Manganese-Catalyzed Hydrogenation of Ketones under Mild and Base-free Conditions

In this paper, several Mn(I) complexes were applied as catalysts for the homogeneous hydrogenation of ketones. The most active precatalyst is the bench-stable alkyl bisphosphine Mn(I) complex fac-[Mn(dippe) (CO)3(CH2CH2CH3)]. The reaction proceeds at room temperature under base-free conditions with a catalyst loading of 3 mol % and a hydrogen pressure of 10 bar. A temperature-dependent selectivity for the reduction of α,β-unsaturated carbonyls was observed. At room temperature, the carbonyl group was selectively hydrogenated, while the C=C bond stayed intact. At 60 °C, fully saturated systems were obtained. A plausible mechanism based on DFT calculations which involves an inner-sphere hydride transfer is proposed.


■ INTRODUCTION
The catalytic reduction of polar multiple bonds via molecular hydrogen plays a significant role in modern synthetic organic chemistry.Within this context, the use of catalytic procedures in combination with hydrogen gas displays an attractive option to develop efficient and cleaner processes. 1In the last few years, well-defined Mn(I) complexes were introduced as powerful players in the field of sustainable hydrogenation chemistry, 2 being active for the hydrogenation of not only aldehydes, 3 ketones, 4 esters, 5 CO 2 , 6 and carbonates 7 but also nitrogen-containing compounds such as imines, 8 nitriles, 9 amides, 10 and heterocycles. 11t is interesting to note that many of these transition-metalcatalyzed hydrogenations rely on metal−ligand bifunctional catalysis (metal−ligand cooperation), where complexes contain electronically coupled hydride and acidic hydrogen atoms.An effective way of bond activation by metal−ligand cooperation involves aromatization/dearomatization of the ligand in pincer complexes in which a central pyridine-based backbone is connected with −CH 2 PR 2 and/or −CH 2 NR 2 substituents.This has resulted in the development of novel and unprecedented iron and manganese catalysis, where this type of cooperation plays a key role in the heterolytic cleavage of H 2 .An overview of well-defined manganese complexes for hydrogenation reactions is depicted in Scheme 1.
An alternative way to activate dihydrogen was recently described by our group.We took advantage of the fact that Mn(I) alkyl carbonyl complexes are known to undergo insertions to form highly reactive acyl intermediates (a wellknown reaction in organometallic chemistry 12 ) which are able to activate dihydrogen, thereby forming the 16e − Mn(I) hydride catalysts (Scheme 2).9c Here, we describe an additive-free hydrogenation of ketones at room temperature, utilizing Mn(I) alkyl carbonyl complexes fac-[Mn(dpre)

■ RESULTS AND DISCUSSION
The catalytic performance of manganese(I) alkyl complexes 1−3 for the hydrogenation of ketones was evaluated.The experiments were performed using Et 2 O as the solvent at 25 °C and 50 bar H 2 pressure and 4-fluoroacetophenone as the model substrate to find the most active catalyst and optimal hydrogenation reaction conditions (Table 1).In the cases of 1 and 2, negligible reactivity was observed (Table 1, entries 1 and 2), while with 3, excellent conversion to the desired product was achieved.The drastic increase in reactivity may be addressed to the increased steric demand of the ligand in comparison to complexes 1 and 2. The importance of the steric demand of the bisphosphine ligand for the reactivity of alkyl complexes was also demonstrated previously for the hydrogenation of alkenes. 13The stability of the active species may be preserved due to increased steric hindrance.It should be noted that the hydrogenation of ketones at room temperature is comparingly rare in the field of manganese(I) chemistry.4f,g So far, Mn(I)-catalyzed base-free hydrogenation reactions are only known for aldehydes, 3a nitriles, 9a N-heterocycles, 11b,c and alkenes. 13n other solvents such as MeOH, CH 2 Cl 2 , or dimethoxyethane (DME), lower reactivities were observed.Interestingly, lowering the hydrogen pressure from 50 to 10 bar resulted in full conversion (Table 1, entry 9), which is comparatively low for manganese-based catalysts.A shorter reaction time (8 h) led to a drastic decrease in conversion (Table 1, entry 11), which might be attributed to an induction period required for catalyst activation.
Having determined 3 as the most active catalyst and to prove its general applicability, various substrates have been tested to establish scope and limitations (Table 2).The catalytic experiments were conducted in the presence of 3 mol % of catalyst at 25 °C and 10 bar hydrogen pressure, a reaction time of 24 h, without the addition of any additives.Within this context, halide-containing substrates (Table 2, entries 4−7) as well as substrates with electron-donating groups (Table 2, entries 11 and 12) gave excellent yields.Lower reactivity could be detected for substrates containing a coordinating amine or pyridine (Table 2, entries 13 and 19).No conversion could be detected for substrate 9, bearing the strongly coordinating nitrile functionality.Furthermore, no reaction was observed in the presence of a nitro group ( In the case of sterically more demanding substrate 15, only a moderate conversion could be achieved.Aliphatic ketones were very efficiently reduced to the corresponding alcohols (Table 2, entries 21−23).However, the reaction time had to be increased to achieve high conversions.Manganese-catalyzed hydrogenations of ketones at room temperature are relatively rare, 4f,g and to the best of our knowledge, an additive-free hydrogenation of ketones has not been reported.Furthermore, a potential temperature-dependent selectivity for the hydrogenation of α,β-unsaturated carbonyls was investigated (Table 3).At room temperature, the high selectivity for the reduction of the carbonyl group could be  detected, whereas the CC bond stays unaltered (Table 3, 24−27).Interestingly, if hydrogenation was carried out at 60 °C, fully saturated systems (Table 3, 28−30) were received as products.Additionally, the catalyst loading could be decreased to 1 mol %.The reaction barrier for the hydrogenation of 1,2disubstituted C−C double bonds is generally higher than for ketones, requiring a higher reaction temperature, as demonstrated previously. 13In the case of citral as the substrate, solely the CO and not the trisubstituted CC bond was hydrogenated (Table 3, 25).This temperature-dependent selectivity for the reduction of α,β-unsaturated carbonyl moieties may be interesting for synthetic applications.
A mechanistic investigation of the introduced system revealed that the reactivity of 3 was drastically lowered upon the addition of 1 equiv of PMe 3 (with 4-fluoroacetophenone as the substrate).This finding indicates the presence of an innersphere reaction, as the strong donor PMe 3 apparently blocks the vacant coordination site of the active catalyst for the incoming substrates.The homogeneity of the system was proven by the Hg drop test as no significant decrease in reactivity could be detected.
The mechanism of hydrogenation of ketones by 3 was investigated in detail by DFT calculations using acetophenone as the model substrate.The resulting free-energy profile is Catalyst initiation, starting from 3, has been reported previously. 13Acetophenone coordination to the 16-electron hydride intermediate forms intermediate A, a κ 1 -(O) complex that rearranges to a η 2 -coordination mode in B. This is a facile process with a barrier of only 4 kcal/mol (TS AB ).From B, there occurs an attack of the hydride on the carbonyl C atom, resulting in C, an alkoxide complex stabilized by an agostic interaction involving the recently formed C−H bond.The formation of C, from B, is also easy with a barrier of only 3 kcal/mol (TS BC ), being a favorable step, from the thermodynamic point of view with ΔG = −6 kcal/mol.The path proceeds with the dihydrogen addition to the alkoxide intermediate, from D to E, overcoming a barrier of 9 kcal/ mol, measured from the pair of molecules (H 2 + alkoxide intermediate) in D to TS DE .This is an endergonic step with ΔG = 9 kcal/mol.Finally, in the last step of the cycle, there occurs H transfer from the H 2 ligand to the alkoxide O atom, regenerating the hydride and forming the O-coordinated alcohol product in F. This is a clearly favorable process (ΔG = −7 kcal/mol) with a barrier of 4 kcal/mol (TS EF ), from E to F. The cycle is closed by the release of the product (1phenylethanol) and the coordination of a new acetophenone molecule, from F back to A, a process with a free energy balance of 5 kcal/mol.The least stable transition state is the one associated with the hydride attack on the carbonyl C atom (TS BC ), and the overall barrier for the catalytic cycle is 14 kcal/mol, measured from the most stable intermediate (D) to TS BC of the following cycle.

■ CONCLUSIONS
In conclusion, the hydrogenation of aromatic and aliphatic ketones using a bench-stable Mn(I) alkyl complex is described.The reaction proceeds under mild conditions (10 bar H 2 , 25 °C) and notably without the addition of any additives.Under these conditions, chemoselective hydrogenation of the carbonyl moiety of α,β-unsaturated carbonyls could be achieved.Interestingly, if the reaction was carried out at 60 °C, 1,2disubstituted CC bonds are additionally reduced, whereas a trisubstituted CC bond stays intact.A detailed reaction mechanism based on DFT calculations is presented.The precatalyst is activated by dihydrogen upon the migratory insertion of the alkyl group into the adjacent CO ligand and consecutive split of the coordinated dihydrogen.The catalytic reaction proceeds via an inner-sphere reaction upon substrate coordination, insertion, dihydrogen activation, and regeneration of the active species due to product release.
General Procedure for the Hydrogenation of Ketones.Inside an Ar-flushed glovebox, ketone substrate (0.38 mmol, 1 equiv) and 3 (3 mol %) were dissolved in 5 mL of Et 2 O and taken up in a syringe.The mixture was injected into a steel autoclave, and the reaction vessel was flushed three times with 10 bar H 2 .The reaction was stirred for the indicated time.The autoclave was depressurized and the sample was taken for GC−MS analysis.The reaction mixture was passed through a pad of silica.The silica pad was rinsed with Et 2 O, and the solvent was gently removed.
Computational Details.The computational results presented have been achieved in part using the Vienna scientific cluster.All calculations were performed using the Gaussian 09 software package. 14Geometry optimizations were obtained using the Perdew, Burke, and Ernzerhof (PBE)0 functional without symmetry constraints, a basis set consisting of the Stuttgart/Dresden ECP basis set 15 to describe the electrons of Mn, and a standard 6-31G(d,p) basis set 16 for all other atoms.The PBE0 functional uses a hybrid generalized gradient approximation, including 25% mixture of Hartree−Fock 17 exchange with DFT 18 exchange−correlation, obtained by the PBE functional. 19Transition-state optimizations were performed with the synchronous transit-guided quasi-Newton method developed by Schlegel et al., 20 following extensive searches of the potential energy surface.Frequency calculations were performed to confirm the nature of the stationary points, yielding one imaginary frequency for the transition states and none for the minima.Each transition state was further confirmed by following its vibrational mode downhill on both sides and obtaining the minima presented on the energy profiles.The electronic energies were converted to free energy at 298.15 K and 1 atm using zero-point energy and thermal energy corrections based on the structural and vibration frequency data calculated at the same level.The free-energy values presented were corrected for dispersion by means of the Grimme DFT-D3 method, 21 with the Becke and Johnson short-distance damping. 22olvent effects (Et 2 O) were considered in all the calculations using the polarizable continuum model initially devised by Tomasi and coworkers, 23 with the radii and nonelectrostatic terms of the SMD solvation model developed by Truhlar et al. 24 ■ ASSOCIATED CONTENT * sı Supporting Information The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.organomet.1c00161.

■ ACKNOWLEDGMENTS
Financial support by the Austrian Science Fund (FWF) is gratefully acknowledged (project no.P 33016-N).Centro de Química Estrutural acknowledges the financial support of Fundacaõ para a Ciencia e Tecnologia (UIDB/00100/2020).

Figure 1 .
Figure 1.Free-energy profile calculated for the hydrogenation of acetophenone.Free energies (kcal/mol) are referred to intermediate A. Scheme 3. Simplified Catalytic Cycle for the Hydrogenation of Ketones

Table 2
Scheme 1. Selected Mn(I) Precatalysts for Hydrogenation Reactions Scheme 2. Formation of the Catalytically Active Species Upon Reaction With Dihydrogen , entry 10), presumably due to the possible undesired redox reactions with the catalyst.

Table 1 .
Optimization Reaction for the Hydrogenation of 4-Fluoroacetophenone a
a b Conversion determined via GC−MS.c 36 h.