Polyfunctional Bis-Lewis-Acid-/Bis-Triazolium Catalysts for Stereoselective 1,4-Additions of 2-Oxindoles to Maleimides

Article abstract of DOI:10.1002/anie.201814453

Achieving enzyme-like catalytic activity and stereoselectivity without the typically high substrate specificity of enzymes is a challenge in the development of artificial catalysts for asymmetric synthesis. Polyfunctional catalysts are considered to be a promising tool for achieving excellent catalytic efficiency. A polyfunctional catalyst system was developed, which incorporates two Lewis acidic/Br?nsted basic cobalt centers in combination with triazolium moieties that are crucial for high reactivity and excellent stereoselectivity in the direct 1,4-addition of oxindoles to maleimides. The catalyst is assembled through click chemistry and is readily recyclable through precipitation by making use of its charges. Kinetic studies support a cooperative mode of action. Diastereodivergency is achievable with either Boc-protected or unprotected maleimide.

Full text of DOI:10.1002/anie.201814453

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Polyfunctional Bis-Lewis-Acid-/Bis-Triazolium Catalysts for
Stereoselective 1,4-Additions of 2-Oxindoles to Maleimides
Authors: Juliane Schmid, Thorsten Junge, Johannes Lang, Wolfgang
Frey, and René Peters
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814453
Angew. Chem. 10.1002/ange.201814453
Link to VoR: http://dx.doi.org/10.1002/anie.201814453
http://dx.doi.org/10.1002/ange.201814453

10.1002/anie.201814453
Angewandte Chemie International Edition
COMMUNICATION
Polyfunctional Bis-Lewis-Acid-/Bis-Triazolium Catalysts for
Stereoselective 1,4-Additions of 2-Oxindoles to Maleimides
Juliane Schmid,[a] Thorsten Junge,[a] Johannes Lang,[a] Wolfgang Frey,[a] and René Peters*[a]
Abstract: Enzyme-like catalytic activity and stereoselectivity yet
lacking the typical high substrate specificity of enzymes is a challenge
in the development of artificial catalysts for asymmetric synthesis.
Polyfunctional catalysts are considered as promising tool for
achieving excellent catalytic efficiency. In this communication a
polyfunctional catalyst system is reported which incorporates two
Lewis acidic/Brønsted basic cobalt centers in combination with
triazolium moieties which are crucial for high reactivity and excellent
stereoselectivity in the direct 1,4-addition of oxindoles to maleimides.
The catalyst is assembled via click chemistry and readily recyclable
via precipitation by making use of its charges. Kinetic studies support
a cooperative mode of action. Diastereodivergency is achievable
using either Boc- or unprotected oxindoles.
necessity for high loadings (up to 20 mol%) of most catalyst
systems, (2) often strongly limited substrate scopes, in part (3)
moderate yields, (4) moderate diastereoselectivities and (5) the
necessity of very low reaction temperatures.
Chiral enantiopure 3,3-disubstituted 2-oxindoles (systematic
name: 2,3-dihydro-2H-indole-2-ones) constitute
a class of
heterocycles which is of high importance for pharmaceutical
applications and developments, but also as synthetic building
blocks in alkaloid synthesis.[1] A number of research projects have
been devoted to enable the stereoselective synthesis of 2-
oxindoles
containing
a
quaternary
all-C-substituted
stereocenter.[1,2] In this context, our group has reported various bi-
and polyfunctional transition metal complexes, which were
employed to catalyze the 1,4-addition of oxindoles
1 to
nitroolefins.[3] Polyfunctional mononuclear Ni(II)-complexes C1
allowed for a diastereodivergent highly enantioselective access of
these adducts (Scheme 1, top).[3a] C1 features a Lewis acidic Ni(II)
center, Brønsted basic phenolate moieties,[4] OH groups as
hydrogen bond donors in the iminoalcohol side arms and an
axially chiral bisimidazolium moiety, which is most likely activating
the Michael acceptor by H bond formation using the acidic C(2)-
H bond and electrostatic interactions.
In the present study, we examined the 1,4-addition[5] of racemic
2-oxindoles 1 to maleimides 2 (Scheme 1, bottom). Two adjacent
stereocenters are generated, one of which is quaternary. Since
enantiopure succinimides also play
a vital role both in
pharmaceutical sciences as well as in organic synthesis, the
integration of both the oxindole and succinimide motifs in one
chiral framework is of interest.[6]
On the other hand, for this reaction type only a limited number of
studies have been reported so far.[7] Despite the progress
achieved by this research, there are still issues such as (1) the
Scheme 1. Top: C1 as diastereodivergent catalyst for the direct Michael
addition of oxindoles to nitroolefins. Bottom: Development of polyfunctional
catalysts C2-M for the title reaction.
[a]
M.Sc. J. Schmid, M.Sc. T. Junge, Dr. J. Lang, Dr. W. Frey, Prof. Dr.
R. Peters
Universität Stuttgart, Institut für Organische Chemie
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
E-mail: rene.peters@oc.uni-stuttgart.de
Herein, we describe the development of a new polyfunctional
bimetallic catalyst type, in which metal centers, triazolium
moieties and possibly OH groups are likely to cooperate.[8] For
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814453
Angewandte Chemie International Edition
COMMUNICATION
high catalytic efficiency and excellent stereocontrol in the title
reaction the triazolium rings were found to be important.
Based on a large number of studies in material sciences, we
speculated that a catalyst architecture in which a 1,2,3-triazolium
moiety is present would allow for stronger H-bonds than
imidazolium rings.[9] With Ni(II)-complex C3e-Ni the product was
formed in a promising yield, but the stereoselectivity was just
moderate (Table 1, entry 1).
In contrast, C3e-Co featuring a cobalt center allowed for high
enantio- and diastereoselectivity, but the product yield was
moderate (entry 2). To improve the efficiency kinetic
investigations were performed. The empirical rate law was
determined from the initial reaction rates with C3e-Co by the
differential method (for details see the Supporting Information).[10]
Eq. (1) reveals that more than one catalyst molecule is involved
in the rate limiting step. This is also in agreement with a positive
non-linear effect.[11] Whereas for oxindole 1a a first order kinetic
is found, the order of maleimide 2A is about 0.5. An explanation
would be a partial substrate saturation. The kinetic order between
2 and 3 for the catalyst is interpreted by competing pathways
involving 2 or even more catalyst species.
Table 1. Development of the new polyfunctional catalyst system.
r = k * [C3e-Co*]2.56 * [2A]0.47 * [1a]1.05
(1)
To accelerate a bimetallic pathway by an intramolecular mode of
action, a catalyst design was explored in which two catalyst
fragments are tethered by a diether linker. Employing C2e-Co
with identical imino alcohol moieties as in C3e-Co and using the
same amount of cobalt centers (5 mol% bimetallic vs 10 mol%
monometallic catalyst) the product yield was improved from 54
to 68% (entry 3). A screening of related catalysts (entries 4-9)
revealed a strong influence of the iminoalcohol side arms on both
reactivity and stereoselectivity. C2f-Co emerged as the most
attractive catalyst, as it combined high yield and excellent
stereoselectivities.
An investigation of the effect of different additives using less
selective catalysts showed that basic additives like NaOAc
strongly reduce both diastereo- and enantioselectivity (compare
entries 10 & 7). In contrast, H2O and HOAc had a slightly positive
effect (compare entries 11, 12 and 3).
The empirical rate law using C2f-Co (eq. (2)) reveals that a single
catalyst entity is involved in the rate limiting step, thus suggesting
an intramolecular bimetallic activation pathway. The partial orders
for both substrates were still about 1 for the oxindole and about
0.5 for the maleimide. A scenario, in which the C-C bond is rate-
limiting is thus also likely in this case.
#
cat.
X
additive (mol%)
yield
[%][a]
D1 : D2[a]
ee D1
[%][b]
1
C3e-Ni
C3e-Co
C2e-Co
C2a-Co
C2b-Co
C2c-Co
C2d-Co
C2f-Co
C2g-Co
C2d-Co
C2e-Co
C2e-Co
10
10
5
-
75
54
68
62
44
45
75
91
17
45
62
69
73 : 27
95 : 5
94 : 6
93 : 7
86 : 14
90 : 10
95 : 5
99 : 1
45 : 55
49 : 51
97 : 3
96 : 4
30
95
94
78
77
2
-
3
-
r = k * [C2f-Co*]0.99 * [2A]0.50 * [1a]0.85
(2)
4
5
-
To receive information about the impact of the triazolium moieties,
monometallic control complexes C4-C6 were compared to C3e-
Co (Table 2). Whereas the latter allowed for high diastereo- and
enantioselectivity, catalyst C4 bearing a benzyl residue rather
than a triazolium unit provided 3a in poor yield with almost no
stereoselectivity (entry 1). Also charged residues like the
pyridinium in C5 or the imidazolium in C6 did not result in much
better results (entries 2 & 3). This shows that not only the charge
of the triazolium is essential for high activity and yield. We thus
suggest that hydrogen bond activation by the polarized C-H bonds
of triazolium groups is essential.[12]
5
5
-
6
5
-
69
92
7
5
-
8
5
-
99
9
5
-
0
10
11
12
5
NaOAc (4)
H2O (10)
HOAc (10)
44
5
97
96
5
Neutral 1,2,3-triazoles are also known as H bond donors in
material sciences.[9] We also prepared bimetallic catalyst C7
containing two triazole rings, but it performed much worse (entry
4) than the corresponding triazolium catalyst C2e-Co, which
might be partly due to a stronger N-ligand character than in the
triazolium salts.[9]
[a] Determined by 1H-NMR from the crude product using a standard. [b]
Determined by HPLC. A minus sign indicated the preferred formation of the
other enantiomer than the one depicted.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814453
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Control experiments.
Table 3. Investigation of the scope.
#
1/3
R
R’
yield
[%][a]
D1 : D2[b]
ee D1
[%][c]
1
a
b
c
d
e
f
Me
H
91
66
70
74
69
70
88
80
66
79
44
77
64
77
95
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99
99
99
99
99
98
99
99
98
99
95
99
99
99
97
2
nPr
H
3
nBu
H
4
CH2cyc-Hex
CH2C6H4-3-OMe
CH2C6H4-3-Br
CH2C6H3-2,4-Cl2
CH2C6H4-4-F
CH2C6H4-4-CN
CH2-1-naphthyl
CH2-2-thiophenyl
Bn
H
#
1
2
3
4
catalyst
C4
X ( mol%)
yield [%][a]
D1 : D2[a]
54 : 46
50 : 50
33 : 67
44 : 56
ee D1 [%][b]
5
H
10
10
10
5
19
11
29
32
0
6
H
C5
25
8
7
g
h
i
H
C6
8
H
C7
15
9
H
[a] Determined by 1H-NMR from the crude product using a standard. [b]
Determined by HPLC. A minus sign indicated the preferred formation of the
other enantiomer than the one depicted.
10
11
12
13
14
15
j
H
k
l
H
Catalyst C2f-Co was applied to various oxindoles carrying
different substituents at either the acidic C(3) or on the aromatic
ring at C(5) or C(6) (Table 3). In all cases the products were
formed as single diastereomers with excellent ee.[13] The only
5-Me
5-OMe
5-Br
6-Cl
m
n
o
Bn
Bn
exception was with
R = Ph, which provided a 60:40
diastereomeric mixture with almost no enantioselectivity (not
shown).
Bn
The synthetic value of this method was also demonstrated on a
1.5 mmol scale providing 666.7 mg of 3a-D1 in almost
diastereopure form (84%, dr > 99:1, ee > 99%). The catalyst could
be readily recycled by precipitation and reused with similar
efficiency (78%, dr > 99:1, ee > 99%).
[a] Yield of isolated product. [b] Determined by 1H-NMR from the crude product.
[c] Determined by HPLC. A minus sign indicated the preferred formation of the
other enantiomer than the one depicted.
Interestingly, preliminary studies with the unprotected maleimide
2B revealed that the other diastereomer 3aB-D2 is accessible
with good enantioselectivity as well, albeit with lower reactivity
and diastereoselectivity (Scheme 2).[14,16]
Unfortunately, no single crystals of C2-Co and C3-Co suitable for
1
X-ray analysis could be obtained so far. H-NMR spectra of the
catalysts are very complex and point to mixtures which also
contain paramagnetic species leading to very broad signals. We
assume an equilibrium of several species and coordination
isomers. ESI-MS data are in agreement with Co(III) as central
metal and the presence of one or two acetate ligands.
Microanalysis of the best catalyst C2f-Co is also compatible with
a mixture containing one to two acetates per Co(III) center.
Scheme 2. Diastereodivergent reaction outcome with unprotected maleimide.
We performed density functional theory (DFT) based calculations
on C3e-Co exhibiting either one or two acetate ligands to gain
further information on its molecular structure and spin state
(Figure 1, the supporting information contains further details). In
the case of one coordinating acetate ligand (Figure 1, left) the
iminoalcohol is deprotonated giving a neutral metal sphere. It was
found that the triplet spin state of the complex is significantly more
stable that the singlet. The calculations thus predict
a
This article is protected by copyright. All rights reserved.

10.1002/anie.201814453
Angewandte Chemie International Edition
COMMUNICATION
paramagnetic complex. An additional neutral water ligand would
be preferentially released from an octahedral coordination sphere
resulting in coordination number 5. In contrast, in case of two
coordinating acetate ligands (Figure 1, right), the calculations
predict a diamagnetic octahedral species, in which one acetate is
bound in a mono- and one in a bidentate way. In addition, the
neutral alcohol moiety is coordinated and forms a hydrogen bond
with the monocoordinated acetate. This interaction may facilitate
the formation of the 5-coordinated complex forming an equilibrium
between the paramagnetic and diamagnetic species.[17] It is
conceivable that the free coordination site of the paramagnetic
species is able to bind the pronucleophile, which could then be
deprotonated, e.g., by the internal alcoholate.
Foundation (DFG) through grant no INST 40/467-1 FUGG
(JUSTUS cluster).
Keywords: asymmetric catalysis • cobalt • cooperative catalysis
• diastereodivergency • hydrogen bonds
[1]
[2]
[3]
[4]
Selected reviews: a) S. Hibino, T. Choshi, Nat. Prod. Rep. 2001, 18, 66;
b) B. S. Jensen, CNS Drug Rev. 2002, 8, 353; c) H. Lin, S. J.
Danishefsky, Angew. Chem. Int. Ed. 2003, 42, 36; d) A. B. Dounay, L. E.
Overman, Chem. Rev. 2003, 103, 2945; e) C. V. Galliford, K. A. Scheidt,
Angew. Chem. Int. Ed. 2007, 46, 8748; e) F. Zhou, Y.-L. Liu, J. Zhou,
Adv. Synth. Catal. 2010, 352, 1381.
Selected Michael additions: a) Y. Kato, M. Furutachi, Z. Chen, H.
Mitsunuma, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2009, 131,
9168; b) R. He, C. Ding, K. Maruoka, Angew. Chem. Int. Ed. 2009, 48,
4559; c) R. He, S. Shirakawa, K. Maruoka, J. Am. Chem. Soc. 2009, 131,
16620, d) Y.-Y. Han, Z.-J. Wu, W.-B. Chen, X.-L. Du, X.-M. Zhang, W.-
C. Yuan, Org. Lett. 2011, 13, 5064.
a) M. Mechler, R. Peters, Angew. Chem. Int. Ed. 2015, 54, 10303; b) J.
Schmid, W. Frey, R. Peters, Organometallics 2017, 36, 4313; c) M.
Mechler, W. Frey, R. Peters, Organometallics 2014, 33, 5492; d) M.
Mechler, K. Latendorf, W. Frey, R. Peters, Organometallics 2013, 32,
112; see also: T. Kull, J. Cabrera, R. Peters, Chem. Eur. J. 2010, 16,
9132.
Reviews: a) M. Shibasaki, N. Kumagai, in Cooperative Catalysis –
Designing Efficient Catalysts for Synthesis; R. Peters (Ed.), Wiley-VCH,
Weinheim, 2015; b) M. Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102,
2187;
[5]
[6]
K. Zheng, X. Liu, X. Feng, Chem. Rev. 2018, 118, 7586.
a) Review: P. Chauhan, J. Kaur, S. S. Chimni, Chem. Asian J. 2013, 8,
328; selected examples for additions to maleimides: b) R. Shintani, W.-
L. Duan, T. Hayashi, J. Am. Chem. Soc. 2006, 128, 5628; c) G. Bartoli,
M. Bosco, A. Carlone, A. Cavalli, M. Locatelli, A. Mazzanti, P. Ricci, L.
Sambri, P. Melchiorre, Angew. Chem. Int. Ed. 2006, 45, 4966; d) for an
alternative approach by our group, see: M. Weber, W. Frey, R. Peters,
Angew. Chem. Int. Ed. 2013, 52, 13223.
[7]
a) Y.-H. Liao, X.-L. Liu, Z.-J. Wu, L.-F. Cun, X.-M. Zhang, W.-C. Yuan,
Org. Lett. 2010, 12, 2896; b) L. Li, W. Chen, W. Yang, Y. Pan, H. Liu, C.-
H. Tan, Z. Jiang, Chem. Commun. 2012, 48, 5124; c) X. Yang, C. Wang,
Q. Ni, D. Enders, Synthesis 2012, 2601; d) J. Zhou, L.-N. Jia, L. Peng,
Q.-L. Wang, F. Tian, X.-Y. Xu, L.-X. Wang, Tetrahedron 2014, 70, 3478;
e) S. Shirakawa, H. Makino, T. Yoshidome, K. Maruoka, Tetrahedron
2014, 70, 7128; f) S. Liu, K. Maruoka, S. Shirakawa, Angew. Chem. Int.
Ed. 2017, 56, 4819; g) N. Di Iorio, L. Soprani, S. Crotti, E. Marotta, A.
Mazzanti, P. Righi, G. Bencivenni, Synthesis 2017, 1519.
Figure 1. DFT calculations of the structure of C3e-Co containing either one or
two acetate ligands at the B3LYP/cc-pVDZ/IEF-PCM[18] (CH2Cl2) level of theory
and suggestion of an equilibrium of both species.
In conclusion, we have reported the development of a novel
type of polyfunctional catalyst, which contains Lewis acidic cobalt
centers and triazolium moieties. This catalyst type allows for
highly enantio- and diastereoselective direct 1,4-additions of 3-
substituted oxindoles to N-protected maleimides generating two
adjacent stereocenters. With unprotected maleimide the
alternative epimer is accessible. After use, the catalyst could be
readily recycled by precipitation and used again with similar
efficiency. Based on kinetic studies a cooperative mode of action
is very likely. Control experiments have revealed the necessity of
the triazolium rings for high stereoselectivity, which is explained
by hydrogen bond activation.
[8]
[9]
For the various concepts of cooperative catalysis, see: R. Peters (Ed.),
Cooperative Catalysis, Wiley-VCH, Weinheim, 2015.
Recent reviews describing CH...X hydrogen bonds using azolium salts as
H-bond donors: a) B. Schulze, U. S. Schubert, Chem. Soc. Rev. 2014,
43, 2522; b) J. Cai, J. L. Sessler, Chem. Soc. Rev. 2014, 43, 6198; c)
general review on H bonds: Pihko, P. M., Hydrogen Bonding in Organic
Chemistry, Wiley-VCH, Weinheim, 2009.
[10] M. J. Pilling, P. W. Seakins, Reaction Kinetics, Oxford University Press:
Oxford, 1995.
[11] T. Satyanarayana, S. Abraham, H. B. Kagan, Angew. Chem. Int. Ed.
2009, 48, 456.
[12] For this H-Bond activation in organocatalysis, see e.g.: a) K. Ohmatsu,
M. Kiyokawa T. Ooi, J. Am. Chem. Soc. 2011, 133, 1307; b) K. Ohmatsu,
Y. Hamajima, T. Ooi, J. Am. Chem. Soc. 2012, 134, 8794; c) S.-K. Chen,
W.-Q. Ma, Z.-B. Yan, F.-M. Zhang, S.-H. Wang, Y.-Q. Tu, X.-M. Zhang,
J.-M. Tian, J. Am. Chem. Soc. 2018, 140, 10099.
Acknowledgements
This work was financially supported by the Deutsche
Forschungsgemeinschaft (PE 818/7-1, project number
310990893). JL acknowledges support by the state of Baden-
Württemberg through bwHPC and the German Research
[13] The absolute configuration of 3i was determined by X-ray crystal
structure analysis. CCDC 1885014 contains the supplementary
crystallographic data which can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814453
Angewandte Chemie International Edition
COMMUNICATION
[14] Selected recent reviews about diastereodivergency: a) L. Lin, X. Feng,
Chem. Eur. J. 2017, 23, 6464; b) M. Bihani, J. C.‐G. Zhao, Adv. Synth.
Catal. 2017, 359, 534; c) I. P. Beletskaya, C. Nájera, M. Yus, Chem. Rev.
2018, 118, 5080.
1968; g) see ref. 3a; h) S. Krautwald, M. A. Schafroth, D. Sarlah, E. M.
Carreira, J. Am. Chem. Soc. 2014, 136, 3020.
[16] The absolute configuration of 3aB-D2 was determined by chemical
correlation (see SI).
[17] Generation of mesoionic carbenes is ruled out, since the PF6 anions are
[15] Selected leading examples for diastereodivergent reactions: a) B. Wang,
F. Wu, Y. Wang, X. Liu, L. Deng, J. Am. Chem. Soc. 2007, 129, 768; b)
Y. Wang, H. Li, Y.-Q. Wang, Y. Liu, B. M. Foxman, L. Deng, J. Am. Chem.
Soc. 2007, 129, 6364; c) A. Nojiri, N. Kumagai, M. Shibasaki, J. Am.
Chem. Soc. 2009, 131, 3779; d) G. Lu, T. Yoshino, H. Morimoto, S.
Matsunaga, M. Shibasaki, Angew. Chem. Int. Ed. 2011, 50, 4382; e) S.-
L. Shi, Z. L. Wong, S. L. Buchwald, Nature 2016, 532, 353; f) H. Zheng,
Y. Wang, C. Xu, X. Xu, L. Lin, X. Liu, X. Feng, Nat. Commun. 2018, 9,
still present in the catalyst.
[18] B3LYP: a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648; B. Miehlich, A.
Savin, H. Stoll, H. Preuss, Chem. Phys. Lett. 1989, 157, 200; cc-pVDZ:
c) T. H. Dunning, J. Chem. Phys. 1989, 90, 1007.
This article is protected by copyright. All rights reserved.

10.1002/anie.201814453
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Layout 1:
COMMUNICATION
All-in-one-tool: Based on kinetic
studies a dinuclear cobalt complex
has been developed for direct 1,4-
additions of oxindoles to maleimides.
Triazolium units were found to be
crucial for excellent enantio- and
diastereoselectivity and high activity.
Juliane Schmid, Thorsten Junge,
Johannes Lang, Wolfgang Frey, and
René Peters*
Page No. – Page No.
Polyfunctional Bis-Lewis-Acid-/Bis-
Triazolium Catalysts for
Stereoselective 1,4-Additions of 2-
Oxindoles to Maleimides
This article is protected by copyright. All rights reserved.