Stereoselective Synthesis of Cyclohepta[b]indoles by Visible-Light-Induced [2+2]-Cycloaddition/retro-Mannich-type Reactions

Article abstract of DOI:10.1002/anie.202101104

A novel method for the concise synthesis of cyclohepta[b]indoles in high yields was developed. The method involves a visible-light-induced, photocatalyzed [2+2]-cycloaddition/ retro-Mannich-type reaction of enaminones. Experimental and computational studies suggested that the reaction is a photoredox process initiated by single-electron oxidation of an enaminone moiety, which undergoes subsequent cyclobutane formation and rapidly fragmentation in a radical-cation state to form cyclohepta[b]indoles.

Full text of DOI:10.1002/anie.202101104

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11211–11216
International Edition: doi.org/10.1002/anie.202101104
German Edition: doi.org/10.1002/ange.202101104
Photocatalysis
Stereoselective Synthesis of Cyclohepta[b]indoles by Visible-Light-
Induced [2+2]-Cycloaddition/retro-Mannich-type Reactions
Xin-Peng Mu, Yuan-He Li, Nan Zheng, Jian-Yu Long, Si-Jia Chen, Bing-Yan Liu, Chun-
Bo Zhao, and Zhen Yang*
Abstract: A novel method for the concise synthesis of
cyclohepta[b]indoles in high yields was developed. The
With this chemistry in mind, we envisaged that the
enaminone[11] motif in substrate 14 (Scheme 1d) could be
activated via electron transfer. The resultant radical cation[12]
method involves
a visible-light-induced, photocatalyzed
[2+2]-cycloaddition/ retro-Mannich-type reaction of enami-
nones. Experimental and computational studies suggested that
the reaction is a photoredox process initiated by single-electron
oxidation of an enaminone moiety, which undergoes subse-
quent cyclobutane formation and rapidly fragmentation in
a radical-cation state to form cyclohepta[b]indoles.
C
yclohepta[b]indoles (Figure 1) bearing an all-carbon qua-
ternary stereogenic center at the indole C3 are motifs existed
in a variety of natural products (Figure 1, 1–6).[1] These
natural products display a broad spectrum of biological
activities, for example, alstonlarsine A (3) exhibits DRAK2
inhibitory activity,[1e] and ajmaline (6), a voltage-gated Na+
channel blocker, is a class Ia antiarrhythmic drug.[2] Much
effort has therefore been devoted to their syntheses.[3]
In 2018, Hiersemannꢀs group[4] reported that cyclohepta
[b]indole 8 could be synthesized via a [2+2]/4p electrocyclic
ring-opening reaction under excitation by a light source
(254 nm) in a quartz tube (Scheme 1a). In 1975, Tamuraꢀs
group[5] developed a [2+2]/retro-Mannich strategy involving
structurally diverse 2-azabicyclo[2.1.1]hexane rings as inter-
mediates (Scheme 1b). This method has been widely used to
synthesize nitrogen-containing molecules.[6] Since 2019, You
et al.,[7] Dhar et al.,[8] Fu et al.,[9] and Koenig et al.[10] inde-
pendently developed methods for synthesizing cyclobutane-
fused polycyclic indoles via energy transfer to the indole
moiety (Scheme 1c).
Figure 1. Cyclohepta[b]indole and associated indole alkaloids.
[*] X.-P. Mu, Dr. N. Zheng, J.-Y. Long, S.-J. Chen, B.-Y. Liu, C.-B. Zhao,
Prof. Dr. Z. Yang
State Key Laboratory of Chemical Oncogenomics and Laboratory of
Chemical Genomics, School of Chemical Biology and Biotechnology
Peking University Shenzhen Graduate School
Shenzhen 518055 (P. R. China)
E-mail: zyang@pku.edu.cn
Dr. Y.-H. Li, Prof. Dr. Z. Yang
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education and
Beijing National Laboratory for Molecular Science (BNLMS)
Peking-Tsinghua Center for Life Sciences
Peking University, Beijing 100871 (P. R. China)
Prof. Dr. Z. Yang
Shenzhen Bay Laboratory, Shenzhen 518055 (P. R. China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202101104.
Scheme 1. [2+2]-based cycloaddition reactions.
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could participate in an indole-based dearomative redox [2+2]
annulation[13] and a subsequent retro-Mannich-type reac-
tion[14] to afford a series of tetracyclic cyclohepta[b]indoles 15.
Here, we report our recent efforts to develop a novel and
concise method for the stereoselective synthesis of structur-
ally diverse tetracyclic cyclohepta[b]indoles via a single-
electron-transfer (SET)-initiated process.
indicates that the annulation was photocatalyzed. We also
tested that other photocatalysts (Table 1, entries 10–15) could
not afford the desired annulated products.
We then synthesized substrates 16a–16s to investigate the
substrate scope. The annulation results obtained under the
optimized reaction conditions are shown in Table 2. Annula-
Table 2: Substrate scope.[a]
We explored the synthetic feasibility with enaminone 14
as the substrate, which was readily synthesized with a new
one-pot protocol via condensation of tryptamine with 1,3-
cyclopentanedione and selective t-butyloxycarbonyl (Boc)
protection.[14d,e] We initially used Ir-based blue phosphores-
cent materials,[15] namely FIrpic,[16] PhFIrpic,[17] and
FCNIrpic,[18] as photocatalysts in the proposed annulation
reaction (Table 1, entries 1–7) because of their high energy
triplet states.[19] These compounds catalyzed the desired
annulation. Product 15 was obtained in 93% yield when the
reaction was performed in the presence of FCNIrpic in
CH3CN at room temperature for 24 h. The relative stereo-
chemistry of 15 was confirmed by X-ray diffraction (XRD;
see Supporting Information).[20] When we performed the
same reaction without visible-light irradiation or without
a catalyst, no reaction occurred (Table 1, entries 8 and 9). This
Table 1: Optimization of reaction conditions.[a]
Entry
Catalyst
Solvent
Yield [%][b]
1
2
3
4
FIrpic
PhFIrpic
FCNIrpic
FCNIrpic
DCM
DCM
DCM
DCE
13
20
67
58
[a] Reaction conditions: substrates 16a–16s (0.2 mmol) and FCNIrpic
(5 mol%) in CH3CN (4 mL) were irradiated by 18 W blue LEDs at room
temperature under argon for 24 h. d.r.=diastereomeric ratio.
5
6
7
8
FCNIrpic
FCNIrpic
FCNIrpic
FCNIrpic
MeOH
Acetone
CH3CN
CH3CN
CH3CN
DCM
DCM
DCM
DCM
DCM
58
80
93
tions performed with substrates bearing electron-donating or
-withdrawing groups at the indole C4, C5, and C6 positions
gave the desired cyclohepta[b]indoles in good to excellent
yields. However, when the indole ring was substituted at C7
with a methoxy group, the yield was low, presumably because
of the steric effect. We prepared substrates 16n and 16o,
which exhibited a methyl or benzyl group at the indole C2,
and investigated the construction of vicinal quaternary
centers. The desired annulation proceeded and products
were obtained in moderate yields. For substrate bearing
a bromide group at the C2 position, an intramolecular
coupling product was obtained (see Supporting Information).
A substrate bearing a chiral amino acid ester at the linker
motif (16p) gave 17p diastereoselectively in 67% yield. When
the enone motif in substrate 14 was replaced with a lactone
(16q) or lactam (16r) moiety, the [2+2] cycloaddition
reaction afforded products 17q and 17r in 49% and 52%
yields, respectively, without a retro-Mannich ring-opening
reaction. The relative stereochemistry of 17q was confirmed
by XRD (see Supporting Information).[20] Acyclic 1,3-dike-
tone product 17s can also be generated in moderate yield,
which is a synthetic precursor for polycyclic indoline-based
natural products[14d,i] (see Supporting Information for details).
N.R.[c]
N.R.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
9
–
10
11
12
13
14
15
Ru(bpy)3Cl2·6H2O
Ru(bpz)3(PF6)2
fac-Ir(ppy)3
Ir(ppy)2(dtbbpy)PF6
Ir[dF(CF3)ppy]2ꢀ(dtbbpy)PF6
Mes-Acr+·ClO4
DCM
[a] Reaction conditions: substrate 14 (0.1 mmol) and catalyst (5 mol%)
in the stated solvent (2 mL) were irradiated by 18 W blue LEDs
(lmax =460 nm) at room temperature under argon for 24 h. [b] Yields
1
determined from H NMR spectra with p-dinitrobenzene as internal
standard. [c] Control experiment conducted in the dark. LEDs=light-
emitting diodes. DCM=dichloromethane. DCE=1,2-dichloroethane.
N.D.=desired product not detected.
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Then we turned our attention to the reaction mechanism.
was irradiated with blue LEDs in the presence of FCNIrpic.
We identified the segment of the substrate that interacts with
FCNIrpic by performing luminescence-quenching experi-
ments on 18 and 19, and comparing the results (Figure 2a):
the fluorescence of the photocatalyst FCNIrpic was quenched
by enaminone 18, while almost no quenching was observed
when FCNIrpic was mixed with indole 19. This indicates that
excited-state FCNIrpic activates the substrate solely by
interacting with the enaminone moiety. To prove that the
enaminone was activated via single electron oxidation[13a–p]
instead of energy transfer,[21] we synthesized compound 20,
and performed a comparative experiment (Figure 2b). It
shows that although the fluorescence of FCNIrpic could be
quenched by enaminone 20, no reaction occurred when 20
Conversely, when we irradiated enaminone 20 with a high-
pressure Hg lamp in the absence of FCNIrpic, the annulation
product 21 was obtained in 77% yield, indicating that once
triplet state 20* is formed, it should undergo [2+2]/retro-
Mannich-type process.[4a,14j] Thus, single electron oxidation
(20!20·+) is a more plausible explanation for the non-
productive luminescence-quenching. Electrochemical studies
performed in CH3CN also show that it is thermodynamically
feasible for the excited photocatalyst (Ep/2III*/II =+ 1.24 V vs.
Ag/AgCl) to oxidize substrate 14 (Ep/2ox =+ 1.18 V vs. Ag/
AgCl) via SET.
The reaction mechanism was further investigated compu-
tationally (Figure 3).[22] Stationary points for the organic
species were located at wB97M-V/def2-QZVP//
wB97X-D/def-TZVP level,[23] which was chosen
to better describe the radical-cation species.[24]
Rates and thermodynamic properties for SET
processes were estimated according to Marcus-
Hush theory using PBE0 functional with
LANL2TZ(f) basis set and pseudopotential for
Ir atoms and def-TZVP basis sets for others.[23d,25]
The functional was chosen to better describe the
transition-metal species.[26] SMD method was
used for solvation effects, including those
involved in external reorganization energies.[27]
The energies mentioned below are all Gibbs free
energies with solvation effects.
This reaction is probably initiated by single-
electron oxidation of substrate 14 to its radical
cation IM1 by excited-state FCNIrpic ([IrIII]*).
This process releases 1.1 kcalmolꢀ1 of free energy,
which is consistent with the electrochemical
analysis (DEox =+ 0.06 eV, ca. 1 kcalmolꢀ1). The
effective activation Gibbs free energy for the SET
process, was estimated to be a reachable 11.9 kcal
molꢀ1 according to the Marcus-Hush theory.
Electronic structure analysis confirmed that the
spin density of IM1 is located almost exclusively
at the enaminone moiety (see Supporting Infor-
mation), which is consistent with the lumines-
cence-quenching experiments.
Aided by a favorable p–p stacking interaction,
the oxidized enaminone moiety in IM1 readily
undergoes radical addition to the indole ring, with
a barrier of only 5.9 kcalmolꢀ1 (via TS1), to form
IM2. Subsequent addition of the benzylic radical
to the iminium moiety requires a barrier of
18.9 kcalmolꢀ1. The resulting radical-cation inter-
mediate IM3 is unstable and has a natural ten-
dency to either fragment back to IM2 (breaking
bond a) or forward to IM4 (breaking bond b). The
Figure 2. a) Luminescence-quenching experiments performed with 10 mM FCNIrpic
solution mixed with given concentration of 18 or 19. Substrate background was
measured with 0.025 molLꢀ1 of 18 or 19 without an Ir catalyst. b) Outcome of
control experiments and luminescence-quenching experiment result with 20. Both
reactions were performed in MeCN for 24 h at r.t. The quenching was measured
with 10 mM FCNIrpic solution mixed with given concentration of 20. Background
caused by direct excitation and florescence of 20 was subtracted from the spectrum
(see the Supporting Information).
regiochemistry of the fragmentation is coupled to
ꢀ
the out-of-plane bending vibration of the N H
ꢀ
bond; when N H vibrates so that the unbonded
single electron is mainly situated in a position
antiperiplanar to bond b (TS3, Figure 3), IM4 can
be readily reached, with a barrier of only 2.0 kcal
molꢀ1. IM4 can then be reduced by previously
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Figure 3. Calculated energy profile. The solvated Gibbs free energies are referenced to a combined system of 14 and the excited-state FCNIrpic
photocatalyst [IrIII]*.
generated [IrII]ꢀ species to zwitterion IM6, which can be
converted to product 15 via intermolecular proton transfer.
An alternative route might involve initial generation of
the [2+2] reaction product IM5 via single-electron reduction
of IM3, and a subsequent closed-shell retro-Mannich reac-
tion. We estimated that the effective activation Gibbs free
energy for SET between IM3 and [IrII]ꢀ is only 0.8 kcalmolꢀ1.
However, this bimolecular process is probably diffusion
controlled, and the overall rate would be slower than the
transformation of IM3 to IM4 via TS3, which is an intra-
cation, is different from that in traditional UV-light-excitation
and energy-transfer processes. This leads to different reac-
tivities and substrate scopes. Further studies to expand this
photoredox catalytic method are currently underway in our
laboratory.
Acknowledgements
We thank Dr. Zi-Ang Nan at Xiamen University for the refine
of the results of X-ray crystallographic analysis, and Dr. Jing
Guo at Sun Yat-sen University for the electrochemical
measurement. Computational studies were performed on
the High-performance Computing Platform of Peking Uni-
versity. This work is supported by National Key R&D
Program of China (Grant No. 2018YFC0310905), National
Science Foundation of China (Grant Nos. 21632002 and
21871012), and Guangdong Provincial Key R&D Program
(Grant No. 2020B0303070002).
molecular process with a barrier of only 2.0 kcalmolꢀ1
.
Furthermore, we could not identify a low-energy pathway
for the subsequent retro-Mannich reaction of IM5 in neutral
solution. For example, direct fragmentation of the neutral
species IM5 to IM6 is endothermic and involves an insur-
mountable 24.1 kcalmolꢀ1 barrier (TS4). Other processes
involving activation of IM5 via intermolecular proton transfer
of the amine or ketone moiety were also determined to have
high barriers (see Supporting Information for details).
On the basis of the computational and experimental
results, we propose that the mechanism of this reaction
involves single-electron oxidation of the substrate by an
excited photocatalyst, and subsequent stepwise cyclization to
form an unstable cyclobutene species. Fragmentation of the
radical cation then occurs and a seven-membered ring is
formed, which then undergoes single-electron reduction and
proton transfer to form the product.
Conflict of interest
The authors declare no conflict of interest.
Keywords: [2+2]/retro-Mannich-type cycloaddition ·
amine radical cation · cyclohepta[b]indole · photoredox catalysis
In conclusion, we have developed a formal photoredox-
catalyzed [2+2]/retro-Mannich-type cycloaddition for the
synthesis of cyclohepta[b]indoles, with FCNIrpic as a visi-
ble-light photocatalyst. A plausible mechanism was proposed
on the basis of luminescence-quenching of model substrates,
comparative experiments, and a computational study. We
found that this reaction, unlike those reported in previous
studies, was initiated by single-electron oxidation of an
enaminone moiety, and followed by subsequent nucleophilic
indole addition to form a cyclobutane structure, which rapidly
fragmented in a radical-cation state to form cyclohepta-
[b]indoles. The active intermediate, an enaminone radical-
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Manuscript received: January 24, 2021
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Revised manuscript received: February 27, 2021
Accepted manuscript online: March 8, 2021
Version of record online: April 7, 2021
11216 www.angewandte.org
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Angew. Chem. Int. Ed. 2021, 60, 11211 –11216