Efficient copper-catalyzed synthesis of C3-alkylated indoles from indoles and alcohols

Article abstract of DOI:10.1016/j.mcat.2021.111462

A highly efficient copper(II) catalyst system for alkylation of indoles with alcohols via hydrogen borrowing method has been developed to afford C3-alkylated indoles in good to excellent yields. Cu(OAc)₂ in the combination with dppm ligand has been found to be the most suitable catalyst system for this alkylation reaction.

Full text of DOI:10.1016/j.mcat.2021.111462

Molecular Catalysis 505 (2021) 111462
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.journals.elsevier.com/molecular-catalysis
Efficient copper-catalyzed synthesis of C3-alkylated indoles from indoles
and alcohols
Ngoc-Khanh Nguyena, Duong Ha Nama, Ban Van Phucc, Van Ha Nguyena,
,
,
Quang Thang Trịnhb, Tran Quang Hungc *, Tuan Thanh Danga *
a Faculty of Chemistry, VNU-Hanoi University of Science, 19 Le Thanh Tong, Hanoi, Viet Nam
b Institute of Research and Development, Duy Tan University, 03 Quang Trung, Danang 550000, Viet Nam
c Institute of Chemistry, Vietnamese Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Hanoi, Viet Nam
A R T I C L E I N F O
A B S T R A C T
Keywords:
A highly efficient copper(II) catalyst system for alkylation of indoles with alcohols via hydrogen borrowing
method has been developed to afford C3-alkylated indoles in good to excellent yields. Cu(OAc)2 in the combi-
nation with dppm ligand has been found to be the most suitable catalyst system for this alkylation reaction.
Alkylation of indole
Cu catalysis
Hydrogen borrowing
Indole functionalization
Sustainable process
1. Introduction
exploring future sustainable processes. Recently, hydrogen borrowing
methodology is an alternative approach to the classical alkylation pro-
The indole framework is one of most popular heterocycles found in
many important drugs, agrochemicals, advanced functional materials
and bioactive natural products [1]. Especially, the indole structure has
been identified as an important pharmacophore in medicinal chemistry
research with representation in over 3000 natural products and 40
medicinal agents [2,3]. The construction of indole structure from simple
building blocks based on the cyclization reactions in the absence or
presence of metal catalysts has been well established [4–6]. On the other
hand, the development of new synthetic methods for the direct func-
tionalization of indoles has gained much attention [7]. The most com-
mon method for the direct alkylation of indoles is the Friedel-Crafts
reaction using alkyl halides and Lewis acid catalysts [8]. However, this
approach gives some drawbacks relating to the use of stoichiometric
amounts of hazardous alkyl halides and Lewis acids, over alkylations,
and poor regioselectivity [8]. It also forms a large amount of salt wastes
which need to be treated after reaction. Recent advances in the devel-
cesses as non-toxic and easily available alcohols are used as alkylating
reagents and the sole by-product is water [13–15]. In term of green and
sustainable processes, this method provides the minimization of haz-
ardous wastes and the avoidance of using toxic and expensive alkyl
halides. Most popular catalysts for hydrogen borrowing processes are
relied on expensive metals such as Ru, Ir, Rh, etc [13–15]. In recent
years, these catalysts have been gradually replaced by earth-abundant
metals (Co, Mn, Fe, etc.) in the combination with well-designed multi-
dentate ligands [16,17].
Due to these significant reports in hydrogen borrowing method, the
direct transition metals-catalyzed alkylation reactions of indoles using
alcohols were disclosed. C3-alkylated indole has been commonly known
as the main product. The catalytic cycle for the formation of C3-
alkylated indole undergoes via three main steps: i) the dehydrogena-
tion of alcohol to form aldehyde and metal-hydride species in the
presence of metal catalyst, ii) the formation of alkylideneindolenine by
the reaction of indole with aldehyde, iii) the hydrogenation of alkyli-
deneindolenine intermediate by metal-hydride species to form desired
product and regenerate metal catalyst for the next catalytic cycle
(Scheme 1) [18–20]. In fact, C3-alkylated indole products could be
formed in high yield and selectivity in the use of several expensive
transition metal catalysts such as Pt [18], Pd [19,20], Ru [19,20] and Ir
¨
opment of new Bronsted acids and organocatalysts have provided
greener processes for the direct functionalization of indoles [9–12].
High catalyst loadings (up to 20 mol%) were often required to give
alkylated products in very good yields. Therefore, the development of
more efficient and green alkylation methods using non-hazardous and
less expensive starting materials would be highly beneficial for
* Corresponding authors.
E-mail addresses: tqhung@ich.vast.vn (T.Q. Hung), dangthanhtuan@hus.edu.vn (T.T. Dang).
https://doi.org/10.1016/j.mcat.2021.111462
Received 20 December 2020; Received in revised form 5 February 2021; Accepted 6 February 2021
Available online 3 March 2021
2468-8231/© 2021 Published by Elsevier B.V.

N.-K. Nguyen et al.
Molecular Catalysis 505 (2021) 111462
Scheme 1. Direct transition metal-catalyzed alkylation of indoles with alcohols via hydrogen borrowing method.
[21–25]. Interestingly, Piersanti et al. applied successfully Ir-catalyzed
alkylation of indoles with amino alcohols in the synthesis of bioactive
natural alkaloids such as Psilocin, Bufotenin, Serotonin and their de-
rivatives [26]. In the recent development of practical alkylation pro-
cesses of indoles with alcohols using base metals as catalysts, the first
iron(II)-phthalocyanine catalyzed alkylation of indoles with alcohols
was reported in moderate to very good yields [27]. One year later,
cyclopentadienone iron carbonyl complexes were found to be highly
efficient catalysts for the alkylation of indoles with a series of alcohols
[28,29]. In 2017, Liu et al. described a highly convenient Co-based
catalytic system by combination of Co(BF4)2.6H2O salt, a tetradentate
phosphine ligand P(CH2CH2PPh2)3, for the methylation of indole with
methanol [30]. To the best of our knowledge, until now, there are no
reports on Cu-catalyzed alkylation of indoles with alcohols via hydrogen
borrowing approach. Herein, we are reporting a highly efficient Cu
(OAc)2/dppm catalyst system for alkylation of indoles with alcohols via
hydrogen borrowing pathway to give C3-alkylated indoles in high
yields.
2. Experimental section
General information: Readily available chemicals and solvents were
used in this research without further purification. Products purification
was performed on silica gel by column chromatography, technical-grade
solvents were used. Reactions were put in magnetic stirrer and moni-
tored by thin layer chromatography using Merck Silica Gel 60 F254 TLC
Table 1
Optimization of the reaction conditions for the Cu-catalyzed alkylation of indole with benzyl alcohol.
Entry
Cu precursor (mol%)
Base (equiv.)
Ligand
Yield (%)a
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuBr2
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH(1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
NaOH (1.0)
KOt-Bu (1.0)
K3PO4 (1.0)
K2CO3 (1.0)
KOH (1.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
KOH (2.0)
none
PPh3
39
52
74
77
42
85
57
60
92
76
66
45
39
61
5
2
XPhos
Xantphos
dpePhos
dppf
3
4
5
6
BINAP
dppp
dppe
7
8
9
dppm
dppm
dppm
dppm
dppm
dppm
dppm
dppm
dppm
dppm
dppm
dppm
dppm
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CuCl2
CuCl
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
–
–
83b)
99
99c)
72d)
66e)
35c)
–
dppm
–
KOH (2.0)
–
Reaction conditions: Indole (0.5 mmol), benzyl alcohol (0.5 mL), Cu precursor (5 mol%), ligand (5 mol%), base (2 equiv.). Reaction was performed under argon; a)
Isolated yields; b) Using 1 mol% Cu(OAc)2, 1 mol% dppm; c) Reaction was completed in 6 h; d) Reaction was carried out in 6 h using 0.3 mL BnOH; e) Reaction was
carried out at 150 ◦C in 6 h.
2

N.-K. Nguyen et al.
Molecular Catalysis 505 (2021) 111462
Table 2
Scope of Cu-catalyzed alkylation of indoles using alcoholsa).
plates. NMR spectra of products were measured in the CDCl3 solvent
using a cryoprob on a Bruker Avance 500 (500 MHz, 1H NMR; 126 MHz,
13C NMR). Chemical shifts (δ) are given in parts per million (ppm) in the
comparison to tetramethylsilane (TMS) for 1H and 13C NMR spectra and
also calibrated using the solvent residual peak. Multiplicities of spectra
using MNova software are reported as following: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad signal or as a
combination of them. Coupling constants (J) are reported in Hertz (Hz).
General procedure for the synthesis of compounds 1¡18: A mixture
of indole (0.5 mmol, 58.6 mg), Cu(OAc)2 (4.54 mg, 5 mol%), dppm (9.6
mg, 5 mol%), KOH (56 mg, 2 equiv.) and benzyl alcohol (0.5 mL, about 5
mmol) were charged in a pressure tube under argon. The pressure tube
was immersed in a pre-heated oil bath at 160 ◦C and stirred for 12 h.
After cooling, the reaction mixture was filtered over a plug of Celite with
hot water to eliminate the benzaldehyde and the excess of benzyl
alcohol. Ethyl acetate was added into the organic phase and this mixture
was dried by sodium sulfate (Na2SO4). The concentrated residue was
purified by column chromatography (Hexane/ethyl acetate).
phosphine ligand could catalyze the formation of C3-alkylated indole at
160 ◦C under argon. Our initial screenings using a catalytic amount of
Cu(OAc)2 (5 mol%) and a monodentate ligand (such as PPh3, Xphos) in
the presence of KOH base only gave the desired product in moderate
yields, as presented in Table 1 (entries 1,2). Interestingly, under this
condition, the yield was improved to 74 % in the employment of Xant-
phos, a bidentate ligand at 160 ◦C (Table 1, entry 3). Based on this good
result, we would continue to examine a series of bidentate ligands
(dpePhos, dppf, BINAP). In these reactions, the combination of Cu
(OAc)2 and BINAP ligand seemed to be a promising catalyst system
which gave 85 % isolated yield of desired product (entry 6). In order to
find the most suitable ligand for this reaction, other bidentate ligands
such as dppp, dppe, dppm were also examined. Up to 92 % isolated yield
of alkylated indole was achieved when the dppm ligand was employed
(entry 9). Further examinations using common copper catalyst pre-
cursors (CuBr2, CuCl2 and CuI; entries 10–12) resulted in inferior results
compared to that of Cu(OAc)2 and this condition was selected as the
catalyst precursor for further investigations using different bases.
Several other bases such as NaOH, KOt-Bu, K3PO4, K2CO3 did not pro-
vide a better yield than our optimized experiment using KOH base
(entries 13–16). Interestingly, when the catalyst loading was reduced to
1 mol%, we still obtained 83 % yield of desired product (entry 17). We
continued with further optimization by increasing KOH amount to 2
equiv., quantitative yield of alkylated product was achieved under
3. Results and discussion
Our first optimization studies for the alkylation of indole using
benzyl alcohol as alkylating reagent showed that homogeneous copper
catalysts obtained in situ from copper salts in the combination with a
3

N.-K. Nguyen et al.
Molecular Catalysis 505 (2021) 111462
Scheme 2. Control experiment.
indoles with benzyl alcohol via hydrogen borrowing strategy giving the
corresponding products. In fact, the alkylation of 5-methoxyindole using
benzyl alcohol gave desired product in 84 % yield (compound 13).
Fluorinated indoles could also be used as starting materials resulted in
87 % and 40 % yields, respectively (compounds 14, 15). The alkylation
of 6-bromoindole and 7-methylindole with benzyl alcohol afforded to
corresponding products in 85 % and 95 % isolated yields, respectively
(compound 16, 17). Unfortunately, when N-methylindole was used in
the alkylation with benzyl alcohol, no trace amount of desired product
was observed under standard condition. From this result, we believe that
the N-methylated benzylideneindolenine intermediate was unable to
form during the course of reaction using N-methylindole.
In order to understand about the hydrogen borrowing mechanism of
this alkylation, we decided to choose a reaction mixture of indole,
benzaldehyde and 3-methylbenzyl alcohol under standard condition
(Scheme 2). After 12 h reaction, we isolated hydrogen transferred
product 1 in 55 % yield, alkylated product 2 in 20 % yield and small
amount of 3-methylbenzaldehyde 2a (32 % yield). It means that Cu-H
species could be formed and then reduced 3-benzylidene-3H-indole in-
termediates to form both products 1, 2 (see a proposed catalytic cycle in
Scheme 3). From this interesting result, we could confirm the true
hydrogen borrowing mechanism which occurred in our copper catalyst
system.
Scheme 3. Plausible catalytic cycle for the alkylation of indoles with alcohols
via hydrogen borrowing pathway.
A plausible mechanism is proposed in Scheme 3 relying on our re-
sults (Table 1, Scheme 2) and previous research on copper catalyzed
reactions. First, the insitu-formed copper complex I could react with
potassium alkoxide to give copper alkoxide (intermediate II) which
subsequently generate copper hydride complex (intermediate III) and an
aldehyde. Then, in the presence of KOH, this aldehyde reacted with
indole molecule to form 3-benzylidene-3H-indole which easily coordi-
nate to copper hydride (III) to afford intermediate IV. Next, the hydride
transfer step from copper hydride to indole ring occurred to give inter-
mediate V which further reacted with potassium alkoxide to form the
alkylated product and regenerate copper alkoxide (intermediate II) for
the next catalytic cycle. Actually, a bidentate ligand (such as dppm)
played a crucial role by stabilizing copper intermediates.
optimized condition. In fact, the alkylation reaction was completed and
gave 99 % yield of product after only 6 h reaction (entry 19). Then we
reduced reaction temperature to 150 ◦C under optimized condition, the
yield dropped to 66 % (entry 21). When we reduced the amount of BnOH
(using 0.3 mL), we obtained lower product yield (72 %) (entry 20). This
issue could be explained by when performing reaction at high temper-
ature (160 ◦C), BnOH (as solvent) slowly evaporated and condensed on
the wall of pressure tube and we realized that an excess amount of BnOH
is required to provide enough Cu-H active species to completely reduce
benzylideneindolenine intermediate to product. Then, we are interested
in investigating the true role of catalyst and base, several control ex-
periments were carried out. Notably, without the attention of Cu cata-
lyst, only trace amount of product was observed in the presence of base
(entry 24). We also realized that base played an important role in this
reaction, in fact, this alkylation reaction did not run in the absence of
base (entry 23).
4. Conclusion
Herein, we have disclosed a practical and highly efficient homoge-
neous Cu(OAc)2/dppm catalyst system for the direct alkylation of in-
doles using alcohols. The chemoselective C3-monoalkylation of indoles
with alcohols (including challenging aliphatic alcohols) was achieved in
good to excellent yields. This practical procedure using simple copper
catalyst system could be useful for preparing complex indoles containing
various functional groups and exploring potential applications in me-
dicinal chemistry and fine chemical industry. Further experimental
studies in the combination with DFT calculation to understand mecha-
nistic insights are currently carried out in our group.
Next, we opened the substrate scope of this Cu-catalyzed alkylation
of indoles with different alcohols. For this purpose, reactions were car-
ried out at 160 ◦C for 12 h compared to the optimized condition (Table 1,
entry 19) to ensure complete conversion even when less reactive
aliphatic alcohols were used. In general, the alkylation of indoles with
benzylic alcohol derivatives were examined which gave moderate to
excellent yields (Table 2). In case of alkylation reaction using fluori-
nated and trifluoromethylated benzyl alcohols, moderate yields of
desired products were obtained (compounds 7-9). Notably, more chal-
lenging aliphatic alcohols could be used as alkylating reagents in the
reaction of indole which afforded to good yields of alkylated products in
24 h (compounds 10-12). Interestingly, the alkylation of substituted
Reaction conditions: a) Indole (0.5 mmol), benzyl alcohol (0.5 mL), Cu
(OAc)2 (5 mol%), dppm ligand (5 mol%), base (2.0 equiv.). Reactions
were carried out under argon; b) Reactions were prolonged to 24 h.
4

N.-K. Nguyen et al.
Molecular Catalysis 505 (2021) 111462
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Declaration of Competing Interest
The authors declare no conflict of interest.
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