Chiral-at-metal iridium complex for efficient enantioselective transfer hydrogenation of ketones

Article abstract of DOI:10.1039/c6cc00972g

A bis-cyclometalated iridium(iii) complex with metal-centered chirality catalyzes the enantioselective transfer hydrogenation of ketones with high enantioselectivities at low catalyst loadings down to 0.002 mol%. Importantly, the rate of catalysis and enantioselectivity are markedly improved in the presence of a pyrazole co-ligand. The reaction is proposed to proceed via an iridium-hydride intermediate exploiting metal-ligand cooperativity (bifunctional catalysis).

Full text of DOI:10.1039/c6cc00972g

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Chiral-at-Metal Iridium Complex for Efficient Enantioselective
Transfer Hydrogenation of Ketones
Cheng Tian,a Lei Gonga and Eric Meggersa,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
A
bis-cyclometalated iridium(III) complex with metal- acetophenone as our initial model reaction (1a→2a, Figure 1).
centered chirality catalyzes the enantioselective transfer
hydrogenation of ketones with high enantioselectivities at
low catalyst loadings down to 0.002 mol%. Importantly, the
rate of catalysis and enantioselectivity are markedly
improved in the presence of a pyrazole co-ligand. The
reaction is proposed to proceed via an iridium-hydride
intermediate
exploiting
metal-ligand
cooperativity
(bifunctional catalysis).
Transition metal catalyzed asymmetric transfer hydrogenation
(ATH) has developed into a popular method for the generation
of non-racemic chiral alcohols and amines using isopropanol,
formic acid/triethylamine or sodium formate as convenient
and inexpensive hydrogen sources.1 Since Noyori’s seminal
discovery of highly enantioselective ATH catalysts based on
ruthenium(II)
half
sandwich
complexes
containing
monotosylated 1,2-diamines,2 transition metals such as Ru(II),3
Os(II),4 Ir(III),5 Rh(III),6 and Fe(II)7 have been combined with a
large variety of different chiral ligands to achieve high turnover
numbers (TON) and turnover frequencies (TOF) for different
substrate classes.8 Here we report a unique catalyst that relies
on metal-centered chirality using exclusively achiral ligands.9
We recently developed a novel class of chiral Lewis acid
catalysts based on octahedral chiral-only-at-metal iridium(III)
and rhodium(III) complexes, in which the octahedral metal
center is coordinated irreversibly by two cyclometalating
bidentate ligands in a propeller-type fashion, complemented
by two exchange-labile acetonitriles.10-17 In these catalysts,
metal-centered chirality (metal centrochirality) is the only
source of chirality. We were wondering if such complexes are
suitable for catalyzing ATH and we used the reduction of
Figure 1 Initial experiments and screening of ligand additives. Conversion
determined by 1H-NMR and enantioselectivity by HPLC on a chiral stationary
phase.
a.College of Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, People’s Republic of China. Email: gongl@xmu.edu.cn,
meggers@chemie.uni-marburg.de
Using ammonium formate as the hydrogen source, the
b.Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg,
Germany
rhodium complex Λ-RhO (1 mol%) catalyzed the reduction of
acetophenone only sluggishly, providing just 16% conversion
Electronic Supplementary Information (ESI) available: Experimental details and
analytical data. See DOI: 10.1039/x0xx00000x
and 69% ee after 24 hours at room temperature, whereas the
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higher congener
conversion after 24 hours and 61% ee. Replacing the
benzoxazole ligands ( IrO against benzothiazole IrS
further improved the outcome reaching 91% conversion after
22 hours with 68% ee. We therefore chose IrS as the
Λ-IrO (1 mol%) gave better results with 90%
Λ
-
)
(
Λ
-
)
Λ
-
catalyst of choice and next investigated the effect of additional
monodentate ligands on the catalysis. The results are shown in
Figure 1. Whereas some ligands such as nBu3P, 2,6-
diaminopyridine or imidazole suppressed the catalytic activity,
others such as tBu3P resulted in a slight improvement of the
enantioselectivity. To our delight, 3,5-dimethylpyrazole
markedly
improved
the
catalytic
activity
and
enantioselectivity. With a reduced catalyst loading of just 0.2
mol%, 3 hours reaction time resulted in a conversion of 53%
with 96% ee. Replacing the methly group at the 5-position with
a phenyl moiety further improved the results with the best
compromise out of reaction rate and enantioselectivity
achieved with 5-(4-methoxyphenyl)-3-methyl-1H-pyrazole.
We used the combination of
best pyrazole additive (10 mol%) for investigating the
substrate scope (1a ) under optimized conditions in THF/H2O
Λ-IrS (0.2-1.0 mol%) and the
-x
(1:1) as the solvent. Figure 2 reveals that the ATH reaction of
acetophenones with electron donating or withdrawing
substitutents within the phenyl moiety provided both high
yields and good enantioselectivities (products 2a-d,f,g) with an
exception of the ortho-methyl substituted substrate (product
2e, 51% ee). Typically, electron withdrawing groups were
slightly less beneficial with regard to enantioselectivity, which
might be due to some contribution from uncatalyzed
background reaction. Other aromatic ketones containing a
naphthyl moiety (product 2h), heteroaromatic ring (products
2i-n), larger aliphatic groups (products 2o-q), or an additional
ester functionality (product 2r), as well as a cyclic ketone
(product 2s) were all well converted. Diaryl ketones also
provided satisfactory results (products 2t,u). As for dialkyl
ketones bearing two primary alkyl chains, for example
affording the alcohols 2v and 2w, high yields (90-94%) while
low ee values (9% and 30% ee, respectively) were achieved.
However,
a substrate with one bulky secondary alkyl
substituent afforded the desired alcohol 2x with 93% yield and
94% ee within 15 hours, suggesting that aliphatic ketones
could also work nicely for selected cases. In addition, it is
worth to mention that the reaction can be scaled up. For
example, 1.0 g of phenyl(o-tolyl)methanone produced 0.99 g
of its corresponding alcohol 2t (yield 99%) with 97% ee in
presence of 0.5 mol% catalyst.‡
Next, we chose 2-acetyl benzothiophene for testing
catalytic performance of the
Λ
system at lower catalyst loadings (1n
-
IrS/monodentate pyrazole
→
2n). As illustrated in
Table 1, the catalyst loading could be reduced to 0.005 mol%
(S/C = 20000) while still keeping a satisfactory reaction time of
108 hours for complete conversion at 60 °C without affecting
the enantioselectivity (entries 1–5). A further reduction to
0.002 mol % catalyst led to a slight drop in enantioselectivity
value (96.6% ee) while a significantly lower reaction rate
prevented full conversion (entry 6).
Figure 2 Substrate scope with prochiral ketones.
Mechanistically, we propose that the precatalyst Λ-IrS bearing
labile acetonitriles undergoes fast ligand exchange with one
pyrazole molecule, followed by reaction with ammonium formate
to generate an active iridium hydride species. With assistance of the
ancillary pyrazole ligand, the subsequent concerted transfer of a
2 | J. Name., 2012, 00, 1-3
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Figure 3 Proposed transition states through the association of the substrate
with a pyrazole-coordinated iridium hydride intermediate explaining the
observed enantioselectivities.
hydride to the carbonyl carbon and a proton to the carbonyl oxygen
leads to formation of the chiral secondary alcohol. The effective
asymmetric induction can be explained by less steric hindrance in
the favored transition state as well as additional π-π stacking
between the aromatic ring of the substrate and one cyclometalating
benzothiazoline moiety of the iridium complex (Figure 3, left side).
The high catalytic efficiency is in parts attributed to the rigid
structure of the catalyst and intermediate limiting the degree
of conformational flexibility, thereby providing entropic
advantages during catalysis. The mechanism is consistent with an
observed R-configuration of the formed chiral alcohol assigned by
comparison of optical rotations with published examples.8e,18
Additionally, the importance of the ancillary pyrazole ligand with
the crucial role of the N-H group is supported by the sluggish results
achieved with closely related additive ligands which lack this N-H,
such as 1,4-dimethyl-1H-pyrazole or 3,5-dimethylisoxazole.19
(Figure 1). A crystal structure of 5-(4-methoxyphenyl)-3-methyl-1H-
pyrazole coordinated to the bis-cyclometalated iridium complex
confirms that the pyrazole prefers a conformation in which the N-H
group is in a perfect position for the proposed bifunctional
catalysis.20
Figure 4 Crystal structure of an iridium chlorido complex with coordinated
pyrazole ligand. ORTEP drawings with 50% thermal ellipsoids. The complex
was crystallized as a racemate but only the Λ-enantiomer is shown.
In conclusion, we here reported
a highly efficient
asymmetric transfer hydrogenation for ketones catalyzed by a
bis-cyclometalated chiral-at-metal iridium(III) complex in the
presence of an additional pyrazole ligand. The reaction is
proposed to proceed through an iridium-hydride intermediate
exploiting metal-ligand cooperativity involving the coordinated
pyrazole ligand. A variety of aryl ketones and even one
aliphatic ketone are well tolerated in the ATH reaction by
affording the secondary alcohols with good to excellent
enantioselectivities at catalyst loadings down to 0.002 mol%.
Applications to other substrate classes such as imines are
ongoing in our laboratory.
Table
1
Asymmetric transfer hydrogenation with 2-acetyl
benzothiophenea
Entry cat. loading
T (°C) t (h)
conv. (%)d ee (%)e
We thank the National Natural Science Foundation of P. R.
China (grant nos. 21272192, 21472154 and 21572184), the
Program for Changjiang Scholars and Innovative Research
Team of P. R. China (PCSIRT), the National Thousand Talents
Program of P. R. China, the Fundamental Research Funds for
the Central Universities (grant no. 20720160027), and the 985
Program of the Chemistry and Chemical Engineering disciplines
of Xiamen University.
1
0.2 mol%
40
40
40
60
60
60
9
quant.
quant.
quant.
quant.
quant.
98.7
2
0.05 mol%
0.01 mol%
0.01 mol%
0.005 mol%
0.002 mol%
30
98.7
3
144
48
98.7
4
98.4
5
108
98.4
6d
120 (240) 51 (56)
96.6 (96.6)
aReaction conditions: A mixture of
methoxyphenyl)-3-methyl-1H-pyrazole
Λ
-IrS (0.002-0.2 mol%), 5-(4-
(0.066 mmol), and
Notes and references
HCOONH4 (6.0 mmol) in THF/H2O (1:1) (0.67 mL) was stirred at
room temperature for 10 min before the substrate 2-acetyl
benzothiophene (0.66 mmol) was added and the solution stirred at
40 or 60 °C for the indicated time.
‡Catalysis on gram-scale: To
a biphasic solution of 5-(4-methoxyphenyl)-3-
methyl-1H-pyrazole (95.9 mg, 0.51 mmol) and HCOONH4 (2.89 g, 45.9 mmol) in
THF/H2O (2.57 mL/2.57 mL) was added the metal catalyst Λ-IrS (24.3 mg, 0.026
mmol) in a brown glass vial. The mixture was stirred for 10 min at room
temperature, then phenyl(o-tolyl)methanone (1t, 1.00 g, 5.10 mmol) was added.
The reaction solution was stirred at 40 °C for 30 h, cooled down to room
temperature and then dried under high vacuum. The residue was purified by
flash chromatography on silica gel (n-hexane/dichloromethane = 1:1 to 1:2) to
afford product 2t as a yellow solid (0.999 g, 5.07 mmol, yield: 99%). Enantiomeric
excess of 97% ee was established by HPLC analysis (Chiralpak OJ column, 250 x
4.6 mm, absorbance at 220 nm, n-hexane/isopropanol = 95:5, flow rate: 1.0
bConversion determined by 1H-NMR.
cEnantioselectivity by HPLC on a chiral stationary phase.
dValues in bracket for a reaction time of 240 hours.
mL/min, 25 °C, tr(minor) = 27.2 min, tr(major) = 30.8 min). [α]20 = +6.8 (c 1.0,
D
CHCl3).
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