ACS Catalysis
Letter
developed a more active MnPNN catalyst, containing an
electron-rich phosphine and an electron-rich pyridine,
affording up to 10 000 TON in the AH of ketones.16 In
2019, Ding and Han reported a lutidine-based chiral PNN
ligand for Mn-catalyzed AH of ketones with improved ee
values.17 The substrate scope was impressive in this study. In
comparison,18−20 chiral PNP ligand would be a promising
category of ligand for controlling stereoselectivity for Mn(I)-
catalyzed hydrogenation of carbonyls.21 Much of the work in
this area has been carried out by Kirchner and Beller. Kirchner
and co-workers prepared a Mn/PNP’ complex with imine
coordination and applied this catalyst in the transfer hydro-
genation of ketones.22 Moderate enantioselectivities (20%−
85% ee) were obtained. In the same year, Beller reported the
application of a chiral PNP pincer ligand in Mn-catalyzed
direct AH of ketone.23 Dialkyl ketones were hydrogenated with
moderate enantioselectivities (30%−84% ee). In our analysis,
the flexibility of the skeleton and the resulting unchained
conformation might be responsible for the insufficient
enantiomeric induction. On the basis of our experiences in
ligand design and homogeneous hydrogenation, we rational-
ized that increasing the rigidity of the backbone by introducing
a 7-membered ring with a ferrocene moiety in fixed
conformation would result in the desired enantioinduction.
According to this philosophy in ligand design, a series of
ferrocene-based chiral PNP’ ligands were readily synthesized
readily (Scheme 1). From commercially available Ugi’s amine,
varied with respect to conversion and enantioselectivity.
Complex Mn/5a, with two phenyl groups on each of its
phosphorus atoms, gave the best results (Table 1, entry10).
¶
Table 1. Screening of Mn Catalysts
¶
Reaction conditions: catalysts were prepared by mixing PNP ligands
with Mn(CO)5Br in toluene at 110 °C; 7a (0.1 mmol, 0.1 M), catalyst
a
(0.001 mmol), KOtBu (0.005 mmol), MeOH (1 mL). Conversions
b
1
were determined by H NMR. ee values were determined HPLC,
c
d
respectively. Acetophenone (1 mmol), MeOH (1 mL). 2 mol %
KOH was applied as base, reaction time 24 h at room temperature.
Reaction carried out with 0.05 mol % catalyst.
Scheme 1. Synthesis of Ferrocene-Based Chiral PNP
Ligands
e
Increasing the concentration of the reaction mixture did not
bring significant changes (entry 7). After screening of different
solvents and bases (see SI), we finally obtained the optimal
condition: using Mn/5a and potassium hydroxide, the AH of
acetophenone resulted in full conversion and 95% ee in
methanol at room temperature (entry 8). However, the
catalytic efficiency was dramatically decreased in the absence
of base (Table S2, entry 21). Under minor-modified
conditions, the turnover number (TON) of this reaction
could reach 2000 (Table 1, entry 9), demonstrating a high
catalytic efficiency.
The reaction scope was investigated under the optimal
conditions (Table 2). In general, alkyl aryl ketones are
hydrogenated with excellent enantioselectivity, with the ee
values for most of the substrates greater than 95%. The
substituents on the phenyl group, regardless of the position,
had significant influence on the enantioselectivity, although
steric hindrance on the ortho-position led to a decrease in yield
(8c and 8d). Likewise, the electronic property of the aryl group
(i.e., electron-rich or electron-poor), did not create obvious
differences in enantiomeric discrimination. However, increas-
ing the steric hindrance on the phenyl slightly lowered the ee’s
(8p and 8r). Heteroaromatic substrates, with their potential to
cause inhibition of hydrogenation through metal coordination,
were compatible in this catalytic system. Substrates with
different alkyl groups also gave desired enantioselectivities and
reactivities (8aa− 8ag). To our delight, dialkyl ketone 8ah and
8ai were hydrogenated smoothly under the reaction conditions
with high enantioselectivities. Ketone with a lactam functional
group was hydrogenated with remarkably high diastereose-
lectivity (8aj), suggesting the potential application of this
a four-step synthesis gave the targeting ligands in good yields.
The modular design enables high tunability on both P sides,
making a mini library of ligands possible for fast screening.
With these ligands in hand, we herein report highly
enantioselective hydrogenation of ketones with a broad reaction
scope and high efficiency (>95% ee, >1000 TON)
Complexation of these ligands with Mn(CO)5Br in boiling
toluene yielded the Mn/PNP catalysts. However, PNP ligand
5c, with two tert-butyl groups on one phosphorus atom, failed
to form a tridentate complex. This was probably due to steric
hindrance for complexation with the manganese precursor (for
details, see SI). These in situ generated Mn complexes were
applied in the AH of acetophenone in methanol. A catalytic
amount of potassium tert-butoxide (5 mol %) was applied as
additive. We found that the performance of each complex
13795
ACS Catal. 2020, 10, 13794−13799