A planar chiral iodo metallocene and a method for preparing the same and a method for preparing a polysubstituted planar chiral metallocene compound

Abstract

The application discloses a kind of planar chiral iodometalate and its preparation method and the method for preparing polysubstituted planar chiral metallocene compound.The method uses simple N,N-dialkylaminomethyl metallocene (ferrocene, ruthenocene) as starting material, under the action of palladium catalyst, chiral amino acid, o-trifluoroacetyl iodobenzene derivative and base, under certain temperature in organic solvent, stirring reaction can obtain 1,2-disubstituted planar chiral iodometalate compound.The raw material used in the method is cheap and easy to obtain, the reaction condition is mild, substrate universality is good, yield is high, and the preparation process is simple.The prepared 1,2-disubstituted planar chiral iodometalate can be used for further synthesis of other functional group polysubstituted planar chiral metallocene compound.

Description

TECHNICAL FIELD

[0001] The present application relates to a planar chiral iodo metallocene, a preparation method thereof and a method for preparing a polysubstituted planar chiral metallocene compound, and belongs to the field of organic synthesis. BACKGROUND

[0002] Planar chiral ferrocene compounds have important applications in catalysis, materials, biomedical fields, etc., and can be widely used as efficient chiral ligands or catalysts in asymmetric catalytic reactions ([1] Fu, G. C. Acc. Chem. Res. 2000, 33, 412; [2] Dai, L.-X.; Tu, T.; You, 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] Arrayás, R.-G.; Adrio, J.; Carretero, J.-C. Angew. Chem. Int. Ed. 2006, 45, 7674; [5] Dai, L.-X.; Hou, X.-L. Chiral Ferrocenes in Asymmetric Catalysis, Wiley, Weinheim, 2010).

[0003] Planar chiral ferrocene compounds have significant advantages and great development space in the field of asymmetric catalysis and industrial applications, and the design and development of this type of ferrocene compounds has become an important research direction in this field. So far, chemists have developed some methods and strategies for synthesizing planar chiral ferrocene compounds. The traditional strategies mainly include the following four kinds: (1) diastereoselective ortho-metalation induced by chiral auxiliary ([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.; Raabe, G. Organometallics 2000, 19, 1648.); (2) enantioselective ortho-metalation using an equivalent of external 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) desymmetrization 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.; Kündig, 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 suffer from poor functional group tolerance, low atom economy, etc.In recent years, transition-metal-catalyzed asymmetric C-H functionalization of ferrocene ortho position has developed rapidly and become an important strategy for the construction of planar chiral ferrocenes ([1] Zhu, D.-Y.; Chen, P.; Xia, J.-B. ChemCatChem 2016, 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.). However, this method requires specific substrates and can only introduce a single functional group, and the types of functional groups that can be constructed are limited, especially the construction of ferrocene ortho carbon-heteroatom bond is rarely reported. Therefore, it is of great significance to develop a general and efficient synthetic strategy to introduce a series of different functional groups at the ortho position of ferrocene for the construction of planar chiral ferrocene. SUMMARY

[0004] In order to solve the problems existing in the prior art, the present application provides a planar chiral iodo metallocene and a preparation method thereof and a method for preparing a polysubstituted planar chiral metallocene compound. The raw materials used in the method are cheap and easy to obtain, the reaction conditions are mild, the substrate has good universality, the yield is high, and the preparation process is simple.

[0005] The technical scheme provided by the present application is as follows:

[0006] In a first aspect, the present application provides a method for synthesizing a planar chiral iodo metallocene, comprising the following steps:

[0007] A method for synthesizing a planar chiral iodo metallocene, characterized by comprising the following steps:

[0008] In inert gas protection, using N, N-dialkylaminomethyl ferrocene or ruthenocene A as starting material, in the presence of iodine reagent B, palladium catalyst C, chiral amino acid D and base E, stirring in organic solvent F until the reaction is completed, extracting, concentrating, column chromatography purification to obtain 1,2-disubstituted planar chiral iodometallic compound G as shown in the reaction formula;

[0009] Wherein, the structure of A is:

[0010] R 1 , R 2 are two independent groups or connected to form a group; if they are independent groups, R 1 , R 2 are selected from C1-C6 alkyl; if R 1 , R 2 are connected to form a group, the group is C1-C6 cycloalkyl, C1-C6 cycloalkyl;

[0011] M is iron or ruthenium;

[0012] R 3 is selected from hydrogen, C6-C12 aryl, N, S substituted C5-C12 heterocyclic aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, C1-C6 aldehyde, C2-C7 epoxy, C2-C11 ester, carboxyl, amide, -TMS or

[0013] The structure of B is:

[0014] R 4 is selected from any one or several of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen. Preferably, R 4 is substituted at position 3, position 4 or position 5, wherein I is position 2.

[0015] The structure of G is:

[0016] Further, R 3 includes hydrogen; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C6-C12 aryl; C2-C11 ester is -(CH2) x -COOR', x is an integer from 0 to 4, R' is C1-C6 alkyl; N, S substituted C5-C12 heterocyclic aryl includes halogen; cyano; C1-C6 aldehyde; acetal includes -TMS;

[0017] Further, R3 The halogen is fluorine, chlorine, bromine, or iodine.

[0018] Further, the palladium catalyst C is selected from any one or several of Pd(OAc)2, Pd(PPh3)2(OAc)2, Pd(TFA)2, Pd(acac)2, Pd(OPiv)2, Pd(PhCN)2Cl2, Pd(MeCN)2Cl2, Pd(PPh3)2Cl2, PdCl2, PdI2, [Pd(allyl)Cl]2.

[0019] Further, the chiral amino acid D has the following structure:

[0020]

[0021] wherein:

[0022] i) R 5 is selected from any one of benzoyl, acetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, ester, C1-C6 alkyl, benzyl;

[0023] ii) R 6 is selected from any one of C6-C12 aryl or C1-C6 alkyl.

[0024] Further, in the chiral amino acid D, R 5 is an ester group -COOR", and R" is C1-C6 alkyl or C6-C12 aryl; R 6 is a C6-C12 aryl group -(CH2) y -Ph, and y is an integer from 0 to 4.

[0025] Further, the base E is selected from any one or several of sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, tri-potassium phosphate, potassium formate, sodium hydroxide, sodium tert-butoxide.

[0026] Further, the solvent F is selected from any one or several of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylene glycol, methyl tert-butyl ether, 1,4-dioxane, 1,3-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C4-12 saturated alkanes, C3-12 fluorinated or chlorinated alkanes, benzene, toluene, xylene, mesitylene, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C3-12 saturated alkyl nitriles.

[0027] Further, the reaction temperature is from 25°C to 120°C.

[0028] Further, the N,N-dialkylaminomethyl ferrocene / ruthenocene A is 1.0 mole equivalent, the amount of iodinating reagent B is 2.0-4.0 mole equivalent, the amount of palladium catalyst C is 0.05-0.2 mole equivalent, the amount of chiral amino acid D is 0.1-0.5 mole equivalent, and the amount of base E is 1.0-3.0 mole equivalent.

[0029] Further, the inert gas includes one of nitrogen and argon.

[0030] The present application uses the readily available N,N-dialkylaminomethyl ferrocene / ruthenocene as a starting material, and the iodinating reagent is stirred in an organic solvent under the action of a palladium catalyst, a chiral amino acid and a base at 25-120°C to obtain a 1,2-disubstituted planar chiral iodinating metallocene. The starting material used in the method is inexpensive and readily available, the reaction conditions are mild, the substrate has good universality, the yield is high, and the preparation process is simple.

[0031] The reaction path of the present application is as follows:

[0032]

[0033] In a second aspect, the present application provides a planar chiral iodinating metallocene prepared by the method of the first aspect.

[0034] In a third aspect, the present application provides the use of a planar chiral iodinating metallocene prepared by the method of the first aspect in the synthesis of other functional group disubstituted or trisubstituted planar chiral metallocene compounds.

[0035] 1. Preparation of 1,2-disubstituted planar chiral metallocene compounds and 1,2,3-trisubstituted planar chiral metallocene compounds, the steps are as follows:

[0036] (1) Preparation of 1,2-disubstituted planar chiral metallocene compounds, including the following steps:

[0037] Under the protection of inert gas, using iodinating ferrocene or ruthenocene G as a starting material, under the action of electrophilic reagent H and base E, stirring in organic solvent F until the reaction is completed, extracting, concentrating and purifying by column chromatography to obtain 1,2-disubstituted planar chiral metallocene compounds as I in the reaction formula;

[0038] The reaction formula is as follows:

[0039]

[0040] Among them:

[0041] H and the corresponding group R 7 is H / R 7, selected from the group consisting of trialkylchlorosilane / trialkylsilyl, diarylchlorophosphine / diarylphosphine, arylformylchloride / arylformyl, diarylketone / diaryloxymethyl, alkylchloroformate / alkoxylacyl, diarylchlorophosphate / diaryloxyphosphineacyl, diaryl sulfide / diaryl sulfide group; the alkyl group is C1-C6 alkyl group, and the aryl group is C6-C12 aryl group.

[0042] Further, the reaction temperature is 25-120°C, and the reaction time is 1-72h.

[0043] Further, the protective gas is argon or nitrogen.

[0044] (2) A method for preparing 1,2,3-trisubstituted planar chiral metallocene compound, comprising the following steps:

[0045] Under the protection of inert gas, using 1,2-disubstituted ferrocene or ruthenocene I as starting material, under the action of electrophile H and base E, stirring in organic solvent F until the reaction is completed, extracting, concentrating and purifying by column chromatography to obtain 1,2,3-trisubstituted planar chiral metallocene compound as J in the reaction formula.

[0046] The reaction formula is as follows:

[0047]

[0048] Among them:

[0049] H and the corresponding group R 8 Indicated as H / R 8 , selected from the group consisting of trialkylchlorosilane / trialkylsilyl, diarylchlorophosphine / diarylphosphine, arylformylchloride / arylformyl, diarylketone / diaryloxymethyl, alkylchloroformate / alkoxylacyl, diarylchlorophosphate / diaryloxyphosphineacyl, diaryl sulfide / diaryl sulfide group; the alkyl group is C1-C6 alkyl group, and the aryl group is C6-C12 aryl group.

[0050] Further, the reaction temperature is 25-120°C, and the reaction time is 1-72h.

[0051] Further, the protective gas is argon or nitrogen.

[0052] 2. A method for preparing 1,2,4-trisubstituted planar chiral metallocene, comprising the following steps:

[0053] Inert gas protection, iodine ferrocene or ruthenium G and aryl halide K as starting material, in the presence of palladium catalyst C, chiral amino acid D, norbornene derivative L and base E, stirring in organic solvent F until the end of the reaction, the reaction mixture is filtered, concentrated, column chromatography purification to obtain 1,2,4-trisubstituted planar chiral metallocene compounds as formula M;

[0054] The reaction is as follows:

[0055]

[0056] Wherein:

[0057] R 9 is selected from one or more of C6-C12 aryl, N, S substituted C5-C12 heterocyclic aryl, C1-C6 alkyl, aldehyde, hydroxyl, amino, cyano, nitro, amido, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, halogen;

[0058] X is bromine or iodine;

[0059] m represents the number of R 9 , 0≤m≤3; when m = 2 or 3, the substituent groups can be the same or different;

[0060] Ar 1 is C6-C12 aromatic and N, S substituted C5-C12 heterocyclic aromatic;

[0061] The structure of norbornene derivative L is:

[0062] Wherein:

[0063] i) R 10 is the substituent on the left five-membered ring, n represents the number of substituents, 0≤n≤8; R 11 is the substituent on the double bond, p represents the number of substituents, 0≤p≤2;

[0064] ii) R 10 , R 11 is selected from any one or more of C6-C12 aryl, N, S substituted C5-C12 heterocyclic aryl, C1-C6 alkyl, aldehyde, carboxyl, hydroxyl, amino, cyano, nitro, amido, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl or halogen;

[0065] iii) when the number of substituents on the left five-membered ring is 2 or more, they can be the same or different; when the number of substituents on the double bond is 2, they can be the same or different;

[0066] iv) R10 and R 11 The kinds of substituent groups can be the same or different.

[0067] Preferably, the norbornene derivative L has the structural formula

[0068] Further, the reaction temperature is 25-120℃, and the reaction time is 1-72h.

[0069] Further, the protective gas is argon or nitrogen.

[0070] The beneficial effects of the present application are as follows:

[0071] 1. The main raw material N,N-alkylaminomethyl ferrocene / ruthenium involved in the present application is a commercialized raw material (its derivative only needs to be synthesized quickly in one to two steps using a simple commercialized raw material ferrocene / ruthenium);

[0072] 2. The iodinating reagent involved in the present application only needs to be synthesized quickly in one step;

[0073] 3. The method of the present application has very good enantioselectivity, and the ee value of the obtained product is as high as 99%;

[0074] 4. The catalyst used in the reaction involved in the method of the present application is a relatively inexpensive metal palladium salt, which is an important improvement and supplement compared to the equivalent organic metal reagent used in other synthesis methods;

[0075] 5. The planar chiral iodinated metallocene prepared by the present application can be used for further synthesis of other functional group disubstituted or trisubstituted planar chiral metallocene compounds. DETAILED DESCRIPTION

[0076] The present application will be further described below through specific examples, and it is worth noting that the present application is not limited to the following examples.

[0077] Example 1: Preparation of compound G-1

[0078]

[0079] A stirring bar of suitable size was placed in a dry 10 mL Schlenk flask, and then palladium acetate (2.2 mg, 0.01 mmol, 0.1 equiv), N-(tert-butoxycarbonyl)-L-valine (6.5 mg, 0.03 mmol, 0.3 equiv), potassium carbonate (27.6 mg, 0.2 mmol, 2.0 equiv), after purging argon three times through a double-row tube, add dry N,N-dimethylformamide DMF (0.9 mL), dry dimethyl sulfoxide (0.1 mL), N,N-dimethylaminomethylferrocene (24.3 mg, 0.1 mmol, 1.0 equiv), and 2,2,2-trifluoromethyl-1-(2-iodo-3-methyl)phenyl ethyl ketone. (94.2 mg, 0.3 mmol, 3.0 equiv) The reaction system was then stirred at 80 °C for 18 hours. After the reaction was completed, it was cooled to room temperature. The reaction was quenched by adding saturated sodium carbonate solution. The mixture was extracted three times with ethyl acetate. The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product G-1 (red oily liquid, yield 68%) was obtained by column chromatography. 1 H NMR (600MHz, CDCl3): 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, CDCl3): 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 forC 13 H 17 FeIN + [M+H + ]369.9750, found 369.9746; HPLC: 98%ee, Daicel Chiralpak OD-Hcolumn, Hexanes / IPA=99 / 1, 1mL / min, λ=254nm, t R (major) = 9.30 min, t R (minor) = 7.48 min; -12.72 (c 0.21, CHCl3).

[0080] Example 2: Preparation of compound G-2

[0081]

[0082] The operating procedure is the same as in example 1, except that the ferrocene substrate used is: 1 -dimethylaminomethyl-1 '-methyferrocene (25.7 mg). Compound G-2 is obtained (red oily liquid, yield 71 %). 1 H NMR (600 MHz, CDC13) δ 4.31 (dd, J = 2.4, 1.4 Hz, 1H), 4.20 (dd, J = 2.7, 1.4 Hz, 1H), 4.16 (t, J = 2.5 Hz, 1H), 3.98 (t, J = 2.0 Hz, 2H), 3.94 (dt, J = 6.2, 1.7 Hz, 2H), 3.34 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 2.23 (s, 6H), 1.94 (s, 3H); 13 C NMR (150 MHz, CDC13) δ 85.8, 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 Fe IN + [M+H + ] 383.9906, found 383.9899. HPLC: 98% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 9.93 min, t R (minor) = 7.82 min; -16.68 (c 0.44, CHCl3).

[0083] Example 3: Preparation of compound G-3

[0084]

[0085] The operating procedure is the same as in example 1, except that the ferrocene substrate used is: 1 -dimethylaminomethyl-1 '-methyferrocene (25.7 mg). Compound G-2 is obtained (red oily liquid, yield 71 %). 1H NMR (400 MHz, CDC13) δ 4.33 (dd, J = 2.4, 1.4 Hz, 1H), 4.22 (dd, J = 2.7, 1.4 Hz, 1H), 4.17 (t, J = 2.6 Hz, 1H), 3.97 (td, J = 3.6, 1.7 Hz, 4H), 3.35 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.0 Hz, 1H), 2.33 (qd, J = 7.5, 1.2 Hz, 2H), 2.23 (s, 6H), 1.15 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 92.8, 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 / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 9.19 min, t R (minor) = 6.96 min; -17.74 (c 0.54, CHCl3).

[0086] Example 4: Preparation of compound G-4

[0087]

[0088] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 '-isopropyl ferrocene (28.5 mg). Compound G-4 was obtained (red oily liquid, yield 60%). 1H NMR (400 MHz, CDC13) δ 4.35 (dd, J = 2.5, 1.4 Hz, 1H), 4.24 (dd, J = 2.6, 1.4 Hz, 1H), 4.18 (t, J = 2.5 Hz, 1H), 4.02 (q, J = 1.7 Hz, 1H), 3.97 (dt, J = 2.7, 1.4 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.35 (d, J = 13.0 Hz, 1H), 3.31 (d, J = 13.1 Hz, 1H), 2.64 (hept, J = 6.9 Hz, 1H), 2.22 (s, 6H), 1.18 (s, 3H), 1.16 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 98.5, 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 / Et2NH = 99 / 1 / 0.1, 0.5 mL / min, λ = 254 nm, t R (major) = 12.81 min, t R (minor) = 9.08 min; -36.26 (c 0.60, CHCl3).

[0089] Example 5: Preparation of compound G-5

[0090]

[0091] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 '-benzylderivative (33.3 mg). Compound G-5 was obtained (red oil, yield 57%). 1H NMR (400 MHz, CDC13) δ 7.29 - 7.23 (m, 2H), 7.21 - 7.12 (m, 3H), 4.36 (dd, J = 2.5, 1.3 Hz, 1H), 4.24 (dd, J = 2.6, 1.4 Hz, 1H), 4.18 (t, J = 2.5 Hz, 1H), 4.01 (ddd, J = 6.1, 4.8, 2.3 Hz, 4H), 3.67 (s, 2H), 3.35 (s, 1H), 3.29 (s, 1H), 2.23 (s, 6H); 13 C NMR (100 MHz, CDC13) δ 141.4, 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 Fe IN + [M+H + ]460.0219, found 460.0217; HPLC: 98% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 13.89 min, t R (minor) = 11.01 min; -31.21 (c 0.70, CHCl3).

[0092] Example 6: Preparation of compound G-6

[0093]

[0094] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 '-(2-ethoxycarbonyl ethyl) ferrocene (33.3 mg). Compound G-6 (yellow oil liquid, yield 56%) was obtained. 1H NMR (400 MHz, CDC13): δ 4.34 (dd, J = 2.4, 1.4 Hz, 1H), 4.23 (dd, J = 2.6, 1.4 Hz, 1H), 4.17 (t, J = 2.6 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.99 (d, J = 1.7 Hz, 3H), 3.95 (q, J = 1.7 Hz, 1H), 3.34 (d, J = 13.0 Hz, 1H), 3.29 (d, J = 13.0 Hz, 1H), 2.68 - 2.61 (m, 2H), 2.49 (dd, J = 8.6, 6.5 Hz, 2H), 2.22 (s, 6H), 1.25 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13): δ 173.1, 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-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 21.01 min, t R (minor) = 18.50 min; -45.98 (c 0.59, CHCl3).

[0095] Example 7: Preparation of compound G-7

[0096]

[0097] The operating procedure was the same as in Example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1’-(2-cyano)ferrocene (29.6 mg). Compound G-7 was obtained (yellowish oil liquid, yield 67%). 1H NMR (400 MHz, CDC13): δ 4.35 (dd, J = 2.5, 1.3 Hz, 1H), 4.26 (dd, J = 2.7, 1.4 Hz, 1H), 4.20 (t, J = 2.5 Hz, 1H), 4.07 (q, J = 2.5, 2.0 Hz, 3H), 4.00 (q, J = 1.6 Hz, 1H), 3.32 (d, J = 13.0 Hz, 1H), 3.27 (d, J = 13.0 Hz, 1H), 2.70 (t, J = 7.5 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.22 (s, 6H); 13 C NMR (100 MHz, CDC13): δ 119.5, 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 FeIN2 + [M+H + ]423.0015, found 423.0009; HPLC: >99% ee, Daicel Chiralpak IA column, Hexanes / IPA / Et2NH = 97 / 3 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 22.48 min; -41.00 (c 0.66, CHCl3).

[0098] Example 8: Preparation of compound G-8

[0099]

[0100] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-1'-bromof errocene (32.2 mg), to obtain compound G-8 (yellowish oil liquid, yield 49%). 1 H NMR (400 MHz, CDC13): δ 4.35 (dd, J = 2.5, 1.3 Hz, 1H), 4.26 (dd, J = 2.7, 1.4 Hz, 1H), 4.20 (t, J = 2.5 Hz, 1H), 4.07 (q, J = 2.5, 2.0 Hz, 3H), 4.00 (q, J = 1.6 Hz, 1H), 3.32 (d, J = 13.0 Hz, 1H), 3.27 (d, J = 13.0 Hz, 1H), 2.70 (t, J = 7.5 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.22 (s, 6H); 13C NMR (100 MHz, CDC13): δ 86.5, 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, found 447.8852; HPLC: 98% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 11.11 min, t R (minor) = 8.74 min; -4.23 (c 0.52, CHCl3).

[0101] Example 9: Preparation of compound G-9

[0102]

[0103] Operating procedure as in example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 '-phenyldimethylferrocene (31.9 mg). Compound G-9 (yellowish oil liquid, yield 59%) was obtained. 1 H NMR (400 MHz, CDC13): δ 7.48 (d, J = 7.4 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 4.58 (d, J = 2.9 Hz, 1H), 4.51 (d, J = 2.6 Hz, 1H), 4.30-4.29 (m, 1H), 4.25 (d, J = 2.8 Hz, 1H), 4.17 (d, J = 2.6 Hz, 1H), 4.10 (t, J = 2.6 Hz, 1H), 3.02 (d, J = 13.3 Hz, 1H), 2.98 (d, J = 13.1 Hz, 1H), 2.14 (s, 6H); 13 CNMR (100 MHz, CDC13): δ 137.2, 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’d for C 19 H 21 FeIN + [M+H+ ]446.0063, found 446.0059; HPLC: 98% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99.5 / 0.5 / 0.1, 0.5 mL / min, λ = 254 nm, t R (major) = 24.96 min, t R (minor) = 23.04 min; 44.37 (c 0.59, CHCl3).

[0104] Example 10: Preparation of compound G-10

[0105]

[0106] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 -(4-methoxycarbonylphenyl)ferrocene (37.7 mg). Compound G-10 was obtained (red oily liquid, yield 52%). 1 H NMR (400 MHz, CDC13): δ 8.02-7.95 (m, 2H), 7.54-7.49 (m, 2H), 4.62 (dt, J = 2.7, 1.4 Hz, 1H), 4.57 (dt, J = 2.8, 1.4 Hz, 1H), 4.37 (td, J = 2.5, 1.2 Hz, 1H), 4.33 (td, J = 2.6, 1.3 Hz, 1H), 4.24 (dd, J = 2.5, 1.4 Hz, 1H), 4.15 (dd, J = 2.6, 1.4 Hz, 1H), 4.10 (t, J = 2.5 Hz, 1H), 3.92 (s, 3H), 3.01 (d, J = 13.2 Hz, 1H), 2.96 (d, J = 13.2 Hz, 1H), 2.12 (s, 6H); 13 C NMR (100 MHz, CDC13): δ 167.2, 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’d for C 21 H 23 FeINO2 + [M+H +]504.0117, found 504.0114; HPLC: 99% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 27.55 min, t R (minor) = 21.69 min; -62.73 (c 0.67, CHCl3).

[0107] Example 11: Preparation of compound G-11

[0108]

[0109] The operating procedure was the same as in Example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 -(4-methylphenyl)ferrocene (33.3 mg), to give compound G-11 (red oil liquid, yield 53%). 1 H NMR (400 MHz, CDC13): δ 7.37 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.7 Hz, 2H), 4.59-4.51 (m, 1H), 4.48 (dd, J = 2.9, 1.6 Hz, 1H), 4.26 (q, J = 2.1 Hz, 1H), 4.23 (dq, J = 3.8, 1.9 Hz, 2H), 4.14 (t, J = 1.9 Hz, 1H), 4.09 (t, J = 2.5 Hz, 1H), 3.04 (d, J = 13.2 Hz, 1H), 2.99 (d, J = 13.2 Hz, 1H), 2.33 (s, 3H), 2.13 (s, 6H); 13 C NMR (100 MHz, CDC13): δ 136.2, 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 Fe IN + [M+H + ]460.0219, found 460.0216; HPLC: 98% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 11.07 min, tR (minor) = 9.87 min; -62.73 (c 0.67, CHCI3).

[0110] Example 12: Preparation of compound G-12

[0111]

[0112] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 -(4,4,5,5-tetramethyl-1,3-dioxocyclopent-2- yl)ferrocene (37.1 mg). Compound G-12 was obtained (red oily liquid, yield 52%). 1 H NMR (400 MHz, CDCI3) δ 5.84 (s, 1 H), 4.46-4.39 (m, 1 H), 4.30 (dd, J = 2.7, 1.4 Hz, 1 H), 4.25 (t, J = 2.5 Hz, 2H), 4.23 (dd, J = 2.6, 1.3 Hz, 1 H), 4.10 (q, J = 2.2 Hz, 1 H), 4.02 (q, J = 2.3 Hz, 1 H), 3.47 (d, J = 13.1 Hz, 1 H), 3.31 (d, J = 13.1 Hz, 1 H), 2.22 (s, 6H), 1.26 (s, 3H), 1.25 (s, 3H), 1.22 (s, 3H), 1.21 (s, 3H); 13 C NMR (100 MHz, CDCI3) δ 98.4, 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 FeINO2 + [M+H + ] 498.0587, found 498.0588; HPLC: 98% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 7.80 min, t R (minor) = 7.01 min; -4.17 (c 0.86, CHCI3).

[0113] Example 13: Preparation of compound G-13

[0114]

[0115] The operating procedure was the same as in Example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 '-methoxycarbonylferrocene (30.1 mg), to give compound G-13 (red oily liquid, yield 39%). 1 H NMR (400 MHz, CDC13): δ 4.72 (d, J = 2.6 Hz, 1H), 4.66 (d, J = 2.5 Hz, 1H), 4.45 (d, J = 2.5 Hz, 1H), 4.34 (d, J = 2.6 Hz, 1H), 4.31 (q, J = 2.6 Hz, 2H), 4.26 (d, J = 2.7 Hz, 1H), 3.84 (s, 3H), 3.29 (d, J = 13.1 Hz, 1H), 3.24 (d, J = 13.1 Hz, 1H), 2.22 (s, 6H); 13 C NMR (100 MHz, CDC13): δ 170.7, 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 FeINO2 + [M+H + ] 427.9804, found 427.9804; HPLC: 98% ee, Daicel Chiralpak IA column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 22.40 min, t R (minor) = 25.77 min; 29.43 (c 0.44, CHCI3).

[0116] Example 14: Preparation of compound G-14

[0117]

[0118] The operating procedure was the same as in Example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 '-methoxycarbonylferrocene (30.1 mg), to give compound G-13 (red oily liquid, yield 39%). 1HNMR (400 MHz, CDC13): δ 7.45 (d, J = 15.8 Hz, 1H), 6.06 (d, J = 15.8 Hz, 1H), 4.39 (t, J = 1.8 Hz, 1H), 4.38-4.36 (m, 1H), 4.35 (d, J = 2.4 Hz, 1H), 4.32 (t, J = 2.3 Hz, 2H), 4.28 (d, J = 2.5 Hz, 1H), 4.26-4.19 (m, 3H), 3.23 (d, J = 13.3 Hz 1H), 3.19 (d, J = 13.3 Hz 1H), 2.20 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDC13): δ 167.1, 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 / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 25.78 min, t R (minor) = 28.73 min; 48.67 (c 0.47, CHCl3).

[0119] Example 15: Preparation of compound G-15

[0120]

[0121] The operating procedure was the same as in Example 1, except that the ferrocene substrate used was: 1-dimethylaminomethyl-l'-(trimethylsilyl)ferrocene (31.5 mg). Compound G-15 was obtained (red oily liquid, yield 50%). 1H NMR (400 MHz, CDC13): δ 4.44-4.38 (m, 1H), 4.32-4.28 (m, 1H), 4.24-4.17 (m, 3H), 4.13-4.08 (m, 1H), 4.06 (t, J = 1.9 Hz, 1H), 3.40 (d, J = 13.1 Hz, 1H), 3.36 (d, J = 13.1 Hz, 1H), 2.26 (s, 6H), 0.25 (s, 9H); 13 C NMR (100 MHz, CDC13): δ 84.9, 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, found 442.0147; HPLC: 98% ee, Daicel Chiralpak OD-H column, Hexanes / IPA = 99 / 1, 1.0 mL / min, λ = 254 nm, t R (major) = 8.85 min, t R (minor) = 4.89 min; -62.73 (c 0.67, CHCl3).

[0122] Example 16: Preparation of compound G-16

[0123]

[0124] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 -(diphenylhydroxymethyl)ferrocene (42.5 mg). Compound G-16 was obtained (yellowish oil liquid, yield 75%). 1 H NMR (400 MHz, CDC13): δ 7.48-7.26 (m, 10H), 4.49 (d, J = 2.4 Hz, 1H), 4.42 (d, J = 2.5 Hz, 1H), 4.38 (d, J = 3.2 Hz, 1H), 4.23 (d, J = 2.5 Hz, 1H), 4.19-4.13 (m, 1H), 4.11 (d, J = 2.6 Hz, 1H), 4.06 (d, J = 3.2 Hz, 1H), 3.30 (d, J = 13.8 Hz, 1H), 3.23 (d, J = 13.8 Hz, 1H), 2.42 (s, 6H); 13C NMR (100 MHz, CDC13): δ 147.6, 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 FeINO2 + [M+H + ] 552.0481, found 552.0480; HPLC: 98% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 13.51 min, t R (minor) = 15.19 min; -62.73 (c 0.67, CHCl3).

[0125] Example 17: Preparation of compound G-17

[0126]

[0127] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: 4-(1,3-dioxolan-2-yl)piperidinylmethyl ferrocene (34.1 mg). Compound G-17 (yellow oil liquid, yield 75%) was obtained. 1 H NMR (400 MHz, CDC13): δ 4.41 (dd, J = 2.5, 1.4 Hz, 1H), 4.31 (dd, J = 2.6, 1.4 Hz, 1H), 4.21 (t, J = 2.5 Hz, 1H), 4.10 (s, 5H), 3.92 (s, 4H), 3.54 (d, J = 13.3 Hz, 1H), 3.43 (d, J = 13.3 Hz, 1H), 2.60 (q, J = 7.1, 5.3 Hz, 2H), 2.49 (dt, J = 11.5, 5.8 Hz, 2H), 1.70 (q, J = 5.9, 5.5 Hz, 4H); 13 C NMR (100 MHz, CDC13): δ 107.3, 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 FeINO2+ [M+H + ]468.0117, found 468.0118; HPLC: 99% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 16.69 min, t R (minor) = 14.70 min; -62.73 (c 0.67, CHCl3).

[0128] Example 18: Preparation of compound G-18

[0129]

[0130] The operating procedure was the same as in example 1, except that the ferrocene substrate used was: N,N-dimethylaminomethyl ferrocenium dichloride (28.8 mg), to obtain compound G-18 (yellowish oil liquid, yield 33%). 1 H NMR (600 MHz, CDC13) δ 4.84 (t, J = 1.7 Hz, 1H), 4.64 (t, J = 1.8 Hz, 1H), 4.53 (t, J = 2.4 Hz, 1H), 4.51 (s, 5H), 3.24 (d, J = 13.2 Hz, 1H), 3.19 (d, J = 13.2 Hz, 1H), 2.28 (s, 6H); 13 C NMR (150 MHz, CDC13) δ 89.3, 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 / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 11.98 min, t R (minor) = 10.71 min; 61.95 (c 1.28, CHCl3).

[0131] Example 19: Preparation of compound G-19

[0132]

[0133] The operating procedure was the same as in Example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 '-methylruthenocene (30.2 mg), to give compound G-19 (yellow oily liquid, yield 42%). 1 H NMR (400 MHz, CDC13) δ 4.76 (dd, J = 2.4, 1.2 Hz, 1H), 4.58 (dd, J = 2.5, 1.2 Hz, 1H), 4.49 (t, J = 2.4 Hz, 1H), 4.43 (q, J = 2.0 Hz, 1H), 4.41 (q, J = 2.0 Hz, 1H), 4.37 (t, J = 1.7 Hz, 2H), 3.16 (d, J = 13.2 Hz, 1H), 3.12 (d, J = 13.2 Hz, 1H), 2.28 (s, 6H), 1.85 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 88.6, 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 for C 14 H 19 INRu + [M+H + ] 429.9600, found 429.9598; HPLC: 96% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 8.60 min, t R (minor) = 7.51 min; -12.06 (c 0.15, CHCl3).

[0134] Example 20: Preparation of compound G-20

[0135]

[0136] The operating procedure was the same as in Example 1, except that the ferrocene substrate used was: 1 -dimethylaminomethyl-1 '-methylruthenocene (30.2 mg), to give compound G-19 (yellow oily liquid, yield 42%). 1H NMR (400 MHz, CDC13): δ 5.60 (s, 1H), 4.86-4.81 (m, 1H), 4.66 (q, J = 1.5 Hz, 1H), 4.64-4.61 (m, 1H), 4.59 (d, J = 1.8 Hz, 1H), 4.54 (t, J = 2.4 Hz, 1H), 4.51 (t, J = 1.7 Hz, 2H), 3.24 (d, J = 13.3 Hz, 1H), 3.19 (d, J = 13.3 Hz, 1H), 2.27 (s, 6H), 1.23 (s, 12H); 13 C NMR (100 MHz, CDC13): δ 97.8, 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 INO2Ru + [M+H + ]544.0281, found 544.0273; HPLC: 98% ee, Daicel Chiralpak IE column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 0.7 mL / min, λ = 254 nm, t R (major) = 15.11 min, t R (minor) = 16.86 min; 19.80 (c 0.30, CHCl3).

[0137] Example 21: Preparation of compound G-1 at gram scale

[0138]

[0139] A stir bar of appropriate size was placed in a dry 250 mL Schlenk flask, followed by palladium acetate (112.3 mg, 0.5 mmol, 0.1 equiv), N-(tert-butoxycarbonyl)-L- valine (325.9 mg, 1.5 mmol, 0.3 equiv), potassium carbonate (4.15 g, 30.0 mmol, 6.0 equiv), and dry N,N-dimethylformamide (45.0 mL) and dry dimethyl sulfoxide (5.0 mL) were added after three vacuum-nitrogen purges through a double-tube, followed by 2,2,2-trifluoromethyl-l-(2-iodo-3-methyl)phenyl ethanone (4.71 g, 15.0 mmol, 3.0 equiv), N,N-dimethylaminomethylferrocene (1.22 g, 5.0 mmol, 1.0 equiv), and the reaction system was stirred at 80 °C for 36 h, then cooled to room temperature, and the reaction was quenched by adding saturated sodium carbonate solution, extracted with ethyl acetate three times, the organic phases were combined and washed with saturated brine three times, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give the product G-1 (1.014 g, red oil, 55% yield, 98% ee) after column chromatography.

[0140] Application Example 1: Preparation of compound I-1

[0141]

[0142] A stir bar of appropriate size was placed in a dry 10 mL Schlenk tube, followed by G-1 (36.9 mg, 0.1 mmol, 1.0 equiv), and 1.5 mL of dry diethyl ether was added after three vacuum-nitrogen purges through a double-tube, and the reaction system was placed at -40 °C, followed by dropwise addition of n-butyllithium (60 μL, 2.5 M in hexane, 0.15 mmol, 1.5 equiv) to the reaction system, and stirring at this temperature for 2 h. Then the reaction system was cooled to -78 °C, and a solution of p-toluenesulfide (61.6 mg, 0.25 mmol, 2.5 equiv) in diethyl ether (0.5 mL) was added dropwise, and stirring was carried out at this temperature for 10 min after dropwise addition was completed, and then the temperature was raised to room temperature and stirring was carried out overnight. After the reaction was completed, water was added to quench the reaction, and extraction was carried out with ethyl acetate three times (10 mL x 3), 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 to give the product I-1 (yellow oil, yield 62%) after column chromatography. 1H NMR (400 MHz, CDC13): δ 7.04 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.53-4.48 (m, 1H), 4.46 (t, J = 1.9 Hz, 1H), 4.31 (t, J = 2.6 Hz, 1H), 4.17 (s, 5H), 3.47 (d, J = 13.2 Hz, 1H), 3.43 (d, J = 13.2 Hz, 1H), 2.25 (s, 3H), 2.05 (s, 6H); 13 C NMR (100 MHz, CDC13): δ 135.6, 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 / Et2NH = 98 / 2 / 0.1, 1 mL / min, λ = 254 nm, t R (major) = 5.75 min, t R (minor) = 9.35 min; 38.13 (c 0.15, CHCl3).

[0143] Application Example 2: Preparation of compound I-2

[0144]

[0145] The operating procedure was the same as in Application Example 1, except that the electrophilic reagent used was diphenylphosphorus chloride (45 μL), to give compound I-2 (red solid, yield 65%). 1 H NMR (400 MHz, CDC13): δ 7.04 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 4.53-4.48 (m, 1H), 4.46 (t, J = 1.9 Hz, 1H), 4.31 (t, J = 2.6 Hz, 1H), 4.17 (s, 5H), 3.47 (d, J = 13.2 Hz, 1H), 3.43 (d, J = 13.2 Hz, 1H), 2.25 (s, 3H), 2.05 (s, 6H); 13C NMR (100 MHz, CDC13): δ 140.2 (d, J = 8.7 Hz), 138.2 (d, J = 8.2 Hz), 135.1 (d, J = 21.6 Hz), 132.6 (d, J = 18.2 Hz), 129.1, 128.2 (d, J = 7.9 Hz), 127.9 (d, J = 6.2 Hz), 127.7, 90.6 (d, J = 25.8 Hz), 76.4 (d, J = 8.8 Hz), 72.8 (d, J = 4.1 Hz), 71.6 (d, J = 4.5 Hz), 69.8, 58.0 (d, J = 9.2 Hz), 45.1; 31 P NMR (162 MHz, CDC13): 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 °C; HPLC: 98% ee, Daicel Chiralpak IG column, Hexanes / IPA / Et2NH = 99 / 1 / 0.1, 1 mL / min, λ = 254 nm, t R (major) = 11.48 min, t R (minor) = 8.90 min; 256.54 (c 0.54, CHCI3).

[0146] Application Example 3: Preparation of compound I-3

[0147]

[0148] Operating procedure as in application example 1, except that the electrophilic reagent used was: benzophenone (45.6 mg), compound I-3 was obtained (yellowish oil liquid, yield 45%). 1 H NMR (400 MHz, CDC13): δ 7.63-7.50 (m, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 7.3 Hz, 1H), 7.21-7.08 (m, 5H), 4.07 (d, J = 2.3 Hz, 2H), 3.97 (s, 5H), 3.81 (t, J = 2.1 Hz, 1H), 3.67 (d, J = 13.3 Hz, 1H), 2.68 (d, J = 13.2 Hz, 1H), 1.99 (s, 6H); 13C NMR (100 MHz, CDC13): δ 150.0, 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 / Et2NH = 98 / 2 / 0.1, 1 mL / min, λ = 220 nm, t R (major) = 4.30 min, t R (minor) = 6.39 min; 121.90 (c 0.23, CHCI3).

[0149] Application Example 4: Preparation of compound I-4

[0150]

[0151] The operating procedure was the same as in Application Example 1, except that the electrophilic reagent used was trimethylchlorosilane (32 μL), to give compound I-4 (red oily liquid, yield 67%). 1 H NMR (400 MHz, CDC13): δ 4.34-4.28 (m, 1H), 4.24 (t, J = 2.4 Hz, 1H), 4.08 (s, 5H), 4.04-3.99 (m, 1H), 3.42 (d, J = 12.5 Hz, 1H), 3.01 (d, J = 12.5 Hz, 1H), 2.11 (s, 6H), 0.28 (s, 9H); 13 C NMR (100 MHz, CDC13): δ 89.2, 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 / Et2NH = 100 / 0.1, 0.5 mL / min, λ = 254 nm, tR (major) = 8.47 min, t R (minor) = 9.56 min; -24.95 (c 0.99, CHCI3).

[0152] Preparation of compound J-1

[0153]

[0154] A stir bar of suitable size was placed in a dry 10 mL Schlenk tube, I-4 (31.6 mg, 0.1 mmol, 1.0 equiv) was added, the reaction system was degassed by double-tube three times, then 1.5 mL of dry ether was added, and the reaction system was placed at -40 °C, then n-butyllithium (60 μL, 2.5 M in hexane, 0.15 mmol, 1.5 equiv) was added dropwise, and after the addition was completed, it was stirred at this temperature for 2 h. Then the reaction system was cooled to -78 °C, (1R,2S,5R)-(-)-menthol (S)-p-toluenesulfinate (69 μL, 0.25 mmol, 2.5 equiv) was added dropwise, and after stirring at this temperature for 10 min, it was warmed to room temperature and stirred overnight. After the reaction was completed, water was added to quench the reaction, and then extracted with ethyl acetate three times (10 mL x 3), 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 to give the product J-1 (red oily liquid, yield 51%). 1 H NMR (400 MHz, CDCI3): δ 7.66-7.59 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.73 (d, J = 2.6 Hz, 1H), 4.35 (s, 5H), 4.19 (d, J = 2.6 Hz, 1H), 3.60 (d, J = 12.8 Hz, 1H), 3.26 (d, J = 12.8 Hz, 1H), 2.33 (s, 3H), 1.92 (s, 6H), 0.26 (s, 9H); 13 C NMR (100 MHz, CDCI3): δ 144.2, 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 Fe NOSSi + [M+H + ] 454.1318, found 454.1320; 221.55 (c 0.64, CHCl3).

[0155] Application Example 6: Preparation of compound M-1

[0156]

[0157] A stir bar of suitable size was placed in a dry 10 mL Schlenk flask, followed by palladium acetate (2.2 mg, 0.01 mmol, 0.1 equiv), N-(tert-butoxycarbonyl)-L-valine (6.5 mg, 0.03 mmol, 0.3 equiv), potassium carbonate (27.6 mg, 0.2 mmol, 2.0 equiv), dry N,N-dimethylformamide (0.4 mL) and dry dimethyl sulfoxide (0.1 mL), G-1 (36.9 mg, 0.1 mmol, 1.0 equiv), 4-iodobenzotrifluoride (18 μL, 0.12 mmol, 1.2 equiv), 1-n-heptyl-2-norbornene (8.3 mg, 0.05 mmol, 0.5 equiv), followed by placing the reaction system in a 80 °C water bath for stirring for 18 hours. After the reaction was completed, the reaction system was cooled to room temperature, saturated sodium carbonate solution was added to quench the reaction, extracted with ethyl acetate three times (10 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give the product M-1 (red oily liquid, yield 57%). (8.3 mg, 0.05 mmol, 0.5 equiv) followed by placing the reaction system in a 80 °C water bath for stirring for 18 hours. After the reaction was completed, the reaction system was cooled to room temperature, saturated sodium carbonate solution was added to quench the reaction, extracted with ethyl acetate three times (10 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give the product M-1 (red oily liquid, yield 57%). 1 H NMR (400 MHz, CDC13): δ 7.52 (s, 4H), 4.98 (d, J = 1.6 Hz, 1H), 4.87 (d, J = 1.6 Hz, 1H), 4.00 (s, 5H), 3.48 (d, J = 13.1 Hz, 1H), 3.34 (d, J = 13.1 Hz, 1H), 2.29 (s, 6H); 13 C NMR (100 MHz, CDC13): δ 142.3, 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 F3FeIN + [M+H +]513.9936, found 513.9935; HPLC: 99% ee, Daicel Chiralpak OD-H column, Hexanes / IPA / Et2NH = 97 / 3 / 0.1, 1 mL / min, λ = 254 nm, t R (major) = 9.01 min, t R (minor) = 7.36 min; 31.30 (c 0.21, CHCl3).

[0158] The above description is merely preferred embodiments of the application, but the application protection scope is not limited to this. Any modification, equivalent replacement and improvement made by any person skilled in the art within the technical range disclosed by the application should be included in the protection scope of the application.

Claims

1. A method for synthesizing planar chiral iodocenene metals, characterized in that, Includes the following steps: Under inert gas protection, starting with compound A, the reaction was carried out in organic solvent F with the help of iodine reagent B, palladium catalyst C, chiral amino acid D and base E, and stirred until the reaction was completed. The reaction mixture was then extracted, concentrated and purified by column chromatography to obtain 1,2-disubstituted planar chiral iodometallocene compound G as shown in the reaction formula. The structure of A is as follows: ; R 1 R 2 It consists of two independent groups or groups connected together to form a single group; if it consists of independent groups, R 1 R 2 Selected from C1-C6 alkyl groups; if R 1 R 2 If it is connected as a single group, then the group is a C1-C7 cycloalkyl, a C1-C7 epoxyalkyl, or an N or S substituted C1-C7 cycloalkyl. M represents iron; R 3 Selected from hydrogen, C6-C12 aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, C1-C6 aldehyde, C2-C7 epoxy alkyl, C2-C11 ester, carboxyl, amide, -TMS or The C2-C11 ester group is -(CH2). x -COOR', x is an integer from 0 to 4, and R' is a C1-C6 alkyl group; The structure of B is: ; R 4 Selected from any one or more of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, and halogen; The structure of G is: ; The palladium catalyst C is selected from any one or more of Pd(OAc)2, Pd(PPh3)2(OAc)2, Pd(TFA)2, Pd(acac)2, Pd(OPiv)2, Pd(PhCN)2Cl2, Pd(MeCN)2Cl2, Pd(PPh3)2Cl2, PdCl2, PdI2, and [Pd(allyl)Cl]2; The structural formula of the chiral amino acid D is: in: i)R 5 It is selected from any one of benzoyl, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, ester, C1-C6 alkyl, and benzyl; ii) R 6 Selected from any one of C6-C12 aryl or C1-C6 alkyl; In the chiral amino acid D, R 5 The ester group is "-COOR", and "R" is a C1-C6 alkyl or C6-C12 aryl group; R 6 The C6-C12 aryl group is -(CH2). y -Ph, y is an integer from 0 to 4; 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. The reaction temperature is 25℃~120℃.

2. The method for synthesizing planar chiral iodocenocene metals according to claim 1, characterized in that, R 3 The radicals are selected from hydrogen; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C6-C12 aryl; halogen; cyano; C1-C6 aldehyde; -TMS; .

3. The method for synthesizing planar chiral iodocenocene metals according to claim 1, characterized in that, The solvent F is selected from methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dimethyl ethylene glycol, methyl tert-butyl ether, 1,4-dioxane, 1,3-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C4-12 saturated alkanes, C3-12 fluorinated or chloroalkanes, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, etc. N , N -Dimethylformamide, N , N -Dimethylacetamide, acetone, N 1-Methylpyrrolidone, acetonitrile, or any one or more of C3-12 saturated alkyl nitriles.

4. A method for preparing 1,2-disubstituted planar chiral metallocene compounds and 1,2,3-trisubstituted planar chiral metallocene compounds using a planar chiral metallocene prepared by any one of claims 1-3, characterized in that: (1) Preparation of 1,2-disubstituted planar chiral metallocene compounds, comprising the following steps: Under inert gas protection, ferrocene iodocarbamate G was used as the starting material. With the electrophilic reagent H and the base E, the mixture was stirred in organic solvent F until the reaction was completed. The reaction mixture was extracted, concentrated, and purified by column chromatography to obtain the 1,2-disubstituted planar chiral metallocene compound as shown in the reaction formula I. The reaction formula is as follows: (2) The preparation method of 1,2,3-trisubstituted planar chiral metallocene compounds is as follows: Under inert gas protection, using 1,2-disubstituted ferrocene I as the starting material, and with the electrophilic reagent H and the base E, the reaction was stirred in organic solvent F until the reaction was completed. The reaction mixture was then extracted, concentrated, and purified by column chromatography to obtain the 1,2,3-trisubstituted planar chiral metallocene compound as shown in the reaction formula J. The reaction formula is as follows: In (1) and (2), H and the corresponding group R 7 or R 8 The group is represented by H / corresponding group and is selected from: trialkylchlorosilane / trialkylsilyl, diarylphosphine chloride / diarylphosphine, arylformyl chloride / arylformyl, diaryl ketone / diarylhydroxymethyl, alkyl chloroformate / alkoxyacyl, diaryl chlorophosphate / diaryloxyphosphonyl, diaryl sulfide / diaryl sulfide; wherein the alkyl group is C1-C6 alkyl and the aryl group is C6-C12 aryl.

5. A method for preparing 1,2,4-trisubstituted planar chiral metallocenes using a planar chiral iodocenene prepared by any one of claims 1-3, characterized in that, Includes the following steps: Under inert gas protection, ferrocene iodocarbamate G and aryl halide K were used as starting materials. The reaction was carried out in organic solvent F with palladium catalyst C, chiral amino acid D, norbornene derivative L and base E. The reaction mixture was then filtered, concentrated and purified by column chromatography to obtain 1,2,4-trisubstituted planar chiral metallocene compounds of formula M. The reaction formula is as follows: in: R 9 Selected from one or more of the following: C6-C12 aryl, N, S-substituted C5-C12 heterocyclic aryl, C1-C6 alkyl, aldehyde, hydroxyl, amino, cyano, nitro, amide, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, and halogen. X is either bromine or iodine; m represents R 9 The number of substituents is 0 ≤ m ≤ 3; when m = 2 or 3, the substituents can be the same or different. Ar 1 These are C6-C12 aromatics and N- and S-substituted C5-C12 heterocyclic aromatics; The structural formula of norbornene derivative L is: in: i)R 10 The substituents on the left five-membered ring are represented by n, where n represents the number of substituents, and 0 ≤ n ≤ 8; R 11 is the substituent on the double bond, p represents the number of substituents, 0≤p≤2; ii) R 10 R 11 Selected from any one or more of C6-C12 aryl, N, S-substituted C5-C12 heterocyclic aryl, C1-C6 alkyl, aldehyde, carboxyl, hydroxyl, amino, cyano, nitro, amide, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl or halogen. iii) When the number of substituents on the left five-membered ring is two or more, they can be the same or different; when the number of substituents on the double bond is two, they can be the same or different. iv) R 10 and R 11 The types of substituents can be the same or different.

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