz,1H),2.23(s,6H),1.94(s,3H)； 13 C NMR(150MHz,CDCl 3 ):δ85.8,84.7,75.8,72.8,72.4,71.2,71.1,70.0,69.5,58.5,47.3,45.2,13.8；HRMS(ESI+FTMS):calc’d for C 13 H 17 FeIN + [M+H + ]369.9750,found 369.9746；HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA＝99/1,1mL/min,λ＝254nm,t R (major)＝9.30min,t R (minor)＝7.48min；/>-12.72(c 0.21,CHCl 3 ).
Example 2: preparation of Compound G-2
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' -methylferrocene (25.7 mg) gave compound G-2 (red oily liquid, 71% yield). 1 H NMR(600MHz,CDCl 3 )δ4.31(dd,J＝2.4,1.4Hz,1H),4.20(dd,J＝2.7,1.4Hz,1H),4.16(t,J＝2.5Hz,1H),3.98(t,J＝2.0Hz,2H),3.94(dt,J＝6.2,1.7Hz,2H),3.34(d,J＝13.0Hz,1H),3.30(d,J＝13.0Hz,1H),2.23(s,6H),1.94(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ85.8,84.7,75.8,72.8,72.4,71.2,71.1,70.0,69.5,58.5,47.3,45.2,13.8；HRMS(ESI+FTMS):calc’d for C 14 H 19 FeIN + [M+H + ]383.9906,found 383.9899.HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝9.93min,t R (minor)＝7.82min；-16.68(c0.44,CHCl 3 ).
Example 3: preparation of Compound G-3
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' -ethylferrocene (27.1 mg) gave compound G-3 (red oily liquid, 55% yield). 1 H NMR(400MHz,CDCl 3 )δ4.33(dd,J＝2.4,1.4Hz,1H),4.22(dd,J＝2.7,1.4Hz,1H),4.17(t,J＝2.6Hz,1H),3.97(td,J＝3.6,1.7Hz,4H),3.35(d,J＝13.0Hz,1H),3.30(d,J＝13.0Hz,1H),2.33(qd,J＝7.5,1.2Hz,2H),2.23(s,6H),1.15(t,J＝7.5Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ92.8,84.7,75.6,71.6,71.5,71.4,70.3,69.8,69.4,58.5,47.1,45.2,21.5,15.1；HRMS(ESI+FTMS):calc’d for C 15 H 21 FeIN + [M+H + ]398.0063,found 398.0063；HPLC:97％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝9.19min,t R (minor)＝6.96min；-17.74(c 0.54,CHCl 3 ).
Example 4: preparation of Compound G-4
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' -isopropylferrocene (28.5 mg) gave compound G-4 (red oily liquid, 60% yield). 1 H NMR(400MHz,CDCl 3 )δ4.35(dd,J＝2.5,1.4Hz,1H),4.24(dd,J＝2.6,1.4Hz,1H),4.18(t,J＝2.5Hz,1H),4.02(q,J＝1.7Hz,1H),3.97(dt,J＝2.7,1.4Hz,1H),3.97-3.90(m,2H),3.35(d,J＝13.0Hz,1H),3.31(d,J＝13.1Hz,1H),2.64(hept,J＝6.9Hz,1H),2.22(s,6H),1.18(s,3H),1.16(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ98.5,84.7,75.5,72.1,71.7,70.5,69.8,69.3,68.3,58.6,47.0,45.2,27.1,23.8,23.7；HRMS(ESI+FTMS):calc’d for C 15 H 21 FeIN + [M+H + ]398.0063,found 398.0063；HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.5mL/min,λ＝254nm,t R (major)＝12.81min,t R (minor)＝9.08min；-36.26(c 0.60,CHCl 3 ).
Example 5: preparation of Compound G-5
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' -benzylferrocene (33.3 mg) gave compound G-5 (red oily liquid, 57% yield). 1 H NMR(400MHz,CDCl 3 )δ7.29-7.23(m,2H),7.21-7.12(m,3H),4.36(dd,J＝2.5,1.3Hz,1H),4.24(dd,J＝2.6,1.4Hz,1H),4.18(t,J＝2.5Hz,1H),4.01(ddd,J＝6.1,4.8,2.3Hz,4H),3.67(s,2H),3.35(s,1H),3.29(s,1H),2.23(s,6H)； 13 C NMR(100MHz,CDCl 3 )δ141.4,128.4,126.2,89.5,84.9,75.8,72.5,72.0,71.9,71.5,70.1,69.6,58.5,47.2,45.2,35.1；HRMS(ESI+FTMS):calc’d for C 20 H 23 FeIN + [M+H + ]460.0219,found 460.0217；HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝13.89min,t R (minor)＝11.01min；-31.21(c 0.70,CHCl 3 ).
Example 6: preparation of Compound G-6
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (2-ethoxycarbonylethyl) ferrocene (33.3 mg) gave compound G-6 (yellow oily liquid, 56% yield). 1 H NMR(400MHz,CDCl 3 ):δ4.34(dd,J＝2.4,1.4Hz,1H),4.23(dd,J＝2.6,1.4Hz,1H),4.17(t,J＝2.6Hz,1H),4.13(q,J＝7.1Hz,2H),3.99(d,J＝1.7Hz,3H),3.95(q,J＝1.7Hz,1H),3.34(d,J＝13.0Hz,1H),3.29(d,J＝13.0Hz,1H),2.68-2.61(m,2H),2.49(dd,J＝8.6,6.5Hz,2H),2.22(s,6H),1.25(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ173.1,89.1,84.9,75.7,72.0,71.9,71.6,70.9,70.0,69.5,60.6,58.5,47.0,45.2,35.9,24.1,14.4；HRMS(ESI+FTMS):calc’d for C 18 H 25 FeINO2 + [M+H + ]470.0274,found 470.0272；HPLC:96％ee,Daicel Chiralpak OD-Hcolumn,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝21.01min,t R (minor)＝18.50min；-45.98(c 0.59,CHCl 3 ).
Example 7: preparation of Compound G-7
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (2-cyano) ferrocene (29.6 mg) gave compound G-7 (yellow oily liquid, 67% yield). 1 H NMR(400MHz,CDCl 3 ):δ4.35(dd,J＝2.5,1.3Hz,1H),4.26(dd,J＝2.7,1.4Hz,1H),4.20(t,J＝2.5Hz,1H),4.07(q,J＝2.5,2.0Hz,3H),4.00(q,J＝1.6Hz,1H),3.32(d,J＝13.0Hz,1H),3.27(d,J＝13.0Hz,1H),2.70(t,J＝7.5Hz,2H),2.50(t,J＝7.2Hz,2H),2.22(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ119.5,86.5,85.3,75.8,72.2,72.1,71.8,70.8,70.0,69.5,58.4,47.0,45.2,25.1,19.3；HRMS(ESI+FTMS):calc’d for C 16 H 20 FeIN 2 + [M+H + ]423.0015,found 423.0009；HPLC:>99％ee,Daicel Chiralpak IA column,Hexanes/IPA/Et 2 NH＝97/3/0.1,0.7mL/min,λ＝254nm,t R (major)＝22.48min；-41.00(c 0.66,CHCl 3 ).
Example 8: preparation of Compound G-8
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' -bromoferrocene (32.2 mg) gave compound G-8 (yellow oily liquid, 49% yield). 1 H NMR(400MHz,CDCl 3 ):δ4.44(t,J＝1.9Hz,1H),4.30(td,J＝2.6,1.3Hz,3H),4.25(dt,J＝2.6,1.3Hz,1H),4.06(td,J＝2.6,1.3Hz,1H),4.03(td,J＝2.6,1.4Hz,1H),3.39(d,J＝13.1Hz,1H),3.31(d,J＝13.1Hz,1H),2.24(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ86.5,78.8,77.4,73.9,73.1,72.0,71.8,71.6,71.0,57.9,46.7,45.3；HRMS(ESI+FTMS):calc’d for C 13 H 16 BrFeIN + [M+H + ]447.8855,found447.8852；HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝11.11min,t R (minor)＝8.74min；-4.23(c 0.52,CHCl 3 ).
Example 9: preparation of Compound G-9
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' -phenylferrocene (31.9 mg) gave compound G-9 (yellow oily liquid, 59% yield). 1 H NMR(400MHz,CDCl 3 ):δ7.48(d,J＝7.4Hz,2H),7.32(t,J＝7.6Hz,2H),7.22(t,J＝7.3Hz,1H),4.58(d,J＝2.9Hz,1H),4.51(d,J＝2.6Hz,1H),4.30-4.29(m,1H),4.25(d,J＝2.8Hz,1H),4.17(d,J＝2.6Hz,1H),4.10(t,J＝2.6Hz,1H),3.02(d,J＝13.3Hz,1H),2.98(d,J＝13.1Hz,1H),2.14(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ137.2,128.6,126.5,126.3,87.2,85.0,76.5,72.7(2),70.9,70.4,70.1,69.2,57.7,47.1,45.1；HRMS(ESI+FTMS):calc’dforC 19 H 21 FeIN + [M+H + ]446.0063,found446.0059；HPLC:98％ee,DaicelChiralpakOD-Hcolumn,Hexanes/IPA/Et 2 NH＝99.5/0.5/0.1,0.5mL/min,λ＝254nm,t R (major)＝24.96min,t R (minor)＝23.04min；44.37(c0.59,CHCl 3 ).
Example 10: preparation of Compound G-10
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (4-methoxycarbonylphenyl) ferrocene (37.7 mg) gave compound G-10 (red oily liquid, 52% yield). 1 H NMR(400MHz,CDCl 3 ):δ8.02-7.95(m,2H),7.54-7.49(m,2H),4.62(dt,J＝2.7,1.4Hz,1H),4.57(dt,J＝2.8,1.4Hz,1H),4.37(td,J＝2.5,1.2Hz,1H),4.33(td,J＝2.6,1.3Hz,1H),4.24(dd,J＝2.5,1.4Hz,1H),4.15(dd,J＝2.6,1.4Hz,1H),4.10(t,J＝2.5Hz,1H),3.92(s,3H),3.01(d,J＝13.2Hz,1H),2.96(d,J＝13.2Hz,1H),2.12(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ167.2,143.0,129.9,127.9,126.0,85.5,85.2,76.8,73.4(2),71.0,70.4(2),69.8,57.7,52.2,47.1,45.1；HRMS(ESI+FTMS):calc’dforC 21 H 23 FeINO 2 + [M+H + ]504.0117,found504.0114；HPLC:99％ee,DaicelChiralpakOD-Hcolumn,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝27.55min,t R (minor)＝21.69min；-62.73(c0.67,CHCl 3 ).
Example 11: preparation of Compound G-11
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (4-methylphenyl) ferrocene (33.3 mg) gave compound G-11 (red oily liquid, 53% yield). 1 H NMR(400MHz,CDCl 3 ):δ7.37(d,J＝7.8Hz,2H),7.13(d,J＝7.7Hz,2H),4.59-4.51(m,1H),4.48(dd,J＝2.9,1.6Hz,1H),4.26(q,J＝2.1Hz,1H),4.23(dq,J＝3.8,1.9Hz,2H),4.14(t,J＝1.9Hz,1H),4.09(t,J＝2.5Hz,1H),3.04(d,J＝13.2Hz,1H),2.99(d,J＝13.2Hz,1H),2.33(s,3H),2.13(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ136.2,134.1,129.3,126.2,87.5,85.1,76.5,72.6,72.5,70.9,70.4,69.8,69.1,47.0,45.1,21.3；HRMS(ESI+FTMS):calc’d for C 20 H 23 FeIN + [M+H + ]460.0219,found 460.0216；HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝11.07min,t R (minor)＝9.87min；-62.73(c 0.67,CHCl 3 ).
Example 12: preparation of Compound G-12
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (4, 5-tetramethyl-1, 3-dioxolan-2-yl) ferrocene (37.1 mg) gave compound G-12 (red oily liquid, 52% yield). 1 H NMR(400MHz,CDCl 3 )δ5.84(s,1H),4.46-4.39(m,1H),4.30(dd,J＝2.7,1.4Hz,1H),4.25(t,J＝2.5Hz,2H),4.23(dd,J＝2.6,1.3Hz,1H),4.10(q,J＝2.2Hz,1H),4.02(q,J＝2.3Hz,1H),3.47(d,J＝13.1Hz,1H),3.31(d,J＝13.1Hz,1H),2.22(s,6H),1.26(s,3H),1.25(s,3H),1.22(s,3H),1.21(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ98.4,87.8,85.5,82.5,82.4,75.7,73.7,72.5,70.2(2C),70.1,70.0,58.3,46.7,45.2,24.3(2C),22.2(2C)；HRMS(ESI+FTMS):calc’d for C 20 H 29 FeINO 2 + [M+H + ]498.0587,found 498.0588；HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝7.80min,t R (minor)＝7.01min；-4.17(c 0.86,CHCl 3 ).
Example 13: preparation of Compound G-13
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' -methoxycarbonyl ferrocene (30.1 mg) gave compound G-13 (red oily liquid, 39% yield). 1 H NMR(400MHz,CDCl 3 ):δ4.72(d,J＝2.6Hz,1H),4.66(d,J＝2.5Hz,1H),4.45(d,J＝2.5Hz,1H),4.34(d,J＝2.6Hz,1H),4.31(q,J＝2.6Hz,2H),4.26(d,J＝2.7Hz,1H),3.84(s,3H),3.29(d,J＝13.1Hz,1H),3.24(d,J＝13.1Hz,1H),2.22(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ170.7,86.3,76.4,75.3,74.5,73.9,73.9,72.7,70.8,70.5,57.7,51.8,46.6,45.2；HRMS(ESI+FTMS):calc’d for C 15 H 19 FeINO 2 + [M+H + ]427.9804,found 427.9804；HPLC:98％ee,Daicel Chiralpak IA column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝22.40min,t R (minor)＝25.77min；29.43(c 0.44,CHCl 3 ).
Example 14: preparation of Compound G-14
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (2-ethoxycarbonyl-1-vinyl) ferrocene (34.1 mg) gave compound G-14 (red oily liquid, 53% yield). 1 HNMR(400MHz,CDCl 3 ):δ7.45(d,J＝15.8Hz,1H),6.06(d,J＝15.8Hz,1H),4.39(t,J＝1.8Hz,1H),4.38-4.36(m,1H),4.35(d,J＝2.4Hz,1H),4.32(t,J＝2.3Hz,2H),4.28(d,J＝2.5Hz,1H),4.26-4.19(m,3H),3.23(d,J＝13.3Hz 1H),3.19(d,J＝13.3Hz 1H),2.20(s,6H),1.33(t,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ167.1,143.9,116.6,86.1,80.7,76.6,74.5,74.4,72.2,71.5,70.8,70.4,60.4,58.2,46.8,45.2,14.5；HRMS(ESI+FTMS):calc’d for C 18 H 23 FeINO2 + [M+H + ]468.0117,found 468.0108；HPLC:98％ee,Daicel Chiralpak IA column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝25.78min,t R (minor)＝28.73min；48.67(c 0.47,CHCl 3 ).
Example 15: preparation of Compound G-15
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (trimethylsilyl) ferrocene (31.5 mg) gave compound G-15 (red oily liquid, 50% yield). 1 H NMR(400MHz,CDCl 3 ):δ4.44-4.38(m,1H),4.32-4.28(m,1H),4.24-4.17(m,3H),4.13-4.08(m,1H),4.06(t,J＝1.9Hz,1H),3.40(d,J＝13.1Hz,1H),3.36(d,J＝13.1Hz,1H),2.26(s,6H),0.25(s,9H)； 13 C NMR(100MHz,CDCl 3 ):δ84.9,77.5,76.7,76.0,75.2,74.6,73.7,69.5,69.1,58.8,46.7,45.2,0.0；HRMS(ESI+FTMS):calc’d for C 16 H 25 FeINSi + [M+H + ]442.0145,found442.0147；HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA＝99/1,1.0mL/min,λ＝254nm,t R (major)＝8.85min,t R (minor)＝4.89min；-62.73(c 0.67,CHCl 3 ).
Example 16: preparation of Compound G-16
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (diphenylhydroxymethyl) ferrocene (42.5 mg) gave compound G-16 (yellow oily liquid, 75% yield). 1 H NMR(400MHz,CDCl 3 ):δ7.48-7.26(m,10H),4.49(d,J＝2.4Hz,1H),4.42(d,J＝2.5Hz,1H),4.38(d,J＝3.2Hz,1H),4.23(d,J＝2.5Hz,1H),4.19-4.13(m,1H),4.11(d,J＝2.6Hz,1H),4.06(d,J＝3.2Hz,1H),3.30(d,J＝13.8Hz,1H),3.23(d,J＝13.8Hz,1H),2.42(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ147.6,147.4,127.7(2),127.1,127.0(2),126.9,99.2,86.3,77.7,76.7,75.1,72.3,71.2,70.6,69.4,69.2,58.6,46.0,45.5；HRMS(ESI+FTMS):calc’d for C 26 H 27 FeINO + [M+H + ]552.0481,found 552.0480；HPLC:98％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝13.51min,t R (minor)＝15.19min；-62.73(c 0.67,CHCl 3 ).
Example 17: preparation of Compound G-17
The procedure was as in example 1, except that the ferrocene substrate used was: 4- (1, 3-Dioxolan-2-yl) piperidine methyl ferrocene (34.1 mg) to give compound G-17 (yellow oily liquid, 75% yield). 1 H NMR(400MHz,CDCl 3 ):δ4.41(dd,J＝2.5,1.4Hz,1H),4.31(dd,J＝2.6,1.4Hz,1H),4.21(t,J＝2.5Hz,1H),4.10(s,5H),3.92(s,4H),3.54(d,J＝13.3Hz,1H),3.43(d,J＝13.3Hz,1H),2.60(q,J＝7.1,5.3Hz,2H),2.49(dt,J＝11.5,5.8Hz,2H),1.70(q,J＝5.9,5.5Hz,4H)； 13 C NMR(100MHz,CDCl 3 ):δ107.3,84.8,74.9,71.7,69.3,69.0,64.3,57.3,51.0,46.6,34.9；HRMS(ESI+FTMS):calc’d for C 18 H 23 FeINO 2 + [M+H + ]468.0117,found 468.0118；HPLC:99％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝16.69min,t R (minor)＝14.70min；-62.73(c 0.67,CHCl 3 ).
Example 18: preparation of Compound G-18
The procedure was as in example 1, except that the ferrocene substrate used was: n, N-dimethylaminomethyl-bis-ruthenium (28.8 mg) gave Compound G-18 (yellow oily liquid, yield)33％)。 1 H NMR(600MHz,CDCl 3 )δ4.84(t,J＝1.7Hz,1H),4.64(t,J＝1.8Hz,1H),4.53(t,J＝2.4Hz,1H),4.51(s,5H),3.24(d,J＝13.2Hz,1H),3.19(d,J＝13.2Hz,1H),2.28(s,6H)； 13 C NMR(150MHz,CDCl 3 )δ89.3,77.8,73.6,71.8,71.7,58.8,45.3,41.6；HRMS(ESI+FTMS):calc’d for C 13 H 17 INRu + [M+H + ]415.9444,found 415.9444；HPLC:91％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝11.98min,t R (minor)＝10.71min；61.95(c 1.28,CHCl 3 ).
Example 19: preparation of Compound G-19
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' -methylruthenium (30.2 mg) gave compound G-19 (yellow oily liquid, 42% yield). 1 H NMR(400MHz,CDCl 3 )δ4.76(dd,J＝2.4,1.2Hz,1H),4.58(dd,J＝2.5,1.2Hz,1H),4.49(t,J＝2.4Hz,1H),4.43(q,J＝2.0Hz,1H),4.41(q,J＝2.0Hz,1H),4.37(t,J＝1.7Hz,2H),3.16(d,J＝13.2Hz,1H),3.12(d,J＝13.2Hz,1H),2.28(s,6H),1.85(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ88.6,78.2,75.6,75.0,72.4,72.3,72.0,71.8,58.4,45.3,43.4,13.5；HRMS(ESI+FTMS):calc’d forC 14 H 19 INRu + [M+H + ]429.9600,found 429.9598；HPLC:96％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7 mL/min,λ＝254 nm,t R (major)＝8.60 min,t R (minor)＝7.51min；-12.06(c 0.15,CHCl 3 ).
Example 20: preparation of Compound G-20
The procedure was as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1' - (4, 5-tetramethyl-1, 3-dioxolan-2-yl) ruthenate (41.7 mg) to give compound G-20 (yellow oily liquid, 32% yield). 1 H NMR(400MHz,CDCl 3 ):δ5.60(s,1H),4.86-4.81(m,1H),4.66(q,J＝1.5Hz,1H),4.64-4.61(m,1H),4.59(d,J＝1.8Hz,1H),4.54(t,J＝2.4Hz,1H),4.51(t,J＝1.7Hz,2H),3.24(d,J＝13.3Hz,1H),3.19(d,J＝13.3Hz,1H),2.27(s,6H),1.23(s,12H)； 13 C NMR(100MHz,CDCl 3 ):δ97.8,91.4,89.6,82.5,82.4,78.6,74.1,73.5,73.3,72.5,71.9,58.3,45.3,42.7,24.4,24.3,22.2,22.2；HRMS(ESI+FTMS):calc’d for C 20 H 29 INO 2 Ru + [M+H + ]544.0281,found544.0273；HPLC:98％ee,Daicel Chiralpak IE column,Hexanes/IPA/Et 2 NH＝99/1/0.1,0.7mL/min,λ＝254nm,t R (major)＝15.11min,t R (minor)＝16.86min；19.80(c 0.30,CHCl 3 ).
Example 21: gram-scale preparation of Compound G-1
A stirrer of an appropriate size was placed in a dry 250mL Schlenk flask, followed by addition of palladium acetate (112.3 mg,0.5mmol,0.1 equiv), N- (t-butoxycarbonyl) -L-valine (325.9 mg,1.5mmol,0.3 equiv), potassium carbonate (4.15G, 30.0mmol,6.0 equiv), and after three times of evacuation through a double-row tube, dry N, N-dimethylformamide (45.0 mL) and dry dimethyl sulfoxide (5.0 mL), 2-trifluoromethyl-1- (2-iodo-3-methyl) phenylethanone (4.71G, 15.0mmol,3.0 equiv), N, N-dimethylaminomethyl ferrocene (1.22G, 5.0mmol,1.0 equiv) then the reaction system was stirred at 80℃for 36 hours, then cooled to room temperature, then saturated sodium carbonate solution was added to the reaction system to quench the reaction, extraction was performed three times with ethyl acetate, the organic phases were combined and washed three times with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the product G-1 (1.014G, red oily liquid, yield 55%,98% ee) was obtained by column chromatography separation.
Application example 1: preparation of Compound I-1
A stirrer of appropriate size was placed in a dried 10mL Schlenk tube, G-1 (36.9 mg,0.1mmol,1.0 equiv) was added, three times of evacuation was performed through a double tube, 1.5mL of dried diethyl ether was added, and the reaction system was left at-40℃and then n-butyllithium (60. Mu.L, 2.5M in hexane,0.15mmol,1.5equiv) was added dropwise to the reaction system, followed by stirring at that temperature for 2 hours after completion of the addition. The reaction system was then cooled to-78 ℃, a solution of p-toluene disulfide (61.6 mg,0.25mmol,2.5 equiv) in diethyl ether (0.5 mL) was added dropwise, stirred at this temperature for 10 minutes after the addition was completed, and then warmed to room temperature and stirred overnight. After the reaction, water was added to the reaction system to quench, extraction was performed three times (10 ml×3) with ethyl acetate, the organic layers were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, followed by column chromatography to obtain the product I-1 (yellow oily liquid, yield 62%). 1 H NMR(400MHz,CDCl 3 ):δ7.04(d,J＝8.1Hz,2H),6.97(d,J＝8.0Hz,2H),4.53-4.48(m,1H),4.46(t,J＝1.9Hz,1H),4.31(t,J＝2.6Hz,1H),4.17(s,5H),3.47(d,J＝13.2Hz,1H),3.43(d,J＝13.2Hz,1H),2.25(s,3H),2.05(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ135.6,133.8,128.4,125.8,86.5,76.3,74.6,70.3,69.4,68.1,55.9,44.3,20.0；HRMS(ESI+FTMS):calc’d for C 20 H 24 FeNS + [M+H + ]366.0973,found 366.0976；HPLC:97％ee,Daicel Chiralpak AD column,Hexanes/IPA/Et 2 NH＝98/2/0.1,1mL/min,λ＝254nm,t R (major)＝5.75min,t R (minor)＝9.35min；38.13(c 0.15,CHCl 3 ).
Application example 2: preparation of Compound I-2
The procedure is as in application example 1, except that the electrophiles used are: diphenyl phosphorus chloride (45 μl) gave compound I-2 (red solid, 65% yield). 1 H NMR(400MHz,CDCl 3 ):δ7.63-7.55(m,2H),7.38(dq,J＝5.6,2.2,1.8Hz,3H),7.26-7.17(m,5H),4.58-4.51(m,1H),4.31(t,J＝2.5Hz,1H),3.93(s,5H),3.90-3.84(m,1H),3.60(dd,J＝13.0,2.5Hz,1H),3.44(d,J＝13.1Hz,1H),2.00(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ140.2(d,J＝8.7Hz),138.2(d,J＝8.2Hz),135.1(d,J＝21.6Hz),132.6(d,J＝18.2Hz),129.1,128.2(d,J＝7.9Hz),127.9(d,J＝6.2Hz),127.7,90.6(d,J＝25.8Hz),76.4(d,J＝8.8Hz),72.8(d,J＝4.1Hz),71.6(d,J＝4.5Hz),69.8,58.0(d,J＝9.2Hz),45.1； 31 P NMR(162MHz,CDCl 3 ):δ-24.5；HRMS(ESI+FTMS):calc’d for C 25 H 27 FeNP + [M+H + ]428.1225,found 428.1222；Melting point:101-102℃；HPLC:98％ee,Daicel Chiralpak IG column,Hexanes/IPA/Et 2 NH＝99/1/0.1,1mL/min,λ＝254nm,t R (major)＝11.48min,t R (minor)＝8.90min；256.54(c 0.54,CHCl 3 ).
Application example 3: preparation of Compound I-3
The procedure is as in application example 1, except that the electrophiles used are: benzophenone (45.6 mg) gave compound I-3 (yellow oily liquid, 45% yield). 1 H NMR(400MHz,CDCl 3 ):δ7.63-7.50(m,2H),7.34(t,J＝7.6Hz,2H),7.24(d,J＝7.3Hz,1H),7.21-7.08(m,5H),4.07(d,J＝2.3Hz,2H),3.97(s,5H),3.81(t,J＝2.1Hz,1H),3.67(d,J＝13.3Hz,1H),2.68(d,J＝13.2Hz,1H),1.99(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ150.0,147.5,127.5,127.3(2),127.1,126.4,126.3,96.3,82.1,77.6,70.7,70.5,69.8,65.4,59.1,44.3；HRMS(ESI+FTMS):calc’d for C 26 H 28 FeNO + [M+H + ]426.1515,found 426.1508；HPLC:98％ee,Daicel Chiralpak AD column,Hexanes/IPA/Et 2 NH＝98/2/0.1,1mL/min,λ＝220nm,t R (major)＝4.30min,t R (minor)＝6.39min；121.90(c 0.23,CHCl 3 ).
Application example 4: preparation of Compound I-4
The procedure is as in application example 1, except that the electrophiles used are: trimethylchlorosilane (32 μl) gave compound I-4 (red oily liquid, 67% yield). 1 H NMR(400MHz,CDCl 3 ):δ4.34-4.28(m,1H),4.24(t,J＝2.4Hz,1H),4.08(s,5H),4.04-3.99(m,1H),3.42(d,J＝12.5Hz,1H),3.01(d,J＝12.5Hz,1H),2.11(s,6H),0.28(s,9H)； 13 C NMR(100MHz,CDCl 3 ):δ89.2,73.3,72.6,71.2,68.7,67.9,58.7,44.1,-0.5；HRMS(ESI+FTMS):calc’d for C 16 H 26 FeNSi + [M+H + ]316.1178,found 316.1177；HPLC:90％ee,Daicel Chiralpak AD column,Hexanes/Et 2 NH＝100/0.1,0.5mL/min,λ＝254nm,t R (major)＝8.47min,t R (minor)＝9.56min；-24.95(c 0.99,CHCl 3 ).
Application example 5: preparation of Compound J-1
A stirrer of appropriate size was placed in a dried 10mL Schlenk tube, I-4 (31.6 mg,0.1mmol,1.0 equiv) was added, three times of evacuation through a double tube, 1.5mL of dried diethyl ether was added, and the reaction system was left at-40℃and then n-butyllithium (60. Mu.L, 2.5M in hexane,0.15mmol,1.5equiv) was added dropwise to the reaction system, followed by stirring at that temperature for 2 hours after completion of the addition. The reaction system was then cooled to-78 ℃, and (1R, 2S, 5R) - (-) -menthol (S) -p-toluene sulfinate (69. Mu.L, 0.25mmol,2.5 equiv) was added dropwise, and after the addition was completed, the mixture was stirred at that temperature for 10 minutes, and then warmed to room temperature and stirred overnight. After the reaction, water was added to the reaction system to quench, extraction was performed three times (10 ml×3) with ethyl acetate, the organic layers were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and then the solvent was removed under reduced pressure, followed by separation by column chromatography to obtain the product J-1 (red oily liquid, yield 51%). 1 H NMR(400MHz,CDCl 3 ):δ7.66-7.59(m,2H),7.18(d,J＝8.0Hz,2H),4.73(d,J＝2.6Hz,1H),4.35(s,5H),4.19(d,J＝2.6Hz,1H),3.60(d,J＝12.8Hz,1H),3.26(d,J＝12.8Hz,1H),2.33(s,3H),1.92(s,6H),0.26(s,9H)； 13 C NMR(100MHz,CDCl 3 ):δ144.2,140.7,129.4,125.5,98.3,91.7,74.9,74.4,71.0,66.8,57.2,44.5,21.5,0.6；HRMS(ESI+FTMS):calc’d for C 23 H 32 FeNOSSi + [M+H + ]454.1318,found 454.1320；221.55(c 0.64,CHCl 3 ).
Application example 6: preparation of Compound M-1
A stirrer of an appropriate size was placed in a dried 10mL Schlenk flask, followed by palladium acetate (2.2 mg,0.01mmol,0.1 equiv), N- (t-butoxycarbonyl) -L-valine (6.5 mg,0.03mmol,0.3 equiv), potassium carbonate (27.6 mg,0.2mmol,2.0 equiv), and after three times of evacuation through a double-row tube, dried N, N-dimethylformamide DMF (0.4 mL) and dried dimethylsulfoxide DMSO (0.1 mL), G-1 (36.9 mg,0.1mmol,1.0 equiv), 4-iodobenzotrifluoride (18. Mu.L, 0.12mmol,1.2 equiv), 1-N-heptyl-2-norbornene were added(8.3 mg,0.05mmol,0.5 equiv) then the reaction system was stirred at 80℃for 18 hours, cooled to room temperature after the completion of the reaction, quenched by adding a saturated sodium carbonate solution to the reaction system, extracted three times with ethyl acetate (10 mL. Times.3), the organic phases were combined and washed with a saturated sodium chloride solution, the organic phases were dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and the product M-1 was obtained by column chromatography (red oily liquid, yield 57%). 1 H NMR(400MHz,CDCl 3 ):δ7.52(s,4H),4.98(d,J＝1.6Hz,1H),4.87(d,J＝1.6Hz,1H),4.00(s,5H),3.48(d,J＝13.1Hz,1H),3.34(d,J＝13.1Hz,1H),2.29(s,6H)； 13 C NMR(100MHz,CDCl 3 ):δ142.3,128.5,128.2,126.0,125.6,125.6,125.6,125.5,87.0,84.4,73.6,73.5,67.5,58.9,46.9,45.4；HRMS(ESI+FTMS):calc’d for C 20 H 20 F 3 FeIN + [M+H + ]513.9936,found 513.9935；HPLC:99％ee,Daicel Chiralpak OD-H column,Hexanes/IPA/Et 2 NH＝97/3/0.1,1mL/min,λ＝254nm,t R (major)＝9.01min,t R (minor)＝7.36min；/>31.30(c 0.21,CHCl 3 ).
The present invention is not limited to the above-mentioned embodiments, but any modifications, equivalents, improvements and modifications within the scope of the invention will be apparent to those skilled in the art.

Claims (10)

1. A method for synthesizing planar chiral iodo-metallocene, comprising the steps of:
under the protection of inert gas, taking N, N-dialkylaminomethyl ferrocene or ruthenium dioxide A as a starting raw material, stirring in an organic solvent F under the action of an iodination reagent B, a palladium catalyst C, chiral amino acid D and alkali E until the reaction is finished, extracting, concentrating and purifying a reaction mixture by column chromatography to obtain a 1, 2-disubstituted plane chiral iodinated metallocene compound G in a reaction formula;
wherein, the structure of A is:
R 1 ，R 2 is two independent groups or is mutually connected to form a group; if it is an independent group, R 1 ，R 2 Selected from C1-C6 alkyl; if R is 1 ，R 2 Is linked to a group, then the group is C1-C7 cycloalkyl, C1-C7 alkylene oxide, N, S substituted C1-C7 cycloalkyl;
m is iron or ruthenium;
R 3 selected from hydrogen, C6-C12 aryl, N, S substituted C5-C12 heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, C1-C6 aldehyde, C2-C7 epoxy, C2-C11 ester, carboxyl, amide, -TMS or
The structure of B is as follows:
R 4 any one or more selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl and halogen;
the structure of G is:
2. the method for synthesizing a planar chiral metallocene according to claim 1, wherein R 3 Including hydrogen; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; a C6-C12 aryl group; C2-C11 ester group is- (CH) 2 ) x -COOR ', x is an integer from 0 to 4, R' is a C1-C6 alkyl group; n, S substituted C5-C12 heteroaryl groups includeHalogen; cyano group; a C1-C6 aldehyde group; the acetal comprises->-TMS；/>
3. The method for synthesizing a planar chiral metallocene iodide according to claim 1, wherein the palladium catalyst C is selected from Pd (OAc) 2 、Pd(PPh 3 ) 2 (OAc) 2 、Pd(TFA) 2 、Pd(acac) 2 、Pd(OPiv) 2 、Pd(PhCN) 2 Cl 2 、Pd(MeCN) 2 Cl 2 、Pd(PPh 3 ) 2 Cl 2 、PdCl 2 、PdI 2 、[Pd(allyl)Cl] 2 Any one or more of the following.
4. The method for synthesizing a planar chiral iodo-metallocene according to claim 1, wherein the chiral amino acid D has a structural formula:
wherein:
i)R 5 any one selected from benzoyl, acetyl, carbobenzoxy, t-butyloxycarbonyl, ester group, C1-C6 alkyl and benzyl;
ii)R 6 any one selected from C6-C12 aryl or C1-C6 alkyl;
in the chiral amino acid D, R 5 Wherein the ester group is-COOR ', and R' is C1-C6 alkyl or C6-C12 aryl; r is R 6 The C6-C12 aryl group in (C1-C12) is- (CH) 2 ) y -Ph, y is an integer from 0 to 4.
5. The method for synthesizing planar chiral metallocene according to claim 1, wherein the base E is selected from any one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, potassium phosphate, potassium formate, sodium hydroxide, and sodium tert-butoxide.
6. The method for synthesizing planar chiral metallocene according to claim 1, wherein the solvent F is selected from any one or more of methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethylethylene diether, methyl t-butyl ether, 1, 4-dioxane, 1, 3-dioxane, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, saturated alkanes of C4-12, fluorinated or chlorinated alkanes of C3-12, benzene, toluene, xylene, trimethylbenzene, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, saturated alkylnitriles of C3-12.
7. The method for synthesizing a planar chiral metallocene according to claim 1, wherein the reaction temperature is 25 ℃ to 120 ℃.
8. A planar chiral iodo-metallocene characterized by: a method according to any one of claims 1 to 7.
9. A process for preparing 1, 2-disubstituted planar chiral metallocene compounds and 1,2, 3-trisubstituted planar chiral metallocene compounds using the planar chiral iodo-metallocene prepared by the process of any one of claims 1 to 7, characterized in that:
(1) The preparation of the 1, 2-disubstituted planar chiral metallocene compound comprises the following steps:
under the protection of inert gas, taking iodized ferrocene or ruthenium G as a starting material, stirring in an organic solvent F until the reaction is finished under the action of an electrophile H and alkali E, extracting, concentrating and purifying a reaction mixture by column chromatography to obtain the 1, 2-disubstituted planar chiral metallocene compound shown as the reaction formula I;
the reaction formula is as follows:
(2) The preparation method of the 1,2, 3-trisubstituted plane chiral metallocene compound comprises the following steps:
under the protection of inert gas, 1, 2-disubstituted ferrocene or ruthenium I is taken as a starting material, under the action of electrophile H and alkali E, stirring is carried out in organic solvent F until the reaction is finished, and the reaction mixture is extracted, concentrated and purified by column chromatography to obtain the 1,2, 3-trisubstituted plane chiral metallocene compound shown as the reaction formula J;
the reaction formula is as follows:
(1) In (2), H and the corresponding radical R 7 Or R is 8 Represented as H/corresponding group selected from: trialkylchlorosilanes/trialkylsilyl groups, diaryl phosphines/diaryl phosphines, aryl methylsAcyl chloride/arylformyl, diaryl ketone/diaryl hydroxymethyl, alkyl chloroformate/alkoxyacyl, diaryl chlorophosphate/diaryloxyphosphonyl, diaryl sulfide/diaryl sulfide; the alkyl is C1-C6 alkyl, and the aryl is C6-C12 aryl.
10. A process for the preparation of a 1,2, 4-trisubstituted planar chiral metallocene using the planar chiral iodo-metallocene prepared by the process according to any one of claims 1 to 7, comprising the steps of:
under the protection of inert gas, taking iodized ferrocene or ruthenium dichloride G and aryl halide K as starting materials, stirring and reacting in an organic solvent F under the action of a palladium catalyst C, chiral amino acid D, norbornene derivatives L and alkali E until the reaction is finished, filtering, concentrating and purifying a reaction mixture by column chromatography to obtain the 1,2, 4-trisubstituted plane chiral metallocene compound shown as the formula M;
the reaction formula is as follows:
wherein:
R 9 one or more selected from C6-C12 aryl, N, S substituted C5-C12 heteroaryl, C1-C6 alkyl, aldehyde, hydroxyl, amino, cyano, nitro, amido, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl and halogen;
x is bromine or iodine;
m represents R 9 M is more than or equal to 0 and less than or equal to 3; when m=2 or 3, the substituent groups may be the same or different;
Ar 1 C6-C12 aromatic hydrocarbon and N, S substituted C5-C12 heterocyclic aromatic hydrocarbon;
the norbornene derivative L has the structural formula:
wherein:
i)R 10 n represents the number of substituents, and n is more than or equal to 0 and less than or equal to 8; r is R 11 P represents the number of substituents, p is more than or equal to 0 and less than or equal to 2;
ii)R 10 ，R 11 any one or more of C6-C12 aryl, N, S substituted C5-C12 heterocyclic aryl, C1-C6 alkyl, aldehyde group, carboxyl, hydroxyl, amino, cyano, nitro, amido, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl or halogen;
iii) When the number of substituents on the five-membered ring on the left side is 2 or more, the substituents may be the same or different; when the number of substituents on the double bond is 2, the substituents may be the same or different;
iv)R 10 and R is 11 The substituents may be the same or different.
CN202311218119.1A 2023-09-20 2023-09-20 Planar chiral iodo-metallocene, preparation method thereof and method for preparing polysubstituted planar chiral metallocene compound Pending CN117362358A (en)

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