Enantioselective Rh(I)-Catalyzed C–H Arylation of Ferroceneformaldehydes

As an important class of platform molecules, planar chiral ferrocene carbonyl compounds could be transformed into various functional groups offering facile synthesis of chiral ligands and catalysts. However, developing efficient and straightforward methods for accessing enantiopure planar chiral ferrocene carbonyl compounds, especially ferroceneformaldehydes, remains highly challenging. Herein, we report a rhodium(I)/phosphoramidite-catalyzed enantioselective C–H bond arylation of ferroceneformaldehydes. Readily available aryl halides such as aryl iodides, aryl bromides, and even aryl chlorides are suitable coupling partners in this transformation, leading to a series of planar chiral ferroceneformaldehydes in good yields and excellent enantioselectivity (up to 83% yield and >99% ee). The aldehyde group could be transformed into diverse functional groups smoothly, and enantiopure Ugi’s amine and PPFA analogues could be synthesized efficiently. The latter was found to be a highly efficient ligand in Pd-catalyzed asymmetric allylic alkylation reactions. Mechanistic experiments supported the formation of imine intermediates as the key step during the reaction.


I. INTRODUCTION
−13 In 2004, Bergman, Ellman, and coworkers made a breakthrough in Rh(I)-catalyzed intramolecular asymmetric C−H alkylation reaction using an imine as a directing group. 14−26 In 2016, Glorius and co-workers achieved remarkable progress in the combination of a rhodium(I) precatalyst with a chiral N-heterocyclic carbene (NHC) or monodentate phosphonite ligand enabled asymmetric C(sp 3 )−H arylation in good yields and enantioselectivity. 27,28Our group recently explicated the mechanism of Rh(I)-catalyzed asymmetric C−H arylation, which first occurs by a directed C−H activation through a concerted metalation− deprotonation (CMD) pathway and the reductive elimination is the turnover-limiting step. 29In these examples, a variety of strong coordination directing groups such as pyridine, thione, thioamide, etc. have been employed to warrant high efficiency and stereoselectivity for Rh(I)-catalyzed asymmetric C−H functionalization reactions; however, these directing groups in general are difficult to remove or undergo subsequent conversions.To date, there are rare examples of rhodiumcatalyzed intermolecular asymmetric ortho-C−H activation of aldehyde derivatives, likely due to the weak coordination ability of the carbonyl group and the potential competitive aldehyde C−H cleavage by rhodium catalysts. 11errocene derivatives have received extensive attention in materials science, medicinal chemistry, and asymmetric catalysis because of their unique electronic and structural properties (Figure 1a).−37 Traditional methods for the synthesis of planar chiral ferrocene carbonyl compounds usually relied on preinstalled chiral auxiliaries, and tedious synthetic steps were needed (Figure 1b). 38The utilization of various reactive metal reagents also resulted in poor functional group compatibility.−57 Therefore, the development of an enantioselective and efficient synthesis of structurally diverse planar chiral ferroceneformaldehydes is highly desirable.
Inspired by these above pioneering results, we recently found that Rh(I)-catalyzed asymmetric C−H arylation of ferroceneformaldehydes was realized by a strategy of the in situ formation of imines (Figure 1c).In the presence of a Rh(I) catalyst derived from chiral phosphoramidite, direct arylation of ferroceneformaldehydes with readily available aryl halides proceeded in excellent enantioselectivity.Herein, we report the results of this study.
As a further demonstration of the utility of this method, a gram-scale reaction of 1a (10 mmol) and 2a was carried out.Pleasingly, the corresponding product 3aa was obtained in 70% yield and >99% ee with only 2.0 mol % of [Rh(C 2 H 4 ) 2 Cl] 2 .The absolute configuration of 3aa was assigned as S p by the Xray diffraction analysis of an enantiopure sample.To further demonstrate the potential utility of this reaction, various transformations of product (S p )-3aa (>99% ee) were carried  out (Figure 3).The aldehyde group could be transformed into diverse functional groups smoothly, such as methyl (4a), vinyl (4b), acetenyl (4c), hydroxyl (4d), primary amine (4e), secondary amine (4f), and tertiary amine (4g) without the loss of enantioselectivity.Meanwhile, the aldehyde group on 3aa could be protected by thiols via simple protocols (4h, 72% yield, 99% ee).In addition, the Perkin reaction could be conducted to generate carboxylic acid 4i (70% yield, >99% ee).Subsequently, starting from (S p )-3aa, chiral benzyl alcohol (R,S p )-5 could be synthesized efficiently in 80% yield and 19:1 dr via Grignard addition (Figure 4).(R,S p )-5 could be transformed into Ugi's amine derivative (R,S p )-6 by a onepot procedure, and its absolute configuration was confirmed by comparing with the literature 61 (see the Supporting Information for details).Meanwhile, the chiral PPFA ligand derivative (R,S p )-7 could be synthesized in 75% yield and >19:1 dr and was found to be an efficient ligand in a Pdcatalyzed asymmetric allylic alkylation reaction (95% yield, 93% ee).In addition, chiral thioether (R,S p )-8 and monophosphine (R,S p )-9 were synthesized in good yields and diastereoselectivity (70−80% yields, >19:1 dr).These transformations further enhance the synthetic utility of the current method.
II.3.Mechanistic Studies.Preliminary experiments were carried out to gain insight into the reaction mechanism.Product 3aa was not observed when the reaction of 1a was carried out in the absence of benzylamine, and only product 13 was obtained in 10% yield (Figure 5a).This shows that the formation of an imine is necessary.In situ NMR and HRMS experiments further confirmed the formation of imine intermediate I (Figure 5b).Notably, a parallel KIE experiment in which the kinetic isotope effect of 1a is only 1.10 (k H /k D ) suggests that C−H cleavage is not the rate-determining step (Figure 5c).The competitive experiment between 4bromoanisole 2a and 4-bromobenzonitrile 2n revealed that substrates bearing an electron-deficient group are more reactive than those with an electron-rich group (Figure 5d).Based on the above studies and a previous report, 27

III. SUMMARY AND CONCLUSIONS
In conclusion, we have developed a highly efficient synthesis of planar chiral ferroceneformaldehyde derivatives by enantioselective Rh(I)-catalyzed C−H arylation with readily available aryl halides under mild reaction conditions.These processes occur with excellent levels of monoarylation selectivity, enantioselectivity, and efficiency.Diverse functional groups were tolerated, and chiral Ugi's amine and PPFA ligand analogues could be synthesized efficiently through simple protocols.The obtained chiral ferrocene ligand was found to be efficient in a Pd-catalyzed asymmetric allylic alkylation reaction.In situ NMR and HRMS experiments confirmed the formation of the imine intermediate.Further studies on enantioselective Rh(I)-catalyzed C−H functionalization reactions toward more diverse chiral molecules are ongoing in this laboratory.
a plausible catalytic cycle was proposed for this enantioselective Rh(I)catalyzed C−H arylation of ferroceneformaldehydes.As shown in Figure 5e, ferroceneformaldehyde 1 is dehydrated with benzylamine to form imine intermediate I.The coordination of I with the Rh precursor generates the intermediate II.Then, the intermediate II first is generated by directed C−H activation through a concerted metalation−deprotonation (CMD) pathway, delivering the intermediate III.Next, the oxidative addition of aryl halide 2 and reductive elimination proceed to give intermediate V. Finally, product 3 is obtained via hydrolysis of intermediate V.

Table 1 .
Optimization of the Reaction Conditions a b Determined using 1,3,5-trimethoxybenzene as an internal standard.c Determined by HPLC analysis with a chiral stationary phase.d Isolated yield.