Complementing Pyridine-2,6-bis(oxazoline) with Cyclometalated N-Heterocyclic Carbene for Asymmetric Ruthenium Catalysis

Article abstract of DOI:10.1002/anie.202004243

A strategy for expanding the utility of chiral pyridine-2,6-bis(oxazoline) (pybox) ligands for asymmetric transition metal catalysis is introduced by adding a bidentate ligand to modulate the electronic properties and asymmetric induction. Specifically, a ruthenium(II) pybox fragment is combined with a cyclometalated N-heterocyclic carbene (NHC) ligand to generate catalysts for enantioselective transition metal nitrenoid chemistry, including ring contraction to chiral 2H-azirines (up to 97 % ee with 2000 TON) and enantioselective C(sp³)?H aminations (up to 97 % ee with 50 TON).

Full text of DOI:10.1002/anie.202004243

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Accepted Article
Title: Complementing Pyridine-2,6-bis(oxazoline) with Cyclometalated
N-Heterocyclic Carbene for Asymmetric Ruthenium Catalysis
Authors: Long Li, Feng Han, Xin Nie, Yubiao Hong, Sergei Ivlev, and
Eric Meggers
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Complementing Pyridine-2,6-bis(oxazoline) with Cyclometalated
N-Heterocyclic Carbene for Asymmetric Ruthenium Catalysis
Long Li,+ Feng Han,+ Xin Nie,+ Yubiao Hong, Sergei Ivlev and Eric Meggers*
Dedicated to the 100th birthday of Rolf Huisgen
Abstract: A strategy for expanding the utility of chiral pyridine-2,6-
bis(oxazoline) (pybox) ligands for asymmetric transition metal
catalysis is introduced by adding a bidentate ligand to modulate the
enantioselective C(sp3)‒H amination reactions with up to 97% ee
and 50 TON (Figure 1c).
electronic properties and asymmetric induction. Specifically,
a
ruthenium(II) pybox fragment is combined with a cyclometalated N-
heterocyclic carbene (NHC) ligand to generate catalysts for
enantioselective transition metal nitrenoid chemistry, including ring
contraction to chiral 2H-azirines (up to 97% ee with 2000 TON) and
enantioselective C(sp3)‒H aminations (up to 97% ee with 50 TON).
The need for enantiopure chiral molecules in the chemical and
pharmaceutical industry leads to a continued quest for efficient
chiral metal catalyst for
a
wide variety of chemical
transformations.[1] Typically, chiral ligands serve as the basis for
the design of non-racemic chiral metal catalysts and a number of
especially versatile chiral ligand families have been dubbed
“privileged ligands”.[2]
Pyridine-2,6-bis(oxazolines) (pybox), first reported by
Nishiyama in 1989,[3] are a highly popular class of chiral ligands
for asymmetric transition metal catalysis (Figure 1a).[4] Their
chirality stems from readily available chiral 2-aminoalcohols and
they serve as strongly coordinating tridentate ligands for a large
variety of transition metals including lanthanides and actinides.
The C2-symmetry of the pybox ligand is desirable since it reduces
the number of stereoisomers after substrate coordination and
transition states during catalysis and provides satisfactory
enantioselectivities for many transformations. Conveniently, the
pybox ligand is just reacted with a metal salt of organometallic
precursor complex, often even in situ in the reaction mixture.
However, the pybox ligand has a severe limitation, namely the
fixation to three imine coordinating groups which, due to their
significant -backbonding properties, lead to a reduced electron
density at the central metal. This may be desired for Lewis acid
catalysis but not for transformations in which a higher electron
density at the metal center is beneficial.
Here we introduce a strategy to increase the utility of chiral
pybox metal complexes for asymmetric catalysis by
complementing pybox with a cyclometalated ligand. Specifically,
the addition of a cyclometalated N-heterocyclic carbene (NHC)
ligand to a ruthenium pybox complex leads to a strong modulation
of the catalytic properties (Figure 1b). This is demonstrated for the
enantioselective isomerization of isoxazoles to chiral 2H-azirines
with up to 97% ee and up to 2000 TON and for two
Figure 1. Chiral pybox metal complexes: Standard complexes, design principle
of this study, and realization.
We commenced our study with the objective to design novel
chiral ruthenium catalysts by complementing the established
pybox ligand with a strongly electron-donating bidentate ligand.
Ruthenium has been proven to show highly versatile catalytic
properties in many complexes but has a significantly lower cost
compared to other platinum-group members.[5] Furthermore,
important for this study, many synthetic methods exist for a
controlled stepwise incorporation of ligands into the coordination
sphere of ruthenium complexes. Thus, we started with the
ruthenium precursor complex [Ru(p-cymene)Cl2]2 and reacted it
with the imidazolium salts 1a-d to obtain the Ru complexes 2a-d
in 90-98% yields, in which ruthenium is cyclometalated with a N-
(4-nitrophenyl)-imidazo[1,5-a]pyridine ligand together with four
labile acetonitrile ligands (Scheme 1).[6] Since cyclometalated
ligands with ruthenium tend to be unstable, we incorporated a
nitro group into the phenyl moiety. Reaction of 2a-d with pybox
ligands 3a-d provided the ruthenium pybox complexes Ru1-Ru7
[*]
Dr. L. Li, F. Han, X. Nie, Y. Hong, Dr. S. Ivlev, Prof. Dr. E. Meggers
Fachbereich Chemie, Philipps-Universität Marburg
Hans-Meerwein-Straße 4, 35043 Marburg (Germany)
E-mail: meggers@chemie.uni-marburg.de
[+]
L. L., F. H. and X. N. contributed equally to this work.
Supporting information for this article can be found under: xxx
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as single diastereomers and single enantiomers in 85-96% yields
increased 74% ee. Gratifyingly, when we further added a
(see Supporting Information for more details). In these complexes, trimethylsilyl (TMS) group to the 3-position of the imidazo[1,5-
ruthenium coordinates to pybox in a meridional tridentate fashion,
is additionally cyclometalated to an imidazo[1,5-a]pyridine ligand,
and contains one acetonitrile ligand. The cyclometalated NHC
ligand is highly electron-donating and should change the
a]pyridine ligand, the ee value improved to excellent 97% (entry
5). Reducing the catalyst loading to 0.5 mol% did not affect the
enantioselectivity (entry 6). A further reduction to 0.1 mol% also
resulted in an unchanged 97% ee when the concentration was
electronic properties of the metal center significantly. Furthermore, increased and the temperature raised to 30 °C in order to speed
the phenyl moiety with its strong -donating ability is oriented
trans to the acetonitrile ligand and should lead to a significant
labilization due to the kinetic trans-effect. A crystal structure of
Ru4 is shown in Figure 2 and confirms this trans-effect[7] with an
elongated Ru-N bond to the coordinated acetonitrile (Ru2-N8 =
2.165 Å) .
up the reaction (entry 7). Even at 0.05 mol% Ru5 a full conversion
was achieved within 3 hours with 97% ee (entry 8). However, at a
further reduced catalyst loading of 0.01, the reaction proceeds
sluggishly with a reduced yield of 73% (7300 TON) but still
respectable 90% ee (entry 9). For comparison, catalysts bearing
a picolinate[9] (RuPic, entry 10) or two acetonitriles (RuMeCN,
entry 11) instead of the cyclometalated NHC displayed only very
low catalytic activity with no enantioselectivities, thus
demonstrating the crucial role of the cyclometalated NHC ligand
for both catalytic activity and asymmetric induction. A brief
substrate scope is shown in Figure 3 and demonstrates the
excellent suitability of Ru5 for the catalytic enantioselective ring
contraction to chiral 2H-azirines.
Table 1. Initial experiments and optimization of reaction conditions.[a]
Scheme 1. Catalyst synthesis.
Entry Catalyst Loading
(mol%)
Conc.
(M)
T (°C) t (h)
Yield
(%)[b]
ee (%)[c]
1
Ru1
Ru2
Ru3
Ru4
Ru5
Ru5
Ru5
Ru5
Ru5
RuPic
1.0
1.0
1.0
1.0
1.0
0.5
0.1
0.05
0.01
1.0
0.05
0.05
0.05
0.05
0.05
0.05
1.0
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
30
30
40
50
50
0.25
0.25
0.25
0.25
0.5
4
95
99
99
99
99
99
99
99
73
30
20
32
58
33
74
97
97
97
97
90
0
2
3
Figure 2. X-ray crystal structure of rac-Ru4. Only one enantiomer is shown. The
hexafluorophosphate anion is omitted for clarity.
4
5
6
Next, we investigated the catalytic properties of these new
types of ruthenium pybox complexes and found that they are
excellent catalysts for the ring contraction of isoxazoles to chiral
2H-azirines.[8] Starting with Ru1 (1 mol%) in which the oxazolines
bear an isopropyl group at the 4-position in a S-configuration,
resulted in a smooth conversion of the isoxazole 1 into the 2H-
azirine 2 within 15 min in 95% yield as determined by NMR, but
with a low enantioselectivity of 32% ee (Table 1, entry 1).
Replacing the isopropyl with a phenyl group (Ru2) resulted in an
improved 58% ee. Moving the phenyl moiety to the 5-position
(Ru3) resulted in a reduced ee of 33%. However, Ru4 bearing
phenyl moieties in both the 4- and 5-position resulted in an
7
3
8
1.0
3
9
4.0
3
10
11
0.05
0.05
24
RuMeCN 1.0
24
0
[a] Reaction conditions: Substrate 4a (0.1 mmol) in CHCl3 (0.05-4 M) with Ru5
(0.01-1 mol%) was stirred at the indicated temperature and time under an
atmosphere of air. [b] 1H NMR yields using 1,2,3-trimethoxybenzene as
internal standard. [c] ee values determined by HPLC on chiral stationary
phase.
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It is also noteworthy to take a closer look at the
stereochemical environment around the central ruthenium atom.
Formally the ruthenium is not a stereogenic center due to the
identical absolute configurations of the two oxazoline moieties.
However, due to the fixed conformations of the two oxazoline
moieties within the meridional tridentate coordination, the
ruthenium center is in fact equivalent to a stereogenic center and
one might call it a “pseudo-stereogenic metal center”.[18]
Figure 3. Substrate scope for the enantioselective ring contraction of isoxazoles
to chiral 2H-azirines.
The transition metal catalyzed enantioselective ring
contraction of isoxazoles to chiral 2H-azirines is reported to
proceed through a transition metal nitrenoid intermediate.[7] We
were therefore wondering if the here developed cyclometalated
ruthenium pybox catalyst system is applicable to other nitrenoid
chemistry. Of particular interest are currently enantioselective
aminations of C(sp3)‒H bonds.[10,11] Indeed, we found that catalyst
Ru5 smoothly cyclizes the sulfonyl azide 6 to provide the
corresponding cyclic sulfonylamide (R)-7 in 99% yield and with
90% ee.[12] Ru5 can also catalyze the C(sp3)‒H amination of the
sulfamyl azide 8 to provide the cyclic sulfamide (S)-9, a useful
precursor for chiral 1,2-diamines,[13] but only in 75% yield and with
merely 70% ee. However, Figure 4 demonstrates that the catalytic
performance can simply be adjusted by changing the substituent
at the 3-position of the imidazo[1,5-a]pyridine ligand. Accordingly,
whereas a TMS group (Ru5) affords the best result for the ring
contraction, a bromine (Ru6) provides a superior result for the
C(sp3)‒H amination to the cyclic sulfonylamide (99% yield, 97%
Figure 4. Reaction matrix for three different reactions and three catalyst
derivatives. Conditions for reaction (1): 0.1 mol% cat, CHCl3, 30 °C, 1 h.
Conditions for reaction (2): 2 mol% cat, DCE, 40 °C, 20 h. Conditions for
reaction (3): 5 mol% cat, DCE, 50 °C, 48 h. [a] 99% yield. [b] 99% yield. [c] 93%
yield.
In conclusion, we here introduced a very simple but highly
effective strategy to design new chiral transition metal catalysts
by adding
a
cyclometalated N-(4-nitrophenyl)-imidazo[1,5-
a]pyridine ligand to a C2-symmetric chiral ruthenium pyridine-2,6-
bis(oxazoline) complex.[19,20] The cyclometalated ligand strongly
modulates the catalytic activity of the ruthenium center and at the
same time exerts an important role in affecting the asymmetric
induction. This was demonstrated for a ring contraction to provide
chiral 2H-azirines (up to 97% ee with 2000 TON) and for
enantioselective C(sp3)‒H aminations of a sulfonyl and sulfamyl
azide (up to 97% ee with 50 TON). Exploring other applications
for cyclometalated Ru-pybox catalysts is ongoing on our
laboratory.
ee) and
a chlorine (Ru7) provides the best yield and
enantioselectivity for the C(sp3)‒H amination of the cyclic
sulfamide (93% yield, 95% ee).[14] The enantioselective C(sp3)‒H
amination of sulfonyl azides and sulfamyl azides was recently
reported by Zhang and coworkers but relied on a synthetically
complicated chiral cobalt porphyrin system.[12,13,15] In contrast, the
cyclometalated ruthenium pybox catalyst system is easy to
synthesize and can be modulated in its catalytic properties in a
straightforward fashion. There is no precedent for using chiral Ru-
pybox catalysts for enantioselective C(sp3)‒H aminations of
organic azides.[16]
Acknowledgements
Funding from the Deutsche Forschungsgemeinschaft is gratefully
acknowledged (ME 1805/15-1).
Keywords: Pybox • asymmetric catalysis • cyclometalation•
ruthenium • 2H-azirine, C(sp3)‒H amination
The here presented strategy to complement the widely used
pybox ligand with an electron-donating cyclometalated ligand
should be applicable to other privileged chiral ligands.[2] In fact,
Krische recently introduced a novel chiral iridium catalyst scaffold
in which the axially chiral BINAP ligand or one of its derivatives is
complemented with an ortho-cyclometalated C,O-benzoate ligand
to provide uniquely effective catalytic activity for a variety of
asymmetric C-C bond formations via hydrogen transfer
processes.[17]
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[14] It is worth noting that the catalysts RuPic and RuMeCN provide the C‒H
amination products 7 and 9 only in low yields of <20% and without any
enantioselectivity. See Supporting Information for more details.
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Entry for the Table of Contents
COMMUNICATION
L. Li, F. Han, X. Nie, Y. Hong, S. Ivlev
and E. Meggers*
Page No. – Page No.
Complementing Pyridine-2,6-
bis(oxazoline) with Cyclometalated N-
Heterocyclic Carbene for Modulated
Asymmetric Ruthenium Catalysis
Teaching an old dog new tricks: Adding a cyclometalated ligand to a chiral ruthenium
pyridine-2,6-bis(oxazoline) (pybox) complex provides strongly modulated electronic
properties and improved asymmetric induction. Applications to enantioselective
nitrenoid chemistry, including ring contractions to chiral 2H-azirines and
enantioselective C(sp3)‒H aminations demonstrate the merit of this strategy to
expand the utility of pybox transition metal complexes.
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