Computational investigations on the phosphine-ligated CuH-catalyzed conjugate reduction of α-β unsaturated ketones: regioselectivity and stereoselectivity

Abstract

Computational investigations on the phosphine-ligated CuH-catalyzed conjugate reduction of α-β unsaturated ketones were performed with the DFT method. Two phosphine-ligated CuH catalysts, Ph₃P–CuH and (R)-SEGPHOS–CuH, were employed to probe the reaction mechanism with the emphasis on regioselectivity and stereoselectivity. The calculations on the Ph₃P–CuH system indicate that there exist two competing reaction pathways: the 1,4- and 1,2-path. The 1,4-path is predicted to be energy-favoured among these reaction paths. The mechanism of the 1,4-path includes two steps: (1) the first step is predicted to be the rate-determining step (RDS), corresponding to the delivery of the hydrogen atom of the CuH catalyst to the β-carbon atom of the substrate, with the formation of the enolate; (2) in the second step, the enolate undergoes a σ-bond metathesis with the hydride source to liberate the final product and regain the catalysts. In the chiral (R)-SEGPHOS–CuH system, the first step of CuH to the unsaturated bond is vital for the distribution of products and therefore responsible for the stereoselectivity of the 1,4-addition. The calculations on the (R)-SEGPHOS–CuH system reproduce the major product in the R-configuration, which is consistent with the experimental observation. The steric hindrance between the bulky substituent moiety of the substrate and the P-phenyl ring of the SEGPHOS–CuH catalyst is identified as the origin of the stereoselectivity for the titled reaction.

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1. Introduction

The asymmetric conjugate reduction of α-β unsaturated carbonyl derivatives is of great interest in organic synthesis.¹ A large number of transition metal catalysts including palladium,² rhodium,³ magnesium,⁴ titanocene,⁵ and copper⁶ have been successfully applied for achieving this transformation. Among these catalysts, copper hydride complexes are the most widely utilized with the greatest synthetic utility, as copper hydride is a mild and selective reducing agent when used in stoichiometric or catalytic quantities. More importantly, the conjugate reduction of α-β unsaturated carbonyl compounds catalyzed by CuH catalysts is highly chemoselective for C=O or C=C double bonds.⁷

In the chemoselective reductions of α-β unsaturated carbonyl compounds catalyzed by copper catalysts (Scheme 1), the pioneering work reported by Stryker demonstrated that achiral phosphine–copper hydrides, such as [(Ph₃P)CuH]₆ exhibited good performance in such reactions.^7,8 In their report, hydrogen molecules together with a catalytic quantity of metal complex were highly regioselective, generating the product of the conjugate reduction or completing the 1,4- and 1,2-reductions to the saturated alcohol.

Scheme 1 CuH-catalyzed conjugate reductions of α-β unsaturated ketones.

Inspired by early work on CuH, Buchwald et al. developed an enantioselective conjugate reduction using a diphosphine-stabilized chiral CuH species generated in situ, where CuCl was used as the copper source, NaOt-Bu as the base and (S)-p-tol-BINAP as the chiral ligand.⁹ In their work, a series of enones, unsaturated esters and lactones underwent a smooth 1,4-reduction, affording good yields and high ee values. For example, they described the use of a CuCl–polymethylhydrosiloxane (PMHS)–(S)-p-tol-BINAP catalyst for the enantioselective 1,4-reduction of acyclic α-β unsaturated esters and cyclic enones.

The addition of alcoholic additives was found to be crucial for higher yields of the desired products and a dramatic increase in the reaction rate. Improvements in both enantioselectivity and reactivity toward sterically hindered systems were accomplished by Lipshutz and co-workers.¹⁰ In a series of publications, they developed a reagent combination of catalytic amounts of copper hydride ligated by a nonracemic ligand, which led to the generation of an extremely reactive species capable of effecting the asymmetric hydrosilylation of conjugated cyclic enones with very high ee values. In their work, the addition of a catalytic amount of [(Ph₃P)CuH]₆–PMHS–SEGPHOS in toluene was sufficient to provide a reagent capable of delivering the hydrogen atom by a 1,4-path with excellent levels of stereoinduction.

As for the mechanism of the 1,4-reduction of enones and ketones catalyzed by copper hydride, a catalytic cycle was suggested by Stryker⁷ and Buchwald.^9d As shown in Scheme 2, the carbophilic copper hydride species initially reacts with the Michael acceptor to form a π-complex. Then, delivery of the hydrogen to the β-carbon atom (C_β) affords the enolate, which undergoes an σ-bond metathesis with the stoichiometric hydride source via a transition state, thus closing the cycle by regaining the catalytically active copper hydride species and releasing the product.

Scheme 2 Proposed catalytic cycle of CuH-catalyzed conjugate reductions of α-β unsaturated ketones.

Despite the general mechanism of the 1,4-reduction of α-β unsaturated carbonyl compounds being available in the literature, the detailed mechanism of such a reaction as well as the origin of the stereochemistry is much less well-known. This is disadvantageous for understanding the effect of the ligand on the regioselective and enantioselective reduction of α-β unsaturated carbonyl compounds, and therefore becomes an obstacle for designing new effective and green ligands for CuH-catalyzed reactions. The focus of the present investigation is aimed at the reaction mechanism and the stereochemistry of the conjugate reduction of unsaturated ketones.

In an attempt to gain a better understanding of the underlying steps of the above reaction at a molecular level and to clarify how the different ligated copper hydride catalysts influence the reaction regioselectivity and enantioselectivity, a theoretical simulation to investigate these aspects of such a reaction system was carried out. This work is expected to be useful for the design of new ligands.

2. Models and computational details

The previous computational literature demonstrated that the M06 (ref. 11) method performed well for copper systems.¹² First, a simple gas-phase system where a diatomic CuH molecule serves as the catalyst was used. The geometrical optimizations of all the intermediates (IM) and transition states (TS) were performed using the M06 method with the 6-31G(d,p)¹³ basis set for all atoms. Details of the preliminary results are listed in the ESI.†

The major work in the present investigation is based on the following two models, which were actually used in the experiments (see Scheme 3.)

Scheme 3 Models used in the simulations.

i: Ph₃P–CuH model

In this section, cyclohexenone 1 was employed as the substrate. The non-chiral phosphine ligand Ph₃P was introduced in the present investigation, and a monomeric ligated CuH species was constructed as the catalyst (Scheme 3). As hydrogen gas and silyl hydrides were both successfully used as the hydride source in the conjugate reduction of α-β unsaturated carbonyl compounds, molecules of hydrogen and SiH₄ were used as the hydride source in this computational investigation. The geometrical optimizations of all IMs and TSs were performed at the 6-31G(d,p) level.

ii: Chiral (R)-SEGPHOS–CuH model

In this section, isophorone 2 was employed as the substrate and a chiral diphosphine ligand (R)-SEGPHOS was introduced into the reaction system. This system has been proven to be excellent in asymmetric hydrosilylations of conjugated cyclic enones ketones with very high ee values.^10g A linear correlation between the ee of the chiral phosphine ligand and that of the product has been observed in the CuH-catalyzed asymmetric reduction of carbonyl compounds,^9a,14 suggesting that the metal complex with a 1 : 1 ratio of ligand to metal is involved. Therefore, the (R)-SEGPHOS–CuH species in monomeric form was used in the calculations. To reduce computational costs, chiral (R)-SEGPHOS bearing phenyl units (Ar = Ph) was used as the chemical model. The geometrical optimizations of all IMs and TSs were employed with the 6-31G(d,p) basis set.

To take the entropy effects in solvents into account, single-point self-consistent reaction field (SCRF) calculations based on the polarized continuum model (PCM)¹⁵ were carried out on the gas-phase optimized geometries for all species in the above two model systems. As toluene was often used as the solvent in experiments,^6b the latter calculations were carried out with a dielectric constant ε = 2.379 for the solvent toluene. For evaluating the solvent effects, the free energy was calculated at the M06/6-31G(d,p) level and added to the gas-phase free energy to obtain the Gibbs energy in toluene (G_solv) at 298.15 K, with radii = UAHF (radii optimized for the HF/6-31G(d) level of theory). Unless otherwise stated, G_solv is used in the discussion and the energy levels refer to the G_solv scale.

All calculations were performed with the Gaussian 09 program.¹⁶ Frequencies were calculated at the same level to confirm each stationary point to be either a minimum (no imaginary frequency) or a saddle point (unique imaginary frequency), and to obtain the zero-point correction.

3. Results and discussion

3.1. Mechanism and regioselectivity of the reaction catalyzed by the Ph₃P–CuH catalyst

In this section, Ph₃P–CuH is used as the model catalyst to probe the reaction mechanism catalyzed by ligated CuH species. Although Stryker’s reagent [(Ph₃P)CuH]₆ is usually used as the copper source to synthesize other CuH species in situ, this species alone has also been confirmed as an effective catalyst for the 1,4-reduction of 1 in experiments.^10a,m The predicted reaction routes are shown in Fig. 1. The energy levels in the Ph₃P–CuH system are shown in Fig. 2.

Fig. 1 Predicted catalytic cycles of Ph₃P–CuH-catalyzed conjugate reductions of α-β unsaturated ketones.

Fig. 2 Energy diagrams along the reaction routes in the Ph₃P–CuH system. Relative Gibbs energies (ΔG_solv, in kJ mol⁻¹) for various species are calculated at the M06/6-31G(d,p) level.

Mechanism. The addition reaction begins with the coordination of the Ph₃P–CuH model catalyst to the substrate 1. This process leads to the formation of two distinct stabilized complexes marked as 1,4- and 1,2-COM1. As shown in Fig. 1, the coordination of Ph₃P–CuH to the C=C double bond in 1 generates the complex 1,4-COM1. This η² complex features two C–Cu bonds of 1.970 and 1.942 Å. On the other hand, the coordination of the CuH to the O-end of the carbonyl in 1 leads to the formation of complex 1,2-COM1. From these two complexes, the addition reaction can complete along two distinct paths and give two different final products.

From 1,4-COM1, the cleavage of the Cu–H bond takes place via 1,4-TS1 with a smaller Gibbs energy barrier of 49.9 kJ mol⁻¹. This step includes the breakage of the Cu–H bond of the catalyst and the formation of the 1,4-addition intermediate 1,4-IM1. 1,4-TS1, characterized by an elongated Cu–H bond of 1.559 Å and a shortened C–H bond of 1.613 Å, is a four-membered cyclic transition state. For 1,4-IM1, the C–H bond shortens to 1.096 Å and the Cu–H bond is stretched to 2.348 Å, which indicates that the C–H bond has already been formed and that the Cu–H bond is broken.

Next, an external H₂ molecule interacts with the copper atom with the formation of a stabilized complex 1,4-COM2-H₂, which is followed by the cleavage of the H–H bond via a six-centred transition state 1,4-TS2-H₂. For 1,4-COM2-H₂, the complex features two C–Cu bonds of 2.065 and 1.998 Å. For 1,4-TS2-H₂, the H–H bond is elongated to 1.008 Å, the Cu–H bond is 1.679 Å and the O–H bond is 1.271 Å. This suggests that the formation of the Cu–H and O–H bonds occurs with the cleavage of the H–H bond. Similarly, when SiH₄ serves as the hydrogen source, it can also donate one hydrogen atom to the substrate by the cleavage of one Si–H bond. For 1,4-TS2-SiH₄, the Si–H bond is elongated to 1.592 Å, the Cu–H bond is 1.715 Å and the O–Si bond is 1.930 Å, suggesting the formation of an O–Si bond and the breakage of one Si–H bond. As a result, either for H₂ or SiH₄, one H atom transfers to the copper centre with the recovery of the CuH catalyst. Meanwhile, the CuH catalyst interacts with the product with the formation of a stabilized complex 1,4-COM3-H₂. For 1,4-COM3-H₂, the O–H bond shortens to 0.965 Å and the Cu–H bond becomes 1.565 Å. This suggests that the Cu–H and O–H bonds have already been formed.

Apart from the 1,4-path, there is another reaction path similar in mechanism. From the complex 1,2-COM1, the addition of CuH to the C=O double bond can take place via 1,2-TS1. Then, an external H₂ or SiH₄ might donate one H atom to the Cu with the recovery of the Ph₃P–CuH catalyst via 1,2-TS2.

Briefly, the entire reaction can be generally divided into two subsequent stages: (1) the addition of Ph₃P–CuH to the unsaturated bonds of the substrate; (2) the recovery of Ph₃P–CuH catalyst. Besides, it was also found that both H₂ and SiH₄ are responsible for regenerating the Ph₃P–CuH catalyst by serving as the hydrogen source for the reaction theoretically. PCM calculations predict that the first reaction step possesses the largest energy barrier along the 1,4 reaction path, which means that the first step should be the rate-determining step (RDS) for the 1,4 reaction. In contrast, the second reaction step is the RDS of the 1,2 reaction.

Regioselectivity. As shown in Fig. 2, when H₂ serves as the hydrogen source, the 1,4-path represents the lowest energy pathway in terms of Gibbs energy, and therefore the 1,4-path represents the most favoured route thermodynamically. Furthermore, the Gibbs energy barrier of the RDS along the 1,4-path (49.9 kJ mol⁻¹) is smaller than that along the 1,2-path (92.6 kJ mol⁻¹), meaning that the 1,4-path is also favoured kinetically.

When SiH₄ serves as the hydrogen source, the entire 1,4-path also represents the lowest energy pathway in terms of Gibbs energy; the Gibbs energy barrier of the RDS along the 1,4-path (49.9 kJ mol⁻¹) being smaller than that along the 1,2-path (56.5 kJ mol⁻¹), meaning that the 1,4-path is also favoured thermodynamically and kinetically.

On the other hand, turnover frequency (TOF)¹⁷ can be also used to judge which route is more favoured. The TOFs are calculated to be 5.83 × 10⁶ and 3.91 × 10⁻² h⁻¹ for the 1,4- and 1,2-path in the Ph₃P–CuH–1–H₂ system, respectively. If SiH₄ is involved in the reaction, the TOFs are 5.83 × 10⁶ and 3.18 × 10⁵ h⁻¹ for the 1,4- and 1,2-path, respectively. The significantly larger TOF for the 1,4-path means that the 1,4-product should be predominant, regardless of whether H₂ or SiH₄ is used as the hydrogen source. This is in good agreement with the experimental observation that most related experiments gave the 1,4-product in 90% yield from 1 under H₂ or silanes.^6b,7

3.2. Stereochemistry of the (R)-SEGPHOS–CuH-catalyzed reaction

Next, the focus of the present investigation turns to the stereo-selectivity of such a reaction. In this section, a chiral diphosphine ligand (R)-SEGPHOS (see computational details) was introduced into the following calculations. As the 1,4-reduction has been proven to be the most energy-favoured in the experiments for the reactions, the present investigation in this section will focus on the 1,4-path. The entire reaction route is shown in Fig. 3 (for simplicity, just the R-out-path to R-product is illustrated; other optimized structures are listed in the ESI†). The most energy-favoured pathways leading to the racemic products are shown in Fig. 4.

Fig. 3 Proposed catalytic cycle of (R)-SEGPHOS–CuH-catalyzed conjugate reductions of α-β unsaturated ketones.

Fig. 4 Energy diagram along the reaction route for the (R)-SEGPHOS–CuH system. Relative Gibbs energies (ΔG_solv, in kJ mol⁻¹) for various species are calculated at the M06/6-31G(d,p) level.

As shown in Fig. 3, the reaction mechanism is generally similar to that for the Ph₃P–CuH-catalyzed reaction. The entire reaction is also composed of two steps: (1) the addition of ligated CuH to the C=C bonds of the substrate; (2) the recovery of the CuH catalyst.

As shown in Fig. 4, TS1 and TS2 are located at the energy summits along the entire reaction with comparable energies. The system must successively overcome two energy summits at TS1 and TS2 to complete the reaction. Therefore, we paid our attention to their structures and energies to probe further details of enantioselectivity. The structure of the TS1s and TS2s are shown in Fig. 5 and 6, respectively.

Fig. 5 Skeleton representation modes of 1,4-addition TS1s in the (R)-SEGPHOS–CuH system.

Fig. 6 Skeleton representation modes of 1,4-addition TS2s in the (R)-SEGPHOS–CuH system.

As shown in Fig. 5, the calculation predicts that the hydrogen molecule is loosely bonded to the C=O of the substrate by a hydrogen bond with H⋯O distance of 2.354 Å in R-out-TS1. For the C₂-symmetry of the (R)-SEGPHOS moiety, the orientation of the substrate is alternatively towards the left or right side with respect to the (R)-SEGPHOS–CuH catalyst in R-TS1 or S-TS1, respectively. On the other hand, the substrate is not a flat molecule and adopts a puckered conformation. This makes the major part of the substrate approximately planar, with the C(CH₃)₂ bent out of this plane in either an out or in direction with respect to the (R)-SEGPHOS–CuH catalyst in out-TS1 or in-TS1, respectively. In these structures, the relative location between the C=C double bond of the substrate and the (R)-SEGPHOS–CuH catalyst is retained; the Cu atom is in the centre of these structures and the substrate is located in the back of the (R)-SEGPHOS–CuH moiety in the front view. These transition states also feature a planar four-member CuH⋯C=C ring, suggesting that the Cu–H bond begins to elongate and formation of the C–H bond occurs.

As shown in Fig. 6, there also exist four transition state TS2s in the system. It should be emphasized that the coordination of a hydrogen atom to the copper centre in the TS2s makes the core structures more crowded. Similar to TS1s, these transition states also feature a planar five-member H⋯C=C⋯Cu⋯H ring, with the C(CH₃)₂ bent out of this plane in an out or in direction with respect to the (R)-SEGPHOS–CuH catalyst in out-TS2 or in-TS2, respectively. In the TS2s, the H–H bond of the hydrogen molecule is enlarged and one hydrogen atom is ready to transfer to the copper centre. The other hydrogen atom gets close to the carbonyl of the substrate.

S8 in the ESI† summarizes the relative energies of these TS1s and TS2s. R-out-TS1 and R-out-TS2 on the energy levels pathway to the product of R configuration are energy-favoured, and therefore the R-product is the predominant product. The calculations place R-out-TS1 9.2 kJ mol⁻¹ below S-out-TS1 in terms of Gibbs energy. The calculations place R-out-TS2 3.1 kJ mol⁻¹ below S-out-TS2 in terms of Gibbs energy. According to the Boltzmann distribution, the calculation predicts an ee value of 98.3% for TS1, and 79.7% for TS2. (The ee value observed experimentally is 98.5%.^10g)

More importantly, according to the Curtin–Hammett principle,¹⁸ the evolution of the most stable intermediate COM2 is vital for the distribution of the final product. Here, along the two energy-favoured paths, the reverse energy barrier via TS1 from COM2 to COM1 is greater than the forward one via TS2 to COM2, meaning that the first reaction step should be irreversible and the evolution of COM2 to the final product is relatively easier. The above results imply that R-out-TS1 and S-out-TS1 could be identified as the competing transition states for the enantioselectivity, and the distribution of the racemic products is closely dependent on the first steps. The most related experimental literature reported that the source of the hydride has no impact on the levels of stereoinduction, suggesting that the enantioselectivity is irrelevant to the second reaction step.^10g Therefore, it is reasonable to consider TS1 as the stereo-controlling transition state for the enantioselectivity of the final products. Compared with R-out-TS1, S-out-TS1 suffers greater steric hindrance between the bulky substituent moiety of the substrate and the P-phenyl ring of the catalyst, which might be the reason for the stereochemistry in such a reaction.

3. Conclusions

The investigations of the Ph₃P–CuH system predict that the 1,4-reduction might be more advantageous over the 1,2-path, for the 1,4-path is the most energy-favoured in the reaction system. The calculations indicate that the mechanism of the 1,4-path in the CuH-catalyzed conjugate reductions of α-β unsaturated ketones includes two steps: (1) CuH species reacts with the α-β unsaturated carbonyl compounds to deliver the hydrogen atom to the C_β atom, obtaining the enolate; (2) the enolate undergoes a σ-bond metathesis with the hydride source to liberate the final product and regain the catalysts. The calculations on the Ph₃P–CuH system suggest that the hydrogen transfer process might be the RDS.

In the chiral (R)-SEGPHOS–CuH system, the calculations correctly reproduce the major product in the titled reaction. The larger steric hindrance between the bulky substituent moiety of the substrate and the P-phenyl ring of the catalyst might be the origin of stereoselectivity of the reaction. R-out-TS1, suffering smaller steric hindrance, is much more stable than its competing S-out-TS1, and therefore the predominant product would be in the R-configuration with a high ee value.

Acknowledgements

The authors are grateful for financial support from the National Science Foundation of China (nos. 20772085 and 21021001) and SRF for ROCS, SEM.

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Footnote

† Electronic supplementary information (ESI) available: Computational methods, energies, optimized geometries and the full citation of the Gaussian 09 program. See DOI: 10.1039/c3ra44015j

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