Asymmetric Nucleophilic Catalysis with an Octahedral Chiral-at-Metal Iridium(III) Complex

Article abstract of DOI:10.1021/acscatal.7b01296

Herein, we report about the design, synthesis, and application of a nucleophilic octahedral chiral-only-at-metal iridium(III) complex. We demonstrate that the enantiopure form of this complex serves as an efficient catalyst for the asymmetric Steglich rearrangement of O-acylated azlactones (up to 96% ee and 99% yield) and the related asymmetric Black rearrangement of O-acylated benzofuranones (up to 94% ee and 99% yield). We provide insight into the mechanisms of these two acyl migration reactions and the catalyst's manner of chiral recognition with crystal structures of the active catalyst and a catalysis intermediate analog, as well as with quantum chemical calculations based on them. Furthermore, we demonstrate that the presented catalyst also efficiently catalyzes the asymmetric reaction between aryl alkyl ketenes and 2-cyanopyrrole to give the corresponding α-chiral N-acyl pyrroles (up to 95% ee and 99% yield).

Full text of DOI:10.1021/acscatal.7b01296

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Article
Asymmetric Nucleophilic Catalysis with an
Octahedral Chiral-at-Metal Iridium(III) Complex
Thomas Cruchter, Michael G. Medvedev, Xiaodong Shen,
Thomas Mietke, Klaus Harms, Michael Marsch, and Eric Meggers
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 23 Jun 2017
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Asymmetric Nucleophilic Catalysis with an Octahedral
ChiralꢀatꢀMetal Iridium(III) Complex
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Thomas Cruchter,† Michael G. Medvedev,‡ Xiaodong Shen,† Thomas Mietke,† Klaus Harms,†
Michael Marsch,† and Eric Meggers*,†
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[†] T. Cruchter, X. Shen, T. Mietke, K. Harms, M. Marsch, E. Meggers*
Fachbereich Chemie, PhilippsꢀUniversität Marburg,
HansꢀMeerweinꢀStrasse 4, 35043 Marburg, Germany
http://www.uniꢀmarburg.de/fb15/agꢀmeggers
Eꢀmail: meggers@chemie.uniꢀmarburg.de
[‡] M. G. Medvedev
(a) Xꢀray Structural Laboratory, A. N. Nesmeyanov Institute of Organoelement
Compounds RAS, Vavilova St. 28, 119991 Moscow, Russian Federation
(b) N. D. Zelinsky Institute of Organic Chemistry RAS,
Leninsky Prospect 47, 119991 Moscow, Russian Federation
TOC graphic
Abstract: Herein, we report about the design, synthesis, and application of a nucleophilic octahedral
chiralꢀonlyꢀatꢀmetal iridium(III) complex. We demonstrate that the enantiopure form of this complex
serves as an efficient catalyst for the asymmetric Steglich rearrangement of Oꢀacylated azlactones (up
to 96% ee and 99% yield) and the related asymmetric Black rearrangement of Oꢀacylated
benzofuranones (up to 94% ee and 99% yield). We provide insight into the mechanisms of these two
acyl migration reactions and the catalyst's manner of chiral recognition with crystal structures of the
active catalyst and a catalysis intermediate analog, as well as with quantum chemical calculations
based on them. Furthermore, we demonstrate that the presented catalyst also efficiently catalyzes the
asymmetric reaction between aryl alkyl ketenes and 2ꢀcyanopyrrole to give the corresponding
αꢀchiral Nꢀacyl pyrroles (up to 95% ee and 99% yield).
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Keywords: Nucleophilic Catalyst / Lewis Base Catalysis / Asymmetric Catalysis / Iridium /
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ChiralꢀatꢀMetal / Acyl Transfer
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Introduction
Over the past twenty years since the introduction of the first "chiral DMAP" reagent by Vedejs and
Chen in 1996 (A, Figure 1),1 a significant amount of work has been spent by many research groups in
developing highly active and at the same time highly selective nucleophilic catalysts capable of
various asymmetric transformations, such as (dynamic) kinetic resolutions of racemic compounds
and desymmetrizations of meso compounds,2−9 Steglichꢀtype acyl migration reactions,9−15 reactions
of ketenes with various substrates,16,17 and others.18
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Figure 1. Vedejs' asymmetric acylation reagent (A) and various chiral nucleophilic catalysts (BꢀE) relying on different
frameworks and types of chirality.
In large part, the developed chiral catalysts rely on 4ꢀdimethylaminopyridine (DMAP) or closely
related 4ꢀpyrrolidinopyridine (PPY) as their catalytically active entities due to their high intrinsic
activity.2,3,11,12,16,19−21 However, powerful nonꢀDMAPꢀtype nucleophilic catalysts have been
developed as well, which rely on amidines,4,9 isothioureas,5,9,13 imidazoles,6,14 Oꢀnucleophiles,7,15
phosphines,8 Nꢀheterocyclic carbenes (NHCs),17 and others.18
A straightforward approach to achieve enantiocontrol in asymmetric transformations is to introduce a
steering stereocenter in proximity to the catalyst's active site – in case of DMAP, in the 2ꢀposition.
However, as efficient steering stereocenters usually comprise sterically demanding moieties, this
typically goes along with significant loss of catalytic activity, as it is the case for acylation reagent A
from Vedejs and Chen, which has to be employed in its Nꢀacylated form in stoichiometric amounts.1
Hence, from the standpoint of catalytic activity, it is desirable to have a remote stereocenter, but this,
on the other hand, often goes along with loss of enantiocontrol.3a,d,12a,b,g,13b,14a This phenomenon has
aptly been called selectivity-reactivity dilemma by Fuji et al.3a and is also encountered in nonꢀplanar
systems, such as catalyst D (Figure 1), although, due to the lack of planarity, less pronounced.4,13,14a
With respect to nucleophilic catalysts, several interesting strategies have been reported to circumvent
low catalytic activity when aiming for high selectivity including strategies that go beyond "classic"
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carbonꢀcentered tetrahedral chirality. In 1996, shortly after Vedejs' and Chen's seminal publication,
Fu and coꢀworkers introduced planarꢀchiral ferroceneꢀfused DMAP derivatives as chiral nucleophilic
catalysts (B, Figure 1),2a which have, up to date, been demonstrated to efficiently catalyze a broad
array of asymmetric transformations and also been extended to analogous ruthenocylꢀfused
derivatives.21 Due to their unrivaled versatility,2,11,16,19 Fu's ferroceneꢀfused DMAP derivatives B
have emerged as a reference standard in asymmetric nucleophilic catalysis.4d,22a Meanwhile, the
concept of creating planarꢀchiral nucleophilic catalysts by ferrocene fusion has been extended by
others to nonꢀDMAPꢀtype catalysts, such as NHCꢀ and amidineꢀbased systems.4d,23 In contrast,
Spivey and coꢀworkers made use of axial chirality by employing axialꢀchiral DMAP derivatives in
the kinetic resolution and desymmetrization of alcohols.3b,c,e,f Ooi and coworkers developed axialꢀ
chiral BINOLꢀderived Oꢀnucleophilic ammonium betaines which they utilized in Steglich
rearrangements of Oꢀacylated azlactones.15 And quite recently, Suga and coꢀworkers reported about
an axialꢀchiral BINOLꢀderived DMAPꢀtype catalyst (C, Figure 1) which they employed in the
Steglichꢀtype rearrangement of Oꢀacylated oxindoles, in the kinetic resolution of alcohols, and in the
desymmetrization of diols.12g Carbery and coꢀworkers developed a helicenoidal DMAP derivative
which they used in the kinetic resolution of alcohols.3h,i And in this context worth mentioning, a
photoꢀswitchable helicalꢀchiral DMAPꢀtype catalyst has recently been reported by Chen, Yu, and coꢀ
workers allowing enantiodivergent Steglich rearrangement of Oꢀacylated azlactones with a single
catalyst.12h
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Inert octahedral metal complexes were introduced and established as structural templates for
asymmetric catalysis first by Belokon, Fontecave, Gladysz, and Ohkuma.24 Our group contributed to
this area with the design of bisꢀcyclometalated iridium complexes as hydrogenꢀbonding catalysts,25
Brønsted base catalysts,26 and enamine catalysts.27,28 In this work, we present the development of a
robust, kinetically inert, octahedral complex with metalꢀcentered chirality featuring a nucleophilic
ligand that can be used as a versatile nucleophilic catalyst in various asymmetric transformations.
Results and Discussion
Inspired by our results with chiralꢀatꢀmetal hydrogenꢀbonding catalysts,25 structurally related
Brønsted base catalysts,26 and by chiral amidineꢀ,4,9 isothioureaꢀ,5,9,13 and imidazoleꢀbased6,14
nucleophilic catalysts reported by Birman and others (e.g. D, Figure 1), we reasoned that it might be
possible to utilize a bisꢀcyclometalated octahedral iridium(III) complex comprising a metalꢀlocated
stereocenter and a bidentate 3Hꢀimidazo[4,5ꢀh]quinoline ligand as a nucleophilic catalyst (E,
Figure 1).28 Indeed, when we added 3 mol% of complexes ΛꢀIr1−ΛꢀIr5 together with 6 mol% of
cesium carbonate to a solution of Oꢀacylated azlactone 1a, we observed in all cases smooth Steglich
rearrangement of substrate 1a to product 2a (Figure 2).10 However, choice of the catalyst's residues
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R1−R3 proved to be crucial in order to obtain 2a with high enantioselectivity. Under nonꢀoptimized
conditions, we found the highest selectivity for complex ΛꢀIr5 with R1 = 2,4,6ꢀ(iPr)3ꢀPh,
R2 = 2,6ꢀ(Me)2ꢀPh, and R3 = Cl providing product 2a with 85% ee (Figure 2).
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complex
ΛꢀIr1
ΛꢀIr2
ΛꢀIr3
ΛꢀIr4
R1
t-Bu
R2
H
R3 ee2a(%)a
H
H
H
H
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2,4,6ꢀ(Me)3ꢀPh
2,4,6ꢀ(Me)3ꢀPh 2,6ꢀ(Me)2ꢀPh
2,4,6ꢀ(iPr)3ꢀPh 2,6ꢀ(Me)2ꢀPh
2,4,6ꢀ(iPr)3ꢀPh 2,6ꢀ(Me)2ꢀPh Cl
H
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ΛꢀIr5
aFull conversion confirmed for all cases by TLC and crude 1H NMR,
clean conversion confirmed by crude 1H NMR; enantioselectivities
determined from crude product mixtures by chiral HPLC analysis.
Figure 2. Evaluation of chiral iridium(III) complexes ΛꢀIr1−ΛꢀIr5 in the Steglich rearrangement of substrate 1a.
Complex ΛꢀIr5 is the HPF6 salt of actual in situ generated catalytically active species ΛꢀIr5', which
is generated from precatalyst ΛꢀIr5 by reaction with a weak Brønsted base, for example cesium
carbonate.29 The entire structural formulas of precatalyst ΛꢀIr5 and active catalyst ΛꢀIr5' are
depicted in Figure 3, together with the threeꢀdimensional structure of catalyst ΛꢀIr5' and the
structural formula of enantiomeric catalyst ꢁꢀIr5', which was concomitantly prepared with ΛꢀIr5'
(see Scheme 1) and also employed as a catalyst in the course of this study.
σ
+
PF6
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
O
O
O
Cl
N
Ir
N
N
Ir
N
Cl
Cl
N
Ir
N
Brønsted
base
N
N
N
=
N
NH
iPr
N
N
N
N
iPr
iPr
O
O
O
iPr
iPr
iPr
iPr
iPr
iPr
Λ
ꢀIr5
ꢀIr5'
Λ
ꢀ
ꢀIr5'
Figure 3. From left to right: (1) Structural formula of precatalyst ΛꢀIr5. (2) Structural formula of active catalyst ΛꢀIr5'
and its threeꢀdimensional structure (obtained from a crystal structure of racꢀIr5'; positional disorder and cocrystallized
solvent molecules omitted for clarity; 50% probability of thermal ellipsoids).30 (3) Structural formula of enantiomeric
catalyst ꢁꢀIr5'.
Synthesis of enantiopure precatalyst Λ/ꢁꢀIr5 and catalyst Λ/ꢁꢀIr5' is depicted in Scheme 1 and
based on methodology previously developed in our group.31 First, reaction of benzoxazole ligand 3
with IrCl3·3H2O in 2ꢀethoxyethanol results in the formation of the corresponding cyclometalated
iridium(III) dimer [IrIII(C^N)2(µꢀCl)]2 (Scheme 1, A; dimer structure not drawn; C^N represents
cyclometalated 3; crystal structure of this dimer is provided in the Supporting Information), which is
cleaved with auxiliary ligand (
iridium(III) complexes Λꢀ( )ꢀIr5 and ꢁꢀ(
flash chromatography (Scheme 1, B).
S
)ꢀ432 in the presence of silver triflate to give diastereomeric
S
S
)ꢀIr5, which are purified and resolved by standard silica
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Scheme 1. Synthesis of precatalyst Λ/ꢁꢀIr5 and catalyst Λ/ꢁꢀIr5' starting from benzoxazole 3 and IrCl3·3H2O. a
Yield of deprotonation step D: 99%. bAlternatively, wash CH2Cl2 solution of Λ/ꢁꢀIr5 with aqueous 0.3 M NaOH and
water.
Auxiliary ligand (S)ꢀ4 is then cleaved off with triflic acid in acetonitrile and replaced by
imidazoquinoline ligand 5 (Scheme 1, C, I−II).33 After anion exchange, chromatographic purification
yields precatalysts ΛꢀIr5 and ꢁꢀIr5 (Scheme 1, C, III).34 As shown in Figure 2, Λ/ꢁꢀIr5 can be
directly used in case an excess of a Brønsted base relative to the catalyst is present in the reaction
mixture leading to in situ formation of active Λ/ꢁꢀIr5'.29 We later found that active catalyst Λ/ꢁꢀIr5'
can be conveniently prepared by passing a CH2Cl2 solution of Λ/ꢁꢀIr5 through a plug of
piperidinomethylated polystyrene beads35 or, alternatively, by washing a CH2Cl2 solution of Λ/ꢁꢀIr5
with diluted aqueous sodium hydroxide followed by thorough washing with water (Scheme 1, D).
Chiral HPLC analysis revealed >99% ee for both Λꢀ and ꢁꢀIr5' and the absolute configurations were
assigned by circular dichroism spectroscopy (Figure 4). Detailed preparation procedures and
characterizations of all presented iridium(III) complexes are provided in the Supporting Information
(SI).
1.0
Racemate racꢀIr5'
80
60
Enantiomer
(>99% ee)
Enantiomer
(>99% ee)
Λ
ꢀIr5'
Enantiomer
Enantiomer
Λ
ꢀIr5 (MeCN, 0.20 mM)
ꢀ
ꢀIr5 (MeCN, 0.20 mM)
0.8
0.6
0.4
0.2
0.0
ꢀꢀIr5'
40
20
0
ꢀ20
ꢀ40
ꢀ60
ꢀ80
210
300
400
λ [nm]
500
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14
15
16
17
18
19
Retention time tR [min]
Wavelength
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Figure 4. Left: CD spectra of enantiomeric precatalysts Λꢀ and ꢁꢀIr5. Right: Superposition of absorptionꢀnormalized
excerpts of the HPLC traces of catalysts racꢀ, Λꢀ, and ꢁꢀIr5'.
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Having identified Λ/ꢁꢀIr5 as a promising precatalyst, we continued focusing on the Steglich
rearrangement of Oꢀacylated azlactones (1→2) and so we first performed a reaction conditions
screening (details in SI). Based on this screening, we identified ethyl acetate as the solvent of choice
as it already provided a high enantioselectivity at 0 °C and further allowed us to lower the
temperature to −30 °C resulting in a significantly enhanced selectivity at a still reasonable reaction
rate. We found loadings of 0.5−1 mol% of precatalyst ΛꢀIr5 and 3 mol% of cesium carbonate as
sufficient for this type of reaction. Next, we investigated its scope (Table 1).
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Table 1. Catalytic enantioselective Steglich rearrangement of Oꢀacylated azlactonesa
entry
1c,d
2c,d
3c,d
4c
5
6
7
8
t (°C)
0
0
time (h)
12
R1
Bn
i-Bu
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
R2
Bn
Bn
Bn
Bn
Me
R3
yield (%)b
97
ee (%)b
88
70
45
93
88
90
91
91
95
94
93
93
96
96
product
2a (R)
2b (R)
2c (R)
2a (R)
2d (R)
2e (R)
2f (R)
2g (R)
2h (R)
2h (R)
2a (R)
pꢀMeOꢀPh
pꢀMeOꢀPh
pꢀMeOꢀPh
pꢀMeOꢀPh
pꢀMeOꢀPh
pꢀMeOꢀPh
pꢀ(t-Bu)ꢀPh
1ꢀNaphtyl
2ꢀNaphtyl
2ꢀNaphtyl
pꢀMeOꢀPh
pꢀMeOꢀPh
t-Bu
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12
72
72
72
72
72
72
72
72
72
72
91
80
95
68
99
89
88
90
94
97
93
91
0
−30
−30
−30
−30
−30
−30
−30
−30
−30
−30
−30
C(CH3)2CCl3
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
9
10e,f
11e
12e,f
13e,g
14e,g,h
2a (R)
entꢀ2i (S)g
entꢀ2i (S)g
72
t-Bu
90
aStandard reaction conditions: substrate 1 (1.0 equiv; approx. 90 µmol) with precatalyst ΛꢀIr5 (1 mol%) and Cs2CO3
(3 mol%) in EtOAc (c = 0.65 M) at the indicated temperature. bIsolated yields; enantioselectivities determined from
d
e
isolated products by chiral HPLC analysis. c0.5 mol% of catalyst were used. c = 0.5 M. Active catalyst Ir5' was used
f
instead of precatalyst Ir5 (no addition of Cs2CO3). Scaledꢀup reactions, entry 10: 400 mg (919 µmol) of substrate 1h;
entry 12: 381 mg (917 µmol) of substrate 1a. gꢁꢀconfigured catalyst ꢁꢀIr5' used (major product: Sꢀconfiguration).
hCD2Cl2 solution of ꢁꢀIr5' left standing for 7 d at 25 °C before usage.
With just 0.5 mol% of precatalyst ΛꢀIr5 in the presence of 3 mol% Cs2CO3 at 0 °C, substrate 1a
(R1 = Bn, R2 = Bn, R3 = pꢀMeOꢀPh) gave product 2a with 88% ee and 97% yield within 12 h
(Table 1, entry 1). We then changed over to substrate 1b with R1 = iꢀBu and obtained product 2b with
moderate 70% ee (entry 2). Subsequently, we switched to 1c with R1 = Me and the selectivity
dropped to 45% ee (2c, entry 3). For 1a being the best substrate so far, we now lowered the
temperature to −30 °C and prolonged the reaction time to 72 h, which led to an increase from 88% ee
to 93% ee for product 2a (entries 1 and 4). Keeping these conditions, we now exchanged the
migrating acyl group R2 = Bn for R2 = Me (1d, entry 5) and R2 = C(CH3)2CCl3 (1e, entry 6), which
gave the products 2d and 2e in 88% ee and 90% ee, respectively, indicating that the catalyst is less
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sensitive to variation of R2 compared to R1. Finally, we screened R3 (entries 7−9, 11, 13) and the best
results were obtained here with substrate 1h with R3 = 2ꢀnaphtyl (2h, 95% ee, 90% yield, entry 9) and
substrate 1i with R3 = tꢀBu (entꢀ2i, 96% ee, 91% yield, entry 13; ꢁꢀconfigured catalyst used).
Importantly, the reactions from entries 11 and 13 were, in contrast to all others discussed so far,
carried out using active catalyst Λ/ꢁꢀIr5' in the absence of Cs2CO3, as we had meanwhile discovered
that both methods, use of HPF6 salt Λ/ꢁꢀIr5 in combination with Cs2CO3 and use of active catalyst
Λ/ꢁꢀIr5' alone, led to identical results, which is visible from entries 4 and 11. All reactions discussed
further below were carried out using catalyst Λ/ꢁꢀIr5' instead of precatalyst Λ/ꢁꢀIr5. In order to
demonstrate the catalyst's stability, we left a dichloromethane solution of catalyst ꢁꢀIr5' standing for
7 d at 25 °C before usage, which then delivered product entꢀ2i with the same selectivity and yield as
freshly prepared ꢁꢀIr5' (entry 14, compare with entry 13; details in SI). In this context worth
mentioning, we did neither observe any decomposition nor any racemization of catalysts Λ/ꢁꢀIr5 and
precatalysts Λ/ꢁꢀIr5' when we stored them as solids for about 6 months at 4 °C under standard
atmospheric conditions. Exemplarily, we scaled up two reactions with substrates 1a and 1h by a
factor of ten (~1 mmol scale) and obtained similar yields and basically identical selectivities as in
case of the corresponding standard scale examples (entries 10 and 12, compare with entries 9 and
11). Noteworthy, all Steglich rearrangements from Table 1 were set up under normal atmosphere
without any special precautions against moisture and oxygen. Stereochemistry assignment details for
Cꢀacylated azlactones 2 are provided in the Supporting Information.
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Table 2. Catalytic enantioselective Black rearrangement of Oꢀacylated benzofuranonesa
entry
1c,d
2d
t (°C)
0 °C
0 °C
0 °C
0 °C
time (h)
18 h
10 h
18 h
48 h
20 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
R1
Ph
Me
Me
Me
Bn
Me
i-Bu
Bn
Me
Me
Me
Me
Me
Me
Me
R2
Ph
Ph
Bn
yield (%)b
N.D.c
99
ee (%)b
30
91
80
82
89
92
90
91
94
94
70
93
product
7a (R)
7b (R)
7c (R)
7d (R)
7e (S)j
7b (R)
7f (R)
3d
99
98
98
98
99
99
99
99
4d,e
iꢀPr
C(CH3)2CCl3
5d
0 °C
6
7
8
9
−15 °C
−15 °C
−15 °C
−30 °C
−30 °C
−30 °C
−30 °C
−30 °C
−30 °C
−30 °C
Ph
Ph
Ph
Ph
Ph
Me
7g (R)
7b (R)
entꢀ7b (S) f
7h (R)
7i (S)j
10f
11
12
13g
14g
15i
93
99
99
C(CH3)2CCl3
C(CH3)2CCl3
Ph
93
7i (S)j
7b (R)
7b (R)
99 (73h)
99
92 (98h)
93
Ph
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aStandard reaction conditions: substrate 6 (1.0 equiv; 70−90 µmol) with catalyst ΛꢀIr5' (1 mol%) in TAA/CPME 2:1
(c = 0.2 M) at the indicated temperature. bIsolated yields; enantioselectivities determined from isolated products by chiral
HPLC analysis (except entry 1: ee of 7a from crude mixture). cNot determined, incomplete after 18 h; ~50% conv. acc. to
d
e
f
TLC. Solvent: TAA, c = 0.3 M. 2 mol% catalyst used. ꢁꢀconfigured catalyst used. gScaledꢀup reactions, entry 13:
h
252 mg (717 µmol) of substrate 6i; entry 14: 830 mg (3.09 mmol) of substrate 6b. Yield and ee after recrystallization
i
j
from methanol. Recovered catalyst used (>99% ee; recovered from entry 14). Actually no inversion of the stereocenter,
product is S-configured due to higher priority of the exocyclic acyl fragment in this particular case.
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Having demonstrated its suitability in the Steglich rearrangement of Oꢀacylated azlactones, we
became curious whether Λ/ꢁꢀIr5' could also be employed in the related Black rearrangement of
Oꢀacylated benzofuranones.36 A short reaction conditions screening revealed that tertꢀamyl alcohol
(TAA) was the solvent of choice for this reaction in terms of selectivity and activity. However, for
reaction temperatures considerably lower than 0 °C we found a 2:1 mixture of TAA (m.p. ~ −10 °C)
and cyclopentyl methyl ether (CPME) more suitable (details in SI). Again, we found low catalyst
loadings of 1−2 mol% as sufficient. Next, we examined the scope of this reaction (Table 2). First, we
tested substrate 6a with R1, R2 = Ph at 0 °C in TAA in the presence of 1 mol% of ΛꢀIr5' (Table 2,
entry 1). Unfortunately, we only found approx. 50% conversion after 18 h and 30% ee for 7a.
However, when we replaced R1 = Ph by R1 = Me, we could isolate product 7b after just 10 h under
identical conditions in 91% ee and 99% yield (entry 2). Next, we replaced the migrating acyl group
R2 = Ph with R2 = Bn (entry 3) and R2 = i-Pr (entry 4), which resulted in a decreased selectivity for
both products (80% ee for 7c and 82% ee for 7d) and in case of the latter in a slower reaction
requiring 2 mol% of catalyst to run to completion within 48 h. However, when we tested substrate 6e
at 0 °C (R1 = Bn and R2 = C(CH3)2CCl3) we obtained product 7e in 89% ee (entry 5). For 6b, being
the best substrate so far, we now lowered the temperature to −15 °C, switched over to
TAA/CPME 2:1, and increased the reaction time to 48 h, which pushed the ee for product 7b to
92% ee (entry 6). Under these conditions, we also tested substrates 6f (R1 = iꢀBu; entry 7) and 6g
(R1 = Bn; entry 8), which gave products 7f and 7g with good ee's (90% and 91% respectively) and in
excellent yields (both 99% yield). Decreasing the temperature further from −15 °C to −30 °C, under
otherwise identical conditions, pushed the ee of product 7b to 94% with no drop in isolated yield
(99%; entries 6 and 9). With enantiomeric catalyst ꢁꢀIr5' we obtained, as expected, the same result
with an inverted R/S product ratio (product entꢀ7b (S), 99% yield, 94% ee, entry 10). Under identical
conditions, we tested another two substrates with different acyl groups R2 (entries 11,12). While
substrate 6h (R2 = Me) with its small methyl group gave product 7h with only moderate 70% ee
(entry 11), substrate 6i (R2 = C(CH3)2CCl3) with its more bulky group gave product 7i with virtually
the same selectivity and yield (99% yield, 93% ee, entry 12) as substrate 6b. Again, we exemplarily
employed ΛꢀIr5' in two scaledꢀup reactions with substrates 6i (0.72 mmol; entry 13) and substrate 6b
(3.1 mmol; entry 14) giving us product 7i with identical and product 7b with slightly diminished
selectivity and both products with identical yields compared to the standard scale experiments
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(entries 9 and 12−14). Noteworthy, product 7b from the scaledꢀup reaction (entry 14) could be
pushed to 98% ee by one recrystallization while maintaining an acceptable yield of 73% (details in
SI). We recovered catalyst ΛꢀIr5' from this scaledꢀup experiment (entry 14) in 94% yield and
>99% ee (procedure and details in SI) and used recovered catalyst ΛꢀIr5' again in a standard scale
reaction with substrate 6b where we virtually obtained the same result as with freshly prepared
ΛꢀIr5' (99% yield, 93% ee, entry 15). Like the Steglich rearrangements from Table 1, all Black
rearrangements from Table 2 were set up under normal atmosphere without any special precautions
against moisture and oxygen. Stereochemistry assignment details for Cꢀacylated benzofuranones 7
and an Xꢀray structure of (S)ꢀ7i are provided in the Supporting Information.
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Having demonstrated that catalyst Λ/ꢁꢀIr5' is capable of catalyzing stereogenic O→C acyl
migrations with high levels of activity and selectivity,37 we wondered if Λ/ꢁꢀIr5' would also be a
suitable catalyst for a completely different type of reaction. So, we focused on the asymmetric
reaction between aryl alkyl ketenes (8) and 2ꢀcyanopyrrole (9) yielding αꢀchiral Nꢀacyl pyrroles (10),
a reaction first reported by Fu and coꢀworkers with catalyst B (see Figure 1).16c In the course of a
short reaction conditions screening (details in SI) we identified toluene and methyl tertꢀbutyl ether
(MTBE) as the solvents of choice38 and a loading of 2 mol% of ΛꢀIr5', an excess of 2.0 eq of
2ꢀcyanopyrrole (9),39 a reaction temperature of 0 °C, and a general reaction time of 48 h as suitable
reaction parameters. Next, we examined the scope of this reaction (Table 3).
Table 3. Catalytic enantioselective addition of 2ꢀcyanopyrrole to aryl alkyl ketenesa
entry
1c
2c
3
4
5
R1
Et
Et
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
R2
Ph
oꢀTol
Ph
pꢀClꢀPh
p-OMeꢀPh
mꢀTol
mꢀTol
Ph
yield (%)b
ee (%)b
89
84
93
90
91
95
95
93
product
10a (S)
10b (S)
10c (S)
10d (S)
10e (S)
10f (S)
10f (S)
10g (S)
10g (S)
10h (S)
96
99
99
99
99
99
98
99
99
99
6
7d
8
Cyclopentyl
Cyclopentyl
Cyclohexyl
9d
10
Ph
Ph
93
93
aStandard reaction conditions: ketene (8; 1.0 equiv; 100−130 µmol) and 2ꢀcyanopyrrole (9; 2.0 equiv) with catalyst
b
ΛꢀIr5' (2 mol%) in toluene (c = 12 mM) at 0 °C for 48 h. Isolated yields; enantioselectivities determined from isolated
c
products by chiral HPLC analysis. Solvent: MTBE used instead of toluene. dScaledꢀup reactions, entry 7: 194 mg
(1.11 mmol) of ketene 8f; entry 9: 209 mg (1.12 mmol) of ketene 8g.
Starting with simple phenyl ethyl ketene (8a), product 10a was obtained in 89% ee (Table 3, entry 1).
Addition of a methyl group in the orthoꢀposition of the ketene's phenyl ring caused the ee to drop to
84% (entry 2; product 10b). However, replacement of phenyl ethyl ketene (8a) by phenyl isopropyl
ketene (8c) improved the ee to 93% (entry 3). Introduction of a methoxy group and a chloro
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substituent in the paraꢀposition of phenyl isopropyl ketene's phenyl ring yielded corresponding
products 10d (entry 4) and 10e (entry 5) with slightly diminished, but still high selectivity (90% ee
and 91% ee, respectively). The highest selectivity was found for mꢀtolyl isopropyl ketene (8f) giving
product 10f in 95% ee (entry 6). Finally, phenyl isopropyl ketene's isopropyl group was replaced by a
cyclopentyl (substrate 8g; entry 8) and a cyclohexyl group (substrate 8h; entry 10), which yielded the
corresponding products (10g,h) both in 93% ee. Again, we exemplarily scaled up two reactions with
ketenes 8f and 8g as substrates by a factor of about ten (~1 mmol scale) and obtained also in case of
the scaledꢀup reactions excellent yields (98% and 99%) and identical selectivities as in case of the
corresponding standard scale examples (entries 7 and 9, compare with entries 6 and 8). Due to the
sensitive nature of ketenes, all reactions from Table 3 were set up under strict exclusion of moisture
and oxygen (details in SI). Stereochemistry assignment details for Nꢀacyl pyrroles 10 are provided in
the Supporting Information.
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Fu and coꢀworkers have demonstrated that αꢀchiral Nꢀacyl pyrroles (10) are useful compounds from a
synthetic point of view, as they can be easily converted into αꢀchiral acids, esters, amides, aldehydes,
and alcohols.16c Taking this and the large number of nucleophilic catalysts reported to date in
account, we were surprised to find no other report apart from Fu's initial publication dealing with this
transformation when this publication was written.40
Now, we turned our attention to the mechanisms of the three investigated reactions. The anticipated
mechanism for the Black rearrangements (6→7) is depicted in Figure 5 using the example of
substrate 6i.11b,36
+
Cl
TfO
N
Ir
N
Cl
N
Λ
Λ
ꢀIr5'
C
C
C
C
N
N
Step I
Step II
Ir
Cl3C
O
N
N
Cl3C
O
N
O
Cl3C
O
N
6i
Me
N
N
O
O
O
O
Cl
ꢀIr5ꢀInt
O
O
C
C
N
( )ꢀ7i
S
Me
Ir
N
Attack from imidazoquinoline's
opposite face blocked by a
2,4,6-triisopropylphenyl moiety
N
O
N
O
Cꢀα Reꢀface attack ꢀ disfavored
CCl3
Me
O
Cꢀα Siꢀface attack ꢀ favored
ꢀIr5ꢀTfO
Λ
O
Figure 5. Left: Anticipated mechanism for the Black rearrangements of Oꢀacylated benzofuranones (6) catalyzed by
ΛꢀIr5' using the example of substrate 6i. Right: Threeꢀdimensional structure of catalysis intermediate analog ΛꢀIr5ꢀTfO
obtained from a crystal structure of racꢀIr5ꢀTfO (altered perspective to provide a clearer view; positional disorder and
cocrystallized solvent molecules omitted for clarity; 60% probability of thermal ellipsoids).30 Preparation and
crystallographic data of racꢀIr5ꢀTfO are provided in the Supporting Information.
At first, the imidazoquinoline ligand's nucleophilic nitrogen atom reacts with the carbonate group of
substrate 6i resulting in the formation of Nꢀacylated intermediate ΛꢀIr5ꢀInt, which is a salt that
consists of a +1 charged iridium(III) complex cation and its associated benzofuranone enolate
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counteranion (Figure 5, Step I). In order to support formation of anticipated ΛꢀIr5ꢀInt
experimentally, we prepared its analog racꢀIr5ꢀTfO, in which we replaced the reactive enolate
counteranion by an inert triflate counteranion, and, to our delight, obtained a crystal structure for
racꢀIr5ꢀTfO, which enabled us to elucidate the threeꢀdimensional structure of ΛꢀIr5ꢀTfO (Figure 5;
details in SI). After formation of ΛꢀIr5ꢀInt, product 7i is finally formed by nucleophilic attack of the
reactive enolate onto the Nꢀacylated complex cation, which goes along with regeneration of catalyst
ΛꢀIr5' (Figure 5, Step II). The stereochemical outcome of the reaction depends on with which of its
prochiral faces the enolate approaches and reacts with the catalystꢀbound acyl group. In this context,
it is important to note that the enolate is only able to approach the acyl group from one of both
imidazoquinoline faces as the opposite face is completely shielded by a bulky 2,4,6ꢀ
triisopropylphenyl group (see Figures 5 and 6). In case of Λꢀconfigured catalyst ΛꢀIr5', approach and
reaction of the enolate with its Siꢀface oriented towards the catalystꢀbound acyl group is obviously
favored leading to predominant formation of the Sꢀenantiomer in case of product 7i. We anticipate
that the Steglich rearrangement of Oꢀacylated azlactones (1→2) follows an analogous
mechanism.11a,12h
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Noteworthy, we verified with a crossover experiment that catalysis intermediates of type ΛꢀIr5ꢀInt
interchange their electrostatically associated enolate counterions which leads to partial formation of
scrambled products (details in SI).
Figure 6. From left to right: (1) Molecular surface of the complex cation of ΛꢀIr5ꢀTfO (Connolly surface, probe
radius: 1.4 Å)41,42 with view on the sterically accessible face of the Nꢀacylated imidazoquinoline ligand. (2) Same
structure as left, tilted by 90 ° resulting in a view on the edge of the Nꢀacylated imidazoquinoline ligand. The blue arrows
in both representations point into the chiral molecular cavity (details in text). (3) Representations of both possible
πꢀconjugated conformers and their calculated relative energies (details in text).
Importantly, the Nꢀbound acyl group of ΛꢀIr5ꢀTfO and ΛꢀIr5ꢀInt gives, in theory, rise to two
coplanar conformers A and B (Figure 6, Right), both allowing favorable conjugation with the
neighboring πꢀsystem. However, only conformer A is found in the crystal structure obtained for
racꢀIr5ꢀTfO. To exclude a misleading crystal packing effect, we carried out a quantum chemical
modeling of both conformations of the racꢀIr5ꢀTfO cation in the absence of crystal effects at the
PBE043ꢀD344/IMCPꢀSR145,46//PBE0ꢀD3/SBKJC47 SMD48(butanol) level of theory (full computational
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details in SI). These calculations revealed that conformer A is indeed 5.3 kcal·mol−1 lower in energy
than B, which affirms that conformer A is clearly preferred in solution as well.49 Having ruled out
excessive conformational freedom of the Nꢀbound acyl group we were now able to shed light on the
underlying manner of chiral recognition of intermediates of type ΛꢀIr5ꢀInt by addition of a
molecular surface to the complex cation of intermediate analog ΛꢀIr5ꢀTfO (Figure 6).41 As depicted
in Figure 6, the target carbonyl moiety of the acyl group is nestled down in a chiral molecular pocket
or molecular cavity (blue arrows in Figure 6), which a prochiral enolate has to enter in order to react
with the acyl group. The "bottom" of this cavity consists of a part of the Nꢀacylated imidazoquinoline
ligand including the target electrophilic carbonyl moiety. And the "walls" of this cavity are shaped of,
from left to right, a 2,4,6ꢀtriisopropylphenyl moiety, the cyclometalated benzoxazole ligand the latter
is bound to, a 2,6ꢀdimethylphenyl moiety being also part of this benzoxazole ligand, and finally the
tail of the Nꢀbound acyl group, which in case of ΛꢀIr5ꢀTfO is the CMe2CCl3 fragment. Figure 6
clearly shows that the second face of the imidazoquinoline ligand is, in contrast, effectively shielded
by another 2,4,6ꢀtriisopropylphenyl moiety. Keeping these considerations at the back of one's mind,
the catalyst screening from Figure 2 becomes more intelligible as Figure 6 clearly visualizes that
appropriate choice of R1 and R2 in the catalyst is essential for both high selectivity and activity. The
slight advantage of ΛꢀIr5 (Figure 2, R3 = Cl) over ΛꢀIr4 (R3 = H) remains somewhat elusive,
chlorine introduction might result in a subtle tilting of the overlying 2,4,6ꢀtriisopropylphenyl moiety
(see Figure 6) or might just cause a subtle change of the electronic properties of the system.
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Reꢀface approach
Siꢀface approach
N
N
O
O
N
N
TSꢀReꢀA
+1.81 kcal—mol−1
TSꢀSiꢀA
0 kcal—mol−1
O
O
O
O
O
O
C = 1.6%
C = 65.6%
TSꢀReꢀB
+0.48 kcal—mol−1
C = 24.3%
TSꢀSiꢀB
+0.98 kcal—mol−1
C = 8.6%
N
N
O
N
N
O
O
O
O
O
O
O
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Figure 7. Quantum chemical modeling of the Black rearrangement's stereogenic step with substrate 6h and a model50 of
catalyst ΛꢀIr5'. Top: Superposition of all four transition states42 and their Newman projections with their relative energies
and contributions (C) (calculated using the CurtinꢀHammett principle). Bottom: Main contributing transition state
TSꢀSiꢀA (Connolly surface, probe radius: 1.4 Å;41 angles of view identical with Figure 6)42 and structural formula of the
simplified model50 of catalyst ΛꢀIr5' used for the quantum chemical calculations (removed fragments shown in orange).
To confirm our mechanistic considerations and to establish the mechanism in greater detail, we
performed a quantum chemical modeling of the Black rearrangement's stereogenic step with substrate
6h and a simplified model50 of catalyst ΛꢀIr5' (Figure 7). In the course of these calculations the four
transition states depicted in Figure 7 were located using the approach recently developed by some of
us51 at the PBE043ꢀD344/IMCPꢀSR145,46//PBE0ꢀD3/SBKJC47 SMD48(butanol) level of theory (see SI
for details). The PBE0 functional was chosen because it is known to be accurate for organic
chemistry calculations43b and has recently been shown to be wellꢀgrounded in theory43c and the
IMCPꢀSR1 basis set was chosen as it incorporates scalarꢀrelativistic effects, which are important for
heavy elements such as iridium in our case46, and retains the correct nodal structures of atoms45a. The
CurtinꢀHammett principle52 was invoked to predict the stereochemical outcome of the rearrangement
to product 7h, which was calculated to be 48% ee (R), which, in consideration of the applied
approximations, is in a very good agreement with the observed 70% ee (R). Favorably, our
calculations benefit from an error cancellation which rises from the fact that the studied transition
states are similar in nature, so systematic errors in them largely cancel out.53 Representations of all
transition states, their relative energies, and their CurtinꢀHammettꢀbased contributions (C) to the
reaction are depicted in Figure 7.
The calculations confirm our underlying idea of a rigid molecular cavity which must be entered by an
enolate in order to react with the acyl group's carbonyl moiety to finally form the product and
correctly predict the stereochemical outcome. Furthermore, they indicate that the unique rigid
framework of the catalyst with its constrained, wellꢀdefined active site should facilitate
(computationally supported) rational design of new related catalysts and tailoring of catalysts (in
silico) to certain substrates or the other way around.54 Noteworthy, comparison of Figures 6 and 7
clearly illustrates that a small migrating acyl group results in a wider molecular cavity, which
understandably can result in diminished selectivity (e.g. 6h). A closer look at the four transition states
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also renders the poor result for substrate 6a consequential as the occuring allꢀplanar, rigid, phenylꢀ
substituted enolate is hardly able to enter the resulting small molecular cavity, which manifests in a
sluggish reaction and a poor selectivity.
For the asymmetric addition of 2ꢀcyanopyrrole (9) to aryl alkyl ketenes (8) two pathways are
reasonable which are depicted in Figure 8 using the example of ketene substrate 8c.16c,22
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Figure 8. Reasonable pathways for the reaction of aryl alkyl ketenes (8) with 2ꢀcyanopyrrole (9) catalyzed by ΛꢀIr5'
using the example of ketene substrate 8c.
The first reasonable pathway starts with proton transfer from 2ꢀcyanopyrrole (9) to ΛꢀIr5' followed
by addition of the generated pyrrolate to ketene 8c, which eventually results in formation of
ΛꢀIr5ꢀInt2, a salt consisting of an Nꢀprotonated +1 charged iridium(III) complex cation and its
associated ketene enolate counteranion (Figure 8, Step A). On the assumption that this pathway is
operational, the observed stereochemical outcome originates from the circumstance that chiral
Brønsted acid ΛꢀIr5ꢀInt2 preferentially protonates the prochiral ketene enolate from the Reꢀface,
which leads to predominant formation of the Sꢀenantiomer of product 10c (Figure 8, Step B). In
Figure 8 the Eꢀenolate is arbitrarily drawn, however, in case this pathway is operational, the ketene
enolate might be existent as an E/Z mixture.22 As discussed for the acyl migration reactions, the
ketene enolate can only approach the protonated imidazoquinoline ligand from one face as the other
one is sterically inaccessible.
The second reasonable pathway starts with addition of catalyst ΛꢀIr5' to ketene 8c, which results in
formation of zwitterionic iridium(III) complex ΛꢀIr5ꢀInt3, which might again exist as an
E/Z mixture (Figure 8, Step C, Eꢀform arbitrarily drawn).22 In case this pathway is operational,
preferred proton transfer to the Reꢀface of the catalystꢀbound ketene enolate from 2ꢀcyanopyrrole (9)
eventually leads to predominant formation of the Sꢀenantiomer of product 10c (Figure 8, Step D).
Again, 2ꢀcyanopyrrole (9) can only approach the imidazoquinoline ligand from one face as the other
one is sterically inaccessible.
In an attempt to clarify which of both cycles (Figure 8) is in operation, we made the following
observations: When we mixed racꢀIr5' in dry CD2Cl2 with excess pꢀchlorophenyl isopropyl ketene
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(8d) at room temperature, we only found H NMR signals belonging to 8d and racꢀIr5' but no
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indication for the formation of a zwitterionic species like ΛꢀIr5ꢀInt3. This result is in agreement with
observations made by Fu and coꢀworkers for their DMAPꢀderived catalyst B (see Figure 1) and
speaks, at first, against the right cycle.16c However, we also did not observe ion pair formation when
we mixed racꢀIr5' with excess 2ꢀcyanopyrrole (9) under identical conditions, we only observed a
weak hydrogenꢀbonding interaction between the Nꢀbound proton of 9 and the nitrogen atom of
racꢀIr5' (details of both experiments in the Supporting Information). This is in contrast to
observations made by Fu and coꢀworkers for catalyst B, who report about ion pair formation for this
experiment.16c Based on their NMR observations together with additional experimental data,
primarily kinetic data, Fu and coꢀworkers carefully assumed that the Brønsted base/acid mechanism
should be in operation in case of catalyst B.16c In contrast, a recent thorough computational study
from Cheong and coꢀworkers arrived at the conclusion that the nucleophilic pathway should be in
operation in case of B.22 For the reaction between phenyl methyl ketene and 2ꢀcyanopyrrole (9)
catalyzed by B, Cheong and coꢀworkers revealed that: 1.) the decisive rate determining step (RDS) of
the nucleophilic pathway is favored by 8.3 kcal·mol−1 over the RDS of the Brønsted base/acid
pathway; 2.) the NMR observed ion pair formed between 9 and B is merely the unproductive resting
state of the catalyst; 3.) the NMR based nonꢀobservation of a zwitterionic intermediate formed
between a ketene and B is consequential due to its endergonic nature (see ref. 16c and 22 for a
detailed discussion).16c,22 Being aware of the different structures and properties of Fu's catalyst B and
our catalyst Λ/ꢁꢀIr5', we at the moment carefully assume, in consideration of the recent calculations
from Cheong and coꢀworkers for B, that for catalyst Λ/ꢁꢀIr5' the nucleophilic catalysis pathway is in
operation as well (Figure 8, right cycle). A study to clarify the situation for catalyst Λ/ꢁꢀIr5' is under
way in our laboratory. At least, we can conclude that the loneꢀpair of the imidazoquinoline's nitrogen
atom is indispensable for this reaction either way as mixing of Nꢀmethylated catalyst (ΛꢀIr5ꢀMe)
with ketene 8c and 2ꢀcyanopyrrole (9) results in no formation of product 10c (preparation of
ΛꢀIr5ꢀMe and experimental details in the Supporting Information).29
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Conclusion
In conclusion, we have developed an airꢀ and moistureꢀstable nucleophilic catalyst (Λꢀ and ꢁꢀIr5')
featuring a remote, iridium(III)ꢀlocated octahedral stereocenter as its exclusive element of chirality
and an imidazoquinoline ligand serving as the catalyst's nucleophilic site. The versatility of this
catalyst was demonstrated for three different enantioselective transformations: the Steglich
rearrangement of Oꢀacylated azlactones to Cꢀacylated azlactones going along with the formation of a
quaternary stereocenter (up to 99% yield and 96% ee), the related Black rearrangement of Oꢀacylated
benzofuranones to Cꢀacylated benzofuranones going along with the formation of an allꢀcarbon
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quaternary stereocenter (up to 99% yield and 94% ee), and finally the addition of 2ꢀcyanopyrrole to
aryl alkyl ketenes giving rise to αꢀchiral Nꢀacyl pyrroles (up to 99% yield and 95% ee), a reaction for
which catalyst Λ/ꢁꢀIr5' is, to the best of our knowledge, after Fu's planarꢀchiral catalyst B the second
reported chiral catalyst so far. Notably, we were able to carry out all these transformations with only
0.5−2 mol% of precatalyst Λ/ꢁꢀIr5 or catalyst Λ/ꢁꢀIr5', partially at temperatures as low as −30 °C,
which underlines the catalyst's high activity. Both the Λꢀ and ꢁꢀenantiomer of the catalyst are
accessible in enantiopure form (>99% ee) by simple flash chromatography of intermediary
diastereomers. We have demonstrated that the catalyst can be recovered in high yield after reaction
completion without deterioration of its enantiopurity and reused again. With crystal structures of
active catalyst racꢀIr5' and catalysis intermediate analog racꢀIr5ꢀTfO (Figures 3 and 5) as well as
with analysis of the active site accessibility of the latter (Figure 6) we have shed light on the catalyst's
manner of chiral recognition and in case of the Black rearrangements we have confirmed our
mechanistic suggestions with explicit quantum chemical calculations (Figure 7). Whether the
reaction between 2ꢀcyanopyrrole and aryl alkyl ketenes follows a Brønsted base/acid pathway or a
nucleophilic pathway (Figure 8) remains somewhat elusive for now and a separate study to clarify the
situation is under way in our laboratory. For the time being, we assume that a nucleophilic catalysis
pathway is active. Future experimental studies with Λ/ꢁꢀIr5' or derivatives thereof will aim at
identifying other asymmetric transformations being suitable for this type of chiral nucleophilic
catalyst and will also seek to shed light on the iridium center's electronic influence on the
imidazoquinoline ligand and hence its influence on the catalytic activity of this ligand and the
catalyst as a whole.
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/acscatal.
Preparation and characterization of the iridium(III) complexes and catalysis substrates, conditions
screenings, experimental procedures for the catalyzed reactions (Figure 1, Tables 1−3),
characterization of the catalysis products, absolute stereochemistry assignments, mechanistic
experiments, quantum chemical calculation details, crystallographic data for racꢀIr5'
(CCDC 1536878), racꢀIr5ꢀTfO (CCDC 1536879), [IrIII(C^N)2(µꢀCl)]2 (C^N is cyclometalated 3;
1
CCDC 1536877), and (S)ꢀ7i (CCDC 1545358), CD spectra of iridium(III) complexes, H and
13C NMR spectra and HPLC traces of iridium(III) complexes and catalysis products.
Acknowledgements: This work was supported by the Deutsche Forschungsgemeinschaft
(ME 1805/11ꢀ1). We thank Vladimir A. Larionov and Alexander F. Smolyakov for establishing the
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contact to M. G. M. who performed the quantum chemical calculations. M. G. M. is grateful to the
Russian Science Foundation grant #17ꢀ13ꢀ01526 for financial support and acknowledges the
computational resources on which the quantum chemical calculations were performed: the IBM Blue
Gene/P supercomputer at Moscow State University’s (MSU) Faculty of Computational Mathematics
and Cybernetics; the Lomonosov supercomputer55 at the Supercomputing Center of MSU; and the
HPC2 supercomputer at the federal center for collective usage at NRC “Kurchatov Institute”
(http://computing.kiae.ru/).
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References
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(20) Articles which focus on the high catalytic activity of DMAP and its derivatives (in addition to
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Chem. Res. 2016, 49, 1279–1291.
(23) Check, C. T.; Jang, K. P.; Schwamb, C. B.; Wong, A. S.; Wang, M. H.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2015, 54, 4264–4268.
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(27) Huo, H.; Fu, C.; Wang, C.; Harms, K.; Meggers, E. Chem. Commun. 2014, 50, 10409–10411.
(28) We would like to note here that we have previously reported a chiralꢀatꢀmetal enamine catalyst
featuring a secondary amine (ref. 27). In a broader sense that catalyst can also be referred to as
"nucleophilic". However, catalysts involving enamine or iminium ion formation should be
clearly distinguished from "classic" nucleophilic catalysts, such as DMAP, as they catalyze
different reactions. See ref. 18a and 18f for a detailed discussion.
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(29) In case cesium carbonate is absent, precatalyst Ir5 is not catalytically active at all and in case
Nꢀmethylated Ir5 (=Ir5ꢀMe; details in SI) is employed instead of Ir5 in the presence of cesium
carbonate, no reaction is observed as well. Detailed evidence for the acid/base behavior of Ir5
and Ir5' and the necessity for a deprotonated imidaqozuinoline ligand for catalytic activity are
provided in detail in the Supporting Information.
(30) (a) Mercury, version 3.7 RC1; The Cambridge Crystallographic Data Centre: Cambridge, UK,
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(33) In principle, (S)ꢀ4 can be replaced by 5 by a oneꢀpot protocol with NH4PF6 as a weak acid in
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(37) Noteworthy, we had also shortly investigated the related Steglichꢀtype acyl migration reaction
N,Oꢀdiacylated oxindole S31 → C,Nꢀdiacylated oxindole S32 with ΛꢀIr5' as catalyst. In a first,
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unoptimized attempt we had obtained S32 in 96% yield and 59% ee (details in SI).
Simultaneously, we had obtained promising results with ketenes as substrates (see Table 3), so
we discontinued working on this reaction.
(38) MTBE was found to give slightly better ee's for the screened ethyl substituted ketenes (details
in SI).
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(39) Noteworthy, we have also attempted this type of reaction with pyrrole, 2ꢀacetylpyrrole, indole,
and carbazole. In contrast to 2ꢀcyanopyrrole (9), we did not detect any conversion with pyrrole,
indole, and carbazole and in case of 2ꢀacetylpyrrole the reaction was very sluggish, so we
finally sticked to 2ꢀcyanopyrrole (9).
(40) In a thorough literature search with CAS SciFinder and Elsevier Reaxys we could only find the
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(50) Initially, we intended to perform the quantum chemical calculations with entire catalyst ΛꢀIr5'
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over to the simplified catalyst model depicted in Figure 7 and substrate 6h. Importantly, in this
catalyst model the shape of the "active center" remains entirely unchanged (details in SI).
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(54) Quite recently, we have demonstrated for hydrogenꢀbonding catalysts that rigid octahedral
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geometry (see ref. 25c and 25d for details).
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