Addition of a Carbene Catalyst to Indole Aryl Aldehyde Activates a Remote δ-sp2 Carbon for Protonation and Formal [4+2] Reaction

Article abstract of DOI:10.1021/acs.orglett.9b01624

The addition of a carbene catalyst to an indole aryl aldehyde leads to the activation of a remote sp² carbon that is five atoms away from the catalyst. The unsaturated Breslow intermediate formed between the catalyst and substrate undergoes an internal redox reaction and remote carbon protonation to generate an analogous azolium vinyl enolate intermediate. Subsequent [4+2] reaction with cyclic imine substrates eventually affords multicyclic pyridoindoles as nearly single diastereomers with excellent enantioselectivities.

Full text of DOI:10.1021/acs.orglett.9b01624

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Addition of a Carbene Catalyst to Indole Aryl Aldehyde Activates a
Remote δ‑sp2 Carbon for Protonation and Formal [4+2] Reaction
Pengcheng Zheng,†,∥ Shuquan Wu,†,∥ Chengli Mou,‡,∥ Wei Xue,† Zhichao Jin,†
and Yonggui Robin Chi*,†,§
†Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
‡Guizhou University of Traditional Chinese Medicine, Huaxi District, Guiyang 550025, China
§Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: The addition of a carbene catalyst to an indole aryl aldehyde
leads to the activation of a remote sp2 carbon that is five atoms away from
the catalyst. The unsaturated Breslow intermediate formed between the
catalyst and substrate undergoes an internal redox reaction and remote
carbon protonation to generate an analogous azolium vinyl enolate
intermediate. Subsequent [4+2] reaction with cyclic imine substrates
eventually affords multicyclic pyridoindoles as nearly single diastereomers
with excellent enantioselectivities.
romatic units are among the most common building
blocks in natural and synthetic functional molecules.
dienolate intermediate II, which subsequenlty reacts with
imine substrate 2a to generate intermediate III via an
enantioselective formal [4+2] cycloaddition process. Elimi-
nation of the NHC catalyst finally gives chiral multicyclic
pyrido[4,3-b]indole product 3 in good to excellent yields and
er values. Interestingly, the pyrido[4,3-b]indole structure
formed in this transformation is found in pharmaceutically
interesting bioactive molecules (Figure 1c).6
A Boc-protected indole aldehyde 1a was chosen as a model
substrate to react with cyclic sulfonic imine 2a (Table 1). A
multicyclic pyrido[4,3-b]indole product 3a could be smoothly
afforded under the catalysis of a variety of NHCs (e.g., Table 1,
entries 1 and 2). Chiral amino-indanol-derived NHC catalyst
4b, first introduced by Bode and co-workers,7 gave desired
product 3a in a promising isolated yield with excellent
enantioselectivity (entry 2). The bases could significantly
influence the reaction yields. The use of Cs2CO3 as the base
could dramatically improve the product yield with little erosion
of the er value (entry 3). Several organic bases tested here
failed to facilitate product formation (e.g., entries 4 and 5).
The solvents also had a clear influence on this catalytic
transformation. The use of ethyl acetate as a solvent led to 3a
in a moderate yield with excellent enantioselectivity (entry 6).
A few other solvents examined here gave only a trace amount
of the desired product (e.g., entries 7 and 8). To our delight,
the yield and er values of 3a were further improved when a
catalytic amount of Cs2CO3 was used as the base, 4b as the
A
Developing asymmetric methods for efficient functionalization
of the aromatic carbons or other atoms adjacent to the
aromatic scaffolds is obviously important. Organic molecule
catalysts have been shown to offer excellent controls on
chemo- and stereoselectivities for many reactions.1 However,
employing organic catalysis for enantioselective transformation
of aromatic compounds remains difficult.2 Specifically, pushing
the power of an N-heterocyclic carbene (abbreviated as NHC
or carbene) catalyst across an all-carbon aromatic ring for the
functionalization of the aromatic sp2 carbons (Figure 1a, A) or
benzylic sp3 carbons (Figure 1a, B) is illusive. In 2013, we
found that by using indole aryl aldehyde as the substrate,
addition of an NHC catalyst to the aldehyde could eventually
lead to enantioselective functionalization of the indole benzylic
carbon (Figure 1a, C).3 The groups of Glorius and Rovis have
found that the introduction of an electronegative Br atom to an
aryl aldehyde could lead to NHC-mediated functionalization of
its benzylic carbon (Figure 1a, D).4 Our lab recently found that
the incorporation of a silicon atom to an aryl carboxylic ester
(Figure 1a, E) could facilitate benzylic carbon functionalization
via NHC organocatalysis.5
Here we disclose that the addition of an NHC catalyst to
indole aryl aldehyde can lead to the functionalization of the
remote δ-sp2 carbon (Figure 1a, F) via an extended Breslow
intermediate (Figure 1a, G). Briefly, reaction of the NHC
catalyst with indole aldehyde substrate 1 forms an extended
homoenolate intermediate I with two potentially nucleophilic
carbons (Figure 1b, the β and δ carbons of intermediate I).
The indole aldehyde δ-sp2 carbon is then protonated to afford
Received: May 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
c
entry
NHC
base
solvent
yield (%)
er
1
2
3
4
5
6
7
8
4a
4b
4b
4b
4b
4b
4b
4b
4b
4b
K2CO3
K2CO3
Cs2CO3
DBU
THF
THF
THF
THF
30
35
80
<5
<5
40
<5
<5
82
40
80:20
96:4
93:7
−
−
96:4
−
−
97:3
97:3
Et3N
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
EtOAc
toluene
CH2Cl2
THF
d
9
10
d,e
THF
a
General conditions (unless otherwise specified): 1a (0.1 mmol), 2a
(0.09 mmol), NHC (0.03 mmol), base (0.1 mmol), solvent (2.0 mL),
b
c
rt, 12 h. Isolated yield of 3a. The er values were determined via
d
HPLC on the chiral stationary phase. Cs2CO3 (0.03 mmol) was used
as the base. 4b (0.02 mmol) was used.
e
formation. Moreover, imine substrates derived from isatin or
benzaldehyde were not effective for this [4+2] cycloaddition
reaction. It is worth noting that all of our reaction products
(3a−3s) were obtained as single diastereomers. Additionally,
our catalytic reactions can be readily scaled without obvious
erosion of either the reaction yield or the product optical
purity (Scheme 2).
We have also carried out this internal redox [4+2]
cycloaddition reaction with a deuterated starting material 1a′
(>99% D) to further understand the reaction mechanism
(Scheme 3, eq 1). The δ carbon of substrate 1a′ was
deuterated in 50% yield through this [4+2] reaction. A fully
deuterated product (3a′) could be obtained from normal
indole aldehyde 1a by adding 10 equiv of D2O to the reaction
system (eq 2). This obseration (partial deuteration) indicates
that the internal redox transformation likely went through a
deprotonation/protonation process (from intermediate I to II,
as shown in Figure 1b). As a technical note, normal product 3a
did not go through proton exchange process with D2O under
the identical catalytic condition (eq 3). This indicates that the
proton shift from intermediate I to II goes through an
intermolecular proton transfer process and the moisture that is
present in the catalytic system may behave as a proton shuttle
for this process.
The Boc protecting group of chiral product 3a could be
easily removed under acidic condition to give free indole
derivative 4a in good yield with retention of optical purity
(Scheme 4).
The absolute configurations of chiral pyrido[4,3-b]indole
products 3 were estimated according to the X-ray analysis on
the single crystals of 3a (Figure 2a). A rationale for the
reaction stereoselectivity is illustrated in Figure 2b.8 The re
face of the γ carbon of dienolate intermediate II is blocked by
the chiral motif of the NHC catalyst, and the re face of the sp2
carbon on substrate 2a is favored due to the steric effect. The
[4+2] reaction between the most favorable faces of substrates
Figure 1. Activation of the sp2 and benzylic sp3 carbons of aromatic
compounds and bioactivities of pyrido[4,3-b]indoles.
NHC precatalyst, and THF as the solvent (entry 9). Further
decreasing the load of NHC catalyst 4b would result in
decrease in the product yield (entry 10). Notably, all of the
products formed in this catalytic process were isolated as
essentially single diastereomers.
With the optimized reaction condition in hand (as stated in
Table 1, entry 9), we examined the substrate scope of this
transformation (Scheme 1). Electron-donating groups were
well tolerated at positions 5 and 6 of the indole aldehyde
substrates, with the desired products produced in moderate to
good isolated yields and excellent enantioselectivities (3a−3f).
The er values of the products were decreased when
substituents were installed at position 4 of the indole ring
(3g). This decrease in the er value is probably due to the steric
hindrance caused by substituents at position 4 (3g). Indole
aldehydes bearing electron-withdrawing groups also worked
well in this reaction, although the product yields slightly
decreased (3h−3k). However, switching the ester groups on
indole aldehyde 1 to other functional groups (e.g., CN, COPh,
or Ph) resulted in no formation of the desired products.
Similarly, both electron-donating (3l−3p) and electron-
withdrawing (3q−3s) groups could be installed on the cyclic
sulfonic imide substrates. Replacing the ester group on the
imine molecules with a phenyl ring led to no product
B
DOI: 10.1021/acs.orglett.9b01624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Scope of Reactions
Scheme 2. Gram Scale Synthesis of 3a
Scheme 3. Isotope Labeling Experiment
Scheme 4. Removal of the Boc Protection Group of 3a
a
Reaction conditions as stated in entry 9 of Table 1. Yields are
isolated yields after purification by column chromatography. The er
values were determined via HPLC on a chiral stationary phase.
2a and intermediate II led to product 3a in an enantio- and
diastereoselective manner.
Figure 2. X-ray analysis of 3a and rationale for stereoselectivity.
In summary, we have developed an organic catalytic method
for remote carbon functionalizatoin of indole aryl aldehydes.
The analogous δ-sp2 carbon of the indol aryl aldehyde is
protonated via a carbene catalyst-enabled internal redox
process to generate an azolium vinyl enolate intermediate.
Subsequent formal cycloaddition with cyclic imines affords
multicyclic pyrido[4,3-b]indoles as single diastereomers with
C
DOI: 10.1021/acs.orglett.9b01624
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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excellent enantioselectivities. Further investigations into
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01624.
Experimental procedures and spectral data for all new
compounds (PDF)
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Accession Codes
CCDC 1817493 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
(4) (a) Janssen-Muller, D.; Singha, S.; Olyschlager, T.; Daniliuc, C.
̈
̈
Corresponding Author
*E-mail: robinchi@ntu.edu.sg.
ORCID
G.; Glorius, F. Org. Lett. 2016, 18, 4444−4447. (b) Chen, D.-F.;
Rovis, T. Synthesis 2016, 49, 293−298.
(5) Wang, H.; Chen, X.; Li, Y.; Wang, J.; Wu, S.; Xue, W.; Yang, S.;
Chi, Y. R. Org. Lett. 2018, 20, 333−336.
Zhichao Jin: 0000-0003-3003-6437
Yonggui Robin Chi: 0000-0003-0573-257X
Author Contributions
∥P.Z., S.W., and C.M. contributed equally to this work.
(6) (a) Ilyn, A. P.; Kuzovkova, J. A.; Potapov, V. V.; Shkirando, A.
M.; Kovrigin, D. I.; Tkachenko, S. E.; Ivachtchenko, A. V. Tetrahedron
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Bioorg. Med. Chem. 2002, 10, 2705−2712. (d) Li, Q.; Deng, A.-J.; Li,
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(7) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298−10299. (b) He, M.; Struble, J. R.; Bode, J. W. J.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the National
Natural Science Foundation of China (21772029, 21472028,
and 21807019), the Natural Science Foundation of Guizhou
University (GZU[2017]35), the Opening Foundation of the
Key Laboratory of Green Pesticide and Agricultural Bioengin-
eering, Ministry of Education, Guizhou University
(2018GDGP0101), and Guizhou University, the Guizhou
Province First-Class Disciplines Project (YiLiu Xueke Jianshe
Xiangmu) [GNYL(2017)008], Guizhou University of Tradi-
tional Chinese Medicine, the Singapore National Research
Foundation (NRF-NRFI2016-06), the Ministry of Education
of Singapore (MOE2013-T2-2-003, MOE2016-T2-1-032, and
RG108/16), an A*STAR Individual Research Grant
(A1783c0008), a Nanyang Research Award Grant, and
Nanyang Technological University.
(8) (a) Mahatthananchai, J.; Zheng, P.; Bode, J. W. Angew. Chem.,
Int. Ed. 2011, 50, 1673−1677. (b) Mahatthananchai, J.; Bode, J. W.
Acc. Chem. Res. 2014, 47, 696−707.
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DOI: 10.1021/acs.orglett.9b01624
Org. Lett. XXXX, XXX, XXX−XXX