# Synthesis of chiral P,S ferrocenyl ligands for catalyst heterogenization and testing in the homogeneous asymmetric hydrogenation of acetophenone

Abdelhak Lachguar, Shagun Chhetri, Ahmad Joumaa, Jean-Claude Daran, Rinaldo Poli, Eric Manoury, Eric Deydier

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Abdelhak Lachguar, Shagun Chhetri, Ahmad Joumaa, Jean-Claude Daran, Rinaldo Poli, et al. Synthesis of chiral P,S ferrocenyl ligands for catalyst heterogenization and testing in the homogeneous asymmetric hydrogenation of acetophenone. Journal of Organometallic Chemistry, 2026, 1048, pp.124049. 10.1016/j.jorganchem.2026.124049. hal-05495443

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# Synthesis of chiral P,S ferrocenyl ligands for catalyst heterogenization and testing in the homogeneous asymmetric hydrogenation of acetophenone

Abdelhak Lachguar<sup>a,b</sup>, Shagun Chhetri<sup>a</sup>, Ahmad Joumaa<sup>a</sup>, Jean-Claude Daran<sup>a</sup>, Rinaldo Poli<sup>a,*</sup>,<sup>●</sup> Eric Manoury<sup>a,*</sup>, Eric Deydier<sup>a,c,**</sup>

## ARTICLE INFO

### Keywords:

Chiral ferrocenyl phosphine

P,S bidendate ligand

Iridium

Asymmetric hydrogenation

Kinetics

## ABSTRACT

Racemic and chiral P,S ferrocenyl ligands bearing a phenol function for further catalyst grafting were synthesized and fully characterized (multinuclear NMR, high-resolution MS, X-ray diffraction). Analogs bearing a methoxy group instead of OH (anisole instead of phenol) were also synthesized to mimic the expected ether formation after grafting in order to assess the ether group influence on catalysis. Good activity and enantioselectivity (up to 78%), similar to non-functionalized ligands, were obtained in the asymmetric hydrogenation of acetophenone. The base concentration appears to have major influence on both activity and enantioselectivity.

## 1. Introduction

Asymmetric hydrogenation is one of the major reactions in the arsenal of organic asymmetric synthetic techniques. This reaction is of particular interest for the pharmaceutical and phytosanitary industries as many products are optically active (examples in Fig. 1), presenting one or more asymmetric centers of paramount importance for the physio/biological action. Indeed, the undesired enantiomer may be less active, inactive (for instance, only S-ibuprophen is analgesic), toxic (e.g. R-Levodopa is toxic, contrary to S-enantiomer) or presenting a different biological activity. In the late 1950s and early 1960s, the prescription of racemic Thalidomide to pregnant women has been a tragic illustration of such chirality effect as >10,000 children were born with severe deformities, the S-Thalidomide enantiomer being a teratogen molecule. Therefore, chirality control is essential for the manufacture of these compounds [1].

Asymmetric hydrogenation using transition metals is a technique of choice for transforming the sp² carbon atoms of alkenes, imines or ketones into sp³ carbons with controlled chirality. Since the pioneering work of W.S. Knowles and R. Noyori on asymmetric catalysis, a number of chiral ligands, mainly amines and phosphines, have been combined with metals such as rhodium, iridium and ruthenium to develop efficient

asymmetric hydrogenation systems under hydrogen pressure or by hydrogen transfer [2]. However, in spite of the large number of efficient catalysts described in the literature, very few have made it to the industrial production stage, e. g. Josiphos [3], probably because of high cost, lack of stability, or inefficient recyclability. In order to meet society's expectations in terms of sustainable development and greener chemistry [4], heterogenization of asymmetric catalytic reactions by grafting chiral catalysts onto solid supports (inorganic solids or polymers) has attracted great attention in the recent decades [5]. This approach combines the advantages of homogeneous catalysis (high activity and selectivity) with the ease of separation and recycling of expensive catalysts, as well as the easier implementation of continuous-flow processes. Moreover, heterogenization of asymmetric catalytic reactions by grafting (via covalent or non-covalent interactions) onto solid supports sometimes leads to increased catalyst stability, activity, and also selectivity due to cooperative surface or confinement effects [6].

We have been interested for several years in the use of bidendate ferrocenyl phosphine ligands (PX; X = O, NHC, S) with planar chirality for application in asymmetric catalysis, since chiral ligands based on ferrocene are well-established (e.g. Josiphos-type [3], Taniaphos [7], Fesulphos [8] and phosphine-oxazolines [9]). In particular, we have

**Dedication:** This article is dedicated to Richard D. Adams to honor his outstanding service as Editor-In-Chief of this journal

* Corresponding authors.

** Corresponding author at: IUT, Département de Chimie, 5 allée du Martinet 81100 Castres, France.

E-mail addresses: rinaldo.poli@lcc-tonouse.fr (R. Poli), eric.manoury@lcc-tonouse.fr (E. Manoury), eric.deydier@iut-tlse3.fr (E. Deydier).

<footnote><sup>a</sup> LCC-CNRS, Université de Toulouse, CNRS, UPS, INPT, Toulouse, France</footnote>

<footnote><sup>b</sup> Faculty of Medical Sciences, UM6P Hospitals, Mohammed VI Polytechnic University, Benguerir 43150, Morocco</footnote>

<footnote><sup>c</sup> Université de Toulouse, IUT, Département de Chimie, 5 allée du Martinet 81100 Castres, France</footnote>
obtained excellent results in the asymmetric hydrogenation of ketones (ee's up to 99.9 %) using complexes 1-R as precatalysts or alkenes (ee's up to 98 %) with the cationic precatalysts 1-R' (Scheme 1) [10].

One of our current objectives is to heterogenize this reaction in order to study the efficiency of the supported catalyst. We propose here to introduce a phenol group on the scaffold of the efficient bidentate P,S ferrocenyl phosphine ligands developed in the team. The advantage of the phenol function is that it allows producing, under mild conditions with a soft base, a phenolate anion capable of binding to a substrate (solid or molecule) presenting a carbon-LG bond (LG = leaving group) by nucleophilic substitution. This reaction leads to grafting through the formation of an ether function (Scheme 2), which is stable within a large spectrum of reaction conditions. It would be carried out on the thio-phosphine (P=S protected form of the ligand) to avoid any possible interference and/or oxidation that could happen with the free phosphine during grafting, followed by deprotection to restore the phosphine donor function. The substrate may be the surface of a solid support such as silica bearing functionalized alkyl chain (e.g. SiCH₂CH₂CH₂Br) or a polymerizable monomer, for instance p-ClCH₂C₆H₄CH=CH₂ which can be used to graft catalysts to polystyrene chains via co-polymerization with styrene. The latter strategy has successfully been used in our team to incorporate styryl triphenylphosphine in polystyrene chains that constitute the core of core-crosslinked micelles of spherical morphology and nanometric dimensions [11], used as catalytic nanoreactors in hydroformylation [11a–11c] and hydrogenation [11d,12] reactions under an aqueous biphasic approach.

We present here the synthesis and characterization of P,S ligands functionalized with (4-hydroxyphenyl) and (4-methoxyphenyl) groups. A catalytic study was carried out to assess the impact of the ether function on the activity and ee of the homogeneous asymmetric hydrogenation of acetophenone as a model substrate. The results of the present investigation are relevant in view of our planned grafting and heterogeneous catalysis investigations.

## 2. Results and discussion

### 2.1. Synthesis of functionalized chiral P,S ferrocenyl ligands

The synthesis of the target phenol-functionalized P,S ferrocenyl phosphine ligands (5) may be envisaged in a two-step process, as shown in Scheme 3. The starting planar-chiral ferrocenyl compound 2 can be prepared in multigram quantities and isolated as a racemic mixture or in a pure enantiomeric form, opening direct access to chiral heterodifunctional ligands [13]. The introduction of the thioether function is straightforward, via an efficient S<sub>N</sub>1 substitution of the OH group of 2 with a thiol, after activation with HBF<sub>4</sub> [14].

Two phenol-containing thiols have been chosen for this study (3a and 3b). Thiol 3a is commercially available, whereas 3b has been prepared using a synthetic strategy that was recently developed in our

group [15]. It is a two-step process starting from the corresponding alcohol, which is first transformed to a thioester by the addition of a catalytic amount of HBF<sub>4</sub> in thioacetic acid (CH<sub>3</sub>COSH) as solvent and the latter was then converted into the thiol by reduction (Scheme 4). The mechanistic study of the first step indicated a complex path, with thio-acetic acid disproportionation to acetic and dithioacetic in the reacting medium; this produced the ester intermediates, which eventually evolved to the desired thioester product. The generation of acetic acid by this disproportionation is the reason for the formation of the observed acetylated form of 3b as a by-product in small amounts, which could be converted to 3b' by hydrolysis under basic conditions. However, 3b' could also be converted to 3b during the second step of the synthesis. The second step is the conversion of the thioacetate 3b' into the expected thiol compound 3b, which has been accomplished with pyrrolidine [16]. This synthetic approach avoids phenol protection/deprotection step.

With both reagents 2 and 3 in hand, we could proceed to the synthesis of the phenol-functionalized and P=S-protected P,S ferrocenyl proligands 4a and 4b. The introduction of the thioether function is realized via an efficient S<sub>N</sub>1 substitution of the OH group of 2 with nucleophile, after activation with HBF<sub>4</sub>. Since the thiol function of compounds 3a and 3b is more nucleophilic than the phenol or alcohol functions, the expected 4a and 4b were obtained in good yields (72 and 65 % respectively) and perfect chemoselectivity after column purification with no need of phenol protection. These compounds will be used in future work for the catalyst grafting on silica surfaces. We envisage to graft the ligands by reaction of the phenol function with an alkyl halide grafted on the silica surface [17], yielding an ether linker (see Scheme 1).

In order to assess the influence of the ether group on catalysis, we synthesized model ligands with 4-methoxy groups instead of phenols (7a and 7b). Their synthesis was straightforward from intermediates 4a and 4b by deprotonation with NaH followed by quenching of the resulting phenolate with methyl iodide (see Scheme 3). The resulting compounds, 6a and 6b, were both characterized by multinuclear NMR and single-crystal X-ray diffraction (Fig. 2). The phosphine donor function was then deprotected in the final step in ca. 90 % yield in the presence of an excess of P(NMe<sub>2</sub>)<sub>3</sub> in refluxing toluene. The reaction is easily followed by <sup>31</sup>P NMR, as the thiophosphine (P=S) signals around 40 ppm shifts to -24 ppm for the free phosphine of ligands 7a and 7b. These ligands have been characterized by multinuclear NMR and by high-resolution MS, and have been used for the asymmetric hydrogenation of acetophenone.

The structures of (S)-4b, (R)-6a and (R)-6b are closely related, as shown in Tables 1 and 2. They are all built from ferrocene by 1,2-disubstitution of one Cp ring with a diphenyl phosphine sulfide group and an organic thioether chain. The absolute configuration is (S) for 4b and (R) for 6b and 6a, since the syntheses leading to the crystallized products were carried out from (S)-2 for the first compound and from (R)-2 for the

<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Examples of optically active pharmaceutical compounds.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**Scheme 1.** Asymmetric hydrogenation catalyzed with iridium complexes.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 2.** Immobilization strategy of chiral P,S ferrocenyl ligands.</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**Scheme 3.** Synthetic pathway to ligands 7.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Scheme 4.** Formation of intermediate 3b.</figcaption></figure>

In all structures, the P=S sulfur atom is located underneath the Cp ring (endo relative to the Fe center), whereas the thioether chain sulfur atom is either exo (in (S)-4b) or endo (in (R)-6a and (R)-6b) and

this seemingly affects the relative conformation of the Cp rings, which are nearly eclipsed in 4b and 6a (torsion angles of 11.03° and 7.35°, respectively) and staggered in (R)-6b (27.89°).
<figure><img src="image_8.png" /><figcaption>Fig. 2. ORTEP representations (S)-4b (left), (R)-6a (center) and (R)-6b (right). Ellipsoids are at the 30 % level.</figcaption></figure>

<table><caption>**Table 1**
Selected bond distances (10⁻¹⁰ m) and angles (°).</caption><thead><tr><th>Selected bond distances<sup>a</sup></th><th>(S)-4b</th><th>(R)-6a</th><th>(R)-6b</th></tr></thead><tbody><tr><td>Fe(1)-CoG(1)</td><td>1.6343(1)</td><td>1.6390(4)</td><td>1.6391(1)</td></tr><tr><td>Fe(1)-CoG(2)</td><td>1.6522(1)</td><td>1.6560(4)</td><td>1.6514(1)</td></tr><tr><td>S(1)-P(1)</td><td>1.9717(10)</td><td>1.9700(8)</td><td>1.9524(9)</td></tr><tr><td>S(2)-C(21)</td><td>1.826(3)</td><td>1.827(2)</td><td>1.800(3)</td></tr><tr><td>S(2)-C(22)</td><td>1.828(3)</td><td>1.780(2)</td><td>1.815(3)</td></tr><tr><td>C-O(1)</td><td>1.370(4)</td><td>1.374(3)</td><td>1.362(3)</td></tr><tr><td>O(1)—C(Me)</td><td></td><td>1.433(3)</td><td>1.420(4)</td></tr><tr><td>P(1)-C(1)</td><td>1.797(3)</td><td>1.799(2)</td><td>1.784(2)</td></tr><tr><td>P(1)-C(121)</td><td>1.817(3)</td><td>1.821(2)</td><td>1.805(2)</td></tr><tr><td>P(1)-C(111)</td><td>1.822(3)</td><td>1.821(2)</td><td>1.805(3)</td></tr><tr><td>C(2)-C(21)</td><td>1.500(4)</td><td>1.497(3)</td><td>1.488(3)</td></tr><tr><td>Cp(1)—C(21)</td><td>−0.0063 (51)</td><td>−0.0260 (36)</td><td>0.0967 (44)</td></tr><tr><td>Cp(1)—P(1)</td><td>0.1405 (44)</td><td>0.1110 (32)</td><td>0.0307 (38)</td></tr><tr><td>Cp(1)—S(1)</td><td>−1.0234 (59)</td><td>−0.5951 (45)</td><td>−1.3118 (51)</td></tr><tr><td>Cp(1)—S(2)</td><td>1.6676 (51)</td><td>1.5399 (38)</td><td>−0.6618 (48)</td></tr><tr><td><strong>Selected angles</strong></td><td><strong>(S)-4b</strong></td><td><strong>(R)-6a</strong></td><td><strong>(R)-6b</strong></td></tr><tr><td>CoG(1)-Fe(1)-CoG(2)</td><td>176.58(1)</td><td>176.86(1)</td><td>178.96(1)</td></tr><tr><td>C(1)-P(1)-C(121)</td><td>105.14(13)</td><td>103.87(10)</td><td>105.14(12)</td></tr><tr><td>C(1)-P(1)-C(111)</td><td>108.29(13)</td><td>103.99(10)</td><td>106.09(12)</td></tr><tr><td>C(121)-P(1)-C(111)</td><td>105.82(13)</td><td>107.19(10)</td><td>104.68(12)</td></tr><tr><td>C(1)-P(1)-S(1)</td><td>114.22(10)</td><td>116.84(7)</td><td>116.25(8)</td></tr><tr><td>C(121)-P(1)-S(1)</td><td>112.20(10)</td><td>111.68(7)</td><td>110.39(9)</td></tr><tr><td>C(111)-P(1)-S(1)</td><td>110.68(10)</td><td>112.41(7)</td><td>113.36(9)</td></tr><tr><td>C(21)-S(2)-C(22)</td><td>101.37(15)</td><td>104.76(10)</td><td>99.30(13)</td></tr><tr><td>C(2)-C(21)-S(2)</td><td>112.8(2)</td><td>113.33(14)</td><td>111.16(17)</td></tr><tr><td>C(5)-C(1)-P(1)</td><td>119.8(2)</td><td>123.38(15)</td><td>125.75(19)</td></tr><tr><td>C(2)-C(1)-P(1)</td><td>132.9(2)</td><td>129.26(16)</td><td>126.80(19)</td></tr><tr><td>C(1)-C(2)-C(21)</td><td>130.1(3)</td><td>127.19(19)</td><td>125.9(2)</td></tr></tbody></table>

## 2.2. Acetophenone asymmetric hydrogenation

Catalytic studies of the efficiency of ligands (R)-7a and (R)-7b in homogeneous asymmetric hydrogenation were realized with acetophenone as a model substrate. As these ligands are models of our target solid-supported ligands, which will eventually be obtained by grafting compounds 4 (Scheme 2) followed by phosphine deprotection, we have two major concerns. Does the introduction of the ether function alter the catalyst reactivity, relative to the previously investigated complexes 1-R under homogeneous conditions? Being inorganic solids such as silica sensitive to basic media, how does the base concentration affect the reaction?

### 2.2.1. Effect of base concentration on activity and enantioselectivity with ligand (R)-7a

The initial experiments were carried out with the less synthetically

<table><caption>**Table 2**
Crystal data for compounds (S)-4b, (R)-6a and (R)-6b.</caption><thead><tr><th>Identification code</th><th>(S)-4b</th><th>(R)-6a</th><th>(R)-6b</th></tr></thead><tbody><tr><td>Empirical formula</td><td>C<sub>30</sub>H<sub>27</sub>FeOPS<sub>2</sub></td><td>C<sub>30</sub>H<sub>27</sub>FeOPS<sub>2</sub></td><td>C<sub>31</sub>H<sub>29</sub>FeOPS<sub>2</sub></td></tr><tr><td>CCDC</td><td>2487745</td><td>2487746</td><td>2487747</td></tr><tr><td>Formula weight</td><td>554.45</td><td>554.45</td><td>568.48</td></tr><tr><td>Temperature, K</td><td>100.01(10)</td><td>110(2)</td><td>110(2)</td></tr><tr><td>Wavelength, Å</td><td>1.54184</td><td>0.71073</td><td>0.71073</td></tr><tr><td>Crystal system</td><td>Orthorhombic</td><td>Orthorhombic</td><td>Orthorhombic</td></tr><tr><td>Space group</td><td>P2<sub>1</sub>2<sub>1</sub>2<sub>1</sub></td><td>P2<sub>1</sub>2<sub>1</sub>2<sub>1</sub></td><td>P2<sub>1</sub>2<sub>1</sub>2<sub>1</sub></td></tr><tr><td>a, Å</td><td>9.2749(1)</td><td>8.7683(19)</td><td>9.0913(2)</td></tr><tr><td>b, Å</td><td>9.6974(1)</td><td>15.323(3)</td><td>14.4702(3)</td></tr><tr><td>c, Å</td><td>28.2391(2)</td><td>19.231(4)</td><td>19.8576(5)</td></tr><tr><td>α, °</td><td>90.0</td><td>90.0</td><td>90.0</td></tr><tr><td>β, °</td><td>90.0</td><td>90.0</td><td>90.0</td></tr><tr><td>γ, °</td><td>90.0</td><td>90.0</td><td>90.0</td></tr><tr><td>Volume, Å<sup>3</sup></td><td>2539.89(4)</td><td>2583.8(10)</td><td>2612.33(10)</td></tr><tr><td>Z</td><td>4</td><td>4</td><td>4</td></tr><tr><td>ρ (calc.). g.cm<sup>-3</sup></td><td>1.447</td><td>1.425</td><td>1.445</td></tr><tr><td>Abs. coefficient, mm<sup>-1</sup></td><td>7.061</td><td>0.830</td><td>0.822</td></tr><tr><td>F(000)</td><td>1148</td><td>1152</td><td>1184</td></tr><tr><td>Crystal size, mm<sup>3</sup></td><td>0.18 × 0.12 ×</td><td>0.150 × 0.080 ×</td><td>0.15 × 0.15 ×</td></tr><tr><td>Theta range, °</td><td>3.130 to 80.303</td><td>1.699 to 33.418</td><td>1.741 to 28.281</td></tr><tr><td>Reflections collected</td><td>30169</td><td>73645</td><td>120849</td></tr><tr><td>Indpt reflections (R<sub>int</sub>)</td><td>5532 (0.0351)</td><td>9713 (0.0704)</td><td>6468 (0.2654)</td></tr><tr><td>Absorption correction</td><td>Multi-scan</td><td>Multi-scan</td><td>Multi-scan</td></tr><tr><td>Max. / min. transmission</td><td>1.0 and 0.48748</td><td>0.7466 and 0.7063</td><td>0.7457 and 0.6874</td></tr><tr><td>Refinement method</td><td>F2</td><td>F2</td><td>F2</td></tr><tr><td>Data/restraints/ parameters</td><td>5532 / 0 / 316</td><td>9713 / 0 / 317</td><td>6468 / 0 / 326</td></tr><tr><td>Goodness-of-fit on F2</td><td>1.037</td><td>1.040</td><td>1.130</td></tr><tr><td>R1, wR2 (I > 2σ(I))</td><td>0.0289, 0.0757</td><td>0.0333, 0.0650</td><td>0.0315, 0.0790</td></tr><tr><td>R1, wR2 (all data)</td><td>0.0292, 0.0758</td><td>0.0460, 0.0693</td><td>0.0318, 0.0792</td></tr><tr><td>Flack's parameter</td><td>0.013(3)</td><td>-0.005(6)</td><td>0.012(6)</td></tr><tr><td>Residual density, e. Å<sup>-3</sup></td><td>0.420 / -0.311</td><td>0.411 / -0.314</td><td>0.397 / -0.533</td></tr></tbody></table>

demanding ligand (R)-7a. Acetophenone hydrogenation was run at room temperature, in isopropanol, under 30 bars of dihydrogen. The catalyst (0.2 mol %) was prepared *in situ* from (R)-7a and [IrCl(COD)]₂ in the presence of variable amounts of base (NaOMe). The conversion and ee were measured by chiral GC after 19 h. Fig. 3 shows that both conversion and ee dropped dramatically as the base concentration was increased. This suggests that the base may disturb ligand complexation, generating a less enantioselective catalyst or mixture of catalysts.

<footnote>ᵃ CoG(n) = center-of-gravity of the cyclopentadienyl ring n (C1-C5 for ring 1 and C6-C10 for ring 2).</footnote>
<figure><img src="image_9.png" /><figcaption>**Fig. 3.** Base concentration influence on both conversion and ee for the acetophenone asymmetric hydrogenation with *in-situ* generation of the catalyst (0.2 mol %) from $[\text{IrCl(COD)}]_2$ and ligand (R)-7a. Conditions: T = 25 °C; p(H₂ = 30 bars); 19 h.</figcaption></figure>

In order to confirm this hypothesis, a second set of reactions was carried out with the synthesized pre-catalyst (R)-8a, which was prepared by addition of two equivalent of (R)-7a to $[\text{IrCl(COD)}]_2$ in dichloromethane solution. The complex precipitated after hexane addition and was obtained as a yellow air sensitive solid. It was characterized by multinuclear NMR and high-resolution mass spectroscopy. Coordination of the phosphine ligand to Ir is clearly confirmed by phosphorus NMR shift from -24.0 ppm for the free ligand to -4.3 for (R)-8a. Fig. 4 shows the evolution of conversion and ee as a function of the base amount. In this case, the ee was essentially invariant (around 35 %, slightly lower than that observed using 1-Ph [10a]), suggesting that the catalyst remained unchanged and stable in the presence of the base. However, the conversion increased dramatically from 22 to 82 % upon increasing the NaOMe amount, illustrating its active role in the reaction mechanism.

These observations agree with previously published computational mechanistic studies [18]. Indeed, these investigations suggested that a base is necessary to generate the more active anionic tetrahydrido complex $[\text{IrH}_4(\text{P,S})]^{-}$, which leads to an operating cycle via a $[\text{Na}^+(\text{MeOH})_n \cdots \text{IrH}_4(\text{PS})^{-}]$ contact ion pair (MeOH was used as a solvent model).

<figure><img src="image_10.png" /><figcaption>**Fig. 4.** Base concentration influence on both conversion and ee of acetophenone asymmetric hydrogenation with 0.2 mol % of pre-catalyst complex (R)-8a. Conditions: T = 25 °C; p(H₂ = 30 bars); 4 h.</figcaption></figure>

### 2.2.2. Asymmetric hydrogenation with ligand (R)-7b

Finally, we investigated the hydrogenation of acetophenone using ligand (R)-7b. Indeed, (R)-7a and (R)-7b are the MeO-substituted versions of the 1-Ph and 1-Bn ligands, respectively, of the previously used precatalysts (Scheme 1) [10a]. The pre-catalyst (R)-8b was thus prepared with the same protocol used to synthesize complex (R)-8a. The acetophenone hydrogenation reaction was run at 21 °C, initially with five equivalents of base (same amount used in the published report) [10a].

Complex (R)-8b led to the production of phenylethanol with the same ee (around 78 %) as the analogous catalyst 1-Bn. The acetophenone conversion (35 % after 2 h and 87 % after 5 h, see Fig. 5), on the other hand, was lower, under our experimental conditions, than that reported for 1-Bn (99 % after 2 h) with 2 mol % catalyst loading. Moreover, as previously observed for the complexes with non-methoxylated ligands (1-Bn and 1-Ph) [11a], 8b gives a higher ee than the aryl analog 8a.

## 3. Conclusions

We have reported herein the synthesis of functionalized P,S ferrocenyl phosphine with a phenol function, with the perspective of catalyst grafting. The ligands bearing methoxy group in the 4 position, the simplest possible models of the ether function in the target grafted version, were evaluated for the asymmetric hydrogenation of acetophenone in a homogeneous phase using different base concentrations. The results showed that the activity and enantioselectivity of the *in-situ* catalyst are both negatively affected by the base. When the reaction was carried out with the isolated pre-catalysts, on the other hand, good catalytic activities and enantiomeric excesses similar to the ones obtained with ligand analogues without methoxy substituent, were observed confirming catalyst stability. The phenol-functionalized ligands synthetized in this paper are then suitable candidates for catalyst grafting.

## 4. Experimental procedures

### 4.1. General considerations

Unless otherwise stated, all manipulations were carried out under argon using glove box and Schlenk tube techniques. Solvents for syntheses were dried and degassed by standard methods before use. 1D- and 2D-NMR spectra were recorded with Bruker Avance 300 and 400 spectrometers. ¹H and ¹³C chemical shifts (δ) are given in ppm. Peaks are labelled as singlet (s), doublet (d), triplet (t), multiplet (m) and broad

<figure><img src="image_11.png" /><figcaption>**Fig. 5.** Base concentration influence on both conversion and ee of the acetophenone asymmetric hydrogenation with 0.2 mol % of complex (R)-8b Conditions: T = 21 °C; p(H₂) = 30 bar; base 5 equiv.</figcaption></figure>
(br). The proton and carbon assignments were performed using COSY, HSQC, HMBC 2D experiments. MS spectra were recorded on a Waters Exo G2 Q TOF instrument. Gas chromatographic analyses were carried out with a Perkin Elmer Clarus 480 instrument using a COL-Velocity-1 column. Abbreviations: CpA = substituent Cp; CpB = unsubstituted Cp; Fc = ferrocenyl; Cq = quaternary carbon.

## 4.2. Synthesis and characterization of compound 3b

2-Thiodiphenylphosphino(hydroxymethyl)ferrocene (2) was prepared in multigram quantities in racemic and enantiopure forms according previous published strategy [13].

### 4.2.1. Synthesis and characterization of compound 3b' and 3b''

To a solution of 4-hydroxybenzyl alcohol (300 mg, 2.42 mmol, 1.0 equiv.) in thioacetic acid (3 mL), tetrafluoroboric acid (54 % w/w solution in diethyl ether; 0.05 mL, 0.36 mmol, 0.15 equiv.) was added. The reaction mixture was stirred for 3 h at room temperature. Upon completion, the excess thioacetic acid was removed under vacuum. The crude residue was purified by silica gel column chromatography using n-hexane/ethyl acetate (80/20) as the eluent to afford two fractions. The desired product, 3b', was recovered from the second fraction as a pale-yellow oil in 70 % yield. ¹H NMR (400 MHz, 298 K, CDCl₃) δ (ppm): 7.16 (d, JHH = 8.7 Hz, 2H, -C₆H₄-O-), 6.80 (d, JHH = 8.7 Hz, 2H, -C₆H₄-O-), 6.72-6.16 (br s, 1H, OH), 4.09 (s, 2H, CH₂), 2.37 (s, 3H, CH₃). ¹³C NMR {¹H} (101 MHz, 298 K, CDCl₃) δ (ppm): 197.38 (s, CO), 155.12 (s, Cq -C₆H₄-O-), 130.20 (s, -C₆H₄-O-), 129.15 (s, -C₆H₄-O-), 115.65 (s, -C₆H₄-O-), 33.20 (s, CH₂), 30.41 (s, CH₃). HR/MS (DCI-CH₄): C₉H₁₁O₂S ([M+H]⁺) 183.0487 (calcd 183.0480). The first eluting fraction corresponded to compound 3b'', which was isolated as a reddish-brown oil in 29 % yield. ¹H NMR (400 MHz, 298 K, CDCl₃) δ (ppm): δ 7.28 (d, JHH = 8.7 Hz, 2H -C₆H₄-), 6.98 (d, JHH = 8.7 Hz, 2H -C₆H₄-), 4.10 (s, 2H, CH₂), 2.34 (s, 3H, CH₃), 2.28 (s, 3H, CH₃). ¹³C NMR {¹H} (75 MHz, 298 K, CDCl₃) δ (ppm): 194.91 (s, -S-C=O), 169.34 (s, -O-C=O), 149.78 (s, Cq -C₆H₄-), 135.28 (s, CH-C₆H₄), 129.90 (s, Cq -C₆H₄-), 121.71 (s, -C-C₆H₄-), 32.79 (s, CH₂), 30.32 (s, CH₃), 21.09 (s, CH₃).

### 4.2.2. Synthesis and characterization of compound 3b

In a Schlenk tube under argon, degassed pyrrolidine (0.901 mL, 10.99 mmol, 2 equiv.) was added dropwise into a dry THF (6 mL) solution of 4-hydroxybenzyl thioacetate 3b' (1 g, 5.50 mmol, 1 equiv.) with steady magnetic stirring at RT. The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (dichloromethane/ethyl acetate 90/10). Compound 3b was obtained as a colorless oil in 70 % yield. ¹H NMR (400 MHz, 298 K, CDCl₃) δ (ppm): 7.21 (d, $^{3}$JHH = 8.5 Hz, 2H, -C₆H₄-O-), 6.80 (d, $^{3}$JHH = 8.5 Hz, 2H, -C₆H₄-O-), 3.72 (d, $^{3}$JHH = 7.4 Hz, 2H, CH₂), 1.78 (t, $^{3}$JHH = 7.3 Hz, 1H, SH). ¹³C{¹H} NMR (101 MHz, 298 K, CDCl₃) δ (ppm): 154.54 (s, Cq -C₆H₄-O-), 133.35 (s, Cq -C₆H₄-O-), 129.37 (s, -C₆H₄-O-), 115.55 (s, -C₆H₄-O-), 28.38 (s, CH₂). HR/MS (DCI-CH₄): C₇H₉OS ([M+H]⁺) 141.0380 (calcd 141.0374).

### 4.2.3. Synthesis and characterization of compound 4a

(2-Diphenylthiophosphinoferrocenyl) methanol, 2, (250 mg, 0.578 mmol) was dissolved in freshly distilled dichloromethane (5 mL) in a Schlenk flask. To this solution, tetrafluoroboric acid, 54 % w/w in diethyl ether, (248 µL, 1.79 mmol, 3 equiv.) was added under argon. The reaction mixture was stirred for 1 min, and then 4-hydroxyphenylthiol 3a (5 equiv.) was added. The resulting mixture was stirred for an additional 5 min. The crude reaction mixture was then filtered through a plug of silica. After solvent evaporation, the organic phase was washed several times with 20 mL of 2 M NaOH, then dried over Na₂SO₄. After solvent removal under vacuum, the crude product was purified by column chromatography on silica gel using pentane then dichloromethane as eluents. Compound 4a was obtained as a yellow solid in 80 % yield.

¹H NMR (300 MHz, 298 K, CDCl₃) δ (ppm) 7.87-7.80 (m, 2H, PPh₂), 7.72-7.66 (m, 2H, PPh₂), 7.59-7.35 (m, 6H, PPh₂), 7.15 (d(AB), JHH = 8.1 Hz, 2H, -C₆H₄-O-), 6.72 (d(AB), JHH = 8.1 Hz, 2H, -C₆H₄-O-), 5.25 (s, 1H, OH), 4.39 (m, 3H, CH₂S and CpB), 4.35-4.23 (m, 6H, 1H CpA and 5H CpB), 4.13 (d(AB), JHH = 13.5 Hz, 1H, CH₂S), 3.80 (s, 1H, CpB). ¹³C{¹H} NMR (101 MHz, 298 K, CDCl₃) δ (ppm): 155.5 (s, Cq SAr), 134.8 (d, JPC = 83 Hz, Cq Ar), 134.3 (s, SAr), 133.8 (d, JPC = 90 Hz, Cq Ar), 132.6 (d, JPC = 10.7 Hz, Ar), 132.5 (d, JPC = 10.8 Hz, Ar), 131.7 (d, JPC = 2.7 Hz, 2 C Ar), 128.6 (d, JPC = 14.5 Hz, Ar), 128.5 (d, JPC = 14.3 Hz, Ar), 127.3 (s, Cq SAr), 116.3 (s, SAr), 88.6 (d, JPC = 12.0 Hz, Cq CpA), 75.0 (d, JPC = 12.5 Hz, CpA), 74.2 (d, JPC = 9.2 Hz, CpA), 74.0 (d, JPC = 95.2 Hz, Cq CpA), 71.3 (s, CpB), 69.5 (d, JPC = 10.4 Hz, CpA); 35.5 (s, CH₂). ³¹P NMR (121 MHz, 298 K, CDCl₃) δ (ppm): 41.7. HR/MS (DCI-CH₄): C₂₉H₂₅OPS₂Fe ([M+H]⁺) 540.0423 (calcd 540.0434).

### 4.2.4. Synthesis and characterization of compound 4b

The same procedure described above for the 4a synthesis was used with 3b, giving compound 4b as a yellow solid in 65 % yield. ¹H NMR (400 MHz, 298 K, acetone-d₆) δ (ppm): 8.28 (s, 1H, OH), 7.94-7.83 (m, 2H, PPh₂), 7.76-7.65 (m, 2H, PPh₂), 7.64-7.40 (m, 6H, PPh₂), 7.07-6.99 (m, 2H, -C₆H₄-O-), 6.80-6.72 (m, 2H, -C₆H₄-O-), 4.61 (q, JHH = 1.7 Hz, 1H, CpA), 4.40 (q, JHH = 2.4 Hz, 1H, CpA), 4.29 (s, 5H, CpB), 4.20 (d(AB), JHH = 13.8 Hz, 1H, CH₂S), 3.84 (q, J = 2.2 Hz, 1H, CpA), 3.74 (d(AB), JHH = 13.8 Hz, 1H, CH₂S), 3.49 (s, 2H, SCH₂). ³¹P NMR (162 MHz, 298 K, acetone-d₆) δ (ppm): 40.93. ¹³C{¹H} NMR (101 MHz, 298 K, acetone-d₆) δ (ppm): 156.24 (s, Cq Ar-OH), 135.14 (d, JPC = 87.1 Hz, Cq PPh₂), 133.89 (d, JPC = 85.9 Hz, Cq PPh₂), 132.26-131.81 (m, 4CH PPh₂), 131.34 (d, JPC = 2.9 Hz, 2CH PPh₂), 131.20 (d, JPC = 2.9 Hz, 2CH PPh₂), 130.01 (s, 2CH -C₆H₄-O-), 129.20 (s, Cq -C₆H₄-O-), 128.15 (d, JPC = 5.6 Hz, CH PPh₂), 128.03 (d, JPC = 5.2 Hz, CH PPh₂), 115.11 (s, 2CH C₆H₄-O-), 90.27 (d, JPC = 12.1 Hz, Cq CpA), 74.62 (d, JPC = 12.4 Hz, CH CpA), 73.96 (d, JPC = 9.3 Hz, CH CpA), 73.40 (d, JPC = 95.1 Hz, Cq CpA), 70.79 (s, CH CpB), 69.24 (d, JPC = 10.3 Hz, CH CpA), 35.96 (s, CH₂S), 29.85 (s, CpA-CH₂S). HR/MS (DCI-CH₄): C₃₀H₂₇OPS₂Fe ([M+H]⁺) 554.0583 (calcd 554.0590).

### 4.2.5. Synthesis and characterization of compound 6a

Compound 4a (200 mg, 0.370 mmol) was mixed with NaH (0.74 mmol) in freshly distilled THF (5 mL) in a Schlenk flask. The reaction mixture was stirred for 30 min at room temperature and then an excess of MeI (6 eq.) was added. When the reaction was completed (monitored by TLC), 5 mL of water were added and the reaction mixture was extracted with dichloromethane and purified by silica column chromatography with a pentane/ether mixture (70/30) as eluent. 6a was obtained as a yellow solid in 80 % yield. ¹H NMR (400 MHz, 298 K, acetone-d₆) δ (ppm): 8.01-7.82 (m, 2H, PPh₂), 7.80-7.65 (m, 2H, PPh₂), 7.66-7.39 (m, 6H, PPh₂), 7.22 (d(AB), JHH = 8.8 Hz, 2H, -C₆H₄-O-), 6.85 (d(AB), JHH = 8.8 Hz, 2H, -C₆H₄-O-), 4.62 (d, JHH = 13.4 Hz, 1H, CpA-CH₂S), 4.38 (s, 1H, CpA), 4.35-4.32 (s, 1H, Cq), 4.30 (s, 5H, 5CH CpB), 4.14 (d, JHH = 13.4 Hz, 1H, CpA), 3.90-3.82 (s, 1H, CpA), 3.78 (s, 3H, OCH₃). ³¹P NMR (162 MHz, 298 K, acetone-d₆) δ (ppm): 40.77. ¹³C NMR (101 MHz, 298 K, acetone-d₆) δ (ppm): 159.18 (s, Cq Ar-OMe), 135.09 (d, JPC = 87.2 Hz, Cq PPh₂), 133.83 (d, JPC = 85.9 Hz, Cq PPh₂), 133.64 (s, 2CH C₆H₄-O-), 132.08 (d, JPC = 10.6 Hz, CH PPh₂), 131.35 (d, JPC = 2.9 Hz, CH PPh₂), 131.22 (d, JPC = 2.9 Hz, CH PPh₂), 130.4 (s, Cq C₆H₄-O-), 128.13 (d, JPC = 3.2 Hz, CH PPh₂), 128.01 (d, JPC = 3.0 Hz, CH PPh₂), 114.40 (s, 2CH C₆H₄-O-), 89.35 (d, JPC = 12.1 Hz, Cq CpA), 74.55 (d, JPC = 12.3 Hz, CH CpA), 74.02 (d, JPC = 9.3 Hz, CH CpA), 73.47 (d, JPC = 95.0 Hz, Cq CpA), 70.78 (s, 5CH CpB), 69.21 (d, JPC = 10.3 Hz, CH CpA), 54.78(s, OCH₃), 34.74(s, CpA-CH₂S).

### 4.2.6. Synthesis and characterization of compound 6b

The same procedure described above for the synthesis of 6a was used with 4b, giving 6b as a yellow solid in 75 % yield. ¹H NMR (400 MHz, 298 K, acetone-d₆) δ (ppm): 7.96-7.78 (m, 2H, PPh₂), 7.75-7.65 (m, 2H, PPh₂), 7.65-7.38 (m, 6H, PPh₂), 7.11 (d(AB), J = 8.5 Hz, 2H, -C₆H₄-O-),
6.82 (d(AB), J = 8.5 Hz, 2H, -C₆H₄-O-), 4.62 (s, 1H, Cp^A), 4.42 (s, 1H, Cp^A), 4.30 (s, 5H, Cp^B), 4.19 (d, JHH = 13.8 Hz, 1H, CH₂-S), 3.85 (s, 1H, Cp^A), 3.77 (s, 3H, OCH₃), 3.74 (d, JHH = 13.8 Hz, 1H, Cp^A-CH₂-S), 3.52 (s, 2H, S-CH₂-). ³¹P NMR (162 MHz, 298 K, acetone-d₆) δ (ppm): 40.88. ¹³C NMR (101 MHz, 298 K, acetone-d₆) δ (ppm): 158.69 (s, Cq Ar-OMe), 135.17 (d, JPC = 87.1 Hz, Cq PPh₂), 133.93 (d, JPC = 85.8 Hz, Cq PPh₂), 132.05 (d, JPC = 10.8 Hz, CH PPh₂), 131.95 (d, JPC = 10.8 Hz, CH PPh₂), 131.28 (d, JPC = 2.9 Hz, CH PPh₂), 131.16 (d, JPC = 3.0 Hz, CH PPh₂), 130.44 (s, Cq Ar), 129.88 (s, Cq Ar), 128.09 (d, JPC = 6.5 Hz, CH PPh₂), 127.97 (d, JPC = 6.3 Hz, CH PPh₂), 113.62 (s, CH-C₆H₄-O), 90.15 (d, JPC = 11.7 Hz, Cq Cp^A), 74.56 (d, JPC = 12.4 Hz, CH Cp^A), 73.87 (d, JPC = 9.3 Hz, CH Cp^A), 73.48 (d, JPC = 95.4 Hz, Cq Cp^A), 70.72 (s, CH Cp^B), 69.14 (d, JPC = 10.4 Hz, CH Cp^A), 54.61 (s, OCH₃), 35.80 (s, S-CH₂), 29.84 (s, Cp^A-CH₂-S).

### 4.2.7. Synthesis and characterization of compound 7a

Compound 6a was dissolved in a mixture of tris(dimethylamino) phosphine (2.5 mL, excess) and toluene (5 mL). The reaction mixture was heated to 100 °C for 24 h. The solvent was removed under vacuum and the remaining residue was dissolved in a mixture of dichloromethane/pentane (70/30) and purified by silica column chromatography. Compound 7a was obtained as a yellow solid in 91 % yield. ¹H NMR (400 MHz, 298 K, CDCl₃) δ (ppm): 7.67-7.57 (m, 2H, PPh₂), 7.47-7.37 (m, 3H PPh₂), 7.34-7.20 (m, 7H, 5H PPh₂ and 2H -C₆H₄-O-), 6.82 (pseudo d, JHH = 8.6 Hz, 2H -C₆H₄-O-), 4.44-4.34 (m, 1H, Cp^A), 4.34-4.18 (m, 1H, Cp^A), 4.10-4.06 (m, 2H, CH₂), 4.03 (s, 5H, Cp^B), 3.87-3.83 (m, 1H, Cp^A), 3.81 (s, 3H, CH₃). ³¹P NMR (162 MHz, 298 K, CDCl₃) δ (ppm): -24.0. ¹³C NMR (101 MHz, 298 K, CDCl₃) δ (ppm): 158.92 (s, Cq-C₆H₄-O-), 139.83 (d, JPC = 8.8 Hz, Cq PPh₂), 137.68 (d, JPC = 8.2 Hz, Cq PPh₂), 135.14 (d, JPC = 21.2 Hz, CH PPh₂), 133.68 (s, CH -C₆H₄-O-), 132.46 (d, JPC = 17.7 Hz, CH PPh₂), 129.16 (s, CH PPh₂), 128.14 (d, JPC = 7.9 Hz, CH PPh₂), 127.93 (d, JPC = 9.5 Hz, CH PPh₂), 127.75 (s, CH PPh₂), 127.21(s, Cq -C₆H₄-O-), 114.36 (s, CH -C₆H₄-O-), 90.41 (d, JPC = 25.7 Hz, Cq Cp^A), 75.76 (d, JPC = 7.9 Hz, Cq Cp^A), 71.64 (d, JPC = 3.6 Hz, CH Cp^A), 71.38 (d, JPC = 3.8 Hz, CH Cp^A), 69.80 (s, CH Cp^A), 69.49 (s, 5CH Cp^B), 55.30 (s, CH₃), 35.94 (d, JPC = 12.1 Hz, Cp^A-CH₂S). HR/MS (DCI-CH₄): C₃₀H₂₇OPSFe ([M+H]⁺) 522.0878 (calcd 522.0870).

### 4.2.8. Synthesis and characterization of compound 7b

The same procedure described above for the synthesis of 7a was used with 6b, giving 7b as a yellow solid in 89 % yield. ¹H NMR (400 MHz, 298 K, CDCl₃) δ (ppm): 7.65-7.57 (m, 2H, PPh₂), 7.45-7.38 (m, 3H, PPh₂), 7.30-7.19 (m, 5H, PPh₂), 7.15 (pseudo d, JHH = 8.7 Hz, 2H -C₆H₄-O-), 6.84 (pseudo d, JHH = 8.7 Hz, 2H, -C₆H₄-O-), 4.49 (m, 1H, Cp^A), 4.32 (m, 1H, Cp^A), 4.02 (s, 5H, Cp^B), 3.85 (m, 1H, Cp^A), 3.83 (s, 3H, CH₃) 3.70 (d (AB), JHH = 13.5 Hz, 1H, CH₂), 3.66 (d (AB), JHH = 13.5 Hz, 1H, CH₂), 3.57 (s, 2H, CH₂). ³¹P NMR (162 MHz, 298 K, CDCl₃) δ (ppm): -24.0. ¹³C NMR (101 MHz, 298 K, CDCl₃) δ (ppm): 158.51 (s, Cq-C₆H₄-O-), 140.03 (d, JPC = 9.2 Hz, Cq PPh₂), 137.74 (d, JPC = 8.4 Hz, Cq PPh₂), 135.20 (d, JPC = 21.5 Hz, CH PPh₂), 132.45 (d, JPC = 18.0 Hz, CH PPh₂), 130.36 (s, Cq-C₆H₄-O-), 129.92 (s, CH -C₆H₄-O-), 129.14 (s, CH PPh₂), 128.14 (d, JPC = 8.1 Hz, CH PPh₂), 127.96 (d, JPC = 6.1 Hz, CH PPh₂), 127.77 (s, CH PPh₂), 113.81 (s, CH -C₆H₄-O-), 90.94 (d, JPC = 26.1 Hz, Cq Cp^A), 75.68 (d, JPC = 8.1 Hz, Cq Cp^A), 71.69 (d, JPC = 3.8 Hz, CH Cp^A), 71.45 (d, JPC = 4.2 Hz, CH Cp^A), 69.84 (s, 5CH Cp^B), 69.43 (s, 1H Cp^A), 55.30 (s, CH₃), 36.41 (s, -S-CH₂-), 30.66 (d, JPC = 11.4 Hz, Cp^A-CH₂-S). HR/MS (DCI-CH₄): C₃₁H₂₉OPSFe ([M+H]⁺) 536.1041 (calcd 536.1026).

### 4.2.9. Synthesis and characterization of compound (8a)

In a Schlenk tube ligand 7a (0.155 mmol), dichloromethane (3 mL) and [Ir(COD)Cl]₂ (52 mg, 0.077 mmol) were introduced. The reaction was stirred for 30 min before addition of pentane (30 mL). The yellow precipitate of the product was recovered by filtration and dried under vacuum (95 % yield). ¹H NMR (400 MHz, 298 K, CDCl₃) δ (ppm):

8.39-8.03 (br s, 2H, PPh₂), 7.89 (d, JHH = 8.3 Hz, 2H, -C₆H₄-O-), 7.72-7.50 (m, 3H, PPh₂), 7.44-7.12 (m, 5H, PPh₂), 6.97 (d, JHH = 8.3 Hz, 2H, -C₆H₄-O-), 5.06 (d (AB syst.), JHH = 12.2 Hz, 1H, Cp^A-CH₂), 4.54 (br s, 1H, Cp^A), 4.30 (br s, 1H, Cp^A), 4.14 (d (AB syst.), JHH = 12.2 Hz, 1H, Cp^A-CH₂), 4.08 (br s, 1H, Cp^A), 4.00 (s, 5H, Cp^B), 3.86 (s, 3H, OCH₃), 3.61-3.36 (m, 2H, COD), 3.33-3.10 (m, 2H, COD), 2.69-2.55 (m, 2H, COD), 2.31-1.90 (m, 4H, COD), 1.47-1.35 (m, 2H, CH₂ COD). ³¹P NMR (162 MHz, CDCl₃) δ (ppm): -4.3. HR/MS (ES+): C₃₈H₃₉OPS⁵⁶Fe¹⁹³Ir (M⁺-Cl) 823.1443 (calcd 823.1438).

### 4.2.10. Synthesis and characterization of compound 8b

The same procedure described above for the synthesis of 8a was used with 7b, giving complex 8b as a yellow solid in 91 % yield. ¹H NMR (400 MHz, 298 K, CDCl₃) δ (ppm): 8.22 (br s, 2H, PPh₂), 7.72-7.52 (m, 3H, PPh₂), 7.34 (d, JHH = 8.3 Hz, 2H, -C₆H₄-O-), 7.30-7.24 (m, 3H, PPh₂), 7.11-6.99 (m, 2H, PPh₂), 6.93 (d, JHH = 8.2 Hz, 2H, -C₆H₄-O-), 4.55 (d (AB syst.), JHH = 12.3 Hz, 1H, Cp^A-CH₂), 4.33 (br s, 1H, Cp^A), 4.20-4.08 (m, 2H, 1H of CH₂-S and Cp^A), 4.02 (d (AB syst.), JHH = 13.5 Hz, 1H, CH₂-S), 3.95 (br s, 1H, Cp^A), 3.86 (s, 3H, OCH₃), 3.77 (s, 5H, Cp^B), 3.72-3.63 (m, 4H, COD), 3.49 (d (AB syst.), JHH = 12.3 Hz, 1H, Cp^A-CH₂), 2.79-2.64 (m, 2H, COD), 2.20-2.06 (m, 4H, COD), 1.50-1.44 (m, 2H, COD). ³¹P NMR (162 MHz, 298 K, CDCl₃) δ (ppm): -6.7. HR/MS (ES+): C₃₉H₄₁OPS⁵⁶Fe¹⁹³Ir (M⁺-Cl) 837.1604 (calcd 837.1594).

### 4.3. Acetophenone asymmetric hydrogenation

In a glove box, 6.4·10⁻³ mmol of pre-catalyst (or a mixture of 6.4·10⁻³ mmol of [IrCl(COD)]₂with 12.8·10⁻³ mmol of P,S ligand), 3.2·10⁻² mmol of MeONa (5 equiv.) and 3.2 mmol of acetophenone (500 equiv.) were dissolved in 2 mL of dry isopropanol. The reaction mixture was transferred into an autoclave and pressurized to 30 bars with dihydrogen. The reaction was stirred and maintained at room temperature for a few hours. After pressure release, the mixture was filtered on silica and analyzed with a chiral GC.

### 4.4. X-ray structural analyses

A single crystal of each compound was mounted under inert perfluoropolyether on the tip of a glass fiber and cooled in the cryostream of either a Rigaku Oxford-Diffraction XCALIBUR Eos Gemini Ultra for 4a or a Bruker APEXII diffractometer for 6a and 6b. The structures were solved by using the integrated space-group and crystal structure determination SHELXT [19] software and refined by least-squares procedures on F² using SHELXL-2014 [20]. All H atoms bonded to carbon atoms were introduced in the calculation at idealized positions and treated as riding atoms. The H atoms bonded to oxygen atoms were located on difference Fourier synthesis maps and their coordinates and Uiso were refined using restraints. The absolute configurations for the three compounds were obtained by refining the Flack parameter [21]. The drawings of the molecules (Fig. 1) were realized with the help of ORTEP32 [22]. Crystal data and refinement parameters are shown in Table 1. Crystallographic data for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication: deposition Number 2487745-2487746-2487747. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK [Fax: int. Code +44(1223)336-033; E-mail: deposit@ccdc.cam.ac.uk].

### CCrediT authorship contribution statement

**Abdelhak Lachguar:** Investigation. **Shagun Chhetri:** Investigation.
**Ahmad Joumaa:** Investigation. **Jean-Claude Daran:** Investigation.
**Formal analysis. Rinaldo Poli:** Writing – review & editing. **Eric Manoury:** Writing – review & editing, Supervision, Data curation, Conceptualization. **Eric Deydier:** Writing – original draft, Supervision, Funding acquisition, Data curation, Conceptualization.
Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We thank the CNRS, the Region Occitanie, the IUT Paul Sabatier and the Syndicat Mixte de Castres (Ph.D. grant to A. Lachguar) for financial support. We thank the “Agence Nationale de la recherche” (Contract ANR- 279498, Flownanocat) for financial support to Shagun Chhetri.

Supplementary materials

Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jorganchem.2026.124049.

Data availability

Data will be made available on request.

References

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