Enantioselective Alkynylation of 2-Trifluoroacetyl Imidazoles Catalyzed by Bis-Cyclometalated Rhodium(III) Complexes Containing Pinene-Derived Ligands

Article abstract of DOI:10.1002/chem.201602372

Chiral rhodium(III) complexes containing two cyclometalating 2-phenyl-5,6-(S,S)-pinenopyridine ligands and two additional acetonitriles are introduced as excellent catalysts for the highly enantioselective alkynylation of 2-trifluoroacetyl imidazoles. Whe

Full text of DOI:10.1002/chem.201602372

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Accepted Article
Title: Enantioselective Alkynylation of 2-Trifluoroacetyl Imidazoles Catalyzed by Bis-
Cyclometalated Rhodium(III) Complexes Containing Pinene-Derived Ligands
Authors: Eric Meggers; Yu Zheng; Lilu Zhang; Klaus Harms
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Chemistry - A European Journal
10.1002/chem.201602372
Enantioselective Alkynylation of 2-Trifluoroacetyl Imidazoles Catalyzed by Bis-
Cyclometalated Rhodium(III) Complexes Containing Pinene-Derived Ligands
Yu Zheng, Klaus Harms, Lilu Zhang,* and Eric Meggers*
[
*] Y. Zheng, Dr. K. Harms, Dr. L. Zhang,* Prof. Dr. E. Meggers*
Fachbereich Chemie
Philipps-Universität Marburg
Hans-Meerwein-Straße 4, 35043 Marburg (Germany)
Email: zhangl@staff.uni-marburg.de, meggers@chemie.uni-marburg.de
Prof. Dr. E. Meggers
College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005 (P. R. China)

Chemistry - A European Journal
10.1002/chem.201602372
Abstract: Chiral rhodium(III) complexes containing two cyclometalating 2-phenyl-5,6-(S,S)-
pinenopyridine ligands and two additional acetonitriles are introduced as excellent catalysts for the
highly enantioselective alkynylation of 2-trifluoroacetyl imidazoles. Whereas the ligand-based chirality
permits the straightforward synthesis of the complexes in a diastereomerically and enantiomerically
pure fashion, the metal-centered chirality is responsible for the asymmetric induction in the course of
the catalysis. Notably, the analogous iridium congeners provide only a low enantioselectivity, whereas
related previously reported benzoxazole- and benzothiazole-based catalysts do not show any catalytic
activity for this reaction under standard reaction conditions.
Chiral Lewis acids are indispensable tools in asymmetric catalysis and are typically composed
of a main group element connected to chiral substituents or a combination out of metal salt and chiral
[
1]
ligand(s). Recently, we introduced a new class of chiral Lewis acids in which a central iridium(III) or
rhodium(III) is cyclometalated by two achiral ligands, thereby generating a propeller-type C -symmetry
2
[
2,3]
[4-14]
with metal-centered chirality
which constitutes the exclusive source of chirality (Scheme 1).
This structural element displays high constitutional and configurational stability, while two additional
acetonitrile ligands are labile and provide access for substrates to coordinate to the Lewis acidic metal
center. We demonstrated that these complexes are powerful chiral Lewis acid catalysts for a variety of
transformations, some activated by visible light. However, all so far reported catalysts (- and -
configured IrO, IrS, RhO, and RhS) are limited to either 2-phenylbenzoxazole or 2-
phenylbenzothiazole ligands as cyclometalating components. Our objective for this study was therefore
twofold: Firstly, we wanted to investigate how the catalytic properties of these cyclometalated
complexes depend on the the nature of the cyclometalating unit, and secondly, we were interested in
simplifying the synthesis of these chiral complexes by employing chiral cyclometalating ligands
instead of achiral ones, thereby drawing from a large body of work regarding diastereoselective
coordination chemistry with chiral ligands and the resolution of diastereomeric mixtures of chiral metal
2

Chemistry - A European Journal
10.1002/chem.201602372
[2]
complexes. Here we now report our progress into this direction by introducing a new member of bis-
cyclometalated chiral Lewis acids which are based on combined metal-centered and ligand-centered
chirality and we demonstrate that they feature a catalytic activity that is notably distinct from our
previous benzoxazole- and benzothiazole-based catalysts.
Scheme 1. Previous design and this work regarding bis-cyclometalated, chiral-at-metal iridium(III)-
and rhodium(III)-based catalysts.
Our work follows stereoselective coordination chemistry developed by von Zelewsky and
[
15-19]
others using readily available pinene-modified chiral pyridine ligands.
Specifically, we reacted 2-
[
17]
phenyl-5,6-(S,S)-pinenopyridine
{(S,S)-1} with RhCl  3 H O or IrCl  3 H O in a 3:1
3
2
3
2
ethoxyethanol-water mixture at 125 °C for 36 hours to afford the respective chloro-bridged dimers
3

Chemistry - A European Journal
10.1002/chem.201602372
[19]

/-2Rh and /-2Ir as mixtures of diastereomers (Scheme 2). Consistent with related studies
using cyclometalating pinene-derived pryridine ligands, the dinuclear complexes are mainly formed as
the homochiral - and -diastereomers and within the coordination sphere the kinetically favored
[
18]
trans arrangement of the pyridine ligands is observed exclusively.
The diastereomers -2Rh and

-2 are formed in slight excess of their -counterparts. Conveniently, the diastereomeric dimers
Ir
can be easily resolved on silica gel chromatography using ethyl acetate:hexane (1:20) as the mobile
phase. The subsequent reaction of the individual diastereomers with AgPF in MeCN at 40 °C converts
6
the chloro-bridged dimers into the individual monomeric bis-acetonitrile complexes -RhPP, -RhPP,

-IrPP, and -IrPP. The high diastereomeric purity (>99% dr) of these complexes was confirmed by
1
H-NMR and the relative and absolute configurations of all four complexes were confirmed by X-ray
crystallography. -RhPP and -RhPP are shown in Figure 1 and reveal the propeller-type ligand
arrangement with a combination of metal-centered and ligand-derived chirality. All complexes display
high constitutional and configurational stability without any significant decomposition or isomerization
upon leaving the complexes dissolved in CH Cl on the benchtop for one week.
2
2
4

Chemistry - A European Journal
10.1002/chem.201602372
Scheme 2. Synthesis of enantiomerically and diastereomerically pure chiral-at-metal iridium(III) and
rhodium(III) complexes containing pinene-derived chiral ligands.

-RhPP
-RhPP
Figure 1. Crystal structures of -RhPP and -RhPP. The hexafluorophosphate counterions are
omitted for clarity. ORTEP drawings with 50% probability thermal ellipsoids.
5

Chemistry - A European Journal
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With the four diastereomerically and enantiomerically pure transition metal complexes in hand
we next investigated their catalytic activity. After some orientational experiments we found that RhPP
is an excellent catalyst for the enantioselective alkynylation of 1-phenyl-2-trifluoroacetyl imidazole
[
20-23]
(3a).
For example, using 3 mol% of -RhPP in the presence of 1.2 equivalents of Et N, the
3
reaction of ketone 3a with phenylacetylene (4a) for 24 hours at room temperature provided the
propargyl alcohol (R)-5a in 89% yield and with 95% ee (Table 1, entry 1). Replacing the N-phenyl
substituent with an isopropyl group (3b) improved the yields of (R)-5b to 94% and enantioselectivity to
9
7% ee (entry 2). However, the best results were achieved with 1-methyl-2-trifluorocetyl imidazole
(3c), providing the propargyl alcohol (R)-5c with 92% yield and >99% ee (entry 3). Noteworthy, using
the diastereomeric catalyst -RhPP afforded the mirror-imaged product (S)-5c with an identical
enantioselectivity of >99% ee and only with a slightly reduced yield of 90% (entry 4). This comparison
of -RhPP with -RhPP unambiguously demonstrates that the asymmetric induction in the course of
the catalysis is mainly controlled by the metal-centered chirality and not the chirality of the ligand.
Control experiments confirm that both the catalyst and a base are necessary for achieving a conversion
(entries 5 and 6). Reduced loadings of -RhPP (entries 7 and 8) and the base triethylamine (entry 9) do
not affect the enantioselectivity but the reaction rate. Conveniently, the catalytic reaction can even be
performed in an open flask since it is not sensitive to air and water (entries 10 and 11). Furthermore,
the iridium congeners - and -IrPP (entries 12 and 13) provide inferior results, whereas our
previously developed catalysts RhO, IrO or IrS are not able to catalyze the conversion 3c+4a5c at
all (entries 14-16). Thus, although the absolute configuration at the ligand does not effect the rate and
degree of asymmetric induction, the nature of the ligand is obviously crucial for an effective catalysis
as cyclometalated phenylbenzoxazoles (RhO and IrO) or phenylbenzothiazoles (IrS) do not provide
active catalysts.
6

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[
a]
Table 1. Initial Experiments.
[
b]
[c]
[d]
Entry Catalyst
Substrate
Base
Conditions
t (h)
Yield (%) ee (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
-RhPP (3.0) 3a
-RhPP (3.0) 3b
-RhPP (3.0) 3c
-RhPP (3.0) 3c
-RhPP (3.0) 3c
Et N (1.2 eq)
nitrogen
nitrogen
nitrogen
nitrogen
nitrogen
nitrogen
nitrogen
nitrogen
nitrogen
air
24
24
24
24
24
24
24
24
24
24
89
94
92
90
0
95 (R)
97 (R)
3
Et N (1.2 eq)
3
Et N (1.2 eq)
>99 (R)
>99 (S)
n.a.
3
Et N (1.2 eq)
3
none
none
3c
Et N (1.2 eq)
0
n.a.
3
-RhPP (2.0) 3c
-RhPP (1.0) 3c
-RhPP (3.0) 3c
-RhPP (3.0) 3c
-RhPP (3.0) 3c
-IrPP (3.0) 3c
-IrPP (3.0) 3c
/-RhO (3.0) 3c
/-IrO (3.0) 3c
/-IrS (3.0) 3c
Et N (1.2 eq)
3
80
51
60
93
88
37
84
0
>99 (R)
>99 (R)
>99 (R)
99 (R)
99 (R)
29 (R)
15 (S)
n.a.
Et N (1.2 eq)
3
Et N (0.3 eq)
3
0
1
2
3
4
5
6
Et N (1.2 eq)
3
Et N (1.2 eq)
air, 1% H O 24
2
3
Et N (1.2 eq)
nitrogen
nitrogen
nitrogen
nitrogen
nitrogen
24
24
24
24
24
3
Et N (1.2 eq)
3
Et N (1.2 eq)
3
Et N (1.2 eq)
0
n.a.
3
Et N (1.2 eq)
0
n.a.
3
[
a] Conditions: trifluoromethyl ketone (0.20 mmol), phenylacetylene (0.60 mmol) and catalyst ( 3.0
mol%) in THF (0.2 mL) were stirred at room temperature for 24 hours. [b] Catalyst loading in
mol% provided in brackets. [c] Isolated yields. [d] Determined by chiral HPLC analysis.
Enantiomeric excess  99.5% ee designated as >99% ee. n.a. = not applicable.
7

Chemistry - A European Journal
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After these promising initial results regarding the enantioselective alkynylation with -RhPP,
we performed a substrate scope under optimized conditions with the trifluoroketone 3c and a variety of
arylacetylenes. As shown in Scheme 3, our method tolerates a variety of substituted phenylacetylenes,
containing alkyl, aryl, electron-donating, and electron-withdrawing substituents. Heteroarylacetylenes
such as 2-pyridylacetylene and 3-thiophenylacetylene are also suitable substrates. Overall, yields range
from 79-99% and enantioselectivities from 97 to >99% ee for the propargyl alcohols (R)-5d-p. -
RhPP also catalyzes the reaction of trifluoroketone 3c with aliphatic acetylenes as shown in Scheme 4
to provide the propargyl alcohols (R)-5q-v in satisfactory yields (55-88%) and with excellent
enantioselectivity (94% to >99% ee). However, it is important to note that satisfactory yields and
excellent enantioselectivity of this reaction is limited to ketones which contain both the CF group as
3
well as the imidazole moiety. For example, replacing the imidazole moiety with a phenyl or the CF3
group with an ethyl group completely abolishes the conversion. Replacing the imidazole moiety with a
less strongly coordinating group such as ethylcarboxylate or benzoyl leads to reduced yields and
reduced enantioselectivities (see Supporting Information for more details). These results imply that a
successful catalysis relies on a strong electronic activation of the carbonyl group by a neighboring CF3
in combination with the efficient coordination of the substrate to the rhodium catalyst.
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Chemistry - A European Journal
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Scheme 3. Substrate scope with respect to arylacetylenes.
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Chemistry - A European Journal
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Scheme 4. Substrate scope with respect to alkylacetylenes and trimethylsilylacethylene.
[
24]
Fluorine substituents play a prominent role in medicinal chemistry. For example, the reverse
transcriptase inhibitor Efavirenz, which is used for the treatment of HIV infections, contains a CF3
group attached to a stereocenter, indicating a demand of methods for the asymmetric construction of
[
22]
stereogenic centers containing CF substituents. The enantioselective alkynylation of trifluoromethyl
3
ketones constitutes an attractive strategy into this direction considering the versatility of propargyl
[
25]
alcohols as synthetic building blocks.
However, catalytic enantioselective methods for the
alkynylation of trifluoromethyl ketones are still limited. Shibasaki reported copper(I) complexes for the
[
20a,b]
direct alkynylation of trifluoromethyl ketones, albeit with very moderate enantioselectivities,
Mikami reported the enantioselective alkynylation of ethyl trifluoropyryvate with alkynylsilanes using
[
20c]
[20e]
a palladium(II)-BINAP catalyst,
whereas Ohshima, Mashima and Nishiyama,
and independently
[
20f]
Gong and Song,
were able to employ terminal alkynes in using rhodium(III)-pincer complexes. Ma
1
0

Chemistry - A European Journal
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reported an efficient titanium(IV)-catalyzed enantioselective alkynylation of trifluoromethyl ketones
[
20d]
using chiral cinchona alkaloids as chiral ligands.
Hayashi introduced an enantioselective
alkynylation of trifluoromethyl ketones catalyzed by chiral Schiff bases in the presence of Me Zn,
2
[
20g]
albeit with only very modest enantioselectivity.
Finally, Wolf recently reported the enantioselective
[20h]
zinc(II)-catalyzed addition of terminal ynamides to trifluoromethyl ketones.
Alltogether, it can be
concluded that each reported method contains limitations with respect to substrate scope and
enantioselectivity. Taking into account the limitation that our here reported method requires an
imidazole substituent next to the carbonyl group, very high enantioselectivities at low catalyst loadings
are achieved for terminal alkynes with aryl and alkyl substituents. Furthermore, the method is
technically undemanding since it does not require precautions with respect to moisture or air.
In conclusion, we here disclosed a new bis-cyclometalated rhodium(III) complex as a highly
effective catalyst for the catalytic enantioselective alkynylation of 2-trifluoroacetyl imidazoles. The
rhodium complex contains pinene-derived chiral ligands which permit the straightforward synthesis of
the complexes as enantiomerically pure single diastereomers. Interestingly, although the asymmetric
induction in the course of the catalysis is mainly controlled by the metal-centered chirality, the
synthesized rhodium complexes feature a catalytic activity that is surprisingly distinct from our
previous benzoxazole- and benzothiazole-based catalysts.
Acknowledgements:
We are grateful for funding from the German Research Foundation (ME 1805/13-1).
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19] The synthesis of the racemic dinuclear complex /-2Ir and a derived non-racemic
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016, 55, 2929–2933.
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23] For the synthesis, properties and applications of trifluoromethyl ketones, see: C. B. Kelly, M. A.
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Keywords: Chiral-at-metal, rhodium, cyclometalation, asymmetric catalysis, alkynylation,
trifluoromethyl.
TOC graphic:
A chiral rhodium(III) complex containing two cyclometalating 2-phenyl-5,6-(S,S)-pinenopyridine
ligands and two additional acetonitriles catalyzes the highly enantioselective alkynylation of 2-
trifluoroacetyl imidazoles. Whereas the ligand-based chirality permits the straightforward synthesis of
the complexes in a diastereomerically and enantiomerically pure fashion, the metal-centered chirality is
responsible for the asymmetric induction in the course of the catalysis.
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