Rapid access to 3-acyl indoles using ethyl acetate/triflic acid couple as the acylium donor and Cu(OAc)2catalysed aerial oxidation of indole benzoins

Article abstract of DOI:10.1039/d0ob01977a

Esters are potential acyl donors but are relatively unexplored for that purpose. A facile installation of acyl groups at the C-3 position of indoles under triflic acid catalysed conditions with easily available and cheap esters as new acylating agents is described herein. Furthermore, heterocycles like N-protected pyrrole, furan and thiophene were also suitable substrates for similar C-2 acylation. Analogous C-3 benzoylated products of indole were obtained, albeit in lower yields, by using methyl benzoate as a benzoyl donor. The benzoylated products were synthesised in much better yields via a copper(ii) catalysed aerial oxidation of indole containing benzoins. This journal is

Full text of DOI:10.1039/d0ob01977a

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Rapid access to 3-acyl indoles using ethyl acetate/
triflic acid couple as the acylium donor and Cu
(OAc)2 catalysed aerial oxidation of indole
benzoins†‡
Cite this: DOI: 10.1039/d0ob01977a
Ranadeep Talukdar
Esters are potential acyl donors but are relatively unexplored for that purpose. A facile installation of acyl
groups at the C-3 position of indoles under triflic acid catalysed conditions with easily available and cheap
esters as new acylating agents is described herein. Furthermore, heterocycles like N-protected pyrrole,
furan and thiophene were also suitable substrates for similar C-2 acylation. Analogous C-3 benzoylated
products of indole were obtained, albeit in lower yields, by using methyl benzoate as a benzoyl donor.
The benzoylated products were synthesised in much better yields via a copper(II) catalysed aerial oxidation
of indole containing benzoins.
Received 27th September 2020,
Accepted 13th October 2020
DOI: 10.1039/d0ob01977a
rsc.li/obc
Esters are underused electrophiles in acylation reactions when use of cheap materials to synthesise those compounds under a
compared to other acylating agents, mostly following biocataly- metal-free strategy would be highly desirable.
tic routes.1,2 A reason for this is that the low reactivity of esters
In a recent report, the efficiency of ethyl acetate acting as
does not easily allow formation of the corresponding acylium an acyl donor under acidic conditions was investigated by
cation intermediates required for acylation of aromatic rings Williams.16 Additionally, the 3-acylation of indoles has already
under general acid-mediated reaction conditions (mimicking been studied using different yet related reagents like ketones,3a
A
Ac1) and thus, there is a requirement to cast new light on this acids,3d,17 anhydrides,18 acetyl chlorides3e,19 or amides.20
long and unsolved problem.
Transition metal catalysis with nitriles,21 α-oxocarboxylic
On the other hand, 3-acyl indoles can be prepared from acids22 and ethyl arylacetates23 has also been used.
indole and other acylating agents, such as expensive and Encouraged by the above results, the author hereby reports the
highly air/moisture sensitive reagents/catalysts,3 esters with use of economically friendly and laboratory abundant ethyl
the aid of Lewis acids,4 or by other methods.5 3-Acyl indoles acetate as a new indole 3-acylating agent under the influence
are useful compounds that are used as building blocks in syn- of catalytic triflic acid in a metal-free technique.
thetic chemistry,6 and are well-known antibacterial7 and anti-
When N-methyl indole (1a) was subjected to acylation in
malarial8 agents (Fig. 1). They are useful against other diseases refluxing ethyl acetate (2a) with 0.4 equivalents of TfOH, the
caused by parasites as well.9 Such molecules are also used as 3-acyl product 3a was isolated in 71% yield within 3 hours of
5-HT6 receptor antagonists,10 antimitotic or anti-tubulin poly- reaction time (first entry, Table 1). The corresponding triflic
merisation agents,11 and to combat HIV,12 diabetes13 or even anhydride reagent afforded 60% product (entry 2), whereas
cancer.14
However, these simple compounds (3-acyl or 3-benzoyl
when using p-TsOH only the decomposed substrate was
indoles) are strikingly expensive commodities (>100–300 $ per
g) when obtained from commercial sources.15 Therefore the
Molecular Synthesis and Drug Discovery Laboratory, Centre of Biomedical Research,
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow-226014, India.
E-mail: ranadeep@chem.iitkgp.ernet.in
†Dedicated to Professor Ramanathan Gurunath on the occasion of his 55th
birthday.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob01977a
Fig. 1 The importance of 3-acyl indole substructures.7,8
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Table 1 Optimization of the yield of 3-acyl indole (3a)a
a Red text signifies acidic conditions, blue text signifies basic con-
ditions. b All yields are isolated yields.
Scheme 1 Substrate scope of the acylation reaction.
observed (entry 3). Similar decomposition took place when 12
N HCl was utilized as the catalyst (entry 4). Catalytic SnCl4 or
H3PO4 gave low yields of 3a (entries 5 and 6). The use of
BF3·Et2O or (CF3CO)2O turned the reactions bleak (entries 7
and 8). Some catalytic basic reagents were also tried in this
reaction (entries 9–11), among which, only DBU gave a respect-
able yield of 3-acyl indole (entry 10). Therefore, the ability of
DBN-type bases to catalyse indole 3-acylations, in addition to
3-benzoylations, was also proved.24 The stoichiometry of TfOH
was examined and the product yield was 48% with 20 mol% of
TfOH, which turned to 69% with 60 mol% TfOH, and then
decreased to 61% with stoichiometric use of the acid (entries
12–14, respectively). Lastly, when the reaction was carried out
with a catalytic amount of TfOH but at ambient temperature,
only 25% yield of 3a was found after prolonged stirring (entry
15).
give 72% of the product (3k). Further investigations on mono-
cyclic heteroaryl substrates, viz. N-benzyl pyrrole, furan and
thiophene, gave the 2-acylation products albeit in lower yields
(3l–3n, respectively). This was achieved using 0.6 equivalents
of the Brønsted acid,24 although further increase in the quan-
tity of acid deteriorated the reaction yields. Thus, this is a very
important procedure for the functionalization of other non-
indole heterocycles as well as being of synthetic interest.
Unfortunately, benzofuran and benzothiophene furnished
only trace yields of the desired products. Using an ester with a
long carbon chain (n = 8, 2b) acid with 1a furnished ketone 3q
in 50% yield.
After obtaining the best condition, an examination of the
substrate scope was carried out by using different
N-substituted indoles (Scheme 1). Moderate yields were
obtained with isopropyl (3b) or n-butyl (3c) N-protected
indoles. N-Benzyl (3d) and N-phenyl (3e) protected indoles
acted as suitable substrates and gave fair yields. Other unsatu-
rated N-protecting groups (3f and 3g) offered similar yields.
Unprotected indole only afforded a complex mixture of pro-
ducts (3h) and no isolation of the desired compound was poss-
ible whatsoever. Interestingly, diindolylmethane gave 58% of
the mono acyl product 3i only with no detected di-acylated
product. N-Benzyl indole with a C-2 methyl substituent gave
70% of the required product (3j). The 5-bromo substituted
substrate displayed similar reactivity under these conditions to
Scheme 2 Synthesis of 3-benzoyl indoles.
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A similar strategy for the 3-benzoylation of the substrates25 require any other reagents except the transition metal salt in a
was developed using methyl benzoate (2c) to afford product catalytic amount.26b To the best of the author’s knowledge
class 4. N-Protecting primary (4a and 4b) or secondary alkyl there is only one other copper(II)-mediated method available to
groups (4c) were used, with subtle increments in the yields afford these indole analogues of benzophenone and this pro-
observed along the series (red yields, Scheme 2). Benzyl (4d) or ceeds via a complicated decarboxylation of α-oxocarboxylic
unsaturated N-protected indoles (4e) gave 16% and 31% yields, acids.27
respectively. The overall yields were significantly less when
When substituted aromatic methyl esters 2d and 2e were
compared to the acylation (Scheme 2, given in red). A parallel used under the first protocol (0.4 equiv. TfOH) ketones 4f and
process for the syntheses of 4 by aerial oxidation of indole sub- 4g were afforded. These compounds were also synthesised in
stituted benzoins (5),26 catalysed by a copper(II) salt in non-dry satisfactory yields using the Cu(OAc)2/O2 oxidation method
acetonitrile solvent was studied and gave relatively improved (Scheme 2). The importance of all these products has already
product yields (blue yields, Scheme 2). Interestingly, it did not been discussed in the introductory section.
To elucidate
a mechanistic path of the Cu(OAc)2/O2
mediated oxidation, some control experiments were performed
using 5a as the substrate. The reactions were designed to prove
the necessity of Cu(OAc)2, oxygen, radical intermediates and
moisture in this protocol. The absence of catalytic oxidant Cu
(OAc)2 did not furnish any reaction (Scheme 3A). Performing
the reaction in the absence of oxygen (Scheme 3B) provided
only a 10% yield of 4a. In the presence of the radical scavenger
TEMPO only a trace amount of 4a was detected, which con-
firmed that a radical mechanism is involved (Scheme 3C). A
similar scenario was observed when moisture free solvent was
used, proving the requirement of water in the reaction
(Scheme 3D).
The general Scheme 4A describes a regular Brønsted acid-
catalysed Friedel–Crafts type acylation of an electron-rich het-
erocycle (1) with an ester (2). Nucleophilic attack of the arene
π-electrons at the carbonyl centre of the acylium ion B or alkyli-
dyne oxonium ion C followed by aromatization of adduct D
gives product 3 or 4. Based on the control experiments
described in Scheme 3, Scheme 4B is shown as a probable
mechanistic route for the aerial oxidative transformation to
give 3-benzoyl indoles (4). The process is started by formation
Scheme 3 Control experiments.
Scheme 4 Probable mechanisms of the acid catalysed 3-acylation of heterocycles by esters (AAc1) and the aerial oxidation of substituted benzoins
5 in presence of Cu(OAc)2.
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In all, this project describes a simple yet synthetically impor-
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Conflicts of interest
There are no conflicts to declare.
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