Octahedral Chiral-at-Metal Iridium Catalysts: Versatile Chiral Lewis Acids for Asymmetric Conjugate Additions

Article abstract of DOI:10.1002/chem.201500922

Octahedral iridium(III) complexes containing two bidentate cyclometalating 5-tert-butyl-2-phenylbenzoxazole (IrO) or 5-tert-butyl-2-phenylbenzothiazole (IrS) ligands in addition to two labile acetonitrile ligands are demonstrated to constitute a highly versatile class of asymmetric Lewis acid catalysts. These complexes feature the metal center as the exclusive source of chirality and serve as effective asymmetric catalysts (0.5-5.0 mol % catalyst loading) for a variety of reactions with α,β-unsaturated carbonyl compounds, namely Friedel-Crafts alkylations (94-99 % ee), Michael additions with CH-acidic compounds (81-97 % ee), and a variety of cycloadditions (92-99 % ee with high d.r.). Mechanistic investigations and crystal structures of an iridium-coordinated substrates and iridium-coordinated products are consistent with a mechanistic picture in which the α,β-unsaturated carbonyl compounds are activated by two-point binding (bidentate coordination) to the chiral Lewis acid.

Full text of DOI:10.1002/chem.201500922

DOI: 10.1002/chem.201500922
Full Paper
&
Organic Synthesis
Octahedral Chiral-at-Metal Iridium Catalysts: Versatile Chiral Lewis
Acids for Asymmetric Conjugate Additions
Xiaodong Shen,[a] Haohua Huo,[a] Chuanyong Wang,[a] Bo Zhang,[a] Klaus Harms,[a] and
Eric Meggers*[a, b]
Abstract: Octahedral iridium(III) complexes containing two
bidentate cyclometalating 5-tert-butyl-2-phenylbenzoxazole
(IrO) or 5-tert-butyl-2-phenylbenzothiazole (IrS) ligands in
addition to two labile acetonitrile ligands are demonstrated
to constitute a highly versatile class of asymmetric Lewis
acid catalysts. These complexes feature the metal center as
the exclusive source of chirality and serve as effective asym-
metric catalysts (0.5–5.0 mol% catalyst loading) for a variety
of reactions with a,b-unsaturated carbonyl compounds,
namely Friedel–Crafts alkylations (94–99% ee), Michael addi-
tions with CH-acidic compounds (81–97% ee), and a variety
of cycloadditions (92–99% ee with high d.r.). Mechanistic in-
vestigations and crystal structures of an iridium-coordinated
substrates and iridium-coordinated products are consistent
with a mechanistic picture in which the a,b-unsaturated car-
bonyl compounds are activated by two-point binding (bi-
dentate coordination) to the chiral Lewis acid.
effective asymmetric catalysis.[9] One highly appealing goal in
this area of research is the development of chiral Lewis acid
catalysts that exhibit a broad generality with respect to reac-
tion types and substrates. Recently, we introduced octahedral
iridium(III) and rhodium(III) complexes as a novel class of chiral
Lewis acid catalysts.[6,10,11] In these complexes, the octahedral
metal center is coordinated irreversibly by two cyclometalating
bidentate ligands in a propeller-type fashion. Two additional
exchange-labile coordinated acetonitriles allow substrates to
become activated by two-point binding. These complexes are
structurally quite simple and only contain achiral ligands, with
metal-centered chirality (metal centrochirality) being the exclu-
sive source of chirality.[2] Importantly, despite the two labile
acetonitrile ligands, the catalysts are configurationally inert
and retain their relative and absolute configurations through-
out the catalysis. In this work, we demonstrate the high versa-
tility of the iridium(III) complexes L-IrO[10] and L-IrS[11]
(Figure 1) as chiral Lewis acid catalysts for a variety of asym-
metric reactions with acceptor-substituted alkenes, including
Introduction
Metal-based asymmetric catalysts are typically constructed
from a central metal ion in combination with one or multiple
chiral ligands so that the catalysts chirality originates from one
or more carbon, sulfur and/or phosphorus stereogenic centers
in the ligand sphere.[1] In contrast, asymmetric catalysts that
draw their chirality exclusively from a chiral metal center[2] are
much less investigated although such catalysts might display
some attractive features, such as structural simplicity (only
achiral ligands required) and an effective chirality transfer in
the course of the reaction due to the direct proximity of the
metal-based stereocenter to the metal-coordinating sub-
strate.[3] Synthetic challenges have hampered the development
of such chiral-at-metal catalysts in the past but were overcome
by our previously introduced methodology of employing coor-
dinating chiral auxiliaries[4] for a convenient synthesis of enan-
tiopure octahedral chiral-at-metal ruthenium(II),[5] rhodium(III),[6]
and iridium(III)[7] complexes, and opened up new avenues for
the straightforward design of highly powerful chiral-only-at-
metal asymmetric catalysts.[8]
Many functional groups in organic chemistry are amenable
to Lewis acid activation in a straightforward and predictable
fashion and chiral Lewis acids are, therefore, attractive tools for
[a] X. Shen, H. Huo, C. Wang, B. Zhang, Dr. K. Harms, Prof. Dr. E. Meggers
Fachbereich Chemie, Philipps-Universität Marburg
Hans-Meerwein-Straße, 35043 Marburg (Germany)
E-mail: meggers@chemie.uni-marburg.de
[b] Prof. Dr. E. Meggers
College of Chemistry and Chemical Engineering
Xiamen University, Xiamen 361005, (P. R. China)
Figure 1. Chiral-at-metal Lewis acid catalysts used in this study. Note that
the metal center constitutes the exclusive source of chirality in these
catalysts.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500922.
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Friedel–Crafts alkylations, Michael additions with CH-acidic
compounds, and cycloadditions.
Asymmetric Friedel–Crafts alkylations
We recently reported that L- and D-IrO can efficiently catalyze
the enantioselective Friedel–Crafts addition of indoles to a,b-
unsaturated 2-acyl imidazoles.[10] We were speculating that the
derivative L- and D-IrS,[11] in which the cyclometalated 2-phe-
nylbenzoxazole is replaced by a 2-phenylbenzothiazole, would
be able to provide a higher asymmetric induction due to the
long CÀS bonds that position the two tert-butyl groups closer
to the two vacant coordination sites. And indeed, when we
evaluated L-IrS (1.0 mol%) for the Friedel–Crafts alkylation of
indole with 2-acyl imidazole 9a, the expected alkylation prod-
uct (S)-10 was obtained with
Results and Discussion
Catalyst synthesis
The chiral-at-metal catalysts can be synthesized with high
enantiomeric purity through a convenient auxiliary-mediated
strategy developed in our laboratory,[7] as shown for the syn-
thesis of L-IrS and D-IrS in Scheme 1. Accordingly, IrCl3 hy-
drate is reacted with 5-tert-butyl-2-phenylbenzothiazole (1),
99% ee at room temperature
compared to 96% ee for L-IrO
(as shown in Figure 2).[14,15] This
trend holds for the Friedel–Crafts
reaction with 3-dimethylamino-
anisole,
for
which
L-IrS
(2.0 mol%) affords (S)-11 a in
97% yield and with excellent
99% ee, compared to 94% ee
when using L-IrO (2 mol%) in-
stead. In contrast, for 2-methoxy-
furane[15a,b] and pyrrole[15a,b,16] the
respective Friedel–Crafts prod-
ucts (S)-12 and (S)-13 were ob-
tained with almost equal enan-
tioselectivities (as shown in
Figure 2). Overall, compared to
L-IrO, L-IrS generally requires
Scheme 1. Auxiliary-mediated synthesis of the enantiomerically pure chiral-at-metal iridium(III) complexes L-IrS
and D-IrS.
synthesized itself in two steps from 1-bromo-4-tert-butylben-
zene,[12] in 2-ethoxyethanol/water 3:1 under reflux to provide
the iridium dimer complex rac-2 in a diastereoselective fash-
ion.[13] The subsequent reaction with the chiral auxiliary ligand
(S)-4-isopropyl-2-(2’-hydroxyphenyl)-2-thiazoline ((S)-3) affords
the iridium(III) complexes L-(S)-4 and D-(S)-4 as a mixture of
diastereomers, which can be resolved easily by standard silica
gel chromatography on a gram scale.[11] Upon reaction in ace-
tonitrile in the presence of the weak acid NH4PF6 and at slight-
ly elevated temperature (508C), these complexes are converted
to virtually enantiopure complexes L-IrS and D-IrS (each
>99% ee) by a stereospecific substitution of the (protonated)
chiral auxiliary with two acetonitrile ligands under retention of
configuration. It is noteworthy that the chiral auxiliary can be
recovered after this reaction in high yield (96%) and without
any loss of enantiomeric purity (ꢀ99.9% ee). The enantiomeric
Figure 2. Chiral octahedral iridium(III) Lewis acid catalysis applied to Friedel–
Crafts alkylations with a,b-unsaturated 2-acyl imidazole 9a.
purity of L-IrS and D-IrS was verified by HPLC on a chiral sta-
tionary phase. No noticeable loss in catalytic performance can
be observed upon storage under argon in a refrigerator (58C)
for several months. The chiral auxiliary (S)-3 can be synthesized
in three steps starting from acid chloride 5 in an overall yield
of 57%: Reaction with the chiral amino alcohol (S)-6 affords
amide 7 (91%), which is cyclized to the thiazoline 8 with P2S5
(93%), followed by ether cleavage with BBr3 (67%).
somewhat elongated reaction times that can be attributed to
the larger steric hindrance around the coordination sites.[17]
However, the reactions can be accelerated by raising the tem-
perature without affecting much the enantioselectivity. For ex-
ample, increasing the temperature for the reaction 9a!(S)-
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nary stereocenter[19] as the reac-
tion of tert-butyl 2-oxocyclopen-
tane-1-carboxylate with 2-acyl
imidazole 9a afforded (S,S)-16 in
85% yield, with 96% ee, and
1.5:1 d.r.. The related Michael
addition of 2,3-dihydro-1-oxo-
1H-indene-2-carboxylic acid tert-
butyl ester to 2-acyl imidazole
9a provided (S,S)-17 in 93%
yield with 97% ee and 22:1 d.r..
As found for the Friedel–Crafts
reactions, the stereoselectivity of
the related catalyst L-IrO was
generally slightly lower.
Table 1. Friedel–Crafts alkylation with a,b-unsaturated 2-acyl imidazoles: Effects of substituents, catalyst load-
ing, and temperature.[a]
Substrate
Product
Cat. loading [mol%]
2.0
T [8C]
t [h]
66
Yield [%][b]
ee [%][c]
R=Me (9a)
(S)-11 a
RT
30
40
50
60
40
40
40
40
97
99
48
25
<20
5
94
99
95 (83)[d]
99
99 (99)[d]
98
96
98
0.5
2.0
2.0
2.0
32
18
24
48
96
99
95
81
98
99
99
96
R=Ph (9b)
R=CO2Et (9c)
R=nBu (9d)
(R)-11 b
(S)-11 c
(S)-11 d
[a] Reaction conditions: 2-acyl imidazoles 9a–d (0.20 mmol), 3-dimethylaminoanisole (0.60 mol), THF (0.1 mL).
[b] Isolated yields. [c] Enantiomeric excess determined by HPLC analysis on chiral stationary phase. [d] Yield
and enantioselectivity for the analogous reaction performed under air shown in brackets.
Asymmetric cycloadditions
We next investigated cycloaddi-
tions with a,b-unsaturated 2-acyl
11 a from room temperature to 608C leads to full conversion
in just 5 h with only a slightly diminished enantioselectivity of
98% ee (Table 1). Interestingly, the reaction is insensitive to air
(Table 1). It is also noteworthy that the catalyst loading can be
decreased for this reaction to 0.5 mol% and that the acyl imi-
dazole substrates 9b–d also provide the respective Friedel–
Crafts alkylation products (R)-11 b, (S)-11 c, and (S)-11 d with
high enantioselectivities (Table 1).
imidazoles (Figure 4). Accordingly, the reaction of 9a with the
nitrone 18 catalyzed by 2.0 mol% of L-IrS provided the 1,3-di-
polar cycloaddition product 19 in a yield of 86% and with ex-
cellent 98% ee, while virtually forming just one diastereomer
(endo/exo>100:1).[20,21] The enantioselectivity was significantly
lower using L-IrO (92% ee). In contrast, for the hetero-Diels–
Alder reaction between 9a or 9e with 2,3-dihydrofurane under
formation of the dihydropyrans 20 and 21, respectively, L-IrO
(2 mol%) turned out to be the catalyst of choice, providing
high diastereo- and enantioselectivities.[22,23] At last, the Diels-
Alder reaction of 9a with isoprene provided the desired prod-
uct 22 with high enantio- and diastereoselectivity.[24]
Asymmetric Michael additions
Next, we investigated the addition of CH-acidic malonodinitrile
and 1,3-dicarbonyl compounds to the Michael acceptor 9a as
shown in Figure 3. By using L-IrS at a loading of 1.0 or
2.0 mol%, the malonodinitrile[18] addition product (S)-14 was
formed in a yield of 95% with 90% ee and the Meldrum’s acid
addition product (S)-15 in a yield of 94% with 91% ee. L-IrS is
also suitable to catalyze the formation of an all-carbon quater-
Scope of acceptor-substituted alkenes
After we revealed that IrO and IrS catalyze the asymmetric
conjugate addition of a wide variety of nucleophiles to a,b-un-
saturated 2-acyl imidazoles, we next investigated the scope
with respect to acceptor substituted alkenes and
used the enantioselective Friedel–Crafts alkylation
with 3-dimethylaminoanisole as our model reaction
(Figure 5). We were pleased to find that a significant
number of the tested acceptor-substituted alkenes
9 f–p[15a,b,25–33] proved to be suitable substrates, pro-
viding the expected products in high yields and high
enantioselectivities, such as the benzimidazole 9 f
(86% yield, 96% ee),[25] 2-thiazole 9g (99% yield,
98% ee),[26] pyridine 9h (87% yield, 97% ee),[27] pyra-
zoles 9k (86% yield, 98% ee), and 9l (99% yield,
95% ee),[30] and a-ketoester 9n (99% yield,
95% ee).[32] Apparently, only substrates that can effi-
ciently coordinate to the iridium catalyst in a biden-
tate fashion give satisfactory results, whereas the
simple a,b-unsaturated carboxylic ester 9p does not
afford any product even at higher catalyst loadings
Figure 3. Chiral octahedral iridium(III) Lewis acid catalysis applied to Michael additions
with a,b-unsaturated 2-acyl imidazole 9a. [a] Reaction performed at 408C instead of
room temperature.
of 5 mol% and an elevated temperature of 608C. On
the other hand, we do not have an explanation for
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the failing or sluggish conversion of some of the other sub-
strates such as the 2-oxazolidinone 9i,[28] 2-thiazolidinethione
9j,[29] phosphonate 9m,[31] and Weinreb amide 9o.[33] However,
we believe that the addition to a,b-unsaturated ketoesters,[32]
a,b-unsaturated N-acyl pyrazoles,[30] a,b-unsaturated 2-acyl
thiazoles[26,8c] and a,b-unsaturated 2-acyl imidazoles[34] are par-
ticularly useful substrates since they are easily converted to
a variety of different carbonyl compounds.
Mechanistic considerations
It is plausible that the catalytic cycle starts with the bidentate
coordination of the a,b-unsaturated carbonyl compound to
the catalyst through the carbonyl and one additional moiety
(e.g. imidazole, benzimidazole, pyrazole, pyridine, or carboxylic
ester) under release of the two labile acetonitrile ligands,
thereby leading to the intermediate A (Figure 6). This two-
Figure 4. Chiral octahedral iridium(III) Lewis acid catalysis applied to cycload-
ditions with a,b-unsaturated 2-acyl imidazoles.
Figure 6. Plausible mechanistic cycle for the reported asymmetric Lewis acid
catalysis.
point binding of the substrate increases the electrophilicity of
the double bond and promotes a nucleophilic addition to the
b-position of the alkene. Figure 7a displays a crystal structure
of such an intermediate A, namely the substrate 9e coordinat-
ed to L-IrO. The space filling model of this structure also con-
vincingly illustrates that the prochiral Si-face is shielded by one
tert-butyl group and therefore guides the nucleophilic addition
to the Re-face. This is consistent with the obtained absolute
configuration of the addition products and leads to the inter-
mediate enolate complex B, which after protonation, provides
the bidentate coordinated substrate (intermediate C). The re-
placement of the coordinated product by a new substrate, fol-
lowed by a new catalytic cycle, presumably occurs through an
intermediate in which the product is monocoordinated (inter-
mediate D) and the sixth coordinate site either filled by aceto-
nitrile or the new substrate. We were able to trap such formed
iridium coordinated product for the conversion 9e!21. Fig-
ure 7b shows that the cycloaddition product 21 is coordinated
to the catalyst through the imidazole moiety and an acetoni-
trile ligand is filling the remaining coordination sphere.
Finally, kinetic experiments (Figure 8) performed with the re-
action 9a!11 a revealed that the rate of the overall catalysis
does not depend on the concentration of the nucleophile 3-di-
methylaminoanisole but is directly proportional to the concen-
Figure 5. Substrate scope with respect to electron acceptor substituted
alkenes.
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of the well-known kinetic stabili-
ty of coordinative bonds to
iridium(III)
in
octahedral
complexes.
Conclusion
In summary, the reactions dis-
cussed here reveal the versatility
of the chiral-at-metal iridium(III)
catalysts. It is quite remarkable
that a single class of chiral Lewis
acid catalysts is capable of effec-
tively catalyzing different reac-
tion types, as demonstrated for
Friedel–Crafts reactions, Michael
additions of CH-acidic com-
pounds, and a variety of cyclo-
additions. A significant variability
also exists with respect to the
a,b-unsaturated carbonyl sub-
strates as long as they allow
a two-point binding to the iridi-
um catalyst. We are convinced
that this novel class of chiral-
only-at-metal catalysts are of sig-
nificant practical value as they
are accessible in a straightfor-
ward fashion, are unproblematic
for long-term storage, provide
excellent yields and asymmetric
inductions at low catalyst load-
ings, can be used at room tem-
Figure 7. a) Crystal structure obtained upon reaction of L/D-IrO with the substrate 9e. See the Supporting Infor-
mation for more details. Only the L-enantiomer is shown and the hexafluorophosphate counteranion is omitted
for clarity. ORTEP drawing with 50% probability thermal ellipsoids and space filling representation with an adjust-
ed orientation. b) Crystal structure obtained upon the reaction of racemic L/D-IrO with substrate 9e overnight,
followed by the addition of 2,3-dihydrofurane. See the Supporting Information for more details. Only the D-enan-
tiomer is shown and the hexafluorophosphate counteranion is omitted for clarity. ORTEP drawing with 50% prob-
ability thermal ellipsoids.
tration of the a,b-unsaturated 2-acyl imidazole 9a, thus dem-
perature or slightly elevated temperatures, and do not require
a stringent exclusion of air and moisture. It has to be noted
that in a previous study we established that the rhodium con-
gener of L- and D-IrO is a somewhat superior catalyst for Mi-
chael additions with CH-acidic compounds.[6] However, the
cost for rhodium is currently significantly higher compared to
iridium which most likely renders the iridium complexes the
catalysts of choice for the here presented reactions.
onstrating that the rate-determining step cannot be the nucle-
ophilic addition to the iridium-coordinated substrate (conver-
sion A!B in Figure 6) but instead must be the replacement of
iridium-coordinated product with a new substrate molecule
(conversion D!A in Figure 6). This is not unexpected because
Keywords: asymmetric catalysis · chiral-at-metal · conjugate
addition · iridium · Lewis acid
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*
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Received: March 8, 2015
Published online on June 1, 2015
Chem. Eur. J. 2015, 21, 9720 – 9726
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim