Asymmetric transfer hydrogenation of arylketones catalyzed by enantiopure ruthenium(II)/pybox complexes containing achiral phosphonite and phosphinite ligands

Article abstract of DOI:10.3390/molecules25040990

A family of complexes of the formula trans-[RuCl₂(L)(R-pybox)] (R-pybox = (S,S)-ⁱPr-pybox, (R,R)-Ph-pybox, L = monodentate phosphonite, PPh(OR)₂, and phosphinite, L = PPh₂(OR), ligands) were screened in the catalytic asymmetric transfer hydrogenation of acetophenone, observing a strong influence of the nature of both the R-pybox substituents and the L ligand in the process. The best results were obtained with complex trans-[RuCl₂{PPh₂(OEt)}{(R,R)-Ph-pybox}] (2c), which provided high conversion and enantioselectivity (up to 96% enantiomeric excess, e.e.) for the reduction of a variety of aromatic ketones, affording the (S)-benzylalcohols.

Full text of DOI:10.3390/molecules25040990

molecules
Article
Asymmetric Transfer Hydrogenation of Arylketones
Catalyzed by Enantiopure Ruthenium(II)/Pybox
Complexes Containing Achiral Phosphonite and
Phosphinite Ligands
Miguel Claros, Eire de Julián, Josefina Díez, Elena Lastra and M. Pilar Gamasa *
Departamento de Química Orgánica e Inorgánica-IUQOEM (Unidad Asociada al CSIC), Centro de Innovación
en Química Avanzada (ORFEO-CINQA), Universidad de Oviedo, E-33006 Oviedo, Principado de Asturias,
Spain; clarosca.mi@gmail.com (M.C.); eiredejulian@gmail.com (E.d.J.); jdv@uniovi.es (J.D.); elb@uniovi.es (E.L.)
* Correspondence: pgb@uniovi.es; Fax: +34-985103446
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Rafael Chinchilla
Received: 28 January 2020; Accepted: 18 February 2020; Published: 23 February 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A family of complexes of the formula trans-[RuCl2(L)(R-pybox)] (R-pybox = (S,S)-iPr-pybox,
(R,R)-Ph-pybox, L = monodentate phosphonite, PPh(OR)2, and phosphinite, L = PPh2(OR), ligands)
were screened in the catalytic asymmetric transfer hydrogenation of acetophenone, observing a strong
influence of the nature of both the R-pybox substituents and the L ligand in the process. The best
results were obtained with complex trans-[RuCl2{PPh2(OEt)}{(R,R)-Ph-pybox}] (2c), which provided
high conversion and enantioselectivity (up to 96% enantiomeric excess, e.e.) for the reduction of a
variety of aromatic ketones, affording the (S)-benzylalcohols.
Keywords: asymmetric catalysis; transfer hydrogenation; alcohols; ruthenium; pybox; phosphonite
ligands; phosphinite ligands
1. Introduction
Asymmetric transfer hydrogenation (ATH) of prochiral ketones catalyzed by transition metal
complexes, displaying well designed chiral ligands, is currently recognized as a powerful and versatile
tool to access enantiopure alcohols [1–13]. In this area, it must be mentioned that the studies focused on
the asymmetric transfer hydrogenation (ATH) of ketones using ruthenium(II) complexes bearing PPh3
and enantiopure C2 or C1 symmetry N,N,N-donor ligands with NH functionality (see Figure 1A–E). Thus,
the groups of Zhang [14] and Beller [15] described the use of in situ-generated ruthenium complexes,
containing bis(oxazolinylmethyl)amine (ambox ligand) (Figure 1A) [14] and pyridine(bis)imidazolines
(pybim ligand) (Figure 1B) [15], respectively. On the other hand, it has also been reported that isolated
ruthenium complexes with C1-symmetry N,N,N donor ligands (Figure 1C–E) [16–18] efficiently catalyze
the asymmetric transfer hydrogenation of aryl ketones. In all of these examples, the presence of the NH
functionality in the enantiopure ligand is a requisite for achieving high reactivity and enantioselectivity.
We have also made some contributions in this field, particularly on the synthesis and catalytic
activity of group 8 metal complexes based on enantiopure N,N,N-ligands, lacking the N-H functionality.
In this context, we reported the complexes cis-[MCl2(L)(R-pybox)] (M = Ru, Os, L = phosphane) and
trans-[MCl2(L)(R-pybox)] (M = Ru, L = phosphane, phosphite; M = Os, L = phosphite) and studied
their catalytic activity toward the asymmetric transfer hydrogenation of aryl ketones. Interestingly, the
efficiency of these catalysts depends not only on the metal and the chiral ligand but also on the nature
of the auxiliary P-donor ligand [19
,20]. Thus, we found that the reduction of different aryl ketones was
best achieved using the combination of Ru(II)/(R,R)-Ph-pybox/phosphane (95%–99% conversion; up to
Molecules 2020, 25, 990; doi:10.3390/molecules25040990
www.mdpi.com/journal/molecules

Molecules 2020, 25, 990
2 of 9
95% e.e.) and Os(II)/(S,S)-iPr-pybox)/phosphite (96%–99% conversion; up to 94% e.e.). However, the
corresponding phosphite ruthenium and phosphane osmium complexes led to lower enantiomeric
excess. The influence of the P-donor ligand was also analyzed by Beller and col. using mixtures of
[RuCl2(η
6-C6H6)]/pybim and monodentate or bidentate phosphanes as the catalyst [15]. In the light of
these findings, we found of interest to move to explore further combinations of ruthenium/osmium
complexes with other phosphorous ligands with different electronic demand and steric requirement.
Continuing our studies on the ATH of ketones using ruthenium(II) complexes, containing pybox
derivatives as the chiral auxiliary and phosphane/phosphite as the achiral phosphorous ligand, we
reported the ATH reaction of aryl ketones catalyzed by ruthenium complexes trans-[RuCl2(L){(S,S)-
iPr-pybox}] and trans-[RuCl2(L){(R,R)-Ph-pybox}], containing monodentate phosphonite (L = PPh(OR)2)
and phosphinite (L = PPh2(OR)) ligands (Figure 1F,G) [21]. Such ligands can be placed between
phosphanes and phosphites in a donor-acceptor ligand scale.
Figure 1. Selected ruthenium(II) complexes, bearing enantiopure C2 or C1 symmetry N,N,N-donor
ligands, used in asymmetric transfer hydrogenation (ATH) of ketones (Examples corresponding to
complexes A–E feature the N-H functionality; structures F–G lack the N-H functionality).
2. Results and Discussion
2.1. Ruthenium(II)/R-pybox Catalysts 1a–1c and 2a–2c
We explored the effectiveness of ruthenium(II) complexes
phosphonite (1a 2a) and phosphinite (1b 2b ) ligands [21], in the ATH reaction of aryl ketones.
showed a single set of signals for the
1–2 (Figure 1F,G), containing achiral
,
,
c,
,c
In accordance with their C2 symmetric structure, complexes 1–2
two oxazoline fragments in the 1H and 13C{1H} NMR spectra. Therefore, the chloro ligands and the
L/pyridine ligands adopted a trans-arrangement.
Moreover, this stereochemistry had been confirmed by single-crystal X-ray analysis for complexes
1a and 2c. An ORTEP-type view of these complexes is shown in Figure 1 (thermal ellipsoids were

Molecules 2020, 25, 990
3 of 9
shown at the 30% probability level, and hydrogen atoms were omitted for clarity), and selected bonding
data are collected in the Table S1 (Supporting Information).
Both structures exhibited a distorted octahedral geometry around the ruthenium atom, which
was bonded to the three nitrogen atoms (R-pybox; R = iPr (1a), Ph (2c)), to the phosphorous atom
(PPh(OMe)2 (1a), PPh2(OEt) (2c)), and to two chlorine atoms. The chlorine atoms were located in a
trans disposition with Cl(1)-Ru(1)-Cl(2) angles of 171.60(6) (1a) and 173.25(5)◦ (2c). The N(2)–Ru(1)–P(1)
angle was close to the linearity (178.3(2) (1a) and 177.76(15)◦ (2c)), and the Ru(1)–P(1) distances were
2.2625(18) (1a) and 2.2829(13) (2c) Å. The Ru(1)–N(1), Ru(1)–N(2), and Ru(1)–N(3) distances, as well
as the N–Ru(1)–N bond angles, fell in the range observed for other related ruthenium(II) pybox
complexes [22,23] (see Table S1, Supporting Information).
2.2. Catalytic Asymmetric Transfer Hydrogenation of Ketones
Then, the above-reported complexes were tested towards the ATH of acetophenone. Thus, Table 1
summarizes the conversion of acetophenone into enriched 1-phenylethanol using the ruthenium(II)
(S,S)-iPr-pybox) (
1) and (R,R)-Ph-pybox (2) catalysts. The electronic nature and steric demand [24,25]
(Tolman electronic parameter (TEP) and cone angles) of the achiral auxiliary phosphonite and
phosphinite ligands used in this report were between those of the phosphane and phosphite ligands,
already studied by us in the ATH of ketones [19].
Table 1. Asymmetric Transfer Hydrogenation of Acetophenone Catalyzed by Ruthenium(II) Complexes
1a–c and 2a–c.
Catalyst
Time (min)
Conv. (%) a
e.e. (%) a
[RuCl2{PPh(OMe)2}(iPr-pybox)] (1a)
1
2
3
4
5
6
7
8
9
15
90
15
15
15
90
15
90
15
63
97
96
95
67
98
48
92
95
16 (R)
20 (R)
43 (R)
62 (R)
5 (S)
11 (S)
46 (S)
46 (S)
63 (S)
[RuCl2{PPh2(OMe)}(iPr-pybox)] (1b)
[RuCl2{PPh2(OEt)}(iPr-pybox)] (1c)
[RuCl2{PPh(OMe)2}(Ph-pybox)] (2a)
[RuCl2{PPh2(OMe)}(Ph-pybox)] (2b)
[RuCl2{PPh2(OEt)}(Ph-pybox)] (2c)
a
Determined by GC with a Supelco β-DEX 120 chiral capillary column.
In a typical experiment, the ruthenium catalyst precursor 1,2 (0.01 mmol, 0.2 mol%) was added to
a solution containing 5 mmol of acetophenone in 45 mL of 2-propanol under an argon atmosphere,
and the solution was stirred initially for 15 min at 82 ◦C. After this time, a solution of 0.24 mmol of
KOtBu in 5 mL of 2-propanol (ketone/catalyst/KOtBu ratio = 500:1:24) was added, and the resulting
mixture was heated for 15 min and then monitored by gas chromatography using a chromatograph
with a Supelco β-DEX 120 chiral capillary column (90 min of stirring time was used in some instances;
see Table 1, entries 2,6,8).
From the results displayed in Table 1, several features worth attention: i) All of the complexes
were active towards the asymmetric reduction of acetophenone, the conversion varying from moderate
(48%–67%, entries 1,5,7) to high (95%–96%, entries 3,4,9) after 15 min of reaction. ii) The efficiency of the
catalyst depended greatly on the auxiliary achiral P-ligand (phosphonite vs. phosphinite). Thus, the
phosphinite complexes 1b
3,4,7,8,9 vs. 1,2,5,6). The values of asymmetric induction obtained were in accordance with the Tolman
electronic parameter (cm−1) and the cone angles (deg) of these achiral ligands [24
25]. iii) Complexes
–c/2b–c were notably superior to the phosphonite complexes 1a/2a (entries
,
1

Molecules 2020, 25, 990
4 of 9
and 2 were able to selectively convert acetophenone into (R)- and (S)-1-phenylethanol, respectively.
Under these conditions tested, the chiral ligand did not significantly affect the efficiency of the reaction
(iPr-pybox, entries 1–4; Ph-pybox, entries 5–9).
Therefore, once the basic reaction conditions were defined, we carried out the optimization of the
reduction of acetophenone using the complex [RuCl2{PPh2(OEt)}(Ph-pybox)] (2c) as catalyst (Table 2).
The following parameters were explored: i) Catalyst loading (entries 1–4): First of all, the amount of
catalyst was varied in the range of 0.1–0.4 mol% (entries 1–4), starting from the basic reaction conditions
(entry 1; ketone/KOtBu ratio of 500:24; 50 mL of 2-propanol). The highest e.e. value was obtained when
0.3 mol% of catalyst was employed (entry 3). Lower ratio of catalyst (0.2 and 0.1 mol%; entries 1–2)
required longer reaction times and/or led to poorer enantiomeric excess, while a little decrease of the
e.e. was observed with 0.4 mol% of catalyst (entry 4). ii) Concentration (entries 5, 6): Then, we studied
the effect of the amount of 2-propanol and found a notable improvement of both conversion and
enantioselectivity as the total amount of 2-propanol increased from 50 mL (entry 3) to 75 mL (entries 5,
6). iii) Base (entries 5–11): Taking the entries 5, 6 as the reference, some other bases were explored
(entries 7–11). We found that KOtBu, NaOH, and NaOtBu behaved more efficiently than KOH and
Cs2CO3 (entries 5–9 vs. 10, 11). Among the former, the base NaOtBu seemed to be slightly superior
(entries: 8, 9 vs. 5, 6). iv) Ketone/catalyst/NaOtBu ratio (entries 8, 12, 13): Decreasing the ratio of base
from 500:1.5:24 (entry 8) to either 500:1.5:12 or 500:1.5:6 (entries 12, 13) resulted in a slightly higher e.e.
Table 2. Optimization of Reaction Conditions for Transfer Hydrogenation of Acetophenone Catalyzed
by Ruthenium Complex [RuCl2{PPh2(OEt)}(Ph-pybox)] (2c) a.
iPrOH
(mL)
Catalyst Loading
(mol %)
Time
(min)
Conversion
(%) b
e.e. (%)
(S) b
Base
Ketone/BaseRatio
1
2
3
4
5
6
7
8
9
10
11
12
13
a
0.2
0.1
0.3
0.4
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
50
50
50
50
75
75
75
75
75
75
75
75
75
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOH
NaOtBu
NaOtBu
KOH
500/24
500/24
500/24
500/24
500/24
500/24
500/24
500/24
500/24
500/24
500/24
500/12
500/6
15
30
15
15
5
15
10
5
10
30
30
5
95
79
91
93
91
97
95
97
97
95
95
96
97
63
67
70
66
87
83
83
89
86
67
78
92
90
Cs2CO3
NaOtBu
NaOtBu
5
Reactions were carried out at 82 ◦C using 5 mmol of acetophenone. Determined by GC with a Supelco
β
-DEX 120
b
chiral capillary column.
Once the reduction of acetophenone was optimized using 2c as a catalyst [26], the ATH of a
number of aryl ketones was studied, and the results are gathered in Table 3. In most cases, the reaction
required short reaction time (5–10 min) and took place with high conversion (around 90%) and excellent
enantioselectivity (87%–96% e.e.). Thus, this pattern was observed for acetophenone, propiophenone,
and 2-acetonaphthone (entries 1, 2 and 3), as well as for electron-rich 3- and 4-methoxyacetophenone
(entries 4 and 5) (3000–4000 TOF) [27]. On the other hand, increasing the steric demand of the substrate,
particularly that of the aryl group, had a great impact on the process in terms of both conversion and
enantiomeric excess. Thus, although the reduction of 2-methoxyacetophenone (entries 6 and 7) was
rather inefficient, isobutyrophenone could be transformed into the alcohol with high enantiomeric
excess and moderate (entry 8) or good conversion (entry 9).

Molecules 2020, 25, 990
5 of 9
Table 3. Transfer Hydrogenation of Ketones Catalyzed by Complex [RuCl2{PPh2(OEt)}(Ph-pybox)] (2c
)
under Optimized Conditions a.
Conversion (%) c
e.e. (%) (S) c
b
TOF (h−1
)
Ketone
Time (min)
1
5
3840
96
92
2
3
4
10
5
3040
3840
3920
97
96
98
96
87
90
5
5
5
3440
86
89
6
45
500
54
72
7
8
90
10
60
500
720
720
75
51
90
68
91
87
9
a
Reactions were carried out at 82 ◦C using 5 mmol of ketone and 2-propanol (75 mL), 0.015 mmol (0.3 mol %)
catalyst, and NaOtBu (acetophenone/catalyst/NaOtBu 500:1.5:12). Calculated TOF (turnover frequency) values at t
= 5 min. Determined by GC with a Supelco β-DEX 120 chiral capillary column.
b
c
Complexes
1
and
2
fulfilled the requirement to be precursors of active species in the catalytic
i
asymmetric transfer hydrogenation of ketones by hydrogen transfer from PrOH/base. Regarding
the stereochemical outcome, the observed results were in accordance with the established reaction
pathway [28–31]. Thus, the hydrogen transfer step had been proposed to occur through a four-membered
cyclic transition state, involving the metal-hydride and the ketone. Such a transition state would
result from i) chloride extraction and metal isopropoxide formation, ii) generation of metal hydride by
β-elimination of propanone (an inner-sphere mechanism), iii) loss of the second chloride to generate
a 16-electron metal hydride, iv) coordination of metal hydride and ketone. Then, the approach of
the ketone to the metal-hydride complex could occur in two ways, involving the re-face or si-face of
the ketone. Figure 2 illustrates the transition states in the case of (R,R)-pybox complexes, showing
that the steric repulsions of the oxazoline- and ketone-phenyl groups make transition state A lower in
energy than transition state
B, providing the (S)-alcohols preferentially [19,32]. Conversely, the use of
(S,S)-pybox complexes favored the formation of the corresponding (R)-alcohols.

Molecules 2020, 25, 990
6 of 9
Figure 2. Proposed transition states for the asymmetric transfer hydrogenation of aryl ketones.
3. Materials and Methods
3.1. General Comments
The reactions were performed under an atmosphere of dry argon using vacuum-line and standard
Schlenk techniques. The reagents were obtained from commercial suppliers and used without further
purification. Solvents were dried by standard methods and distilled under argon before use [19
The precursor complexes trans-[RuCl2(
2-C2H4){(S,S)-iPr-pybox}] and trans-[RuCl2( 2-C2H4){(R,R)-
Ph-pybox}] [33 34] and the complexes
2 [21] were prepared by reported methods. The 1H, 13C{1H}, and
,21].
η
η
,
1–
31P{1H} NMR spectra of complexes 1a–c and 2a– c were reported in the Supplementary Materials [21].
3.2. X-ray Crystal Structure Determination of Complexes 1a·2CHCl3 and 2c·2.5CH2Cl2
Suitable crystals for X-ray diffraction analysis were obtained by slow diffusion of n-hexane into a
solution of the complexes in chloroform (1a) or dichloromethane (2c). The most relevant crystal and
refinement data are collected in Table S2 in the Supporting Information.
The diffraction data of both complexes were recorded on an Oxford Diffraction Xcalibur Nova
(Agilent, Santa Clara, CA, USA) single-crystal diffractometer, using Cu-Kα radiation (λ = 1.5418 Å).
Images were collected at a 62 mm fixed crystal-detector distance, using the oscillation method, with
1◦ oscillation and variable exposure time per image (6.5–35 s (for 1a) and 30–110 s (for 2c)). The data
collection strategy was calculated with the program CrysAlis Pro CCD [35]. Data reduction and cell
refinement were performed with the program CrysAlis Pro RED [35]. Empirical absorption correction
was applied using the SCALE3 ABSPACK algorithm, as implemented in the program CrysAlis Pro
RED [35].
The software package WINGX [36] was used for space-group determination, structure solution,
and refinement. The structures were solved by Patterson interpretation and phase expansion using
DIRDIF [37]. In the crystals of 1a and 2c, 2CHCl3 (for 1a) or 2.5CH2Cl2 solvent molecules (for 2c) per unit
formula of the complex were present. For complex 2c also, other highly disordered solvent molecules
were found, which were impossible to refine using conventional discrete-atom models. To resolve
these issues, the contribution of solvent electron density was removed by SQUEEZE/PLATON [38].
Isotropic least-squares refinement on F2 using SHELXL2013 [39] was performed. During the final
stages of the refinements, all the positional parameters and the anisotropic temperature factors of
all the non-H atoms were refined. The H atoms were geometrically placed, riding on their parent
atoms with isotropic displacement parameters set to 1.2 times the Ueq of the atoms to which they were
attached (1.5 for methyl groups). For both complexes, the maximum residual electron density was
located near heavy atoms.
The function minimized was [w(Fo2
values are collected in the Table S2 in the Supporting Information) with
−
Fc2)/w(Fo2)]1/2, where w = 1/[
σ
2(Fo2) + (aP)2 + bP] (a and b
(Fo2) from counting statistics
σ

Molecules 2020, 25, 990
7 of 9
and P = (Max (Fo2, 0) + 2Fc2)/3. Atomic scattering factors were taken from the International Tables for
X-Ray Crystallography [40]. The crystallographic plots were made with PLATON [38].
CCDC 1,545,753 (1a·2CHCl3) and CCDC 1,545,754 (2c·2.5CH2Cl2) contain the supplementary
crystallographic data for this paper. These data could be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
3.3. General Procedure for Hydrogen Transfer Reactions
The ruthenium catalyst precursor 1, 2 (0.01 mmol) was placed in a three-bottomed Schlenk flask
containing 5 mmol of ketone in 45 mL of 2-propanol under an argon atmosphere. The solution was
heated at 82 ◦C for 15 min, and then a solution of 0.24 mmol of the base in 5 mL of 2-propanol was
added, and the reaction mixture stirred for the time given in Tables 1–3. The course of the reaction was
monitored by gas chromatography using a chromatography Agilent Model HP-6890 equipped with a
Supelco β-DEX 120 chiral capillary column. The enantiomeric ratio and the absolute configuration of
the major enantiomer were determined by GC (retention times) and optical rotations, respectively, and
compared with literature values. The resulting alcohols and the starting ketones were, in all cases, the
only products detected.
4. Conclusions
The present study showed that complexes featuring the combination Ru(II)/R-pybox [(S,S)-iPr-
pybox, (R,R)-Ph-pybox]/P-donor ligand (methoxy-phosphonites and methoxy- and ethoxy-phosphinites)
were active catalysts toward the ATH reaction of arylketones. The best results were obtained using
the complex trans-[RuCl2{PPh2(OEt)}{(R,R)-Ph-pybox}] (2c), providing (S)-benzylalcohols in high yield
(87%–98 %) and enantioselectivity (up to 96 % e.e.). These results were in the range of those previously
described using the complexes cis- and trans-[RuCl2(L) {(R,R)-Ph-pybox}] (L = PPh3, PiPr3) and were
superior to those obtained using the complexes with phosphite ligands trans-[RuCl2(L){(R,R)-Ph-pybox}]
(L= P(OMe)3, P(OPh)3)). On the other hand, they confirmed that the nature of the achiral P-donor
ligand did influence the efficiency of the catalyst. The values of asymmetric induction obtained were
in accordance with the Tolman electronic parameter (cm−1) and the cone angles (deg) of these achiral
ligands. Moreover, this report illustrated the utility of chiral ligands, lacking the N-H functionality, thus
complementing previous works of ATH processes based on chiral N-H ligands.
Supplementary Materials: The following are available online. GC spectra for all the reactions of the Tables 1–3.
Selected Bond Distances (Å) and Angles (deg) for Complexes 1a·2CHCl3 and 2c·2.5CH2Cl2 (Table S1). Crystal
Data and Structure Refinement for Complexes 1a·2CHCl3 and 2c·2.5CH2Cl2 (Table S2).
Author Contributions: M.C., E.d.J., and M.P.G. conceived and designed the experiments. M.C. and E.d.J.
performed the studies on the catalytic asymmetric transfer hydrogenation of ketones and synthesized the
complexes employed in this work. M.C. prepared the single crystals, and J.D. conducted the X-ray analysis of
complexes 1a and 2c. All authors have given approval to the final version of the manuscript. E.L. and M.P.G.
provided supervision, financial support via projects and wrote the paper.
Funding: This research was funded by the MICINN of Spain (CTQ2011-26481, CTQ2015-69583-R, and RTI2018-
094605-B-I00).
Acknowledgments: E. de J. thanks the FICYT (Principado de Asturias, Spain) for the award of corresponding
Ph.D. (BP12-158).
Conflicts of Interest: The authors have declared that there is no conflict of interest.
References and Notes
1.
2.
3.
Demmans, K.Z.; Olson, M.E.; Morris, R.H. Asymmetric Transfer Hydrogenation of Ketones with Well-Defined
Manganese(I) PNN and PNNP Complexes. Organometallics 2018, 37, 4608–4618. [CrossRef]
Chelucci, G.; Baldino, S.; Baratta, W. Recent Advances in Osmium-Catalyzed Hydrogenation and
Dehydrogenation Reactions. Acc. Chem. Res. 2015, 48, 363–379. [CrossRef]
Wang, D.; Astruc, D. The Golden Age of Transfer Hydrogenation. Chem. Rev. 2015, 115, 6621–6686. [CrossRef]

Molecules 2020, 25, 990
8 of 9
4.
Foubelo, F.; Nájera, C.; Yus, M. Catalytic asymmetric transfer hydrogenation of ketones: Recent advances.
Tetrahedron Asymmetry 2015, 26, 769–790. [CrossRef]
5.
6.
Ito, J.; Nishiyama, H. Recent Topics of Transfer Hydrogenation. Tetrahedron Lett. 2014, 55, 3133–3146. [CrossRef]
Bartoszewicz, A.; Ahlsten, N.; Martín-Matute, B. Enantioselective Synthesis of Alcohols and Amines by
Iridium-Catalyzed Hydrogenation, Transfer Hydrogenation, and Related Processes. Chem. Eur. J. 2013, 19,
7274–7302. [CrossRef] [PubMed]
7.
8.
9.
Malacea, R.; Poli, R.; Manoury, E. Asymmetric hydrosilylation, transfer hydrogenation, and hydrogenation
of ketones catalyzed by iridium complexes. Coord. Chem. Rev. 2010, 254, 729–752. [CrossRef]
Morris, R.H. Asymmetric hydrogenation, transfer hydrogenation and hydrosilylation of ketones catalyzed
by iron complexes. Chem. Soc. Rev. 2009, 38, 2282–2291. [CrossRef] [PubMed]
Wang, C.; Wu, X.; Xiao, J. Broader, Greener, and More Efficient: Recent Advances in Asymmetric Transfer
Hydrogenation. Chem. Asian J. 2008, 3, 1750–1770. [CrossRef]
10. Ikariya, T.; Blacker, A.J. Asymmetric Transfer Hydrogenation of Ketones with Bifunctional Transition
Metal-Based Molecular Catalysts. Acc. Chem. Res. 2007, 40, 1300–1308. [CrossRef]
11. Wu, X.F.; Xiao, J.L. Aqueous-phase asymmetric transfer hydrogenation of ketones—A greener approach to
chiral alcohols. Chem. Commun. 2007, 2449–2466. [CrossRef] [PubMed]
12. Gladiali, S.; Alberico, E. Asymmetric transfer hydrogenation: Chiral ligands and applications. Chem. Soc. Rev.
2006, 35, 226–236. [CrossRef] [PubMed]
13. Noyori, R.; Hashiguchi, S. Asymmetric Transfer Hydrogenation Catalyzed by Chiral Ruthenium Complexes.
Acc. Chem. Res. 1997, 30, 97–102. [CrossRef]
14. Jiang, Y.; Jiang, Q.; Zhang, X. A New Chiral Bis(oxazolinylmethyl)amine Ligand for Ru-Catalyzed Asymmetric
Transfer Hydrogenation of Ketones. J. Am. Chem. Soc. 1998, 120, 3817–3818. [CrossRef]
15. Enthaler, S.; Hagemann, B.; Bohr, S.; Anilkumar, G.; Tse, M.K.; Bitterlich, B.; Junge, K.; Erre, G.; Beller, M.
New Ruthenium Catalysts for Asymmetric Transfer Hydrogenation of Prochiral Ketones. Adv. Synth. Catal.
2007, 349, 853–860. [CrossRef]
16. Du, W.; Wang, Q.; Yu, Z. Ru(II) pyridyl-based NNN complex catalysts for (asymmetric) transfer hydrogenation
of ketones at room temperature. Chin. J. Catal. 2013, 34, 1373–1377. [CrossRef]
17. Ye, W.; Zhao, M.; Yu, Z. Ruthenium(II) Pyrazolyl–Pyridyl–Oxazolinyl Complex Catalysts for the Asymmetric
Transfer Hydrogenation of Ketones. Chem. Eur. J. 2012, 18, 10843–10846. [CrossRef]
18. Ye, W.; Zhao, M.; Du, W.; Jiang, Q.; Wu, K.; Wu, P.; Yu, Z. Highly Active Ruthenium(II) Complex
Catalysts Bearing an Unsymmetrical NNN Ligand in the (Asymmetric) Transfer Hydrogenation of Ketones.
Chem. Eur. J. 2011, 17, 4737–4741. [CrossRef]
19. Cuervo, D.; Gamasa, M.P.; Gimeno, J. New Chiral Ruthenium(II) Catalysts Containing 2,6-Bis(40-(R)-
phenyloxazolin-20-yl)pyridine (Ph-pybox) Ligands for Highly Enantioselective Transfer Hydrogenation of
Ketones. Chem. Eur. J. 2004, 10, 425–432. [CrossRef]
20. Vega, E.; Lastra, E.; Gamasa, M.P. Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Enantiopure
Osmium(II) Pybox Complexes. Inorg. Chem. 2013, 52, 6193–6198. [CrossRef]
21. De Julián, E.; Menéndez-Pedregal, E.; Claros, M.; Vaquero, M.; Díez, J.; Lastra, E.; Gamasa, P.; Pizzano, A.
Practical synthesis of enantiopure benzylamines by catalytic hydrogenation or transfer hydrogenation
reactions in isopropanol using a Ru-pybox catalyst. Org. Chem. Front. 2018, 5, 841–849. [CrossRef]
22. Menéndez-Pedregal, E.; Díez, J.; Manteca, A.; Sánchez, J.; Bento, A.C.; García-Navas, R.; Mollinedo, F.;
Lastra, E. Antitumor activity of new enantiopure pybox-ruthenium complexes. Dalton Trans. 2013, 42,
13955–13967. [CrossRef] [PubMed]
23. Cuervo, D.; Menéndez-Pedregal, E.; Díez, J.; Gamasa, M.P. Mononuclear ruthenium(II) complexes bearing
the (S,S)-iPr-pybox ligand. J. Organometal. Chem. 2011, 696, 1861–1867. [CrossRef]
24. Tolman, C.A. Steric effects of phosphorus ligands in organometallic chemistry and homogeneous catalysis.
Chem. Rev. 1977, 77, 313–348. [CrossRef]
25. Tolman, C.A. Electron donor-acceptor properties of phosphorus ligands. Substituent additivity. J. Am.
Chem. Soc. 1970, 92, 2953–2956. [CrossRef]
26. In order to get access to the corresponding (R)-alcohols, the optimization of the ATH reaction of ketones
using the iPr-pybox catalyst 1c was attempted. Unfortunately, following the optimization pattern described
for complex 2c (entry 13, Table 2) only moderate results (up to 96% conversion and 61% e.e.) could be
achieved in the reduction of acetophenone (unpublished results).

Molecules 2020, 25, 990
9 of 9
27. The reduction of aryl ketones with electron-withdrawing susbstituents (2-,3- and 4-bromoacetophenone)
using the catalyst [RuCl2{PPh2(OEt)}{(R,R)-Ph-pybox}] (2c) led to poorer results (<23% conversion and <
45% ee) (unpublished results).
28. Samec, J.S.M.; Bäckvall, J.-E.; Andersson, P.G.; Brandt, P. Mechanistic aspects of transition metal-catalyzed
hydrogen transfer reactions. Chem. Soc. Rev. 2006, 35, 237–248. [CrossRef]
29. Clapham, S.E.; Hadzovic, A.; Morris, R.H. Mechanisms of the H2-hydrogenation and transfer hydrogenation
of polar bonds catalyzed by ruthenium hydride complexes. Coord. Chem. Rev. 2004, 248, 2201–2237. [CrossRef]
30. Bäckvall, J.E. Transition metal hydrides as active intermediates in hydrogen transfer reactions. J. Organomet.
Chem. 2002, 652, 105–111. [CrossRef]
31.
Pà
mies, O.; Bäckvall, J.-E. Studies on the Mechanism of Metal-Catalyzed Hydrogen Transfer from Alcohols
to Ketones. Chem. Eur. J. 2001, 7, 5052–5058. [CrossRef]
32. Unfortunately, all attempts to synthesize the cis-dichloro (R,R)-Ph-pybox complexes containing phosphonite
and phosphinite ligands have failed, leading to either trans-dichloro isomers (2a-2c) or an uncharacterized
mixture of products, thus precluding a comparative study of the trans-complexes 2 and the corresponding
cis-complexes (unpublished results). cis.
33. Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Aoki, K.; Itoh, K. Chiral Ruthenium(II)–Bis(2-oxazolin-2-
yl)pyridine Complexes. Asymmetric Catalytic Cyclopropanation of Olefins and Diazoacetates. Bull. Chem.
Soc. Jpn. 1995, 68, 1247–1262. [CrossRef]
34. Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. New Chiral Ruthenium Bis(oxazolinyl)pyridine
Catalyst. Efficient Asymmetric Cyclopropanation of Olefins with Diazoacetates. J. Am. Chem. Soc. 1994, 116,
2223–2224. [CrossRef]
35. CrysAlisPro CCD and CrysAlisPro RED; Oxford Diffraction Ltd.: Abingdon, UK, 2008.
36. Farrugia, L.J. WinGX and ORTEP for Windows: An update. J. Appl. Crystallogr. 2012, 45, 849–854. [CrossRef]
37. Beurskens, P.T.; Beurskens, G.; de Gelder, R.; Smits, J.M.M.; García-Granda, S.; Gould, R.O.; Smykalla, C. The
DIRDIF Program System, Technical Report of the Crystallographic Laboratory; University of Nijmegen: Nijmegen,
The Netherlands, 2008.
38. Spek, A.L. PLATON: A Multipurpose Crystallographic Tool; University of Utrecht: Utrecht, The Netherlands, 2016.
39. Sheldrick, G.M. SHELXL2013: Program for the Refinement of Crystal Structures; University of Göttingen:
Göttingen, Germany, 2014.
40. International Tables for X-Ray Crystallography; Kynoch Press: Birminghan, UK, 1974; Volume 4.
Sample Availability: Samples of the compounds are not available from the authors.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).