Design of Ru(II)-NHC-Diamine Precatalysts Directed by Ligand Cooperation: Applications and Mechanistic Investigations for Asymmetric Hydrogenation

Article abstract of DOI:10.1021/jacs.0c00985

A modular synthesis of Ru(II)-NHC-diamine complexes from readily available chiral N-heterocyclic carbenes (NHCs) and chiral diamines is disclosed for the first time. The well-defined Ru(II)-NHC-diamine complexes show unique structure and coordination chem

Full text of DOI:10.1021/jacs.0c00985

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Article
Design of Ru(II)-NHC-Diamine Precatalysts Directed by Ligand Cooperation:
Applications and Mechanistic Investigations for Asymmetric Hydrogenation
Wei Li, Tobias Wagener, Lars Hellmann, Constantin G. Daniliuc,
Christian Mück-Lichtenfeld, Johannes Neugebauer, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00985 • Publication Date (Web): 20 Mar 2020
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Journal of the American Chemical Society
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Design of Ru(II)-NHC-Diamine Precatalysts Directed by Ligand Coop-
eration: Applications and Mechanistic Investigations for Asymmetric
Hydrogenation
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Wei Li,* Tobias Wagener, Lars Hellmann, Constantin G. Daniliuc, Christian Mück-Lichtenfeld,
Johannes Neugebauer,* and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Mꢀnster,
Germany
ABSTRACT: A modular synthesis of Ru(II)-NHC-diamine complexes from readily available chiral N-heterocyclic carbenes
(NHCs) and chiral diamines is disclosed for the first time. The well-defined Ru(II)-NHC-diamine complexes show unique
structure and coordination chemistry including an unusual tridentate coordination effect of 1,2-diphenylethylenediamine.
The isolated air-and moisture-stable Ru(II)-NHC-diamine complexes act as versatile precatalysts for the asymmetric hy-
drogenation of isocoumarines, benzothiophene 1,1-dioxides, and ketones. Moreover, based on the identification of reaction
intermediates by stoichiometric reactions and NMR experiments, together with the DFT calculations, a possible catalytic
cycle was proposed.
1. INTRODUCTION
diamine complexes would not only confirm the previous
proposal but also provide us a new platform to design
NHC-based catalysts directed by the ligand cooperation
concept. Herein, we report the synthesis and structure de-
termination of the chiral ruthenium precatalysts and re-
lated complexes (Scheme 1, b). Unprecedented procedures
for the preparation of air- and moisture-stable Ru(II)-
NHC-diamine precatalysts from commercial or other read-
ily available materials were described in this endeavor. Fur-
thermore, the newly established catalysts were successfully
applied to asymmetric hydrogenations of several im-
portant substrate classes. In the end, detailed mechanistic
studies of asymmetric hydrogenation catalyzed by the
Ru(II)-NHC-diamine complexes was conducted.
The development of new chiral catalysts is key to im-
prove efficiency and selectivity in asymmetric catalysis,
even to discover new modes of catalysis and new reactions.1
Conventionally, the chiral environment of a transition-
metal catalyst is optimized by the modification of the
structure of a single chiral ligand. However, this strategy is
limited to ligand structures which can be readily accessed.
Even though much endeavor and time is spent on the lig-
and optimization, satisfactory results are often out of reach.
The utilization of ligand cooperation is an alternative strat-
egy, which has the potential to accelerate the optimization
process through a simple mix of two different chiral ligands
(Scheme 1, a). Remarkably, the introduction of a second,
readily available ligand not only adds a new tunable site
but also offers a practical way to avoid the tedious syn-
thetic problems caused by the modification of a compli-
cated ligand.2
Scheme 1. Ligand Cooperation Strategy for the Design
of New Chiral Catalysts
Noyori’s elegant Ru(II)-bisphosphine-diamine catalyst is
a representative example utilizing the ligand cooperation
concept (Scheme 1, b).3 Since then, the cooperation of chi-
ral phosphines and chiral diamines was applied widely in
asymmetric catalysis. Nevertheless, novel cooperative sys-
tems beyond phosphine-type ligands has been rarely inves-
tigated for late transition metals.2,4 Inspired by Noyori’s
catalyst and our ongoing interest in N-heterocyclic car-
benes (NHCs),5,6 we recently reported a new combination
of chiral NHC and chiral diamine ligands for the Ru(II)-
catalyzed enantioselective hydrogenation of isocouma-
rins.7 However, the proposed Ru(II)-NHC-diamine species
was only supported by control experiments. Undoubtedly,
the isolation and characterization of the Ru(II)-NHC-
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2. RESULTS AND DISCUSSION
chromatography on silica gel in 3% yield and 40% yield,
1
respectively. In contrast, the combination of (R,R)-
SINpEt∙HBF4, and (S,S)-DPEN gave only trace amounts of
Ru(II)-NHC-diamine complexes thus demonstrating a
strong matched/mismatched effect. X-ray and NMR anal-
yses revealed that ruthenium complex C2 is structurally
similar to complex C1. Unexpectedly, ruthenium mono-
chloride C3 contains an unusual tridentate binding of the
diamine through an additional cyclometalation. This
metal–carbon bond is formed through C–H activation at
the 2-positon of the phenyl ring (13C NMR shift: δ 176.5 in
toluene-d8).10 Similar to C1 and C2, the chelating NHC lig-
and in C3 binds via carbene coordination and η2-naphthyl
coordination. Despite the polar carbon–metal bond, com-
plex C3 is not sensitive to air and moisture in the solid state.
However, C3 decomposes in solution over time. C3 was
also confirmed to remain a single conformer in solution by
NMR spectroscopy (in C6D6, toluene-d8, or THF-d8). It is
noteworthy that the addition of an excess of HCl (4.0 M in
dioxane) to the C3 solution (n-hexane, toluene, or THF)
did not convert the mono-chloride complex to dichloride
complex C2. Likewise, treatment of dichloride C2 with a
strong base like NaOt-Bu did not yield mono-chloride C3.
According to the same one pot procedure, precatalyst C4,
C4a, C5 and C6 were prepared (Table 1).
2.1. Synthesis and Structure of Ru(II)-NHC-Diamine
Complexes. First, we developed a stepwise way to install
a chiral NHC ligand and a chiral diamine ligand into one
ruthenium complex (Figure 1). We hypothesized that silver
carbene complexes could serve as carbene transfer agents
for the synthesis of the ruthenium complexes as this strat-
egy had previously been used for the synthesis of palladium
and gold complexes.8 The NHC silver complex C0 was pre-
pared from imidazolinium chloride (R,R)-INpEt∙HCl and
Ag2O according to the literature.9 The desired heteroleptic
complex C1 was obtained in 56% overall yield following the
transmetallation of the NHC from silver complex C0 to the
ruthenium precursor and subsequent replacement of ben-
zene with (R,R)-1,2-diphenylethylenediamine (DPEN). The
isolated complex C1 is stable to air and moisture and can
be stored in an ordinary vial for months. X-ray crystallo-
graphic analysis of C1 indicated a distorted octahedral ge-
ometry of the ruthenium center with a trans-dichloro ge-
ometry. Interestingly, the NHC ligand is acting as a chelate
ligand with a dative carbene bond and an additional η2-co-
ordination of the naphthyl ring to ruthenium. This was fur-
ther verified by the distinct NMR signals at δ 4.99 (1H NMR,
HC12), δ 92.0 (13C NMR, C11), and δ 72.7 (13C NMR, C12).
The NMR analysis of trans-RuCl2(INpEt)(DPEN) C1 shows
that C1 exists as a single conformer in solution (C6D6,
CDCl3, or THF-d8).
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Figure
1.
Synthesis
and
structure
of
trans-
RuCl2(INpEt)(DPEN) C1. Selected bond lengths (Å) and bond
angles (deg) of C1: Ru1–C1, 1.986(6); Ru1–N4, 2.135(5); Ru1–N3,
2.187(5); Ru1–C12, 2.218(5); Ru1–C11, 2.239(6); Ru1–Cl2,
2.4265(16); Ru1–Cl1, 2.4266(16); C11–C12 1.418(8); C1–Ru1–N3,
177.6(3); N4–Ru1–N3, 78.46(18); Cl2–Ru1–Cl1, 62.53(5); C12–
Ru1–C11, 37.1(2).
Figure
2.
Synthesis
and
structure
of
trans-
Furthermore, we developed a one-pot procedure for the
synthesis of Ru(II)-NHC-diamine complexes (Figure 2).
The direct isolation of the Ru(II)-NHC-diamine species
formed in situ by reacting [Ru(2-methylallyl)2(COD)],
NHC precursor (R,R)-SINpEt∙HBF4, diamine ligand (R,R)-
DPEN and NaOt-Bu in n-hexane was unsuccessful. We ra-
tionalized that the introduction of a chloride ligand might
stabilize the ruthenium complex, thus simplifying the pu-
rification and isolation. After quenching the reaction with
HCl solution (4.0 M in dioxane), ruthenium dichloride C2
and ruthenium mono-chloride C3 were isolated by flash
RuCl2(SINpEt)(DPEN) C2 and RuCl(SINpEt)(DPEN) C3. Sel-
ected bond lengths (Å) and bond angles (deg) of C2: Ru1–C1,
1.984(3); Ru1–N4, 2.146(3); Ru1–N3, 2.214(2); Ru1–C12, 2.222(3);
Ru1–C11, 2.229(2); Ru1–Cl2, 2.4205(7); Ru1–Cl1, 2.4211(7); C11–
C12, 1.423(5); C1–Ru1–N4, 103.22(11); C1–Ru1–N3, 172.73(11); N4–
Ru1–N3, 78.58(9); C12–Ru1–C11, 37.30(12); Cl2–Ru1–Cl1,
160.63(2). Selected bond lengths (Å) and bond angles (deg) of
C3: Ru1–C1, 1.953(9); Ru1–C32, 2.061(9); Ru1–N4, 2.153(7); Ru1–
C12, 2.192(8); Ru1–N3, 2.203(7); Ru1–C11, 2.206(7); Ru1–Cl1,
2.549(2); C1–Ru1–C32, 99.3(3); C1–Ru1–N3, 173.8(3); N4–Ru1–
N3, 75.5(3); C32–Ru1–Cl1, 160.0(3).
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Journal of the American Chemical Society
Table 1. Catalyst Test for the Enantioselective Hydro-
genation of Isocoumarinsa
scope of isocoumarin derivatives was hydrogenated while
tolerating differential position and electronic nature of the
substituents as well as functional groups like thiophenes or
methyl ethers (see supporting information for further de-
tails).
1
2
3
4
5
6
7
8
Next, we explored the enantioselective hydrogenation of
benzothiophene 1,1-dioxides. The chiral 2,3-dihydroben-
zothiophene 1,1-dioxide framework is a versatile motif in
the pharmaceutical research and agrochemistry.14 Recently,
the Pfaltz group reported a novel way to prepare chiral 2,3-
dihydrobenzothiophene 1,1-dioxides by the iridium-cata-
lyzed asymmetric hydrogenation of substituted benzothi-
ophene 1,1-dioxides.15,16 Remarkably, high reactivity and en-
antioselectivity of the hydrogenation of substituted ben-
zothiophene 1,1-dioxides were obtained with the ruthe-
nium complex C3 (Scheme 2). After optimizing the reac-
tion conditions, 2-methylbenzo[b]thiophene 1,1-dioxide 3a
was smoothly reduced under mild conditions using 0.5 mol%
of precatalyst C3 and a low H2 pressure (5 bar) furnishing
the corresponding product 4a in 99% yield and 97:3 e.r.
The absolute configuration of 4a was determined to be S
by comparing its optical rotation data to the literature.15
The effect of substituents on the phenyl ring was probed.
Electron-poor substrate 3d provided the corresponding
product 4d with excellent enantioselectivity and in a good
yield, while the electron-rich substrates provided slightly
lower e.r. values (4b and 4c). Halogen substituents F, Cl,
and Br were well-tolerated under the mild reaction condi-
tions (4e–g). Substrates containing longer alkyl chains and
functional groups were hydrogenated with good e.r. values
and excellent yields (4h–j). Poor enantioselectivity was ob-
served when 2-phenylbenzothiophene 1,1-dioxide was used,
due to the deprotonation of the product’s chiral center un-
der the basic conditions.
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entry
precatalyst
time (h)
yield (%)b
trace
trace
80
e.r.c
N.D.
N.D.
98:2
1
C1
C2
24
24
18
18
18
18
18
2
3
4
5
6
7
C3
C4
C5
83
98.5:1.5
97:3
80
C6
C4a
78
96:4
65
72:28
aReactions were carried out with 1a (0.2 mmol), the indi-
cated ruthenium complex (0.004 mmol, 2 mol%), and NaOt-
Bu (0.02 mmol, 10 mol%) in n-hexane (4.0 mL) under 50 bar
H2 at 15 oC for the indicated time. bIsolated yields. cDetermined
by HPLC analysis using a chiral stationary phase.
2.2. Applications of Ru(II)-NHC-Diamine Com-
plexes in the Catalytic Asymmetric Hydrogenation.
The isolated ruthenium complexes were then tested as
precatalysts for the enantioselective hydrogenation. Asym-
metric hydrogenation of 3-substituted isocoumarins is a
direct way to form chiral 3-substituted 3,4-dihydroisocou-
marins which represents a key motif in a wide range of nat-
ural products and biological active molecules.11,12 Using the
isolated precatalysts, the enantioselective hydrogenation
of 3-substituted isocoumarines was probed (Table 1). A
strong base like NaOt-Bu was determined to be necessary
to activate the precatalysts. Only trace amounts of product
were obtained in the presence of dichloride ruthenium
complex C1 or C2 (Table 1, entry 1 and 2). Notably,
RuCl(SINpEt)(DPEN) C3 exhibited a good activity under
basic conditions (entry 3), giving the desired product 2a in
80% yield and 98:2 e.r.13 Next, variations on the chiral dia-
mine ligand were investigated. Complex C4 with (1R,2R)-
1,2-di-p-tolylethane-1,2-diamine gave slightly better results,
delivering the product in 83% yield and 98.5:1.5 e.r. (entries
4). Further para-substituents on the diamine were tested
and gave comparable results (entries 5 and 6). However,
additional substituents in the ortho position turned out to
be unfavorable for the enantioselective hydrogenation of
1a (entry 7). Diamines containing meta-substituents were
previously tested through the in-situ system, giving lower
enantioselectivities and yields.7a We then explored the sub-
strate scope of the reaction using the optimized conditions
(Table 1, entry 4) as shown in the SI (Page S36). A broad
Scheme 2. Ruthenium-Catalyzed Asymmetric Hydro-
genation of Benzothiophene 1,1-Dioxidesa
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