Facile access to bis(indolyl)methanes by copper-catalysed alkylation of indoles using alcohols under air

Article abstract of DOI:10.1016/j.tetlet.2021.152936

Bis(3-indolyl)methanes (BIM) are important and present in the structure of many alkaloid and bioactive compounds (anti-inflammatory, anticancer, antiobesity, antimicrobial, etc.). Herein, we have reported an air stable and convenient Cu(OAc)₂ c

Full text of DOI:10.1016/j.tetlet.2021.152936

Tetrahedron Letters 68 (2021) 152936
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile access to bis(indolyl)methanes by copper-catalysed alkylation
of indoles using alcohols under air
Ngoc-Khanh Nguyen a, Duc Long Tran a, , Tran Quang Hung b,c, Tra My Le a, Nguyen Thi Son a,
⇑
Quang Thang Trinh d, Tuan Thanh Dang a, , Peter Langer e,f,
⇑
⇑
a Faculty of Chemistry, Hanoi University of Science, Vietnam National University (VNU), Viet Nam
b Institute of Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Hanoi, Viet Nam
c Graduate University of Science and Technology, 18 Hoang Quoc Viet Street, Cau Giay District, Hanoi city, Viet Nam
d Institute of Research and Development, Duy Tan University, 03 Quang Trung, Danang 550000, Viet Nam
e Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
f Leibniz-Institute of Catalysis e. V. at the University of Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Bis(3-indolyl)methanes (BIM) are important and present in the structure of many alkaloid and bioactive
compounds (anti-inflammatory, anticancer, antiobesity, antimicrobial, etc.). Herein, we have reported an
air stable and convenient Cu(OAc)2 catalyst for alkylation of indoles with alcohols to give bis(3-indolyl)
methanes in very good yields.
Received 7 December 2020
Revised 1 February 2021
Accepted 11 February 2021
Available online 20 February 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Bis(3-indolyl)methane synthesis
Copper catalysis
Indole functionalization
Alkylation
Sustainable process
Introduction
containing several indole moieties, requires other synthetic
approaches [13,17–23]. Because of the importance of BIM deriva-
The indole structure is an important type of heterocycle present
in many drugs, agrochemicals, advanced materials and bioactive
natural products [1–22]. The indole moiety is an important phar-
macophore in medicinal chemistry and occurs in over 3000 natural
products and 40 drugs [2,3]. Notably, bis(3-indolyl)methanes
(BIMs) are an important subgroup of indoles, due to their presence
in the core structure of many pharmacologically important natural
products (arundine, arsindoline A, barakacin, vibrindole A, etc. [2–
22]. For example, arundine is known as a potential agent for the
treatment of breast cancer [4]. Vibrindole A was successfully used
in the treatment of irritable bowel syndrome, fibromyalgia and
chronic fatigue [5]. In addition, BIM derivatives have found many
applications in the exploration of new bioactive compounds (anti-
cancer, anti-inflammatory, antiobesity, antimetastatic, antimicro-
bial, etc.) (Fig. 1) [13–21].
tives in medicinal chemistry, the development of efficient path-
ways for their preparation has received much attention. Most
reports are based on the reaction of indoles with aldehydes or
ketones in the presence of Lewis or Bronsted acids [7–13]. As a
consequence of the growing demand for green and sustainable
processes, methods for the preparation of BIMs by direct transition
metal-catalysed coupling reactions of indoles with alcohols have
been described [24–30]. Grigg et al. reported the observation of
BIM as a side product during their research in the Ir-catalysed alky-
lation of indoles with alcohols [24]. In 2012, Liu et al. described the
preparation of BIM derivatives in good yields based on the Ru-
catalysed alkylation reaction of indoles with benzylic alcohols
[28]. One year later, the Ohta group demonstrated an efficient
Ru-catalysed alkylation of indole with benzyl alcohols (24 h at
110 °C) [27]. Very recently, in 2020, Srimani and coworkers
reported alkylation reactions of indoles with alcohols to afford
either C3-alkylated products or BIMs by tuning reaction conditions
[25]. In these reactions an acridine-derived ruthenium pincer com-
plex was employed as the catalyst. Hikawa and Yokoyama devel-
oped an interesting Pd-catalysed domino reaction for the
synthesis of BIMs involving C3–H benzylation of indoles and
Conventional syntheses of indole derivatives rely on the cycliza-
tion of simple building blocks in the absence or presence of metal
catalysts [7–16]. However, the formation of large molecules
⇑
Corresponding authors.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
https://doi.org/10.1016/j.tetlet.2021.152936
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Ngoc-Khanh Nguyen, Duc Long Tran, Tran Quang Hung et al.
Tetrahedron Letters 68 (2021) 152936
Table 2
Scope in the synthesis of bis(3-indolyl)phenylmethanes.
Fig. 1. Several natural alkaloids and pharmaceutically active compounds containing
BIM derivatives.
benzyl CAH functionalization in water [26]. In 2014, Sekar and
coworkers described a practical FeCl2/BINAM catalyst system in
the combination with dicumyl peroxide oxidant which could be
used for the preparation of BIMs in moderate yields [29]. Recently,
Ni nanoparticles, supported on ionic liquid-functionalized mag-
netic silica, were found to be an efficient catalyst for the synthesis
of BIMs under air [30]. In 2019, a convenient method for the prepa-
ration of BIMs by alkylation of indoles and alcohols using Fe3O4@-
SiO2@TPP-Cu as the photocatalyst under blue LED light irradiation
was reported [31]. In general, the methods for preparation of BIM
derivatives often require the use of expensive or well-designed cat-
alysts under harsh reaction conditions which makes it difficult to
find broad synthetic applications.
In order to develop a practical procedure for the preparation of
BIM derivatives, we were interested in exploring direct alkylations
of indoles using inexpensive alcohols as alkylating reagents and
simple metal salts as the catalyst. Herein, we report, for the first
time, a robust, ligand-free Cu-catalysed method for the convenient
synthesis of bis(3-indolyl)phenylmethane derivatives under air.
Results and discussion
In order to optimize the reaction, we chose indole and benzyl
alcohol as the key starting materials in the presence of several
Table 1
Optimization of the reaction conditions for the synthesis of bis(3-indolyl)
phenylmethane.
Reaction condition: Indole (0.3 mmol), benzyl alcohol (0.9 mmol), Cu(OAc)2 (5 mol
a)
%), base (1.0 equiv.); Reactions were carried out at 120 °C.
Entry
Catalyst (mol%)
Base (equiv.)
Yield (%)a)
copper catalysts. After screening several conditions using homoge-
neous copper catalysts in combination with several ligands at high
temperature (higher than 120 °C), we only obtained mixtures of
hydrogen transferred product and bis(3-indolyl)phenylmethane
(BIM). Interestingly, we observed that BIM could be often formed
in higher selectivity at lower temperature. After having carried
out several control experiments, we obtained promising yields of
BIM product using only Cu(OAc)2 as a single catalyst in the absence
of any ligand under air (Table 1). CuCl and CuCl2 catalysts were also
examined which, however, did not give better yields of BIM
1
2
3
4
5
6
7
8
9
CuCl (5)
CuCl2 (5)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOt-Bu (1.0)
LiOt-Bu (1.0)
LiOt-Bu (1.0)
–
32
45
67
40
96
87
–
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (5)
Cu(OAc)2 (1)
Cu(OAc)2 (5)
–
LiOt-Bu (1.0)
LiOt-Bu (1.0)
9
Cu(OAc)2 (5)
12b)
Reaction conditions: Indole (0.3 mmol), benzyl alcohol (0.9 mmol); a)Isolated yield.
reaction was carried out under argon atmosphere.
b)
2

Ngoc-Khanh Nguyen, Duc Long Tran, Tran Quang Hung et al.
Tetrahedron Letters 68 (2021) 152936
presence of base (LiOt-Bu), nucleophilic addition of another indole
molecule to 3-benzylidene-3H-indole takes place by a Michael-
type reaction to afford the final BIM product. Ramon et al. showed
by labelled experiments, that in the Cu-catalysed reaction of alco-
hols with amines hydrogen is transferred to the product [13].
Based on this result, we believe that intermediate A is converted
to copper hydride (intermediate B) which easily reacts with oxygen
to form a copper hydroperoxide complex (intermediate C). The for-
mation of copper hydride and copper hydroperoxide complexes as
intermediates was well studied in previous reports of related
transformations [32–36]. In the absence of any ligand, the solvent
(benzyl alcohol) can bind to the coordination free site of copper
intermediate C to give intermediate D which is further converted
to hydrogen peroxide to regenerate the copper alkoxide (interme-
diate A) for the next catalytic cycle.
Conclusion
Scheme 1. Proposed catalytic cycle for the formation of BIM products.
Herein, we have reported a practical, robust and efficient
method for the direct alkylation of indoles with alcohols under
air. The products, BIM derivatives, represent important core struc-
tures in natural products and medicinal chemistry and were iso-
lated in very good yields The reactions are based on the use of
inexpensive Cu(OAc)2 as homogeneous catalyst. The procedure is
advantageous in comparison with previous methods which need
to be carried out under inert gas atmosphere using expensive tran-
sition metal catalysts and ligands. Further experimental studies in
combination with DFT calculations to better understand the mech-
anism of this reaction are currently carried out in our group.
product. Indeed, in the presence of Cu(OAc)2 as catalyst (5 mol%),
we achieved 67% yield of BIM product at 100 °C. Subsequently,
we tried to improve the yield by changing the base. In fact, LiOt-
Bu was found to be the most suitable base in this transformation
which gave up to 96% yield of the desired product (Table 1, entry
5). Notably, up to 87% yield of product was obtained when a low
catalyst loading (1 mol%) was employed (Table 1, entry 6). In order
to gain some further insights in this transformation, additional
control experiments were carried out. Firstly, we only observed
trace amounts of product in the absence of base or catalyst (Table 1,
entry 7, 8). Then, the role of oxygen as a key oxidant could be con-
firmed when we performed this reaction under argon atmosphere.
In fact, the BIM product was only obtained in very low yield (12%)
after 24 h reaction time (Table 1, entry 9). Under this condition, C3-
alkylated indole was formed as a side product in 25% yield. Based
on this result, we believe that oxygen serves as essential oxidant
in this reaction.
Funding information
This research is funded by Vietnam National Foundation for
Science and Technology Development (NAFOSTED) under grant
number 104.01-2018.30.
Declaration of Competing Interest
With optimized conditions in hand, we further explored the
scope of this reaction using various alcohols (Table 2). Firstly, a ser-
ies of benzyl alcohols were used in the alkylation of indoles. A vari-
ety of BIM derivatives, with tolerance of both electron donating
and withdrawing groups, were prepared in good to excellent iso-
lated yields (Table 2). Indeed, the Cu(OAc)2-catalysed alkylation
reaction of indole with parent benzyl alcohol gave a better yield
than those of indole with other benzyl alcohol derivatives. It is
worth to be mentioned, that product 1 represents an antibiotic
and natural product named turbomycin B [7]. Subsequently, reac-
tions of substituted indole derivatives were studied which gave
very good yields of the corresponding BIMs (Table 2, compounds
1–15). Interestingly, when 5-methoxyindole was employed, up to
98% yield of BIM product was obtained (compound 12). The reac-
tion of 5-nitroindole, bearing to a strong electron withdrawing
group, resulted in lower yield of BIM product 15, due to lower
nucleophilicity of the indole. The reactions of indole with aliphatic
alcohols only gave desired BIM products in moderate yield under
100 °C. Therefore, we increased reaction temperature to 120 °C
which gave correstponding products 16, 17 in higher yields (92%
and 75%, respectively). Unfortunately, the alkylation of N-methyl
indole with benzyl alcohol did not give any trace of BIM product
18.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152936.
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