Chiral-at-Ruthenium Catalyst with Sterically Demanding Furo[3,2-b]pyridine Ligands

Article abstract of DOI:10.1002/ejic.201801362

A sterically demanding derivative of a previously introduced chiral-at-metal ruthenium(II) catalyst scaffold is introduced. It is composed of two bidentate furo[3,2-b]pyridyl functionalized N-heterocyclic carbene ligands. Their cis-coordination generates helical chirality and a stereogenic ruthenium center. Two additional labile acetonitriles compose the catalytic site which is highly shielded by two 2-(tert-butyl)furo[3,2-b]pyridine moieties. The synthesis of the non-racemic ruthenium catalyst and its catalytic properties for the enantioselective alkynylation of 2,2,2-trifluoroacetophenone and pentafluorobenzaldehyde are reported and compared with sterically less demanding derivatives.

Full text of DOI:10.1002/ejic.201801362

A Journal of
Accepted Article
Title: Chiral-at-Ruthenium Catalyst with Sterically Demanding Furo[3,2-
b]pyridine Ligands
Authors: Tianjiao Cui, Jie Qin, Klaus Harms, and Eric Meggers
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To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.201801362
Link to VoR: http://dx.doi.org/10.1002/ejic.201801362

European Journal of Inorganic Chemistry
10.1002/ejic.201801362
COMMUNICATION
Chiral-at-Ruthenium Catalyst with Sterically Demanding Furo[3,2-
b]pyridine Ligands
[
a]
[a]
[a]
[a]
Tianjiao Cui, Jie Qin, Klaus Harms, and Eric Meggers*
Dedication ((optional))
Abstract:
A
sterically demanding derivative of
a
previously
being achiral, the helical arrangement of the two cis-coordinated
bidentate PyNHC ligands provides a metal-centered - (left-
handed screw sense) or -configuration (right-handed screw
sense). The complexes Ru1 and Ru2 were demonstrated to be
excellent catalysts for the enantioselective alkynylation of
trifluoromethyl ketones including an application to the
introduced chiral-at-metal ruthenium(II) catalyst scaffold is
introduced. It is composed of two bidentate furo[3,2-b]pyridyl
functionalized N-heterocyclic carbene ligands. Their cis-coordination
generates helical chirality and a stereogenic ruthenium center. Two
additional labile acetonitriles compose the catalytic site which is
highly shielded by two 2-(tert-butyl)furo[3,2-b]pyridine moieties. The
synthesis of the non-racemic ruthenium catalyst and its catalytic
properties for the enantioselective alkynylation of 2,2,2-
trifluoroacetophenone and pentafluorobenzaldehyde are reported
and compared with sterically less demanding derivatives.
enantioselective
intermediates of the anti-HIV drug efavirenz.
synthesis
of
key
propargyl
alcohol
[
15,17]
Here we report
the synthesis and catalytic properties of the sterically more
demanding chiral-at-ruthenium catalysts Ru3 in which we
replaced the two pyridines with 2-(tert-butyl)furo[3,2-b]pyridine
moieties. This creates a more extended propeller with high steric
crowding around the catalytic site near the two exchange-labile
acetonitrile ligands. We show that this steric crowding has a
profound influence on catalytic activity and enantioselectivity.
Introduction
Chiral transition metal complexes are an important class of
asymmetric catalysts and typically synthesized by reacting metal
salts or organometallic precursors with carefully tailored chiral
ligands.[ Recently, an alternative design strategy has emerged
in which the overall chirality is the consequence of the
asymmetric coordination of exclusively achiral ligands around a
central metal, thereby implementing metal-centered chirality.[3-11]
Such complexes have been dubbed “chiral-at-metal” to indicate
that the overall chirality formally originates from a stereogenic
metal center in order to distinguish this design approach from
conventional chiral transition metal complexes, which frequently
also possess metal-centered chirality but induced by the chiral
ligand sphere.[12-14] This chiral-at-metal approach has the appeal
of structural simplicity. More importantly, without the requirement
of chiral motifs in the ligand sphere, untapped opportunities
emerge for the design of novel catalyst architectures with
potentially novel overall properties.
2]
Figure 1. Previous designs and this work regarding chiral-at-metal ruthenium
catalysts.
Results and Discussion
We recently introduced chiral-at-ruthenium asymmetric
catalysts bearing two configurationally stable bidentate N-(2-
pyridyl)-substituted N-heterocyclic carbene (PyNHC) ligands in
addition to two labile acetonitriles (Figure 1).[15,16] With all ligands
The multistep synthesis of the imidazolium ligand 1 is shown in
the Supporting Information. Reaction of RuCl
3
hydrate with 1 in
ethylene glycol at 200 °C followed by treatment with AgPF
6
provided the racemic complex rac-Ru3 in 66% yield (Scheme 1).
Reaction of this racemic complex with the salicyloxazoline (S)-2
under basic conditions afforded the complex -(S)-3 as a single
diastereomer in 34% yield. Likewise, reaction of rac-Ru3 with
the salicyloxazoline (R)-3 provided the enantiomeric complex -
[
a]
T. Cui, J. Qin, Dr. K. Harms, Prof. Dr. E. Meggers
Fachbereich Chemie
Philipps-Universität Marburg
Hans-Meerwein-Straße 4, 35043 Marburg (Germany)
E-mail: meggers@chemie.uni-marburg.de
(
R)-3 in 30% yield. A crystal structure of -(S)-3 is shown in
Figure 2 and establishes the relative and abolute configuration
of this intermediate. Treatment of this complex and its
enantiomer with TFA in MeCN followed by anion metathesis
https://www.uni-marburg.de/fb15/ag-meggers
Supporting information for this article is given via a link at the end of
the document.
with NH
4 6
PF provided the complexes -Ru3 (54% yield) and -
Ru3 (44% yield) as single enantiomers.
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European Journal of Inorganic Chemistry
10.1002/ejic.201801362
COMMUNICATION
The -enantiomer of a crystal structure of rac-Ru3 is
shown in Figure 3 and reveals an undistorted octahedral
coordination sphere around the stereogenic ruthenium center
with the two mesityl groups stacking with the fura[3,2-b]pyridine
2
heteroaromatic ligands. The C -symmetric complex shows a
helical, propeller-type arrangement of the two bidentate ligands.
The ruthenium center at the two labile acetonitrile ligands, which
constitutes the catalytic site, is significantly shielded by the two
2-(tert-butyl)fura[3,2-b]pyridine moieties.
Figure 2. X-ray structure of -(S)-3. ORTEP drawing with 50% probability
thermal ellipsoids. Solvent and counterion are omitted for clarity.
Figure 3. X-ray structure of rac-Ru3. Only the -enantiomer is shown. ORTEP
drawing with 50% probability thermal ellipsoids. Solvent and counterion are
omitted for clarity.
Next, we investigated the catalytic properties of this chiral-at-
ruthenium catalyst. Complexes Ru1 and Ru2 were recently
demonstrated to be excellent catalysts for the enantioselective
alkynylation of trifluoromethyl ketones.[
15,17,18]
We therefore used
2,2,2-trifluoroacetophenone (4) with
the
reaction
of
phenylacetylene as a first model reaction. Interestingly, whereas
-Ru1 or -Ru2 at a catalysts loading of 0.5 mol% in the
Scheme 1. Synthesis of the enantiomerically pure chiral-at-metal ruthenium
complexes - and -Ru3.
3
presence of catalytic amounts of the base Et N at 60 °C
provided the propargylic alcohol (S)-5 with high yields and high
enantioselectivities, no reaction occured with the fura[3,2-
b]pyridine complex -Ru3 (Scheme 2). We attribute this to the
high steric hindrance induced by the two 2-(tert-butyl)fura[3,2-
b]pyridine moieties.
A computational study by Houk and
coworkers on this enantioselective alkynylation of trifluoromethyl
ketones catalyzed by such chiral-at-ruthenium complexes
support a mechanism with an inner-sphere acetylide transfer
from an intermediate ruthenium acetylide to the ruthenium-
coordinated trifluoromethyl ketone through a highly compact
four-membered transition state.[19] The requirement in this
catalytic mechanism for
a simultaneous binding of both
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European Journal of Inorganic Chemistry
10.1002/ejic.201801362
COMMUNICATION
substrates to the ruthenium center apparently leads to a
significant steric crowding and a high sensitivity to additional
steric effects which might explain the diminished catalytic activity
of Ru3 for this transformation.
Asymmetric catalysis procedure: The reaction 6  (R)-7 catalyzed by
-Ru3 is provided as a representative example. A dried Schlenk tube (10
mL) was charged with -Ru3 (2.4 mg, 0.002 mmol) and
pentafluorobenzaldehyde (39.2 mg, 0.20 mmol) in THF (0.50 mL). The
Due to these disappointing results we turned our attention to
aldehydes as sterically less demanding substrates for an
enantioselective alkynylation. As our model reaction we chose
the alkynylation of pentafluorobenzaldehyde (6) with
phenylacetylene. Interestingly, when performed in the presence
tube was purged with nitrogen, and Et N (5.6 L, 0.04 mmol) was added
3
via syringe, followed by the addition of phenylacetylene (61.3 mg, 0.60
mmol). The vial was sealed and the reaction stirred at 60 °C for 24 h
under an atmosphere of nitrogen. Then, the solvent was removed under
reduced pressure and the residue was purified by flash chromatography
on silica gel (EtOAc/n-hexane = 1:50) to afford the propargylic alcohol
of 1.0 mol% ruthenium catalysts, 0.2 equivalents of Et
3
N at
60 °C, -Ru1 and -Ru2 provided the propargylic alcohol (S)-7
(
(
S)-7.[20] 1H NMR (300 MHz, Chloroform-d)  7.42 – 7.33 (m, 2H), 7.26
dtd, J = 7.2, 5.5, 5.0, 2.1 Hz, 3H), 5.90 (d, J = 8.0 Hz, 1H), 2.61 (d, J =
with only low yields and low enantioselectivities. In contrast, the
fura[3,2-b]pyridine complex -Ru3 afforded (S)-7 in a yield of
2% and with 91% ee under identical reaction conditions.[ For
20]
8.0 Hz, 1H). Enantiomeric excess was established by HPLC analysis
using a Daicel Chiralcel AS-H column. (HPLC conditions: UV-detection at
254 nm, mobile phase n-hexane/isopropanol = 95:5, flow rate 1.0 mL/min,
9
aldehyde 6, the high steric hindrance of -Ru3 is an advantage
and leads to a higher yield and higher enantioselectivity of the
alkynylation product.
R R
column temperature 25 °C, t (major) = 7.7 min, t (minor) = 12.5 min).
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (ME 1805/15-
) for financial support of this research.
1
Keywords: chiral-at-metal • metal-centered chirality • ruthenium
fura[3,2-b]pyridine• alkynylation
•
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European Journal of Inorganic Chemistry
10.1002/ejic.201801362
COMMUNICATION
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European Journal of Inorganic Chemistry
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Chiral catalyst
T. Cui, J. Qin, K. Harms, E. Meggers*
Page No. – Page No.
Chiral-at-Ruthenium Catalyst with
Sterically Demanding Furo[3,2-
b]pyridine Ligands
Text for Table of Contents
A chiral-at-metal ruthenium catalyst composed of two cis-coordinate N-(furo[3,2-b]pyridyl)-substituted N-heterocyclic carbene
ligands in addition to two acetonitriles is introduced. The two 2-(tert-butyl)fura[3,2-b]pyridine moieties generate a high steric
crowding at the site of catalysis which affects both catalytic activity and asymmetric induction.
This article is protected by copyright. All rights reserved.