Asymmetric catalysis with substitutionally labile yet stereochemically stable chiral-at-metal iridium(III) complex

Article abstract of DOI:10.1021/ja4132505

A metal-coordination-based high performance asymmetric catalyst utilizing metal centrochirality as the sole element of chirality is reported. The introduced substitutionally labile chiral-at-metal octahedral iridium(III) complex exclusively bears achiral

Full text of DOI:10.1021/ja4132505

Communication
pubs.acs.org/JACS
Asymmetric Catalysis with Substitutionally Labile yet
Stereochemically Stable Chiral-at-Metal Iridium(III) Complex
Haohua Huo,† Chen Fu,† Klaus Harms,† and Eric Meggers*,†,‡
†Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Strasse, 35043 Marburg, Germany
̈
‡College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s Republic of China
S
* Supporting Information
Recently, we introduced inert chiral-at-metal iridium(III)
complexes as asymmetric catalysts in which the catalysis is
mediated through the ligand sphere.5,6 We hypothesized that
the high configurational inertness of iridium(III) complexes
might permit retaining metal-centered chirality even in the
presence of exchange-labile ligands, and we selected Λ-1 and Δ-
1 for investigating the scope of asymmetric catalysis with
reactive but configurationally stable chiral-at-metal complexes
(Figure 1). The C2-symmetrical complex 1 contains two
ABSTRACT: A metal-coordination-based high perform-
ance asymmetric catalyst utilizing metal centrochirality as
the sole element of chirality is reported. The introduced
substitutionally labile chiral-at-metal octahedral iridium-
(III) complex exclusively bears achiral ligands and
effectively catalyzes the enantioselective Friedel−Crafts
addition of indoles to α,β-unsaturated 2-acyl imidazoles
(19 examples) with high yields (75%−99%) and high
enantioselectivities (90−98% ee) at low catalyst loadings
(0.25−2 mol %). Counterintuitively, despite its substitu-
tional lability, which is mechanistically required for
coordination to the 2-acyl imidazole substrate, the metal-
centered chirality is maintained throughout the catalysis.
This novel class of reactive chiral-at-metal complexes will
likely be of high value for a large variety of asymmetric
transformations.
etal coordination is arguably one of the most powerful
Mapproaches for activating substrates toward chemical
transformations. Consequently, chiral metal complexes are
employed extensively in industry and academia for the catalytic
synthesis of nonracemic chiral compounds.1 A guiding principle
for the design of such metal-coordination-based asymmetric
catalysts is the generation of a chiral environment around the
metal, which is typically introduced through the association
with chiral mono- or multidentate organic ligands. In theory,
instead, implementing chirality directly at the reactive metal
center−exploiting the metal as a source of centrochirality−
would be highly attractive since the close proximity of the metal
to the coordinating substrate promises a highly effective
transfer of chirality during the asymmetric induction.2,3
However, a considerable obstacle for the realization of such
reactive chiral-at-metal asymmetric catalysts constitutes the
retention of the relative and absolute metal-centered config-
uration during the reaction, since the coordination number at
the metal varies during each catalytic cycle and thereby
provides ample opportunities for the stereochemistry of the
metal to scramble.1
Figure 1. Enantiomers of a substitutionally labile yet configurationally
stable chiral-at-metal IrIII complex.
cyclometalating 5-tert-butyl-2-phenylbenzoxazoles and two
labile acetonitrile ligands. Despite all ligands being achiral,
metal-centered chirality leads to a Λ- (left-handed propeller)
and Δ-enantiomer (right-handed propeller).
The synthesis of the complexes Λ-1 and Δ-1 is
straightforward and draws from methodology recently
developed in our laboratory.7−9 Accordingly, the reaction of
IrCl3·3H2O with benzoxazole 2 affords the cyclometalated
racemic iridium(III) dimer rac-3 in a diastereoselective fashion
(Scheme 1). The subsequent reaction of rac-3 with the chiral
auxiliary ligand (S)-4-isopropyl-2-(2′-hydroxyphenyl)-2-thia-
zoline {(S)-4} provides the two diastereomeric complexes Λ-
(S)-5 and Δ-(S)-5 which can be resolved by standard silica gel
chromatography, followed by the conversion to virtually
enantiopure Λ-1 and Δ-1 (each >99% ee), respectively, through
the stereospecific substitution of the chiral auxiliary ligand
(upon protonation by NH4PF6) by two acetonitrile ligands.
A crystal structure of Δ-1 confirms the assigned absolute
metal-centered configurations (Figure 2). HPLC traces using a
chiral stationary phase are shown in Figure 3 and reveal the
high enantiopurity of the synthesized complexes Λ-1 and Δ-1.
We here wish to report the successful sought-after realization
of a substitutionally labile (reactive) yet configurationally stable
chiral-at-metal high performance asymmetric catalyst.4 In our
design, the metal center serves the dual function of activating a
substrate by metal coordination and at the same time comprises
the configurationally stable sole element of chirality, thus
entirely relying on achiral ligands in the coordination sphere.
Received: December 31, 2013
Published: February 15, 2014
© 2014 American Chemical Society
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Interestingly, these substitutionally labile chiral-at-metal com-
plexes are configurationally stable, as Λ-1 did not show any
significant sign of configurational lability or decomposition
upon standing in CH2Cl2 on the benchtop for 8 days, as
verified by 1H NMR and chiral HPLC analysis (see Supporting
Information).
Scheme 1. Synthesis of Complexes Λ-1 and Δ-1
We next investigated the catalytic activity of Λ-1 and selected
the enantioselective Friedel−Crafts alkylation of α,β-unsatu-
rated 2-acyl imidazoles as our model system.10 Revealingly, the
reaction of 6a with indole (1.5 equiv) in the presence of 1 mol
% Λ-1 afforded the Friedel−Crafts alkylation product (S)-7a
with high enantioselectivity (95% ee) albeit with only a slow
conversion of just 35% after 20 h at room temperature in
MeCN (Table 1, entry 1). A solvent screening revealed that
Table 1. Enantioselective Friedel−Crafts Addition of Indole
a
to α,β-Unsaturated 2-Acyl Imidazole 6a Catalyzed by Λ-1
conv
b
ee
(%)
c
entry solvent
conditions
(%)
1
2
3
4
5
6
7
8
MeCN
MeOH
1.5 equiv indole (0.75 M), rt, 20 h
1.5 equiv indole (0.75 M), rt, 20 h
35
70
95
95
94
96
96
96
96
97
CH2Cl2 1.5 equiv indole (0.75 M), rt, 20 h
90
THF
THF
THF
THF
THF
1.5 equiv indole (0.75 M), rt, 20 h
2.5 equiv indole (2.5 M), rt, 20 h
as entry 5 plus air
85
100
100
88
as entry 5 plus air and 1% H2O
2.5 equiv indole (2.5 M), 0 °C, 36 h
100
a
Reaction conditions: Imidazole 6a (0.30 mmol), indole (0.45 or 0.75
mmol), and Λ-1 (1.0 mol %) in the indicated solvent (0.60 or 0.30
mL) were stirred at the indicated temperature under argon or air.
b
c
1
Conversion determined by H NMR. Determined by chiral HPLC
analysis.
MeOH, CH2Cl2, and THF, among others, provide higher
catalysis rates (entries 2−4). Optimization of the reaction
conditions with THF as the solvent by increasing the
concentration of 6a and the equivalents of indole (2.5 equiv)
led to full conversion at room temperature within 20 h and a
high ee of 96% (entry 5). Interestingly, the reaction is
insensitive to air (entry 6) and water (entry 7), and the
enantioselectivity can be further improved by reducing the
temperature, reaching 97% ee at 0 °C (entry 8).
Figure 2. Crystal structure of Δ-1. The hexafluorophosphate
counteranion is omitted for clarity. ORTEP drawing with 50%
probability thermal ellipsoids.
Next, we tested the scope of catalyst Λ-1. Table 2 shows that
a selection of 13 substituted indoles provide the desired
Friedel−Crafts alkylation products (S)-7a−m with high
enantioselectivities (90−98% ee) in yields of 75−99% in the
presence of 1−2 mol % of Λ-1 (Table 2). Electron acceptor
substituted less reactive indoles require a somewhat increased
catalyst loading (2.0 mol %) (entries 4 and 5), while the more
reactive 2-methyl indole needs a lower reaction temperature to
achieve a high ee value (entry 12). The substrate scope with
respect to different α,β-unsaturated 2-acyl imidazoles 6b−g is
shown in Table 3 and demonstrates that, upon adjustment of
the catalyst loading (1−2 mol % Δ-1 or Λ-1), reaction
temperature (0 °C or room temperature), and concentration
(1.0 or 2.0 M 6b−g), very good to excellent enantioselectivities
(91−98% ee) and yields (78−99%) are achieved for each
system (entries 1−6). The α,β-unsaturated 2-acyl imidazole 6g,
Figure 3. Chiral HPLC traces demonstrating the enantiopurity of
synthesized Λ-1 and Δ-1. HPLC conditions: Daicel Chiralcel IB, 250
mm × 4.6 mm, flow rate = 0.5 mL/min, 0.1% aq. TFA with MeCN as
eluent (20−43% in 60 min).
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Table 2. Enantioselective Friedel−Crafts Addition of Substituted Indoles to α,β-Unsaturated 2-Acyl Imidazole 6a Catalyzed by
a
Λ-1
b
indoles
c
d
entry
R1
R2
R3
R4
Λ-1 (mol %)
T (°C)
t (h)
yield (%)
ee (%)
1
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
H
1.0
1.0
1.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
20
18
22
48
48
18
22
22
18
18
22
36
40
97 (7a)
98 (7b)
99 (7c)
75 (7d)
77 (7e)
91 (7f)
99 (7g)
82 (7h)
92 (7i)
91 (7j)
90 (7k)
93 (7l)
96
94
94
92
94
95
96
95
94
94
95
98
90
2
H
Me
MeO
Br
H
3
H
H
4
H
H
5
H
Cl
H
6
MeO
H
H
H
7
H
Me
Bn
Bn
Bn
Bn
Me
Me
8
H
H
9
H
Me
MeO
H
10
11
12
13
H
MeO
H
H
H
H
rt
97 (7m)
a
Reaction conditions: Indoles 8a−m (0.75 mmol), imidazole 6a (0.30 mmol), and Λ-1 (1.0 or 2.0 mol %) in THF (0.30 mL) were stirred at the
b
c
d
indicated temperature under argon. Indoles 8a−m consecutively listed from entry 1 to 13. Isolated yields of the indicated products. Determined
by chiral HPLC analysis.
The C2-symmetrical iridium complex 1 was designed to serve
as a chiral Lewis acid by activating α,β-unsaturated 2-acyl
imidazoles through bidentate N,O-coordination. A proposed
model for the asymmetric induction in the course of the indole
addition that is consistent with the experimental results is
shown in Figure 4 and demonstrates that one face of the alkene
Table 3. Enantioselective Friedel−Crafts Addition of Indole
to α,β-Unsaturated 2-Acyl Imidazoles 6b−g Catalyzed by Λ-
a
1 or Δ-1
b
imidazoles
cat.
T
t
yield
c
ee
d
entry
R5
Et
R6
(mol %)
(°C)
(h)
(%)
(%)
1
2
Me
Me
Me
Me
Me
iPr
iPr
iPr
Δ-1 (2.0)
Δ-1 (2.0)
Δ-1 (2.0)
Λ-1 (1.0)
Δ-1 (1.0)
Δ-1 (1.0)
Δ-1 (0.5)
Δ-1 (0.25)
0
48
20
48
16
24
24
44
60
89 (9a)
97 (9b)
78 (9c)
98 (9d)
97 (9e)
99 (9f)
97 (9f)
91 (9f)
96
91
93
93
98
97
97
97
nBu
iPr
rt
rt
rt
rt
rt
rt
rt
e
3
4
5
6
7
8
Ph
CO2Et
Me
Figure 4. Proposed model for the asymmetric induction in the
transition state in which one face of the alkene is blocked by the C2-
symmetrical catalyst.
Me
Me
a
Reaction conditions: Imidazoles 6b−g (0.30 mmol), indole (0.75
is sterically shielded effectively by one of the tert-butyl groups.
mmol), and Δ-1 or Λ-1 (0.25−2.0 mol %) in THF (0.30 mL) were
It is worth noting that the high lability of the coordinated
b
1
stirred at the indicated temperature under argon. 6b−g consecutively
MeCN ligands of catalyst 1, which can be confirmed by H
c
NMR,11 is a consequence of the strong trans-effect of the Ir−C
bonds. Thus, the mechanistic mode of action of catalyst 1 relies
on the coordinative lability of the MeCN ligands in
combination with the high configurational stability of the
remaining octahedral coordination sphere in order to retain the
metal-centered chirality at all times.
In conclusion, we here report a novel class of asymmetric
transition metal catalysts in which the metal fulfills a dual
function by coordinatively activating a substrate and at the same
time serving as the sole source of chirality. Whereas typical
metal-coordination-based asymmetric catalysts rely on chiral
ligands for their asymmetric induction, the here introduced bis-
listed from entry 1 to 6. Isolated yields of the indicated products.
d
Determined by chiral HPLC analysis. R-configuration: entries 1, 2,
and 4−8. S-configuration: entry 3. Increased concentration of 6c (2.0
M) in order to speed up the reaction.
e
bearing an N-isopropyl substituent at the imidazole instead of a
methyl group, even allows catalyst loading reduction to 0.25
mol % without altering the enantioselectivity (97% ee) (entries
6−8). This reflects a respectable turnover number of 364, while
not affecting the stereochemical integrity of the metal-centered
chirality during all the catalytic cycles.
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Men
́
age, S.; Hamelin, O.; Charnay, F.; Pec
́
aut, J.; Fontecave, M. Inorg.
cyclometalated iridium(III) complex 1 is distinguished by its
simplicity, as it just contains two achiral cyclometalating
phenylbenzoxazoles and two labile acetonitriles. The high
configurational stability of the octahedral iridium chiral center is
unexpected considering that labile ligands generally reduce the
activation barrier for isomerization. Beyond its conceptual
appeal, bis-cyclometalated octahedral iridium(III) complex 1
might be of high practical value, as it provides an excellent
substrate scope for the highly enantioselective Friedel−Crafts
addition of indoles to α,β-unsaturated 2-acyl imidazoles at low
catalyst loadings (0.25−2 mol %), while at the same time
catalyst 1 displays a high solvent tolerance, does not rely on
cryogenic temperatures, and can even be used under open flask
conditions.12 This high performance indicates the value of a
direct chirality transfer from the chiral metal to the coordinated
substrate. Investigations of reactive chiral-at-metal iridium(III)
complexes as catalysts for other asymmetric transformations are
underway in our laboratory.
Chem. 2003, 42, 4810−4816. For other contributions on octahedral
catalysts with exclusive chirality-at-metal, see: (b) Hamelin, O.;
Rimboud, M.; Pecaut, J.; Fontecave, M. Inorg. Chem. 2007, 46,
́
5354−5360. (c) Kawasaki, T.; Omine, T.; Sato, M.; Morishita, Y.; Soai,
K. Chem. Lett. 2007, 36, 30−31. (d) Ganzmann, C.; Gladysz, J. A.
Chem.Eur. J. 2008, 14, 5397−5400.
(5) (a) Chen, L.-A.; Xu, W.; Huang, B.; Ma, J.; Wang, L.; Xi, J.;
Harms, K.; Gong, L.; Meggers, E. J. Am. Chem. Soc. 2013, 135, 10598−
10601. (b) Chen, L.-A.; Tang, X.; Xi, J.; Xu, W.; Gong, L.; Meggers, E.
Angew. Chem., Int. Ed. 2013, 52, 14021−14025.
(6) For chiral octahedral iridium(III) complexes in asymmetric
catalysis, see: (a) Paredes, P.; Díez, J.; Gamasa, M. P. Organometallics
2008, 27, 2597−2607. (b) Owens, C. P.; Varela-Alvarez, A.;
Boyarskikh, V.; Musaev, D. G.; Davies, H. M. L.; Blakey, S. B.
Chem. Sci. 2013, 4, 2590−2596. (c) Carmona, D.; Ferrer, J.; García,
N.; Ramírez, P.; Lahoz, F. J.; García-Orduna, P.; Oro, L. A.
́
̃
Organometallics 2013, 32, 1609−1619.
(7) Helms, M.; Lin, Z.; Gong, L.; Harms, K.; Meggers, E. Eur. J. Inorg.
Chem. 2013, 4164−4172.
(8) Gong, L.; Wenzel, M.; Meggers, E. Acc. Chem. Res. 2013, 46,
2635−2644.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and chiral HPLC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
(9) For the synthesis of nonracemic cyclometalated iridium(III)
S
complexes, see also: (a) Urban, R.; Kramer, R.; Mihan, S.; Polborn, K.;
̈
Wagner, B.; Beck, W. J. Organomet. Chem. 1996, 517, 191−200.
(b) Schaffner-Hamann, C.; von Zelewsky, A.; Barbieri, A.; Barigelletti,
F.; Muller, G.; Riehl, J. P.; Neels, A. J. Am. Chem. Soc. 2004, 126,
9339−9348. (c) Haberhauer, G.; Oeser, T.; Rominger, F. Chem.
Commun. 2005, 2799−2801. (d) Yang, L.; von Zelewsky, A.; Stoeckli-
Evans, H. Chem. Commun. 2005, 4155−4157. (e) Yang, L.; von
Zelewsky, A.; Nguyen, H. P.; Muller, G.; Labat, G.; Stoeckli-Evans, H.
Inorg. Chim. Acta 2009, 362, 3853−3856. (f) Chepelin, O.; Ujma, J.;
Wu, X.; Slawin, A. M. Z.; Pitak, M. B.; Coles, S. J.; Michel, J.; Jones, A.
C.; Barran, P. E.; Lusby, P. J. J. Am. Chem. Soc. 2012, 134, 19334−
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Commun. 2013, 49, 6546−6548.
AUTHOR INFORMATION
Corresponding Author
meggers@chemie.uni-marburg.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge funding from the German Research
Foundation (ME 1805/4-1) and the Philipps-Universitat
Marburg. H.H. thanks the China Scholarship Council for a
stipend.
■
(10) For catalytic enantioselective indole and pyrrole alkylations with
α,β-unsaturated 2-acyl imidazoles, see: (a) Evans, D. A.; Fandrick, K.
R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942−8943. (b) Evans, D.
A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249−2252. (c) Evans, D. A.;
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2007, 129, 10029−10041. (d) Boersma, A. J.; Feringa, B. L.; Roelfes,
G. Angew. Chem., Int. Ed. 2009, 48, 3346−3348.
̈
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