A new method for the synthesis of planar chiral metallocene compounds realized by the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences

On October 24, 2022, Beijing time, the You Shuli team of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, published a research result entitled “Kinetic resolution of planar chiral metallocenes using Rh-catalysed enantioselective C–H arylation” in the journal Nature Synthesis.

This research group uses the strategy of combining prefunctional grouping and kinetic separation to realize the asymmetric synthesis of planar chiral metallocene compounds, which can be used as a very efficient general means to realize the asymmetric synthesis of various 1, 2- and 1, 3-disubstituted and multi-substituted metallocene compounds.

The corresponding author of the paper is researcher You Shuli; The first author is Dr. Chenxu Liu.

Planar chiral molecules have a wide range of applications in synthetic chemistry, biomedicine, and materials science, especially as highly effective catalysts or ligands for asymmetric catalysis (Figure 1a). Therefore, the development of methods for the efficient introduction of planar chirality has attracted extensive attention from chemists. Transition metal-catalyzed asymmetric carbon-hydrogen bond functional grouping reactions have made great progress over the past few decades, providing highly atomic and step-economical methods for the synthesis of chiral molecules. It is worth noting that the synthesis of multiple planar chiral 1,2-disubstituted metallocenes has been achieved by asymmetric hydrocarbon bond functional grouping (Figure 1b). However, in the past work, each catalytic system can only introduce a specific functional group, and there is still a lack of universal catalytic systems to achieve the introduction of various functional groups. At the same time, due to the lack of efficient synthesis methods for planar chiral 1, 3-disubstituted metallocene, the relevant application research is limited. Therefore, it is of great significance to develop efficient synthesis methods for various functional grouped 1, 2-disubstitution and 1, 3-di-substituted planar chiral ferrocene compounds.

You Shuli’s research team at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences has been engaged in the asymmetric synthesis of planar chiral metallocene compounds (Acc. Chem. Res. 2017, 50, 351; Trends Chem. 2020, 2, 737.)。 Recently, they have achieved a series of asymmetric synthesis of 1, 2-disubstitution, 1, 3-disubstitution, and multi-substituent planar chiral metallocene by pre-introducing a series of functional groups at the 2- or 3-position of metallocene with guide groups, combined with the strategy of kinetic splitting (Figure 1d). The reaction is not only mild, selective, but also compatible with various functional groups.

Figure 1: Asymmetric synthesis of planar chiral metallocene compounds

Through reasonable substrate design and systematic screening, the authors determined the optimal conditions for the reaction: using vinyl rhodium chloride and TADDOL-derived chiral monophosphine ligands as catalysts, lithium tert-butoxide as bases, and THF as solvents can achieve excellent s-value control. The synthesis of planar chiral metallocene compounds can be achieved under very mild conditions and good S-value control can be achieved. After determining the optimal reaction conditions, the substrate is investigated for universality (Figure 2). First, a series of 1, 2-disubstituted metallocene compounds are investigated. Whether ferrocene pyridine or ruthenocene pyridine has a variety of alkyl, alkenyl and aryl substituents at the 2-position, the reaction is well compatible. In addition, when various heteroatoms such as silicon, sulfur, and fluorine atoms are introduced into the 2-position, the reaction can still achieve good results.

Figure 2: 1, 2-Representative substrate for disubstituted metallocene

The authors also tried a series of 1, 3-disubstituted ferrocene substrates (Figure 3), and when the trimethylsilyl group was attached to the 3-position of pyridine ferrocene, the reaction could give very good S-value control and excellent region selectivity control under standard reaction conditions. When the 3-position is aryl, the s value of the reaction decreases slightly. At the same time, a series of substituted pyridine guides and various aryl bromides are also well compatible with the reaction, but when the parasite of aryl bromide is connected with electron-absorbing substituents, the s value of the reaction will decrease slightly.

Figure 3:1, Representative substrate of 3-Disubstituted ferrocene

In addition, the authors also scaled up the reaction to 2.0 mmol, and the reaction still achieved results comparable to small reactions. The obtained planar chiral ferrocene compounds can be applied to the synthesis of novel planar chiral N,P-ligands, which in turn can be applied to asymmetric allyl substitution and asymmetry[3+2]Cycloaddition reaction. The authors also performed kinetic experiments, respectively (Rp)-1aand (Sp)-1aPut into a standard reaction to rate detect it, find (Rp) –1awith (Sp)-1aThe ratio of the rates is 195, which coincides with the experimentally calculated s value (207).

This study provides a new method for synthesizing planar chiral metallocene compounds, and realizes the asymmetric synthesis of a series of metallocene compounds by combining prefunctional grouping and kinetic resolution. This method provides a new way for the synthesis of planar chiral 1, 2-disubstitution, 1, 3-disubstitution, and multi-substituted metallocene compounds. (Source: Web of Science)

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