A Bulky Chiral N-Heterocyclic Carbene Nickel Catalyst Enables Enantioselective C?H Functionalizations of Indoles and Pyrroles

Article abstract of DOI:10.1002/anie.201904774

An enantioselective nickel(0)-catalyzed C?H functionalization of indoles and pyrroles that does not require the typical Lewis basic directing groups is disclosed. The reaction provides access to valuable tetrahydropyridoindoles and tetrahydroindolizines in high yields and enantioselectivity under mild reaction conditions. The process is characterized by a clear endo-cyclization preference to yield the sought-after six-membered-ring products. Key for the success of the activation and selectivity in the cyclization was the development of a novel chiral SIPr carbene ligand analogue with very bulky flanking groups.

Full text of DOI:10.1002/anie.201904774

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Accepted Article
Title: A Bulky Chiral N-Heterocyclic Carbene Nickel Catalyst Enables
Enantioselective C–H Functionalizations of Indoles and Pyrroles
Authors: Johannes Diesel, Daria Grosheva, Shota Kodama, and
Nicolai Cramer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904774
Angew. Chem. 10.1002/ange.201904774
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Angewandte Chemie International Edition
10.1002/anie.201904774
COMMUNICATION
A Bulky Chiral N-Heterocyclic Carbene Nickel Catalyst Enables
Enantioselective C–H Functionalizations of Indoles and Pyrroles
[
a]
[a]
[a]
[a]
Johannes Diesel, Daria Grosheva, Shota Kodama and Nicolai Cramer *
Abstract:
An
enantioselective
nickel(0)-catalyzed
C–H
functionalization has been established as a complementary and
powerful tool for the construction of molecular complexity from
functionalization of indoles and pyrroles without the need for the
typical Lewis-basic directing groups is disclosed. The reaction
provides access to valuable tetrahydropyridoindoles and
tetrahydroindolizines in high yields and enantioselectivities under
mild reaction conditions. The process is characterized by a clean
endo-cyclization preference to yield the sought-after six-membered
ring products. Key for the success of the activation and selectivity in
the cyclization was the development of a novel chiral SIPr carbene
ligand analogue with very bulky flanking groups.
[9,10]
simple precursors.
Important advances have been made in
[
11]
the site-selective functionalization of indoles. Enantioselective
functionalization methods of indole generally rely on the use of
covalently bound directing groups placed at the nitrogen atom or
the C3-carbon atom. For instance, Bergman and Ellman
reported C3-aldimine-directed enantioselective indole
annulations with a Rh(I)-catalyst and Shibata disclosed C3-
ketone-directed Ir(I)-catalyzed annulations (Scheme 1).
Yoshikai developed a achiral regio-divergent C2-annulation of
indoles utilizing cobalt catalyst and different achiral
N-heterocyclic carbene (NHC) ligands in conjunction with a
[
12]
[12a,b]
[
12c,d]
a
Indoles and pyrroles are prevalent structures in a broad variety
of natural products and pharmaceuticals.
[
1]
For example,
[13]
covalent aldimine directing group.
The iridium(I)-catalyzed
[
2]
[3]
marketed drugs such as tolmetin and ribociclib contain a
pyrrole and a pyrrolopyrimidine core, respectively (Figure 1). As
prominent substructure, the tricyclic tetrahydropyrido indole
scaffold is present in biologically active molecules, like PKC
inhibitor Ro 32-0432 and CRTH2 antagonist MK-7246, as
well as in numerous indole alkaloids exemplified by
enantioselective addition of indole to norbornene is a rare
[14]
example
for
an
undirected
approach.
Recently,
enantioselective C–H functionalizations with abundant 3d-metal
[12g-h, 15, 16]
catalysts have gained significant momentum.
In this
[
4]
[5]
0
[17]
[18]
context, asymmetric [Ni ]NHC-catalyzed processes - aided in
several cases by
a
Lewis-acid co-activation
- enabled
[
6]
alstoscholarisine A and vincamine. Moreover, the antiviral
agent CMV423 contains a related tetrahydroindolizine core.
[19]
[20]
selective C-H functionalizations of pyridones, pyridines and
[
7]
[21]
benzimidazoles.
However, the undirected enantioselective
functionalization of the important electron-rich heterocycles
pyrrole and indole remains an open challenge.
Nakao and Hartwig reported an undirected C2-functionalization
of electron-rich heterocycles using an achiral nickel-NHC
[
22]
catalyst system for anti-Markovnikov hydroarylations.
We
[
19,23]
[24]
recently reported
a chiral NHC
family having large
[
25]
modulation opportunities based on Gawley’s carbene. Herein,
we introduce new members of this ligand family and apply them
as steering ligands in Ni-catalyzed directing group-free
enantioselective C–H functionalizations of indoles and pyrroles
(
Scheme 1).
Figure 1. Representative biologically active indole / pyrrole derivatives and
examples with tricyclic tetrahydropyridoindole cores.
In this respect, a broad range of construction and modification
[
8]
methods of indoles have been devised. More recently, C–H
[
a]
J. Diesel, Dr. D. Grosheva, S. Kodama, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
CH-1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: https://lcsa.epfl.ch/
Supporting information for this article is given via a link at the end of
the document
Scheme 1. Enantioselective C–H annulations of indoles and pyrroles.
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Angewandte Chemie International Edition
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COMMUNICATION
We commenced the development of the enantioselective C–H
cyclization with indole substrate 1a using Ni(cod) as nickel
2
source, a screening deck of stable chiral NHC-ligand precursor
salts and NaOtBu for the in situ generation of the free carbene
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L8
L8
L8
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
80
80
80
80
80
80
80
80
80
80
80
60
60
60
59
76
49
0
38:62
-
3
80
54
47
25
61
57
93
85
95
45
94
93
91
43:57
62:38
52:48
70:30
85:15
93:7
92:8
91:9
80:20
94:6
95:5
95:5
(
Table 1). The parent imidazol-2-ylidene ligand L1 (Ar=Ph,
1
R =H) gave 2a with 49 % yield and 38:62 enantiomeric ratio,
favoring the (R)-enantiomer (entry 1). Ligands L2 (R =Cl) and
L3 (R =Me) with a substituted imidazol-2-ylidene backbone
4
58
1
1
5
50
showed no improvement (entries
2
and 3). Using
6
84
acenaphthoimidazolylidene-derived L4 resulted in a sluggish
reaction with an almost racemic product 2a (entry 5). The
saturated dihydroimidazol-2-ylidene analog L5 having otherwise
the same substituents of L1 gave 2a in similar yield, but
7
78
8
100
100
100
55
intriguingly with
a
62:38 selectivity favoring the opposite
9
(
S)-enantiomer (entry 4). We continued the ligand survey with
[
19]
10
modifications on the aryl side-arms of L1 and L5.
3,5-Xylyl-
bearing ligand L6 gave 2a in 61 % yield and with 70:30 er in
favor of the (S)-enantiomer (entry 6). Again, increasing the bulk
from L1 to L6 reversed the enantioselectivity. We wondered if
these unusual reversal effects induced by the side-arm bulk and
11
12
100
100
100
13
PhCF
3
core saturation would be additive and designed L7,
a
[
d]
dihydroimidazol-2-ylidene version with 3,5-xylyl groups. Indeed,
using L7 improved the (S)-preference to 85:15 er (entry 7). This
trend could be further reinforced by replacing the 3,5-xylyl units
with sterically more demanding 3,5-di-tert-butyl phenyl groups
14
PhCF3
[a] Reaction conditions: 0.05 mmol 1a, 10 mol% Ni(cod) , 11 mol% L*·HCl, 50
mol% NaOtBu, 0.25 M, 24 h. [b] Determined by H NMR with an internal
standard. [c] Determined by HPLC analysis with a chiral stationary phase.
2
d] With 5 mol% Ni(cod) , 5.5 mol% L8·HCl, 25 mol% NaOtBu, 0.5 M, 24 h.
2
1
(
L8). Cyclized product 2a was obtained in 93:7 er (entry 8).
[
Additional benefit of L8 was its much higher reactivity resulting
in complete conversion of 1a, 93 % yield of 2a and complete
endo-selectivity in the cyclization. An X-ray crystal structure
analysis of the hydrochloride salt of L8 provides a good visual of
the
A1,3-strain minimized structure and of the shielding
generated by the very bulky 3,5-di-tert-butyl phenyl groups
[
26]
2
(
Figure 2). Replacement of the methyl group at the R -position
of the ligand scaffold by an electron donating methoxy group
L9) or a bulky tert-butyl group (L10) had very little effect on the
(
reaction performance (entries 9-10). In contrast, omission of this
2
substituent (R =H, L11) significantly reduced the conversion,
yield and enantioselectivity of the reaction (entry 11). Carbene
L8 allowed as well for a reaction temperature of 60 °C, which
slightly increased the enantioselectivity (entry 12). Switching the
solvent to trifluorotoluene improved the enantiomeric ratio to
95:5 (entry 13) and enabled a reduction in catalyst loading to 5
mol% without any loss in reactivity and selectivity (entry 14).
[
a]
Table 1. Optimization of the enantioselective indole C-H cyclization
Figure 2. X-ray crystal structure of L8·HCl (the majority of the hydrogen atoms
are omitted for clarity).
With the optimized reaction conditions, the scope of the
enantioselective cyclization was evaluated (Scheme 2). A variety
of 5-substituted indoles underwent cyclization smoothly and
gave tetrahydropyridoindoles 2 with excellent enantioselectivities.
Although both electron-donating (1b) and electron-withdrawing
(
1c) groups provide almost identical selectivity, 1b reacts slower
and requires a higher catalyst loading. In terms of functional
group tolerance, the B(pin)-group of 1d remained untouched.
Substituents at the 6- and 7-position of the indole core do not
alter the reaction performance (1e-1g, 1i). An ester moiety in the
[
b]
[b]
[c]
Entry L*
Solvent
T, °C
% conv.
% yield
er
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Angewandte Chemie International Edition
10.1002/anie.201904774
COMMUNICATION
[
27]
[a]
4-position induces a small drop in the enantioselectivity.
X-
Table 2. Enantioselective cyclization of indoles with substituted alkenes.
Ray crystal structure analysis of 2a allowed determination of its
[
26]
absolute configuration.
Noteworthy, in addition to indoles,
other pharmaceutically relevant azaheterocycles such as
pyrrolopyridine 1k and pyrrolopyrimidine 1l engaged in the
cyclization. No potential detrimental effect of the coordinating
nitrogen atom on the reaction performance was observed and
the corresponding cyclization products 2k and 2l were obtained
in excellent yields and enantioselectivities. The more C–H acidic
benzimidazole, a substrate considered as more facile for C–H
Entry
1
1
2
% yield
80
er
1n
97:3
[
21,28]
funtionalizations,
also underwent selective endo-cyclization
using our catalyst system.
2
1o
83
96.5:3.5
3
4
5
6
1p
84
82
86
97:3
1q
75:25
1r
83.5:16.5
90.5:9.5
[
[
b]
c]
(E)-1s
84
78
7
(Z)-1s
33:67
[
2 3
a] 5 mol% Ni(cod) , 5.5 mol% L8·HCl, 25 mol% NaOtBu, 0.5 M in PhCF
at 60 °C for 24 h, isolated yield; [b] 10:1 endo/exo cyclization ratio [c] 5:1
endo/exo cyclization ratio.
Scheme 2. Enantioselective C–H functionalization of indoles and related aza-
heterocycles. Reaction conditions: 5 mol% Ni(cod)
mol% NaOtBu, 0.5 M in PhCF at 60 °C for 24 h. [a] With 10 mol% Ni(cod)
1 mol% L8·HCl, 50 mol% NaOtBu.
2
, 5.5 mol% L8·HCl, 25
3
2
,
Moreover, pyrroles were found to be competent substrates,
enabling access to valuable tetrahydroindolizine scaffolds.
1
[31]
Noteworthy, reports on asymmetric C–H functionalizations of the
C2-position of pyrrole are scarce. They are either limited in
Concerning the substitution pattern and length of the alkenyl
tether of 1, longer alkyl chains R, additionally decorated with a
second alkene moiety or a benzyl ether, reacted very well and
[
14, 32]
scope, or deliver the product in modest enantioselectivity.
The inherent high reactivity of the pyrrole scaffold is challenging
[
33]
and frequently leads to undesired side products. Annulations
capitalizing on the high nucleophilicity of pyrrole have been
provided
products
2n-2p
in
excellent
yield
and
enantioselectivities (Table 2, entries 1-3). The formation of the
seven-membered ring system of 2q via an eight-membered
nickelacycle intermediate proceeded smoothly, albeit in
[
34]
realized enantioselectively.
Such Friedel-Crafts pathways
deliver branched exo-cyclization products governed by the
higher stability of 2° carbenium-ions. In contrast, we observed a
complementary endo-cyclization reactivity which is in
accordance with the mechanistic proposals for nickel-catalyzed
[
29]
moderate enantioselectivity (entry 4).
Indole 1r with
trimethylsilyl-bearing alkene cyclized under standard conditions
in high yields. The enantioselectivity of product 2r was
attenuated, presumably as a result of the bulky silyl group
located directly at the formed stereogenic center (entry 5).
Besides 1,1-disubstitued olefins, internal 1,2-substituted olefins
such as (E)-1s smoothly cyclized delivering (+)-2s in good yield
and enantioselectivity (entry 6). The reaction of cis-configured
olefins such as (Z)-1s is less selective, both in terms of
[
35]
hydroarylations.
Moreover, this mechanism is supported by
-1a resulted
deuterium-transfer experiments. Reaction with [D]
1
in a complete deuteration of the stereogenic carbon atom. No
intermolecular cross-over deuteration was observed (see SI for
details). For example, electronically toned-down pyrroles 3
reacted faster and yielded exclusively endo-cyclization product 4
(Scheme 3). 2-Methyl ester bearing pyrroles 3a-3c underwent
[30]
enantioselectivity and exo/endo cyclization ratio.
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COMMUNICATION
C–H annulation in good yields and with excellent
enantioselectivity. As previously noted, substrates with a bulky
alkenyl trimethylsilane group gave product 4d with lower
enantioselectivity. Substrate 3e having a trans-configured 1,2-
disubstituted olefin cyclized in good yield. Pyrrole 3f, bearing the
methyl ester at the 3-position engaged equally well in the
[4]
R. A. Bit, P. D. Davis, L. H. Elliott, W. Harris, E. Keech, H. Kumar,
G. Lawton, A. Maw, J. S. Nixon, D. R. Vesey, J. Wadsworth, S. E.
Wilkinson, C. H. Hill, J. Med. Chem., 1993, 36, 21.
[
5]
6]
M. Gallant et. al., Bioorg. Med. Chem. Lett., 2011, 21, 288.
X.-W. Yang, C.-P. Yang, L.-P. Jiang, X.-J. Qin, Y.-P. Liu, Q.-S. Shen,
Y.-B. Chen, X.-D. Luo, Org. Lett. 2014, 16, 5808.
[
[7]
R. Snoeck et. al., Antiviral Res. 2002, 55, 413.
cyclization, leading to
2
5
a
3:1 mixture of the 5- (4f) and
-annulated (4f’) products. The sterically more accessible
-position was clearly favored and 4f was isolated in 57% yield.
[8]
a) R. J. Sundberg in Indoles, Academic Press, London, 1996; b) D. F.
Taber, P.K. Tirunahari, Tetrahedron, 2001, 67, 7195.
[9]
Selected recent reviews: a) Z. Dong, Z. Ren, S. J. Thompson, Y. Xu, G.
Dong, Chem. Rev. 2017, 117, 9333; b) J. He, M. Wasa, K. S. L. Chan,
Q. Shao, J.-Q. Yu, Chem. Rev. 2017, 117, 8754; c) J. R. Hummel, J. A.
Boerth, J. A. Ellman, Chem. Rev. 2017, 117, 9163; d) D.-S. Kim, W.-J.
Park, C.-H. Jun, Chem. Rev. 2017, 117, 8977; e) K. Murakami, S.
Yamada, T. Kaneda, K. Itami, Chem. Rev. 2017, 117, 9302.
[
10] Selected reviews on enantioselective C–H functionalizations: a) J.
Wencel-Delord, F. Colobert, Chem. Eur. J. 2013, 19, 14010; b) C.
Zheng, S.-L. You, RSC Advances 2014, 4, 6173; c) D.-W. Gao, J.
Zheng, K.-Y. Ye, C. Zheng., S.-L. You in Asymmetric Functionalization
of C–H Bonds, (Ed.: S.-L. You), Royal Society of Chemistry, Cambridge,
U. K., 2015, p. 141. d) C. G. Newton, S.-G. Wang, C. C. Oliveira, N.
Cramer, Chem. Rev. 2017, 117, 8908; e) T. G. Saint-Denis, R.-Y. Zhu,
G. Chen, Q.-F. Wu, J.-Q. Yu, Science 2018, 359, 759.
[
11] a) A. H. Sandtorv, Adv. Synth. Catal. 2015, 357, 2403; b) J. A. Leitch, Y.
Bhonoah, C. G. Frost, ACS Catal. 2017, 7, 5618.
[
12] a) R. K. Thalji, J. A. Ellman, R. G. Bergman, J. Am. Chem. Soc. 2004,
126, 7192; b) R. M. Wilson, R. K. Thalji, R. G. Bergman, J. A. Ellman,
Org. Lett. 2006, 8, 1745; c) S. G. Pan, N. Ryu, T. Shibata, J. Am. Chem.
Soc. 2012, 134, 17474; d) H. Takano, N. Ryu, T. Shibata, Adv. Synth.
Catal. 2015, 357, 1131; e) P.-S. Lee, N. Yoshikai, Org. Lett. 2015, 17,
Scheme 3. Enantioselective C–H functionalization of pyrroles. Reaction
conditions: 5 mol% Ni(cod) , 5.5 mol% L8·HCl, 25 mol% NaOtBu, 0.5 M in
PhCF at 60 °C for 24 h; [a] with 10 mol% Ni(cod) , 11 mol% L8·HCl, 50 mol%
NaOtBu.
2
22; f) D. F. Fernandez, M. Gulias, J. L. Mascarenas, F. Lopez, Angew.
3
2
Chem. Int. Ed. 2017, 56, 9541; g) J. Loup, D. Zell, J. C. A. Oliveira, L.
Ackermann, Angew. Chem. Int. Ed. 2017, 56, 14197; h) F. Pesciaioli, U.
Dhawa, J. C. A. Oliveira, R. Yin, M. John, L. Ackermann, Angew. Chem.
Int. Ed. 2018, 57, 15425.
In conclusion, we have reported highly enantioselective
Ni(0)-catalyzed C−H functionalizations of indoles and pyrroles
without the need for the typical Lewis-basic directing groups.
The reaction provides access to synthetically relevant
tetrahydropyridoindoles and tetrahydroindolizines. Key for the
success of the activation and selectivity in the cyclization was
the development of a new chiral SIPr ligand analogue with very
bulky flanking groups. The work showcases the benefits of the
broad modularity of this chiral carbene ligand class and further
underlines its potential as a general ligand system in different
catalytic enantioselective transformations.
[13] Z. Ding, N. Yoshikai, Angew. Chem. Int. Ed. 2013, 52, 8574.
[14] C. S. Sevov, J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 2116.
[
15] For representative examples, see: a) P. A. Donets, N. Cramer, J. Am.
Chem. Soc. 2013, 135, 11772; b) G. Song, W. W. N. O, Z. Hou, J. Am.
Chem. Soc., 2014, 136, 12209; c) J. Yang, N. Yoshikai, J. Am. Chem.
Soc. 2014, 136, 16748; d) H. Ohmiya, H. Zhang, S. Shibata, A.
Harada, M. Sawamura, Angew. Chem. Int. Ed. 2016, 55, 4777; e) S.
Fukagawa, Y. Kato, R. Tanaka, M. Kojima, T. Yoshino, S. Matsunaga,
Angew. Chem. Int. Ed. 2019, 58, 1153; f) K. Ozols, Y.-S. Jang, N.
Cramer, J. Am. Chem. Soc. 2019, 141, 5675.
[16] a) P. Gandeepan, T. Mꢀller, D. Zell, G. Cera, S. Warratz, L. Ackermann,
Chem. Rev. 2019, 119, 2192; b) Ł. Woźniak, N. Cramer, Trends Chem.,
2019, DOI:10.1016/j.trechm.2019.03.013.
[
17] a) M. R. Chaulagain, G. J. Sormunen, J. Montgomery, J. Am. Chem.
Soc. 2007, 129, 9568; b) Y. Sato, Y. Hinata, R. Seki, Y. Oonishi, N.
Saito, Org. Lett. 2007, 9, 5597; c) J. S. E. Ahlin, P. A. Donets, N.
Cramer, Angew. Chem. Int. Ed. 2014, 53, 13229; d) R. Kumar, H.
Tokura, A. Nishimura, T. Mori, Y. Hoshimoto, M. Ohashi, S. Ogoshi,
Org. Lett. 2015, 17, 6018; e) P. A. Donets, N. Cramer, Angew. Chem.
Int. Ed. 2015, 54, 633; f) J. S. Ahlin, N. Cramer, Org. Lett. 2016, 18,
Acknowledgements
This work is supported by the Swiss National Science
o
Foundation (n 157741). We thank Dr. R. Scopelliti and Dr. F.
Fadaei Tirani for X-ray crystallographic analysis of compounds
L8·HCl and 2a.
3
242; g) R. Kumar, Y. Hoshimoto, E. Tamai, M. Ohashi, S. Ogoshi, Nat.
Commun. 2017, 8, 32; h) H. Wang, G. Lu, G. J. Sormunen, H. A. Malik,
P. Liu, J. Montgomery, J. Am. Chem. Soc. 2017, 139, 9317; i) Y. Cai,
J.-W. Zhang, F. Li, J.-M. Liu, S.-L. Shi, ACS Catal. 2019, 9, 1.
Keywords: Asymmetric Catalysis • Nickel • Chiral NHC ligands •
C‒H Activation • Heterocycles
[
18] a) Y. Nakao, A. Yada, S. Ebata, T. Hiyama; J. Am. Chem. Soc. 2007,
129, 2428; b) Y. Nakao, Y. Yamada, N. Kashihara, T. Hiyama, J. Am.
Chem. Soc., 2010, 132, 13666. c) S. Okumura, S. Tang, T. Saito, K.
Semba, S. Sakaki, Y. Nakao, J. Am. Chem. Soc. 2016, 138, 14699; d)
W. Guan, G. Zeng, H. Kameo, Y. Nakao, S. Sakaki, Chem. Rec. 2016,
[
[
[
1]
2]
3]
A. Li, Tetrahedron, 2015, 71, 3535.
L. J. Cordrey, J. Am. Geriatr. Soc., 1976, 24, 440.
S. Kurt, Oncology Times, 2014, 36, 39.
16, 2405.
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Angewandte Chemie International Edition
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COMMUNICATION
[
[
[
19] J. Diesel, A. Finogenova, N. Cramer, J. Am. Chem. Soc. 2018, 140,
4489.
20] W.-B. Zhang, X.-T. Yang, J.-B. Ma, Z.-M. Su, S.-L. Shi,
J. Am. Chem. Soc. 2019, 141, 5628.
21] a) Y.-X. Wang, S.-L. Qi, Y.-X. Luan, X.-W. Han, S. Wang, H. Chen, M.
Ye, J. Am. Chem. Soc. 2018, 140, 5360; b) J. Loup, V. Müller, D.
Ghorai, L. Ackermann, Angew. Chem. Int. Ed. 2019, 58, 1749.
22] Y. Schramm, M. Takeuchi, K. Semba, Y. Nakao, J. F. Hartwig, J. Am.
Chem. Soc. 2015, 137, 12215.
[
[
23] Independently, a backbone modification was reported: Y. Cai, X.-T.
Yang, S.-Q. Zhang, F. Li, Y.-Q. Li, L.-X. Ruan, X. Hong, S.-L. Shi,
Angew. Chem., Int. Ed. 2018, 57, 1376.
[24] D. Janssen-Müller, C. Schlepphorst, F. Glorius, Chem. Soc. Rev. 2017,
46, 4845.
[
25] A. Albright, R. E. Gawley, J. Am. Chem. Soc. 2011, 133, 19680.
26] Crystallographic data for L8·HCl and 2a: CCDC 1910565 and 1910564
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
27] Indoles with substituents at the C3-position react sluggishly.
28] a) K. L. Tan, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2001,
[
[
[
123, 2685; b) K. L. Tan, R. G. Bergman, J. A. Ellman, J. Am. Chem.
Soc. 2002, 124, 13964; c) K. L. Tan, R. G. Bergman, J. A. Ellman, J.
Am. Chem. Soc. 2002, 124, 3202; d) A. S. Tsai, R. M. Wilson, H.
Harada, R. G. Bergman, J. A. Ellman, Chem. Commun. 2009, 3910; e)
H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2007, 129, 12404; f) D. Zhao,
W. Wang, F. Yang, J. Lan, L. Yang, G. Gao, J. You, Angew. Chem. Int.
Ed. 2009, 48, 3296; g) Q. Wang, S. L. Schreiber, Org. Lett. 2009, 11,
5178; h) D. Monguchi, T. Fujiwara, H. Furukawa, A. Mori, Org. Lett.
2009, 11, 1607; i) K. Muto, T. Hatakeyama, J. Yamaguchi, K. Itam,
Chem. Sci. 2015, 6, 6792; j) S. Nakanowatari, T. Müller, J. C. A.
Oliveira, L. Ackermann, Angew. Chem. Int. Ed. 2017, 56, 15891.
29] The attempted cyclization of a substrate for an eight-membered ring
failed and the starting material was recovered.
[
[
30] A trisubstituted olefin does not react under the present conditions.
31] a) O. Baudoin, D. Guenard, F. Gueritte, Mini-Rev. Org. Chem. 2004, 1,
[
333; b) F. Schrꢁder, S. Franke, W. Francke, H. Baumann, M. Kaib, J. M.
Pasteels, D. Daloze, Tetrahedron 1996, 52, 13539; (c) M. Movassaghi,
A. E. Ondrus, Org. Lett. 2005, 7, 4423.
[
[
[
[
32] J. A. Schiffner, T. H. Wꢁste, M. Oestreich, Eur. J. Org. Chem. 2010,
2
010, 174.
33] W. J. Olivier, J. A. Smith, A. C. Bissember, Org. Biomol. Chem., 2018,
6, 1216.
1
34] a) A. Shemet, E. M. Carreira, Org. Lett. 2017, 19, 5529; b) Z. Liu, A. S.
Wasmuth, S. G. Nelson J. Am. Chem. Soc. 2006, 128, 10352.
35] a) J. S. Bair, Y. Schramm, A. G. Sergeev, E. Clot, O. Eisenstein,
J. F. Hartwig, J. Am. Chem. Soc. 2014, 136, 13098; b) A. J. Nett, J.
Montgomery, P. M. Zimmerman, ACS Catal. 2017, 7, 7352.
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Angewandte Chemie International Edition
10.1002/anie.201904774
COMMUNICATION
COMMUNICATION
Johannes Diesel, Daria Grosheva,
Shota Kodama, Nicolai Cramer*
Page No. – Page No.
A Bulky Chiral N-Heterocyclic
Carbene Nickel Catalyst Enables
Enantioselective C–H
Functionalizations of Indoles and
Pyrroles
An enantioselective directing-group free Ni(0)-catalyzed C–H functionalization of indoles
provides access to tetrahydropyridoindoles and tetrahydroindolizines in high yields and
enantioselectivities under mild reaction conditions. The activation and selective
cyclization is enabled by a novel chiral SIPr carbene ligand analogue with very bulky
flanking groups.
This article is protected by copyright. All rights reserved.