FeCl3-catalyzed sequential cyclization for the construction of 12-aryl 5,7-dihydropyrido[2,3-b:6,5-b']diindoles

Article abstract of DOI:10.1016/j.tetlet.2020.152334

A facile approach to prepare 12-aryl 5,7-dihydropyrido[2,3-b:6,5-b']diindoles via tandem cyclizations is described. FeCl₃ is used as the catalyst for the reaction between o-aminophenylacetonitriles and aromatic aldehydes, generating 5,7-dihydropyrido[2,3-b:6,5-b']diindoles derivatives in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2020.152334

Journal Pre-proofs
FeCl3-catalyzed sequential cyclization for the construction of 12-aryl 5,7-di‐
hydropyrido[2,3-b:6,5-b']diindoles
Xiaoqian Chen, Lin Li, Changfeng Wan, Jin-Biao Liu
PII:
S0040-4039(20)30807-8
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152334
TETL 152334
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 June 2020
27 July 2020
3 August 2020
Please cite this article as: Chen, X., Li, L., Wan, C., Liu, J-B., FeCl3-catalyzed sequential cyclization for the
construction of 12-aryl 5,7-dihydropyrido[2,3-b:6,5-b']diindoles, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.152334
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1
Tetrahedron Letters
FeCl3-catalyzed sequential cyclization for the construction of 12-aryl 5,7-
dihydropyrido[2,3-b:6,5-b']diindoles
Xiaoqian Chen a, Lin Li a, Changfeng Wan*a and Jin-Biao Liu*b
aCollege of Chemistry and Chemical Engineering and Key Laboratory of Functional Small Organic Molecule, Ministry of Education, Jiangxi Normal
University, Nanchang 330022, China. E-mail: wanfeng@jxnu.edu.cn
bFaculty of Materials Metallurgy and Chemistry, Jiangxi University of Science and technology, Ganzhou 341000, China. E-mail: liujinbiao@jxust.edu.cn.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile approach to prepare 12-aryl 5,7-dihydropyrido[2,3-b:6,5-b']diindoles via tandem
cyclizations is described. FeCl3 is used as the catalyst for the reaction between o-
aminophenylacetonitriles and aromatic aldehydes, generating 5,7-dihydropyrido[2,3-b:6,5-
b']diindoles derivatives in moderate to high yields.
Available online
Keywords:
FeCl3
Tandem cyclizations
Aminophenylacetonitrile
Aromatic aldehyde
5,7-Dihydropyrido[2,3-b:6,5-b']diindole
α-carboline represents a core scaffold that occur in a number of
natural products, some of which exhibit a wide range of
biological and pharmacological activities, such as high
cytotoxicity, anticancer properties and CNS activities.[1] For
example, grossularine-1 and grossularine-2 marine alkaloids
isolated from Dendrodoa grossularia, possess high
cytotoxicityagainst solid human tumour cell lines.[2] Similarly,
N,N-didesmethylgrossularine-1 from Indonesian ascidian
Polycarpa aurata exhibits inhibitory activity against tumour
necrosis factor (TNF-a) production.[3] Furthermore, mescengricin
reaction of triazoles,[7] intramolecular hetero Diels-Alder
cycloaddition-aromatization,[8]
transition metal-catalyzed
coupling-cyclization,[9] as well as annulation of pyridine ring to
indole derivative,[10] have been reported. Notably, Langer et al.
developed an efficient two-step procedure for the preparation of
5,7-disubstituted 5,7-dihydro-pyrido[2,3-b:6,5-b’]diindoles, via a
double Suzuki cross-coupling reaction followed by a fourfold
Buchwald-Hartwig amination reaction (Scheme 1a).[11] The
electrochemical and photochemical properties of 5,7-dihydro-
pyrido[2,3-b:6,5-b’]diindoles were investigated in their work.
However, methodologies previously reported conditions required
the synthesis to include noble metal catalysts, strong acidic
conditions, multi-steps and/or specific oxidants.
from
a culture of Streptomyces griseoflavus has shown
significantly prevent L-glutamate toxicity (Figure 1).[4] Besides
medical applications, carboline derivatives have been used as
electronic transport units in host materials, bacause of their
promising electronical and photophysical properties.[5]
In the past few years, the employ of iron salts as the catalyst
or promoter in synthetic chemistry has sparked tremendous
interest in the scientific community.[12] Owning to iron salts’ low
price, non-toxicity and environmentally benign character, iron
salts show great advantages in terms of sustainable chemistry and
represent an attractive alternative to other noble metals.[13] Our
previous work has been focused on heterocyclic synthesis and
cascade reaction.[14] Recently, we developed two facile protocols
for the synthesis of α-carbolines via FeCl3-promoted tandem
cyclization process.[15] Herein, we report a novel FeCl3-catalyzed
synthetic method to 12-aryl 5,7-dihydropyrido[2,3-b:6,5-
b']diindoles via the reaction between o-aminophenylacetonitrile
and aromatic aldehydes (Scheme 1b). In the presence of FeCl3,
three heterocyclic rings can be formed through a sequential
cycloaddition-Friedel-Crafts-alkylation-condensation-
Figure 1. Biological active molecules containing α-carboline
structure.
Owning to the α-carbolines’ marked biological and
photoelectrical activities, much effort has been devoted to the
synthesis of the privileged α-carboline scaffold.[6] Recently, a
series of useful methods including modified Graebe−Ullman
dehydrogenation process at once.

2
11
12
13
14
15c
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
PhCl
110
110
110
110
110
68
55
39
43
77
1,4-dioxane
DMF
DMSO
toluene
aReaction conditions: 1a (0.5 mmol), 2a (0.2 mmol), catalyst (10 mol%),
b
c
solvent (1 mL), 110 °C under air, 4 h. Isolated yields of 3a. Catalyst (20
Scheme 1 (a) Synthesis of 5,7-disubstituted 5,7-dihydro-pyrido[2,3-b:6,5-
b’]diindoles via the Pd-catalyzed two-step couplings; (b) FeCl3-catalyzed
synthesis of 12-aryl 5,7-dihydropyrido[2,3-b:6,5-b']diindoles discussed in
this work.
mol%).
With the optimized conditions in hand (see entry 2 in Table 1),
the substrate scope for the reactions of o-aminophenylacetonitrile
1a with various ArCHO 2 was then studied (Table 2). As for the
ArCHO 2, when the phenyl containing p-, m-, or o-Me
substituent, the reaction proceeded smoothly, producing the 12-
aryl 5,7-dihydropyrido[2,3-b:6,5-b']diindoles 3b-d in 68-83%
yields under standard conditions. ArCHO with tertiary butyl
group could also take part in the reaction (3e), but strong
electron-donating groups (MeO or Me2N) resulted in lower
yields (65% of 3f and 41% of 3g).
Initially, we applied Fe(OTf)3 as the catalyst to the model
reaction of 2-(2-(methylamino)phenyl)aceto-nitrile 1a with
benzaldehyde 2a. To our delight, the desired product 12-phenyl
5,7-dihydropyrido[2,3-b:6,5-b']diindoles 3a was obtained in 72%
yield after 4 h at 110°C (Table 1, entry 1). This reaction
underwent tandem cycloaddition-Friedel-Crafts alkylation-
condensation-dehydrogenation process. Encouraged by the result,
other iron/copper salts were investigated, such as FeCl3,
FeCl3·6H2O, Cu(OTf)2 and Cu(OAc)2·2H2O (Table 1, entries 2-
5). It could be found that FeCl3 was the best choice, giving rise to
the product 3a in 78% yield (Table 1, entry 2). Bronsted acid
(TfOH) was also tried, but only 31% yield was obtained (Table 1,
entry 6). Lowered temperatures result in a dramatic drop in yield
(Table 1, entries 7 and 8). No product was observed in the
absence of any iron salts (Table 1, entry 9). The result indicates
that iron salts play an important role in the tandem cyclizations
procedures. Subsequently, the effect of solvents in this
transformation was evaluated [ClCH2CH2Cl, PhCl, 1,4-dioxane,
DMF and DMSO] (Table 1, entries 10-14). The result revealed
that toluene was the most suitable solvent. When the amount of
FeCl3 was inhanced to 20 mol%, 3a was isolated in a comparable
yield (Table 1, entry 15, 77%).
Table 2 The reaction of o-aminophenylacetonitrile 1 with
ArCHO 2.a,b
Table 1 Optimization of reaction conditions.a
T/°C
yieldb
[%]
entry
catalyst
solvent
1
Fe(OTf)3
FeCl3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
ClCH2CH2Cl
110
110
110
110
110
110
60
72
78
52
54
24
31
23
0
2
3
FeCl3·6H2O
Cu(OTf)2
Cu(OAc)2·2H2O
TfOH
aReaction conditions: 1a (0.5 mmol), 2 (0.2 mmol), FeCl3 (10 mol%), toluene
(1 mL), 110 °C under air, 4 h. bIsolated yields of 3.
4
5
The strong electron-withdrawing group CN on the benzene
ring was also tolerant, and the corresponding product 3h was
obtained in 71% yield. Other halogenated ArCHO could also
participated in the reaction, forming the products 3i-o in good
yields. Heteroaryl aldehyde were also tolerant in this reaction
and showed 59% yields (3p). Then we investigated the effect of
the substituent groups on the NH2 of 1. Methyl- and ethylamino
substituted 1 could also take part in the cyclizations, forming the
6
7
Fe(OTf)3
FeCl3
8
rt
9
-
110
110
0
10
FeCl3
63
products
3q-y
in
good
yields.
When
2-(2-

3
aminophenyl)acetonitriles 1 contained Br atom, the reaction went
soomthly to give 3z in 75% yield. However, when alkyl aldehyde
(heptaldehyde or cyclohexanecarbaldehyde) was used as the
substrate, no desired product was obtained.
2a). Furthermore, when indol-2-amine hydrochloride was treated
with base, and then added into the reaction under the standard
conditions, 52% yield of 3q was observed as well (Scheme 2b).
This result probably indicated that indol-2-amine A would be the
key intermediate for this tandem process.
Moreover, to expand the practicality of this synthesis method,
a gram-scale reaction of 1a (25 mmol) and 2b (10 mmol) was
carried out, and the desired product 3b was obtained in 61%
yield (2.12 gram).
To explore photophysical properties of synthesized
compounds, we performed UV-Vis absorption and fluorescence
measurements of selected compounds 3g, 3h, 3i, 3t and 3x. The
UV-Vis absorption spectra show absorption bands with maxima
around 300 nm and 370 nm exhibiting analogous fine structures
(Figure 2). As for the fluorescence emission spectra, the
fluorescence intensity of N-Me substituted products (3t and 3x)
was distinctly lower than N-H products (3g, 3h and 3i) (Figure 3).
It could be attributed to the resonance of the fused ring structure,
which was suppressed by the N-Me group.
Scheme 2 Control experiments.
Furthermore, it was found that Schiff base was generated in
the reaction process by TLC, which could gradually release
aldehyde. Based on the result and other works,[15b,16] a plausible
reaction pathway is proposed in Figure 4. Firstly, 1a generated
intermediate A through intramolecular cyclization under the
catalysis of iron salt. Intermediate A rapidly reacted with 2a to
form intermediate B by activation of FeCl3. Then intermediate C
was generated through tautomerization, which underwent Fridel-
Crafts reaction producing intermediate D. Subsequently, an
intramolecular nucleophilic addition process occured to give
intermediate E. Because of the instability of E, the release of a
molecule of NH3 from E generated F. Finally, the target product
3a was formed via an aromatization process.
Figure 2. UV-Vis absorption spectra of 3g, 3h, 3i, 3t and 3x (10
μM in MeOH).
Figure 4. Proposed reaction pathway to 12-aryl 5,7-dihydropyrido[2,3-b:6,5-
b']diindoles.
In summary, we herein reported a novel method for the
synthesis of 12-aryl 5,7-dihydropyrido[2,3-b:6,5-b']diindoles
through
condensation-dehydrogenation reaction. In the presence of cheap
FeCl3, variety of multisubstituted 12-aryl 5,7-
tandem cycloaddition-Friedel-Crafts
alkylation-
Figure 3. fluorescence emission spectra (λex = 360 nm) of 3g, 3h,
3i, 3t and 3x (1 μM in MeOH).
a
dihydropyrido[2,3-b:6,5-b']diindoles were obtained in moderate
to high yields. The synthetic method developed here represents a
practical strategy to construct five-ring fused heterocyclic
scaffold.
To gain insight into the mechanism, two control experiments
were carried out. As described in Scheme 3a, when only 1q was
carried out in the standard conditions, the result was complicated.
But indol-2-amine A could be determined by GC-MS (Scheme
Acknowledgements

4
This work was supported by the Natural Science Foundation of
China (Nos. 21402068, 21961014 and 21762018), the Natural
Science Foundation of Jiangxi Province (No. 20192BCBL23009).
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carbolines and alpha-carbolines, Tetrahedron, 2010, 66, 1827-
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/
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Highlights
 Three heterocyclic rings can be
formed through a sequential
cycloadditions.
 A facile approach to prepare 12-
aryl 5,7-dihydropyrido[2,3-b:6,5-
b']diindoles.
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construction of 12-aryl 5,7-dihydropyrido[2,3-b:6,5-
b']diindoles
Xiaoqian Chen , Lin Li , Changfeng Wan and Jin–Biao Liu