# Asymmetric Hydrosilylation of Ketones Catalyzed by Diaminocyclohexane/Zinc Complexes: A Comparative Study and Mechanistic Insight

Caitlyn Dussart, Joseph El Khoury, Aline Maisse-françois, Christophe Gourlaouen, Stéphane Bellemin-laponnaz

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Caitlyn Dussart, Joseph El Khoury, Aline Maisse-françois, Christophe Gourlaouen, Stéphane Bellemin-laponnaz. Asymmetric Hydrosilylation of Ketones Catalyzed by Diaminocyclohexane/Zinc Complexes: A Comparative Study and Mechanistic Insight. European Journal of Organic Chemistry, 2025, 28 (39), 10.1002/ejoc.202500677. [https://hal-05374265](https://hal-05374265)

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# Asymmetric Hydrosilylation of Ketones Catalyzed by Diaminocyclohexane/Zinc Complexes: A Comparative Study and Mechanistic Insight

Caitlyn Dussart, Joseph El Khoury, Aline Maisse-François, Christophe Gourlaouen, and Stéphane Bellemin-Laponnaz*

The catalytic enantioselective hydrosilylation activity of zinc is investigated in the presence of two ligands derived from cyclohexane-1,2-diamine: N,N'-dibenzylcyclohexane-1,2-diamine (1) and a cage-like structure composed of six cyclohexane-1, 2-diamine units (2). The reaction proceeds rapidly, achieving complete conversion within minutes and affording alcohol products with enantiomeric excesses of up to 94%. Despite the favorable

results with the cage-like ligand (2), no significant advantage over ligand (1) is observed. In a second part, to gain insight into the reaction mechanism, various mechanistic experiments are conducted alongside density functional theory calculations. The findings suggest that ligand-selective silylation leads to the formation of a zinc hydride species, which is likely the active catalytic intermediate in this system.

## 1. Introduction

Asymmetric hydrosilylation of carbonyl compounds provides an efficient route to chiral secondary alcohols through the intermediate formation of alkoxysilanes. This method, first introduced by Ojima in 1972 using rhodium complexes,[1] remains a fast and effective strategy for synthesizing chiral alcohol building blocks. Building on the development of chiral rhodium catalysts, researchers have expanded this approach to include asymmetric reductions of carbonyl groups using various noble and rare metals such as tungsten (W), molybdenum (Mo), rhenium (Re), and ruthenium (Ru).[2] In recent years, increasing attention has been directed toward first-row transition metals as more sustainable and robust catalytic alternatives. As a result, metals like titanium, iron, cobalt, copper, and especially zinc have been successfully employed in the asymmetric reduction of ketones.[2,3] The first outstanding example of enantioselective Zn-catalyzed hydrosilylation was published by

Mimoun et al. in the late 90s and showed good enantioselectivities toward aryl ketones.[4] Following on from the study of chiral nitrogen ligands, other groups have used a similar approach to explore the efficiency of chiral diamines, mainly around chiral structures such as diphenylethylenediamine and diaminocyclohexane. Two main procedures have emerged for zinc catalysis: a two-step method with the formation of an alkoxysilane in an aprotic solvent, followed by its hydrolysis,[4-6] or a one-step procedure in protic solvent, with the direct formation of the chiral alcohol.[7-9]

Zinc-catalyzed hydrosilylation has been the subject of numerous mechanistic studies and several catalytic schemes have been proposed. It is interesting to note that no single mechanism has emerged, which seems to be the same situation as with rhodium, where three types of mechanism can be discerned depending on salt precursor, silane, ligand or experimental conditions.[10-13] Despite the diversity of studies, no single, clear mechanism has been established for either method. For the two-step method, Mimoun et al. suggested three possible mechanisms, either by hydrogen transfer from a Zn-H species or via a seven-membered intermediate ring by insertion of the ketone into the metal-ligand bond. Gawronski et al. have also proposed a mechanism involving a Zn-H species that reacts directly with the ketone, activated by hydrogen bonding with the ligand (i.e., through the formation of NH···O=C hydrogen bond).[14] For zinc-catalyzed hydrosilylation assisted by alcohol activators, Carpentier et al. presented a mechanism based on the Zn-H intermediate.[8] Additionally, Mikami[9] and Gawronki[15] have shown the positive catalytic impact of the presence of a diol as an additive in the zinc-catalyzed reaction. Mikami and his coworkers proposed a concerted 6-membered-ring mechanism, with the cooperation of the silane, the zinc-diol-diamine catalyst and the ketone, without the formation of a zinc hydride intermediate. Also, Gawronski's density functional theory (DFT) calculations suggested that the Zn-H species is the key intermediate.[15]

C. Dussart, J. El Khoury, A. Maisse-François, S. Bellemin-Laponnaz

IPCMS, DMO

Université de Strasbourg

CNRS-UMR7504

23 rue du Loess, Strasbourg 2 BP 43 67034, Cedex, France

E-mail: bellemin@unistra.fr

C. Gourlaouen

Laboratoire de Modélisation et Simulations Moléculaires

UMR7140-Chimie de la Matière Complexe

Institut Le Bel - 4

rue Blaise Pascal, Strasbourg CS 90032, 67081, Cedex, France

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Supporting information for this article is available on the WWW under https://doi.org/10.1002/ejoc.202500677

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© 2025 The Author(s). European Journal of Organic Chemistry published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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<figure><img src="image_6.png" /><figcaption>**Scheme 1.** General reaction of the asymmetric hydrosilylation of ketones, catalyzed by zinc-diamine complexes, and molecular structure of ligands used.</figcaption></figure>

Of all the systems studied with zinc, trans-DiAminoCycloHexane diamine DACH-type is the chiral structure of choice for the development of this catalysis. Among all the opportunities for improving enantioselective catalysis, the possibility of creating a confined chiral cavity is a concept that is attracting a great deal of interest.[16] For example, Kwit, Gawronki et al. have recently investigated the use of macrocyclic ligands containing two or three diamine units.[14,15] On the other hand, in the field of materials science,[17,18] porous organic materials have been introduced using this type of chemical structure and an interesting cage (i.e., 2) based on DACH moiety has been developed for gas and chiral molecule separations.[19–21] To the best of our knowledge, (2) has not been used in asymmetric catalysis.

Given the strong performance of DACH-like ligands in the asymmetric reduction of ketones,[4–6] we first explored cage 2 as a potential ligand for zinc-catalyzed asymmetric hydrosilylation and compared its performance to that of (N,N'-dibenzyl)-(S,S)-1, 2-diaminocyclohexane (1, Scheme 1). This comparison led to the development of an improved experimental procedure over previously reported methods. In the second part of our study, we focused on ligand 1, conducting several investigations to clarify mechanistic aspects that remained unclear in these systems. DFT calculations, supported by experimental insights, point to a highly reactive Zn–H species stabilized via monocoordination by the ligand.

## 2. Results

### 2.1. Ligand 1 Versus Ligand 2: Optimization and Scope

Inspired by the original experimental conditions of Mimoun and Kwit,[4–6] we set conditions using a 1/1 ligand/zinc ratio at 3.5 mol% in toluene at room temperature for 24 h. Depending on the silane

<table><caption>**Table 1.** Impact of silane on the conversion and the enantioselectivity of the hydrosilylation of acetophenone.</caption><thead><tr><th>Entry<sup>a)</sup></th><th>Ligand</th><th>Silane</th><th>Reaction time</th><th>Conv. [%]<sup>b)</sup></th><th>e.e. [%]<sup>b)</sup></th></tr></thead><tbody><tr><td>1</td><td>1</td><td>PMHS</td><td>1 day</td><td>83</td><td>65</td></tr><tr><td>2</td><td>1</td><td>PhSiH<sub>3</sub></td><td>–</td><td>&gt;99</td><td>81</td></tr><tr><td>3</td><td>1</td><td>Ph<sub>2</sub>SiH<sub>2</sub></td><td>–</td><td>&gt;99</td><td>78</td></tr><tr><td>4</td><td>1</td><td>MePhSiH<sub>2</sub></td><td>–</td><td>14</td><td>81</td></tr><tr><td>5</td><td>1</td><td>(EtO)<sub>2</sub>SiH</td><td>–</td><td>12</td><td>81</td></tr><tr><td>6</td><td>1</td><td>Et<sub>3</sub>SiH</td><td>–</td><td>0</td><td>0</td></tr><tr><td>7</td><td>1</td><td>[Me<sub>3</sub>SiO]<sub>2</sub>MeSiH</td><td>–</td><td>3</td><td>66</td></tr><tr><td>8</td><td>1</td><td>PhSiH<sub>3</sub></td><td>15 min</td><td>&gt;99</td><td>81</td></tr><tr><td>9</td><td>2</td><td>PhSiH<sub>3</sub></td><td>–</td><td>&gt;99</td><td>82</td></tr><tr><td>10</td><td>1</td><td>Ph<sub>2</sub>SiH<sub>2</sub></td><td>15 min</td><td>&gt;99</td><td>82</td></tr><tr><td>11</td><td>2</td><td>Ph<sub>2</sub>SiH<sub>2</sub></td><td>–</td><td>&gt;99</td><td>80</td></tr></tbody></table>

<sup>a)</sup>General conditions: (S,S)-1 or (S,S)-2 (12 µmol, 3.5 mol%) and ZnEt<sub>2</sub> (12 µmol, 3.5 mol%), toluene (1.5 mL), r.t., 30 min, then addition of acetophenone (0.344 mmol, 1 equiv.) and silane (0.413 mmol, 1.2 equiv.), r.t., reaction time. Reaction quenched by 2 mL of 1 M NaOH in MeOH/H<sub>2</sub>O (1/1), r.t., 30 min;

<sup>b)</sup>Conversion and e.e. were determined by chiral GC (see Supporting Information).

used, 1 has already shown an excellent conversion (99%) with 78% e.e. for the reduction of acetophenone.[6] Acetophenone was used as a model substrate for our optimization and mechanistic studies. Table 1 describes a representative selection of reaction behavior as a function of the silane used.

The temperature, zinc salt and catalyst loading were also investigated in order to optimize the conditions. Table 1 displays selected results of the screening using acetophenone as substrate and various silanes as reagent, in the presence of chiral ligand 1 or 2.

Using the previously optimized conditions, we tested different aryl-alkyl ketone substrates in the presence of the two chiral ligands 1 or 2. Table 2 shows the results (enantiomeric excess, yield and absolute configuration of the chiral products) for 12 different substrates. The best enantiomeric excess is obtained with 1-indanone as substrate, with 94% e.e. in the presence of 1% and 91% e.e. in the presence of 2.

## 3. Mechanistic Investigation Using Ligand 1

### 3.1. Synthesis of the Zinc Complex

In order to gain more insight into the mechanism, we investigated the reactivity of ZnEt<sub>2</sub> with ligand 1. Colorless needle crystals suitable for X-ray diffraction studies were formed after the addition of diethylzinc (238 µL, 0.1 M in toluene, 0.024 mmol, 1 equiv.) to a toluene solution of 1 (0.024 mmol in 3 mL of toluene) under argon at –30 °C. The molecular structure of complex 3 in the solid state was determined by X-ray diffraction and is depicted in Figure 1 along with the principal bond lengths and angles.
<figure><img src="image_7.png" /><figcaption>**Table 2.** Substrate scope of the reaction system under the optimal conditions.<sup>a)</sup></figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Figure 1.** X-ray crystallographic structure of (S,S)-DACH-ZnEt<sub>2</sub> complex 3. Hydrogens are omitted for clarity except the hydrogens H(1) and H'(1) bound to the nitrogen atoms. Selected bond length (Å) and angles (°): Zn(1)–C(11), 1.998(6); Zn(1)–N(1), 2.245(4); C(11)–Zn(1)–C'(11), 137.0(4); C(11)–Zn(1)–N(1), 109.3(2); N(1)–Zn(1)–N'(1), 78.9(2); H(1)–N(1)–N'(1)–H'(1), 176(3); N(1)–C(8)–C'(8)–N'(1), 55(3). CCDC deposition number 2425336.</figcaption></figure>

The coordination around the metal is distorted tetrahedral with a N(1)–Zn(1)–N'(1) bite angle of 78.9(2)° and a C(11)–Zn–C'(11) angle of 137.0(4)°. The calculated geometry index $\tau_4$ that can

quantitatively describe the geometry adopted by four-coordinate complexes is 0.81, according to Houser et al.[22] The Zn–N bond length of 2.245(4) Å and the Zn–C bond length of 1.998(6) Å are comparable with previously characterized examples of such complexes.[4,15] The molecule adopts C<sub>2</sub> symmetry, with both nitrogen in (R) configuration; the two hydrogen atoms H(1) and H'(1) are therefore located *anti* to each other.

## 3.2. NMR Studies

The behavior of complex 3 in solution and in the presence of diphenylsilane was studied using ¹H NMR and diffusion-ordered NMR spectroscopy (DOSY). For this purpose, we prepared an equimolar mixture of 1 and ZnEt<sub>2</sub> at a concentration of 20 mM in toluene-<i>d</i><sup>8</sup> (see Supporting Information part IV.A). A few bubbles were observed in the solution, indicative of gas formation, which was confirmed by a signal at δ = 0.81 ppm in the ¹H NMR spectra, characteristic of the presence of ethane. Analysis of the ¹H NMR spectrum revealed the presence of a major species in agreement with complex 3 and the presence of a minor compound that contains only one ethyl ligand (complex 4, Equation (1)). The DOSY experiment failed to differentiate between the two species, which were too close in molar mass. The estimated molecular weight, based on the diffusion coefficient, is 420 ± 70 g mol<sup>-1</sup> (Table 3, Entry 1; M<sub>w</sub> of complex 3 = 418 g mol<sup>-1</sup>). Entry 2 displays the diffusion coefficient of diphenylsilane in toluene-<i>d</i><sup>8</sup>, whereas Entry 3 displays the DOSY results of the interaction between ZnEt<sub>2</sub>, ligand 1 and diphenylsilane. Based on the Einstein–Stokes equation and the SEGWE methodology developed by Morris and his coworkers,[23] the diffusion coefficient and an estimate of the molecular weight of compounds in 1-Zn-Ph<sub>2</sub>SiH<sub>2</sub> mixture show the presence of three species: complexes 3 and 4, diphenylsilane and an unknown species, which could be a dimer of 4.[24]

<figure><img src="image_9.png" /><figcaption>**Table 3.** The diffusion coefficient of compounds and their estimated molecular weight in ¹H DOSY NMR experiments done in toluene-<i>d</i><sup>8</sup> at a 20 mM concentration.</figcaption></figure>

<table><thead><tr><th>Entry<sup>a)</sup></th><th>Diffusion coefficient [m<sup>2</sup> s<sup>-1</sup>]</th><th>Estimated molecular weight [g mol<sup>-1</sup>]</th><th>Proposed structure</th></tr></thead><tbody><tr><td>1<sup>b)</sup></td><td>8.73e<sup>-10</sup></td><td>420 ± 68</td><td><b>3</b></td></tr><tr><td>2<sup>c)</sup></td><td>13.8e<sup>-10</sup></td><td>169 ± 27</td><td>Ph<sub>2</sub>SiH<sub>2</sub></td></tr><tr><td>3<sup>d)</sup></td><td>8.95e<sup>-10</sup></td><td>399 ± 64</td><td><b>3</b> + <b>4</b></td></tr><tr><td>–</td><td>16.1e<sup>-10</sup></td><td>126 ± 20</td><td>Ph<sub>2</sub>SiH<sub>2</sub></td></tr><tr><td>–</td><td>6.80e<sup>-10</sup></td><td>713 ± 116</td><td>[4]<sub>2</sub></td></tr></tbody></table>

<footnote><sup>a)</sup>General conditions: (S,S)-1 or (S,S)-2 (3.5 mol%) and ZnEt<sub>2</sub> (3.5 mol%), freshly distilled toluene (1.5 mL), r.t., 30 min, then addition of phenylsilane (0.413 mmol, 1.2 equiv), cool down to -30 °C, addition of the substrate (0.344 mmol, 1 equiv.) for 15 min. Reaction quenched by 2 mL of 1 M NaOH in MeOH:H<sub>2</sub>O (1:1), r.t., 30 min. E.e. were determined by chiral GC or chiral HPLC.</footnote>

<footnote><sup>a)</sup>Estimated based on SEGWE methodology with a possible error of 16.2% in toluene-<i>d</i><sup>8</sup>; [23] <sup>b)</sup>Equimolar solution of 1 and ZnEt<sub>2</sub> in toluene-<i>d</i><sup>8</sup>; <sup>c)</sup>Ph<sub>2</sub>SiH<sub>2</sub> in toluene-<i>d</i><sup>8</sup>; <sup>d)</sup>Equimolar solution of 1, ZnEt<sub>2</sub> and Ph<sub>2</sub>SiH<sub>2</sub> in toluene-<i>d</i><sup>8</sup>.</footnote>
<figure><img src="image_10.png" /></figure>

### 3.3. Kinetic Isotope Effect, Stoichiometry of the Silane and NonLinear Study

To investigate the H/D impact on the catalysis, the hydrosilylation reaction was carried out with acetophenone and a stoichiometric mixture of $Ph_2SiH_2$ and $Ph_2SiD_2$ (1:1) in toluene (Figure 2a, see Supporting Information part IV.B). Analysis of the product's H/D ratio revealed a stoichiometric mixture of alcohols using either $ZnEt_2$ or $ZnMe_2$ as zinc precursor.

The impact of silane stoichiometry on yield and enantioselectivity was evaluated. Figure 2b,c shows the results of reaction conversions and enantiomeric excesses as a function of the number of equivalents of silane with respect to the substrate, i.e.,

<figure><img src="image_11.png" /><figcaption>**Figure 2.** a) Investigation of the kinetic isotope effect: hydrosilylation of acetophenone in presence of $Ph_2SiH_2$ and $Ph_2SiD_2$; b) evolution of conversion and enantiomeric excess as function of the number of equivalent of phenylsilane; and c) evolution of conversion and enantiomeric excess as function of the number of equivalent of diphenylsilane (standard conditions with acetophenone as substrate, in toluene at room temperature in all cases, using $ZnEt_2/(S,S)-1$ 3.5 mol% as catalyst).</figcaption></figure>

acetophenone. Phenylsilane $PhSiH_3$ and diphenylsilane $Ph_2SiH_2$ were used in the study (see Supporting Information part IV.C). The results show that the enantioselectivity of the product is not affected by the stoichiometry of the silane. The conversions also show that for $Ph_2SiH_2$, only one silane hydride was reacted, but for $PhSiH_3$, two silane hydrides were reacted.

Finally, the correlation between the enantioselectivity of the product and the enantioselectivity of the ligand used was also studied. A strictly linear relationship was obtained under standard conditions, as displayed on Figure S1, Supporting Information (see Supporting Information part IV.C), i.e., $e.e_{Product} = f(e.e_{Ligand})$, using 3.5 mol% at r.t. in toluene.[25,26]

### 3.4. DFT Calculations

DFT calculations were conducted to gain deeper insight into the reaction mechanism. We began by examining the interaction between diethylzinc and ligand (S,S)-1 (see Supporting Information for computational details), which resulted in the formation of complex 3. This complex gave rise to several potential conformers, with the most stable one (structure 3a) exhibiting a binding free energy of $ΔG = -5.3$ kcal mol⁻¹. The computed geometry of 3a closely matches the experimental structure, showing Zn–N bond lengths of ≈2.28 Å and Zn–C bond lengths of 2.01 Å. Further exploration into a potential reaction pathway involving ketone activation by complex 3 revealed that its Lewis acidity is insufficient to facilitate silane reduction.

Starting from 3a, we found a reaction path leading to structure 4 via a one-step reaction mechanism from conformer 3b (Figure 3). Conformers 3a and 3b differ only in the orientation of the ethyl chain of the zinc complex. The proton transfer is exergonic by -7.7 kcal mol⁻¹ but is associated with a barrier of 27.4 kcal mol⁻¹ (through transition state TSH). Such a barrier is consistent with experimental observations. Despite the greater stability of 4, the relatively high energy barrier ensures the kinetic stability of structure 3a, which will only slowly evolve toward 4 at room temperature. The height of the barrier can be attributed to the uneasy decoordination of the ethylate anion in the TSH transition state with a Zn–C distance of 2.343 Å. Finally, we investigated the possibility of a second deprotonation of the ligand in complex 4 and found that such a reaction is endergonic with a $ΔG$ of +1 kcal mol⁻¹ (the transition state to generate this species has not been calculated).

We next investigated the mechanism of the hydrosilylation of acetophenone with diphenylsilane in the presence of the Lewis acidic zinc complex 4. Again, we initially hypothesized that a ketone coordinated to complex 4 would be attacked by the silane. Although such reaction pathways were identified, they exhibited prohibitively high activation barriers, exceeding 35 kcal mol⁻¹. As an alternative, we explored a preliminary interaction between complex 4 and the silane. This interaction proved to be relatively weak ($ΔG = +16.8$ kcal mol⁻¹, intermediate 11; see Figure 4). However, the nucleophilic nitrogen ligand was found to be capable of attacking the silane via an $SN_2$-like mechanism, leading to the formation of a Si–N bond and a zinc hydride species. This step is
<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /><figcaption>**Figure 3.** Computed mechanism for the formation of 4, starting from ligand (S,S)-1 and diethylzinc. Energies are in kcal mol⁻¹.</figcaption></figure>

<figure><img src="image_14.png" /><figcaption>**Figure 4.** Computed mechanism for the addition of diphenylsilane on 4. Energies are in kcal mol⁻¹.</figcaption></figure>

significantly exergonic (ΔG = -3.0 kcal mol⁻¹, intermediate I2), and the associated transition state TS1 is energetically accessible (ΔG‡ = +24.4 kcal mol⁻¹). These findings suggest that the silylated zinc complex I2 may act as the active species in this catalytic system, providing a lower-energy pathway for zinc hydride formation.

Binding of the ketone to the zinc complex intermediate I2 results in the formation of an intermediate species (I2bis, Figure 5) with identical energy. This interaction facilitates hydride transfer to the ketone, yielding an alkoxide intermediate via transition state TS2. This transition state is relatively low in energy (ΔG = +11.7 kcal mol⁻¹), making the step exergonic and leading to the (S)-configured alcohol product. We also examined the

alternative pathway leading to the (R)-enantiomer. The corresponding transition state, TS2(R), is significantly higher in energy (ΔG = 16.5 kcal mol⁻¹, Figure 5), as are the associated intermediates I2bis(R) and I3(R). The lower energy of TS2 compared to TS2(R) can be attributed to a stabilizing interaction in TS2 between a phenyl ring on the silane and the aromatic on the ketone, an interaction that is absent in TS2(R) (see Supporting Information for structural details). This energetic difference between TS2 and TS2(R) aligns with the experimentally observed enantioselectivity. To complete the catalytic cycle, an additional silane molecule approaches and interacts with the zinc complex (forming I3bis). The alkoxide then reacts with the silane to give
<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /><figcaption>**Figure 5.** Computed mechanism of the Zn-catalyzed hydrosilylation. Energies are in kcal mol⁻¹.</figcaption></figure>

intermediate **I4**, where the silane adopts a trigonal bipyramidal geometry. In the final step **I5**, the zinc hydride is regenerated via cleavage of the Si–H bond, releasing the silylated alcohol. This final transformation proceeds through a very low-energy transition state (TS4, ΔG = -13.6 kcal mol⁻¹).

## 4. Discussion

This study compares two nitrogen-based ligands in the zinc-catalyzed enantioselective hydrosilylation of aryl ketones: the N,N'-dibenzylcyclohexane-1,2-diamine ligand **1** and its equivalent in the form of a molecular cage **2**. Ligand **1** was synthesized from enantiopure diaminocyclohexane via diimine reduction (77% yield).[24] Ligand **2** is a chiral cage derived from the same skeleton, developed by Cooper et al. for chiral separations.[24] It was prepared by condensing six equivalents of enantiopure diaminocyclohexane with four equivalents of 1,3,5-triformylbenzene to form the diimine cage CC3,[19] followed by sodium borohydride reduction to give cage **2** (79% yield).[20] We then investigated the hydrosilylation of acetophenone with a zinc source using standard conditions, inspired by Mimoun[4] and Kwit.[6] **Table 1** describes a representative selection of reaction behavior as a function of the silane used. Aryl silanes such as phenylsilane or diphenylsilane are the reagents of choice for the reaction under study (Entries 1–3). All other silanes used were not efficient, which is consistent with previous investigations except for phenylsilane.[6] We also found that with arylsilanes, reaction times could be considerably reduced, down to 15 min (Entries 8–11). Full conversion was observed regardless the ligand, giving the product in 81% e.e with **1** and 82% ee with **2**. Notably, either dimethyl or diethyl zinc could be used without any influence on the conversion and e.e of the reaction. It is worth noting

that, in theory, the molecular cage **2** can accommodate up to six metal centers. However, when we conducted the reaction using two equivalents (or more) of zinc relative to ligand **2**, no significant effect on the catalytic performance was observed.

Having established the experimental conditions (–30 °C, 3.5 mol% cat., 15 min.), we tested different substrates in the presence of ligand **1** or ligand **2** (Table 2). It appears that both ligands are in the same order of magnitude in terms of efficiency, with ligand **1** being overall the better choice. The best results were obtained with indanone for ligand **1** (94% e.e.) and with acetophenone for ligand **2** (88% e.e.). The greatest difference in efficacy between the two ligands was observed with 4-methylacetophenone as substrate (78% e.e. vs. 88% e.e., for **1** and **2**, respectively). This comparison indicates that while ligand **2** performs well in terms of activity and enantioselectivity, it offers no significant advantage over the simpler system, ligand **1**.

Focusing on the most efficient system, we then carried out mechanistic studies to elucidate the mechanism, noting several contradictions in the literature on this subject. Diethylzinc and ligand **1** were mixed stoichiometrically under argon in toluene-d⁶ (Equation (1)). Analysis by ¹H NMR is consistent with the formation of the expected complex ZnEt₂ **3**, the -CH₂- group on zinc being in the form of an AB system in the spectrum. The molecular structure of the zinc complex was thus established in the solid state (Complex **3**, see Figure 3). However, in solution, with time, a decrease of intensity of [Ethyl] signals was observed, concomitant with the formation of ethane (δ = 0.81 ppm) in the solution. This gas evolution was accelerated by temperature. The additional complex could be deduced from NMR studies and confirmed by mass spectrometry. The second complex formed **4**, is the result of the loss of an ethyl group, and the ligand is therefore of the LX type.

The mixture was also analyzed using DOSY NMR spectroscopy. However, due to the similar molecular weights of the
<figure><img src="image_17.png" /></figure>

two complexes, it was not possible to distinguish them individually (Table 3, Entry 1). Upon addition of diphenylsilane to the solution, the formation of the minor species was accelerated. DOSY analysis then revealed a signal corresponding to an estimated molecular weight of 710 ± 116 g mol⁻¹, which was attributed to a dimer of compound 4, based on analogy with a known related dimeric species.[24] The ¹H NMR spectrum of the mixture primarily displays signals corresponding to the zinc complex 3 and free diphenylsilane. HMQC ²⁹Si-¹H experiments (Figure S2, see Supporting Information part IV.E) revealed at least three distinct ²⁹Si signals, along with several weaker ones. Additionally, a singlet at 4.50 ppm—unassociated with any silicon atom—was observed. This signal, also present in the ¹H NMR spectrum of a similar system involving phenylsilane, may indicate the presence of a hydride.

Investigation of potential nonlinear effects revealed a strictly linear relationship between e.e.p and e.e.L, consistent with a mononuclear active species. We also found that the enantioselectivity of the reaction is not impacted by the number of equivalent of silane (see Figure 2b,c). Interestingly, a conversion of around 60% was observed if only 0.3 equivalents of PhSiH₃ phenylsilane was used, and a conversion of 50% was observed in the presence of 0.5 equivalents of diphenylsilane Ph₂SiH₂ and the e.e.p's were all identical. This suggests that the silane reagent is not directly involved in the enantioselective step, but must be the hydride source for another active species.

We complemented our experimental studies with DFT calculations, which suggest that compound 3 may undergo ethane elimination to form zinc species 4, via an α-hydride elimination. However, the activation barrier for this transformation is relatively high, rendering compound 3 kinetically stable, consistent with experimental observations (Figure 3). Importantly, neither compound 3 nor 4 appears to be the actual catalyst (high energy barriers have been calculated). Instead, compound 4 is proposed to react with the silane to generate a silylated-ligand zinc hydride complex, likely the catalytically active species (Figure 4, I2). DFT analysis of the monoligated complex I2, first reacting with acetophenone and then with an additional equivalent of silane, reveals a catalytic cycle characterized by low activation barriers (<15 kcal mol⁻¹), as illustrated in Figure 5. This mechanism is supported by several consistent observations: i) the rate-determining step coincides with the enantioselective hydride transfer to the carbonyl group; ii) the calculated barriers align with experimental data, reflecting a reaction that proceeds within minutes at -30 °C; and iii) the low barriers explain the absence of significant kinetic isotope effects.

## 5. Conclusion

In summary, our study was conducted in two parts. First, we investigated the hydrosilylation reaction catalyzed by zinc complexes with diaminocyclohexane-derived ligands, specifically focusing on N,N'-dibenzyl-1,2-diaminocyclohexane 1 and its chiral molecular cage derivative 2. Using diphenylsilane or phenylsilane as hydride sources, the reactions proceeded rapidly,

completing in under 15 min, with yields reaching up to 100% and enantiomeric excesses of 94% with ligand 1 and 91% with ligand 2. Despite the favorable outcomes of ligand 2 in terms of both activity and enantioselectivity, the results indicate that it does not provide a significant advantage over the simpler ligand 1 system.

In the second part of the study, we focused on elucidating the mechanistic aspects of the reaction with ligand 1, as these remained unclear in the literature. Computational studies revealed that the ligand directly participates in the formation of the zinc hydride species I2. In this complex, the ligand coordinates to zinc in an η¹ fashion, facilitating ketone reduction through a highly favorable energy pathway. These findings suggest that although the active catalytic species is formed only in trace amounts, it exhibits high reactivity, which makes its direct detection particularly challenging.

## Acknowledgements

The authors thank Corinne Bailly and Dr. Nathalie Gruber (University of Strasbourg) for the X-ray structural determinations. This work was supported by IdEx Unistra (no. ANR 10 IDEX 0002), and by SFRI STRAT'US project (no. ANR 20 SFRI 0012) and EUR QMAT ANR-17-EURE-0024 under the framework of the French Investments for the Future Program. The author also would like to thank the Région Grand Est for its partial financial support. This research was also funded in part by the French National Research Agency (ANR) under the project ANR-23-CE07-0023. The authors thank the HPC of Strasbourg for computing time.

## Conflict of Interest

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

**Keywords:** asymmetric catalysis · homogeneous catalysis · hydrosilylation · zinc

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Manuscript received: July 2, 2025

Revised manuscript received: July 23, 2025

Version of record online: October 7, 2025