Synthesis and characterization of enantiopure planar–chiral phosphorus-linked diferrocenes

Six new homochiral diferrocenyl derivatives have been synthesized, one of which is purely planar–chiral. Even if the two diferrocene subunits are identical, they are distinguished due to their positions relative to the substituents at the phosphorous prochiral centre.

In the course of an ongoing synthetic project on cyclic diferrocenylphosphines, we obtained a group of planar-chiral diferrocenyl compounds useful as precursors for subsequent cyclization. Here we report the crystal structures of two symmetric compounds [(Fc A ) 2 (Ph)P], one of which contains four stereogenic centres (two C chiral and two planar chiral centres), i.e.

Introduction
Metallocenes decorated with at least two different substituents on the same ring are planar-chiral (Schaarschmidt & Lang, 2013). They are useful as voluminous asymmetry-inducing groups in asymmetric transformations (Stepnicka, 2008). Even beyond academic research, disubstituted ferrocenes have been used in industrial asymmetric synthesis, for instance, in the hydrogenation of imines (Blaser et al., 2007).

Melting points
The melting points were measured on a Reichelt Thermovar Kofler apparatus and are uncorrected.

Chiral high-performance liquid chromatography (HPLC)
HPLC analysis was performed on an Agilent Technologies 1200 series system using a Chiralcel OD-H chiral column.

NMR spectroscopy
Routine NMR spectra were recorded on a 400 MHz Bruker AVIII 400 spectrometer operating at 400.27 ( 1 H), 100.66 ( 13 C) and 162.04 MHz ( 31 P) with an autosampler. The 1 H and 13 C{ 1 H} NMR spectra used for substance characterization were recorded either on a 600 MHz Bruker AVIII 600 spectrometer operating at 600.25 ( 1 H) and 150.95 MHz ( 13 C) or on a Bruker AVIII 700 spectrometer operating at 700.40 ( 1 H) and 176.13 MHz ( 13 C). 13 C NMR spectra were recorded in J-modulated mode. NMR chemical shifts are referenced to nondeuterated CHCl 3 residual shifts at 7.26 ppm for 1 H NMR and to CDCl 3 at 77.00 ppm for 13 C NMR. Coupling patterns in the 1 H and 13 C NMR spectra are denoted using standard abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and p (pseudo). For the 13 C NMR spectra, carbon resonances were identified as C q , CH, CH 2 and CH 3 .

High-resolution mass spectroscopy (HRMS)
HRMS were recorded by a Bruker Maxis ESI oa-RTOF mass spectrometer equipped with a quadrupole analyzer ion guide.

Figure 2
(a) Chemical structure and (b) displacement ellipsoid plot of divinyl 6. The ellipsoid probability level of this figure and all subsequent figures is 50%.

Refinement
The structures were solved by direct methods and refined using full-matrix least-squares techniques. Non-H atoms were refined with anisotropic displacement parameters. H atoms were inserted at calculated positions and refined using a riding model. C-H bond lengths in the aromatic and olefin bond systems were constrained at 0.950 Å , aliphatic CH 2 groups at 0.990 Å and aliphatic CH 3 groups at 0.980 Å . The default values of SHELXL (Sheldrick, 2008) were used for the ridingatom model. Fixed U iso values of 1.2 times were used for all C(H) and C(H,H) groups, and fixed U iso values of 1.5 times were used for all C(H,H,H) and O(H) groups. Details for each compound are summarized in the CIF file under the keyword '_refine_special_details'.
The position of the acidic atom H1B at 8b was stabilized using a length-fixing restraint. Several reflections, primarily inner ones, have been omitted to avoid wrong interpretations.
The amine H atom of compound 9b was refined taking account of the two possible configurations of the N atom. The choice was stable and in agreement with the position of available electron density.
Crystal data, data collection and structure refinement details are summarized in Table 1.

Results and discussion
The syntheses carried out in the framework of this study are summarized in Fig. 1. The structure of the central diferrocene precursor 2 has been deposited previously (Steiner & Pioda, 1999) in the Cambridge Structural Database (Groom et al., 2016). First, we eliminated the dimethylamine groups of 2 to obtain divinyl structure (S p ,S p )-5 by heating in acetic anhydride according to . The sensitive phosphine was then protected by reaction with elemental sulfur to quantitatively produce divinylphosphine sulfide (S p ,S p )-6, shown in Fig. 2  . The substance was readily isolated as orange crystals upon removal of the solvent. Cyclization attempts of 6 via ring-closing metathesis (RCM) failed, possibly due to the separation of the vinyl C atoms, steric strain in the product or interference of the Grubbs catalyst with the phosphine sulfide. However, Lewis acid-catalyzed hydrovinylation afforded the desired allcarbon backbone .    For an alternative approach, we replaced the diamino groups with more capable leaving groups in order to close the ring with bidentate nucleophiles. In one of these attempts, we replaced the amines by acetate groups using acetic anhydride. The resulting diacetate (R,S p ,S p ,R)-7 crystallized upon removal of the solvent (Fig. 3). Alternatively, the reactive phosphino group was protected by reaction with elemental sulfur to yield phosphine sulfide (R,S p ,S p ,R)-3 (Honegger & Widhalm, 2019a). In contrast to the unprotected phosphine, we could not obtain the diacetate from derivative (R,S p ,S p ,R)-3, but from the reaction mixture, three compounds, namely, (S p ,S,S p ,R)-8a (Fig. 4), (S p ,S,S p ,R)-8b (Fig. 5) and (R,S p ,R,S p ,R)-8c ( Fig. 6) with acetate, hydroxy or vinyl side groups instead, could be isolated, indicating that the substitution was followed by elimination or cleavage of the acetyl group.
In the symmetric diferrocenes (S p ,S p )-6 and (S p ,S p )-7, the ferrocene subunits are identical. Fig. 8 shows a system developed to distinguish them into an re-site and an si-site. Taking divinyl compound (S p ,S p )-6 as an example, both ferrocene units are planar-chiral (S p ). The P atom in compound (S p ,S p )-6 is prochiral; if any of the two vinylferrocene groups are modified, the ferrocene substituents become distinguishable and the P atom thus a chiral centre. Fig. 9 shows a hypothetical Markovnikov regioselective addition of HNu to divinyl (S p ,S p )-6, Nu standing for a generalized nucleophile. Depending on whether HNu is added to the re-site or si-site vinyl group, the P atom becomes an (S)-or (R)-chiral centre, respectively. The two possible products are diastereomers since the reaction turns the P-atom centre from prochiral to centre-chiral. In addition, this reaction introduces a new chiral centre, but in a diastereoselective fashion since one of the two sites is blocked by the other ring of the ferrocenyl unit (Marquarding et al., 1970). The two possible products are diastereomers, differing only in the resulting configuration of     the P atom (epimers). In the compounds presented in this article, we know the configuration at the (S p )-disubstituted ferrocene will be selectively (R), since the approach of the nucleophile from the (S)-site is blocked by the other cyclopentadienyl (Cp) ring (Marquarding et al., 1970). Fig. 9 illustrates this by rotating the two possible products by 180 for better comparison with the other product; again, only the configuration of the P atom differs. We only observed the formation of one of the two possible diastereomers, hence the reaction proceeds diastereoselectively, as was observed for different reactions throughout this study. Typically, the re-site of the symmetrical (S p ,S p )-precursors was more reactive.
Thus, the vinylferrocene groups are diastereotopic and their respective NMR shifts can be distinguished despite their apparent equality in connectivity when neglecting stereochemical aspects. In fact, protons attached to the inner vinyl protons in (S p ,S p )-6 differ so greatly in chemical shift that one of the two is found at a higher field than even aromatic protons ( = 8.1 ppm;.
The preferred conformation of ferrocenyl units with both Cp rings is a perpendicular arrangement, with the reactive referrocene closer to the small sulfur residue and the less reactive si-ferrocene shielded by the bulkier phenyl group.
For the asymmetric diferrocene compounds (S p ,S,S p ,R)-8a, (S p ,S,S p ,R)-8b and (S p ,S,S p ,R)-9b, the ferrocenyl at the smaller sulfur group bears the more bulky substituent (acetate, hydroxy and benzyl), while the other ferrocenyl unit at the larger phenyl ring is substituted with a sterically less demanding vinyl group. Only hydroxyacetate (S p ,R,S p ,R)-8c shows the opposite preference. The preferred geometry might be mainly controlled by subtle inter-and intramolecular steric interactions as nointeractions could be detected. The protic H atoms in compounds 8b, 8c (O-H group) and 9b (N-H group) form intramolecular hydrogen bonds with the -system of the P-substituted phenyl group.
Since we obtained the sufficiently stable compound (S p ,S p )-6 in large enough quantities, we tested its asymmetry-inducing performance as a ligand in an in-situ formed Pd II complex used for asymmetric allylic alkylation according to Widhalm et al. (1996). This purely planar-chiral compound achieved an enantiomeric excess of 35%, which is less than what we found for previously known (R,S p ,S p ,R)-2 (57%). Regardless, the coordination structure of (S p ,S p )-6 and Pd II remains an interesting question since neither phosphine (S p ,S p )-5 nor its phosphine oxide analog were able to activate Pd II . We could not isolate the catalytically active Pd II complex to study its structure, but we speculate that the phosphine sulfide might act as an electron donor to form a dative bond in transitionmetal catalysts.

Figure 8
The re/si nomenclature for diferrocenes developed in the framework of this study to distinguish between the two ferrocenyl subunits.

Conclusion
We present the crystal structures of six homochiral phosphorous-linked diferrocenes. All the ferrocene units are planarchiral (S p ) and five of the compounds include one or two centre-chiral C atoms (R) also. Interestingly, the molecules lack strong intermolecular interactions and exhibit no -stacking, even though most of the C atoms are aromatic. Compounds 8b, 8c and 9b include acidic H atoms (RO-H and R 2 N-H) capable of forming hydrogen bridges with the -electron systems of the phenyl ring.