Synthesis of 1H-Pyrrolo[1,2-a]indoles via Lewis Acid-Catalyzed Annulation of Propargylic Alcohols with 2-Ethynylanilines

Article abstract of DOI:10.1002/adsc.201901409

A novel highly efficient, environmentally benign Lewis acid-catalyzed, and protection-free protocol for the construction of valuable polycyclic products bearing a 1H-pyrrolo[1,2-a]indole scaffold is described, starting from readily available propargylic alcohols and 2-ethynylanilines. The one-pot transformation entails the cleavage of one C?O bond, and the construction of two C?N bonds and one C?C double bond. This unique operationally simple method is performed under mild conditions and in air, producing water as the only byproduct; it is scalable and demonstrates good functional group compatibility and broad scope.

Full text of DOI:10.1002/adsc.201901409

Title: Synthesis of 1H-pyrrolo[1,2-a]indoles via Lewis Acid-Catalyzed
Annulation of Propargylic Alcohols with 2-Ethynylanilines
Authors: Li-Juan Du, Ya-Ping Han, Hong-Yu Zhang, yuecheng Zhang,
Jiquan Zhao, and Yong-Min Liang
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
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the VoR from the journal website shown below when it is published
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901409
Link to VoR: http://dx.doi.org/10.1002/adsc.201901409

10.1002/adsc.201901409
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201
Synthesis of 1H-Pyrrolo[1,2-a]indoles via Lewis Acid-Catalyzed
Annulation of Propargylic Alcohols with 2-Ethynylanilines
Li-Juan Du,a Ya-Ping Han,a* Hong-Yu Zhang,a Yuecheng Zhang,a* Jiquan Zhao,a and
Yong-Min Liangb
a
School of Chemical Engineering and Technology, Hebei University of Technology, Tianjin 300130, P. R. of China.
E-mail: 2019070@hebut.edu.cn, yczhang@hebut.edu.cn
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
b
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
well as halogenation reagents, have provided a
versatile and powerful tool for the construction of a
broad variety of highly functionalized complex
carbocyclic and heterocyclic scaffolds. These types of
motifs are valuable starting points and are abundant
in biologically active natural products and functional
materials.[5]
Abstract. A novel highly efficient, environmentally benign
Lewis acid-catalyzed, and protection-free protocol for the
construction of valuable polycyclic products bearing a 1H-
pyrrolo[1,2-a]indole scaffold is described, starting from
readily available
propargylic
alcohols and 2-
ethynylanilines. The one-pot transformation entails the
cleavage of one C-O bond, and the construction of two C-N
bonds and one C-C double bond. This unique operationally
simple method is performed under mild conditions and in
air, producing water as the only byproduct; it is scalable
and demonstrates good functional group compatibility and
broad scope.
Polycyclic indoles represent an important class of
fused heterocycles, and are the core structural motifs
of a wide array of agrochemicals and pharmaceuticals.
Among them, 1H-pyrrolo[1,2-a]indoles are of great
interest in organic synthesis and medicinal chemistry
due
pharmacological activities, such as antitumor,
antimalarial, antiviral, and anti-implantation
to
their
significant
biological
and
Keywords: 1H-pyrrolo[1,2-a]indole derivatives; Lewis
acid-catalyzed; propargylic alcohols; 2-ethynylanilines;
nucleophilic addition
activities.[6] For example, a novel alkaloid isatisine A,
isolated from the leaves of Isatis indigotica Fort, used
in traditional Chinese medicine, exhibits inhibitory
activities against viral diseases including viral
pneumonia, influenza, and hepatitis.[7] Mitomycin C,
belonging to the family of antitumor antibiotics
isolated from Streptomyces caespitosus was identified
as a clinical agent for the treatment of a series of solid
A major challenge in modern organic synthetic
chemistry is the development of synthetically useful
methods for the strategically efficient and selective
assembly of complex heterocycles, carbocycles and
condensed molecular structures from readily
accessible starting materials.[1-2] Tandem reaction
processes incorporating multistep reactions into a
single one pot procedure provide elegant routes to
complex carbon or hetero frameworks from relatively
simple precursors, thus highlighting the fundamental
demands of an “ideal synthesis”.[3] Over the past few
decades, significant research efforts have been
devoted to developing organic synthetic methodology
focused on environmentally benign, atom-economical,
operational simplicity pathways, taking into account
the purpose of “green environmental protection and
sustainability”. Propargyl alcohols and their
derivatives, bearing alkynyl and hydroxyl (ester)
functional groups, have become increasingly
important starting materials and have been
extensively used as building blocks for the synthesis
of functional materials, pharmaceuticals, and
bioactive compounds.[4] In particular, cascade
annulations of propargyl alcohols and their
derivatives catalyzed by Lewis and Brønsted acids, as
tumors.[8] 5-Hydroxytryptamine, as
a
critical
neurotransmitter, participates in a broad variety of
motor, sensory, and behavioral processes.[9]
Figure 1. Selected examples bearing the 1H-pyrrolo[1,2-
a]indole scaffold
1
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10.1002/adsc.201901409
Advanced Synthesis & Catalysis
Scheme 1. Summary of the previous and current studies
towards the 1H-pyrrolo[1,2-a]indole scaffold
Table 1. Optimization of the Reaction Conditions of 1a
with 2-Ethynylanilinea, b
temp
(°C)
yield
(%)b
entry catalyst (mol %)
solvent
t (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Zn(OTf)2 (20)
Al(OTf)3 (20)
Y(OTf)3 (20)
AgOTf (20)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
40
40
40
40
40
40
50
60
70
80
80
80
80
80
80
80
80
80
4
4
4
4
4
4
4
4
4
4
6
8
10
6
6
6
6
6
52%
54%
19%
61%
14%
64%
69%
70%
73%
81%
87%
83%
80%
81%
72%
11%
trace
trace
Yb(OTf)3 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (15)
Cu(OTf)2 (10)
Cu(OTf)2 (15)
Cu(OTf)2 (15)
Cu(OTf)2 (15)
Flinderole C containing a unique rearranged skeleton
isolated from the Papua New Guinean plant F.
amboinensis is one of the most selective and effective
known inhibitors against malaria.[10] Yuremamine, an
alkaloid isolated from the stem bark of Mimosa
hostilis, was identified as having the ability to treat
burns and other skin afflictions, and has
hallucinogenic and psychoactive effects.[11]
CH3CN
toluene
1,4-
Due to the critical importance and ubiquity of this
framework in organic and medicinal chemistry, the
development of facile and efficient tandem
procedures and alternative methods to access the 1H-
pyrrolo[1,2-a]indole structural motif from easily
prepared starting materials is particularly desirable.[12]
In 2012, the Shi group reported a magnesium-
catalyzed cascade reaction of aniline-tethered
alkylidenecyclopropanes and aldehydes for the
construction of functionalized pyrrolo[1,2-a]indoles
19
Cu(OTf)2 (15)
80
6
trace
dioxane
a
Unless otherwise noted, all reactions were performed
with 1a (0.1 mmol) and 2-ethynylaniline 2a (2.0 equiv) in
solvent (2.0 mL). b Yields are given for isolated products.
analysis and NMR spectroscopy (see the Supporting
Information)[15]. Among the various Lewis acid
catalysts evaluated for this transformation, Cu(OTf)2
exhibited superior catalytic activity, increasing the
product yield to 64% (entries 2-6). A subsequent
adjustment in the reaction temperature revealed that
the reaction attained its highest catalytic activity for
the production of 3a at 80 °C (entries 7-10). The yield
was further improved to 87% by prolonging the
reaction time to 6 h (entry 11). Moreover, lowering
the catalyst loading to 15 mol % led to a slightly
diminished yield. (entries 14-15). A brief evaluation
of several representative solvents, such as THF,
CH3CN, toluene, and 1,4-dioxane indicated that DCE
was the optimal solvent. Ultimately, the optimal
reaction conditions were determined to be: alkynol
substrate 1a (0.1 mmol) and 2-ethynylaniline 2a (2.0
equiv), in the presence of Cu(OTf)2 (15 mol %) in
DCE (2.0 mL) at 80 °C for 6 h under an air
atmosphere.
(Scheme 1a).[13] Recently,
a
facile copper(II)
trifluoromethanesulfonate-catalyzed Friedel−Crafts
alkylation/annulation cascade reaction for the
synthesis of diverse 9H-pyrrolo[1,2-a]indoles,
employing substituted indoles and 1,2-dicarbonyl-3-
enes as the substrates, has been developed by the
Chen group (Scheme 1b).[14] These intriguing
discoveries have stimulated our interest in exploring
new synthetic strategies for accessing these
compounds. Herein, we report an unprecedented
copper(II)
trifluoromethanesulfonate-catalyzed
cascade cyclization of propargylic alcohols and 2-
ethynylanilines as a facile, highly efficient, and atom-
economical synthesis of 1H-pyrrolo[1,2-a]indole
derivatives under mild conditions.
The initial conditions entailed propargylic alcohol
1a (0.1 mmol) as the model substrate reacting with 2-
ethynylaniline 2a (0.2 mmol) in the presence of
commonly used Zn(OTf)2 (20 mol %) in DCE at
40 °C for 4 h under an air atmosphere (Table 1, entry
1). Gratifyingly, the desired product 3a was detected
and obtained in 52% yield, and its molecular structure
was explicitly established by X-ray crystallographic
With the optimal conditions in hand, the scope of
the propargylic alcohols was evaluated next and the
results are depicted in Scheme 2. A wide variety of
aryl(hetero)-substituted propargyl alcohols bearing
electron-rich or electron-deficient substituents
coupled smoothly with 2-ethynylaniline 2a,
2
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10.1002/adsc.201901409
Advanced Synthesis & Catalysis
Scheme 2. Transformation of Propargylic Alcohols to 1H-
pyrrolo[1,2-a]indoles a, b
Alkynol substrates containing substituents of varying
electron-donating (OMe, Me, Et, and 3,5-diMe;
3a−3i), electron-withdrawing character (Ph, COOMe;
3m−3n), and halogen substituents (F, Cl, and Br;
3j−3l), attached at any position of the aromatic ring
(R), were compatible with this transformation and
generated corresponding products 3a−3n in yields
ranging from 24% to 91%. Generally, substrates with
electron-rich substituents were more favorable than
those containing electron-deficient groups. In
addition, halo-substituted 1H-pyrrolo[1,2-a]indole
derivatives could be used as handles for further cross-
coupling reactions. Thienyl-substituted propargylic
alcohol 1q was amenable to this transformation and
gave the corresponding product 3q in 41% yield.
Symmetrical propargylic alcohols functionalized with
electron-donating (Me, 3s−3t) and electron-
withdrawing substituents (Cl, 3u) were all suitable
substrates, generating the corresponding products in
moderate to excellent yields. Furthermore, this
transformation was applicable to a range of
unsymmetrical alkynol substrates bearing electron-
rich and electron-deficient substituents (3w−3ac).
However, substrates containing electron-withdrawing
moieties, such as nitro and cyano groups, as well as
the alkyl substituent n-propyl, did not undergo the
cascade annulation reaction under the standard
conditions.
Subsequently, we conducted analogous batch
reactions with respect to 2-ethynylanilines under the
optimized conditions (Scheme 3). Various 2-
ethynylaniline substrates 2ad–2aj, bearing a range of
halogen and alkyl groups on the aromatic ring moiety
(R), were suitable for this cyclization reaction,
delivering 1H-pyrrolo[1,2-a]indoles 3ad–3aj in
moderate to good yields. 4-Substituted 2-
ethynylaniline substrates bearing either electron-
Scheme 3. Transformation of Propargylic Alcohols to 1H-
pyrrolo[1,2-a]indoles a, b
aUnless otherwise noted, all reactions were performed with
1 (0.1 mmol) and 2a (2.0 equiv) in the presence of
Cu(OTf)2 (15 mol %) in DCE (2.0 mL) at 80 °C for 6 h.
bYields are given for isolated products.
furnishing the polycyclic products in moderate to
good yields. Meanwhile, various substituent groups
could be incorporated in different positions of the
benzene ring (R), affording ortho-, meta-, and para-
substituted 1H-pyrrolo[1,2-a]indole derivatives.
aUnless otherwise noted, all reactions were performed with
1 (0.1 mmol) and 2 (2.0 equiv) in the presence of Cu(OTf)2
b
(15 mol %) in DCE (2.0 mL) at 80 °C for 6 h. Yields are
given for isolated products.
3
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10.1002/adsc.201901409
Advanced Synthesis & Catalysis
withdrawing or electron-donating groups, such as F,
Cl, Br, and methyl on the aromatic ring (R) were
found to be tolerated, giving the desired products
(3ad−3af, 3aj) in 31−51% yields. The reactions of 5-
substituted 2-ethynylanilines (5ag–5ai) with 1a
proceeded smoothly, furnishing moderate to good
yields of the corresponding cascade annulation
products. In general, 5-substituted 2-ethynylanilines
reacted smoothly to deliver the corresponding
products in good yields, displaying superior reactivity
compared to the 4-substituted 2-ethynylaniline
substrates.
intermediate B onto the terminal alkyne followed by
the release of a proton produces the intermediate C,
which could be further converted into intermediate D
by protonation. Intramolecular nucleophilic attack of
intermediate D to the carbocation site gives
intermediate E, which could produce intermediate F
by release of a proton. The desired product 3 is
afforded via a proton exchange process with the
regenerated catalyst.
Scheme 5. Proposed Mechanism for the Formation of 1H-
pyrrolo[1,2-a]indoles
To further showcase the synthetic compatibility of
our developed reaction system, a gram scale
experiment was performed under the standard
conditions for 14 h, and the corresponding cascade
annulation product 3a was isolated in 63% yield. The
result portrays the potentials of this transformation in
the synthetic industry.
To explore the transformation process of the
reaction, some necessary inhibition experiments were
carried out, the radical scavengers 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) and 2,6-di-
tert-butyl-4-methylphenol (BHT) were added into the
reactions (Scheme 4a, b). The desired products were
isolated in 11% and 78% yield, which excluded that a
radical process might be involved. When propargylic
alcohol 1a was used as the substrate to react with 1H-
indole 4 under the standard conditions, the expected
product 3a was not detected, and the reaction of 2-
ethynylaniline (2a) could not give corresponding
product 1H-indole 4 under the optimal conditions,
indicating that 1H-indole 4 was not a intermediate of
this transformation (Scheme 4c, d).
In summary, we have established a novel and
Scheme 4. Verification Experiments for the Mechanism
efficient
Lewis
acid-catalyzed
sequential
intermolecular nucleophilic addition and 5-endo-dig
carbocyclization of propargylic alcohols with 2-
ethynylanilines, thereby to afford the synthetically
valuable 1H-pyrrolo[1,2-a]indole derivatives in
moderate to excellent yields under mild reaction
conditions.
This
protocol
offers
versatile,
environmentally benign, and atom-economical
method of accessing the tricyclic structural motif,
featuring good functional group compatibility, readily
available starting materials, highly efficient catalytic
system, operational simplicity.
Experimental Section
General Procedure for the Synthesis of Compounds 3
The reactions of propargylic alcohols 1 (0.1 mmol), and
substituted 2-ethynylanilines 2 (2.0 equiv), Cu(OTf)2 (15
mol %) in DCE (2.0 mL) were conducted at 80 °C under
an air atmosphere for 6.0 h. The reactions were completed
by TLC monitoring. The resulting mixtures were cooled
down to room temperature. The mixtures were evaporated
under reduced pressure. The residues were further purified
by chromatography on silica gel (ethyl acetate/petroleum
ether 1:100) to afford the corresponding products 3.
Based on the above results and previous
literature[16-17], a tentative mechanism accounting for
this cascade annulation is depicted in Scheme 5. The
active propargyl intermediate A, which is formed in
situ from propargylic alcohol 1 in the presence of a
Lewis acid catalyst, would react with nucleophilic 2-
ethynylaniline to yield intermediate B. The
Scale-Up Experiment
subsequent
5-endo-dig
carbocyclization
of
4
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10.1002/adsc.201901409
Advanced Synthesis & Catalysis
The reaction of propargylic alcohols 1a (3.2 mmol), and 2-
ethynylaniline 2a (2.0 equiv), Cu(OTf)2 (15 mol %) in
DCE (10.0 mL) was conducted at 80 °C under an air
atmosphere for 14.0 h. The reaction was completed by
TLC monitoring. The resulting mixture was cooled down
to room temperature. The mixture was evaporated under
reduced pressure. The residue was further purified by
chromatography on silica gel (ethyl acetate/petroleum
ether 1:100) to afford the corresponding product 3a in 63%
yield (0.83 g).
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Acknowledgements
Acknowledgements Financial support was received from the
National Natural Science Foundation of China (Grant No.
21776056), the Natural Foundation of Hebei Province (CN)
(Grant No. B2018202253).
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10.1002/adsc.201901409
Advanced Synthesis & Catalysis
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10.1002/adsc.201901409
Advanced Synthesis & Catalysis
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