Decarboxylative Coupling Reaction of 2-(1H-Indol-3-yl)acetic Acids with Indole, Azaindole, Benzimidazole and Indazole Derivatives

Article abstract of DOI:10.1002/adsc.201900688

3,3′-Diindolylmethanes (DIMs) are an important class of indole alkaloids that exhibit anti-inflammatory and anti-cancer effects. Herein, we report on a new, mild and efficient copper(II)-promoted decarboxylative coupling reaction of 2-(1H-indol-3-yl)acetic acid derivatives (1 a–h) with a variety of (substituted) indoles (2 a–t) yielding (un)symmetrically substituted DIMs (3 a–z, 3 aa–ai). Reaction of 2-(1H-indol-3-yl)acetic acid (1 a) with 7-azaindole led to the 3,3′-connected DIM analog 5 d, while 4-, 5-, and 6-azaindoles and benzimidazole reacted at the N1-nitrogen atom. Reaction of 1 a with 1H-indazoles led to a mixture of 1- and 2-substituted indazole derivatives. The new method allows large-scale synthesis of biologically active DIMs. (Figure presented.).

Full text of DOI:10.1002/adsc.201900688

Title: Decarboxylative coupling reaction of 2-(1H-indol-3-yl)acetic acids
with indole, azaindole, benzimidazole and indazole derivatives
Authors: Thanigaimalai Pillaiyar, Muhammed Uzair, Saif Ullah, Gregor
Schnakenburg, and Christa E. Müller
This manuscript has been accepted after peer review and appears as an
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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
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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.201900688
Link to VoR: http://dx.doi.org/10.1002/adsc.201900688

10.1002/adsc.201900688
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Decarboxylative coupling reaction of 2-(1H-indol-3-yl)acetic
acids with indole, azaindole, benzimidazole and indazole
derivatives
Thanigaimalai Pillaiyar,a,* Muhammed Uzair,a Saif Ullah,a Gregor Schnakenburg,b and
Christa E. Müllera
a
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4,
D-53121 Bonn, Germany
E-mail: thanigai@uni-bonn.de; Phone: +49-228-73-2360
Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. 3,3’-Diindolylmethanes (DIMs) are an important class of indole alkaloids that exhibit anti-inflammatory and anti-
cancer effects. Herein, we report on a new, mild and efficient copper(II)-promoted decarboxylative coupling reaction of 2-(1H-
indol-3-yl)acetic acid derivatives (1a-h) with a variety of (substituted) indoles (2a-t) yielding (un)symmetrically substituted
DIMs (3a-z, 3aa-ai). Reaction of 2-(1H-indol-3-yl)acetic acid (1a) with 7-azaindole led to the 3,3’-connected DIM analog 5d,
while 4-, 5-, and 6-azaindoles and benzimidazole reacted at the N1-nitrogen atom. Reaction of 1a with 1H-indazoles led to a
mixture of 1- and 2-substituted indazole derivatives. The new method allows large-scale synthesis of biologically active DIMs.
Keywords: C-C bond formation; decarboxylative coupling; diindolylmethanes; unsymmetrical diindolylmethanes; large-
scale synthesis
reaction of (3-indolylmethyl)trimethylammonium
Introduction
iodides with substituted indole derivatives.[12]
Although
the
reaction
is
efficient,
(3-
Diindolylmethanes (DIMs) are an important class of
indole alkaloids that consist of two indole rings
connected by a methylene unit. Unsubstituted DIM, a
major bioactive metabolite of glucobrassicin found in
cruciferous vegetables, is clinically evaluated for the
treatment of prostate cancer,[1] and there is preclinical
evidence for its activity against other types of cancer
as well.[2,3,4] Several recent studies reported on various
biological targets for DIM including the
arylhydrocarbon receptor,[5-7] the immunostimulatory
G protein-coupled receptor 84 (GPR84),[8] the histone
deacetylase-1 (HDAC-1)[9] and the cannabinoid
receptor 2 (CB2).[10]
To optimize the potency of DIM derivatives for
specific targets with the aim to develop a drug,
synthetic procedures are required that allow broad
modification of the scaffold. Most of the described
synthetic methods for DIM derivatives only yield
symmetrical products.[11] However, binding sites of
protein targets are typically unsymmetrical in nature.
Recently, we reported on a general and efficient
synthetic approach towards unsymmetrical DIMs by
indolylmethyl)trimethylammonium iodides have to be
prepared as starting compounds requiring an
additional step, and the formation of trimethylamine as
a by-product reduces the atom economy. Therefore,
we decided to search for new alternative
methodologies to prepare (un)symmetrical DIMs.
Recently, decarboxylative coupling reactions of
carboxylic acids have become of primary importance
for C-C and C-X (X = N, P, S) bond formation.[13]
Carboxylic acids are commercially available or easily
accessible, non-toxic, and highly stable, and therefore
represent ideal starting materials.[14] Decarboxylative
coupling reactions are simple to operate and generally
do not produce toxic by-products. We have now
developed
an
efficient
Cu(II)-promoted
decarboxylative coupling reaction of indole-2-(1H
indol-3-yl)acetic acid derivatives for the preparation of
3,3’-diindolylmethanes,
which
provides
a
straightforward access to
a
wide range of
(un)symmetrical 3,3’-DIMs. The developed procedure
has a broad substrate scope with excellent functional
group tolerance, it proceeds with high regioselectivity
1
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10.1002/adsc.201900688
Advanced Synthesis & Catalysis
and atom economy. Moreover, it represents the first
reported procedure for the preparation of (aza)DIM
derivatives by a decarboxylative coupling reaction,
which can be utilized for the synthesis of
unsymmetrical as well as symmetrical DIM
derivatives.
When, reversely, the amount of 2a was increased from
0.57 mmol to 1.14 mmol, the yield of the product was
increased to 83% (entry 25) within a reaction time of
2 h. Increasing the amount of 2a to 1.71 mmol (3
equiv.) did not lead to further increase in the yield
(80%, entry 26).
Next, we investigated how temperature affected the
reaction (see Table S1). Upon increasing the
temperature from 115 to 125 C, the yield of the
Results and Discussion
o
product was slightly reduced to 74% (entry 1).
The decarboxylation coupling reaction of 2-(1H-indol-
3-yl)acetic acid (1a) with 5-methoxyindole (2a) was
initially investigated as a model reaction (see Table 1).
No product was formed when the reaction was carried
out without the presence of catalyst and oxidant (entry
1). Next, different oxidants and catalysts were
screened. A mixture of Cu(OAc)2·H2O (1 equiv.) as an
oxidant with 10 mol% Ag2CO3 as a catalyst in
acetonitrile at 115 °C for 8 h (entry 2, 55% yield)
exhibited higher reactivity than the addition of
Pd(OAc)2 as a catalyst (entry 3, 37% yield). Various
oxidants including Ag2CO3, 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ), Na2S2O8, tert-butyl
peroxide, benzoquinone, H2O2, PhI(OAc)2, or O2 in the
presence of 10 mol% Cu(OAc)2·H2O, did not improve
the yield (entry 3-11, 15-39 %) or resulted only in trace
amounts of product (entry 5, 7). As a next step, the
reaction was performed only in the presence of catalyst.
With Pd(OAc)2 as a catalyst, no product was formed
(entry 12), while Cu(OAc)2·H2O or Ag2CO3 led to
39% or 30% product formation (entry 13, 14),
respectively. Interestingly, when Ag2CO3 (entry 15) or
Cu(OAc)2·H2O (entry 16) were used as oxidants in the
reaction, the formation of product was increased to
45% or 60%. When the amount of the oxidant
Cu(OAc)2·H2O was increased from 0.57 mmol to 1.14
mmol, no significant change was observed (62% yield,
entry 17). These observations imply that
Cu(OAc)2·H2O alone as an oxidant without any
catalyst is effective for the decarboxylative coupling
reaction.
o
Reducing the temperature from 115 C to 100, 90 or
80 oC reduced the yield (entries 2-4) or resulted in no
reaction (entry 24).
As a next step, the effect of solvent was
investigated (see Table S1). Solvents such as DMF
(entry 6, yield 60%), ethanol (entry 7, yield 35%),
chlorobenzene (entry 10, yield 20%), DMSO (entry 11,
yield 57%), or H2O (entry 13, yield 30%) did not
improve the yield as compared to acetonitrile. In
dichloromethane (entry 8), dichloroethane (entry 9),
and tetrahydrofuran (entry 12), no reaction was
observed.
With the optimized conditions (Cu(OAc)2·H2O,
o
115 C for 2 h in ACN, Table 1, entry 25), we
investigated the scope of the reaction employing
various indole derivatives, which were reacted with
carboxylic acid 1a to prepare unsymmetrical DIMs
(3a-p, Table 2). In general, the reactions of 1a with
differently substituted indoles proceeded well and
yielded the desired products in good to excellent yields
(55-83%).
Table 2. Exploration of the scope of the reaction
employing various indoles[a-d]
The screening of oxidants including CuO (entry 18,
yield 52%), Cu(0) (entry 19, yield 53%), CuF2 (entry
20, yield 51%), CuCl2 (entry 21, no reaction), AuCl2
(entry 22, no reaction) and CuSO4·5H2O (entry 23,
yield 41%) did not improve the yield as compared to
Cu(OAc)2·H2O or did not result in product formation
at all (entry 21 and 22). This result suggests that
Cu(OAc)2·H2O is superior to other oxidants.
We next investigated the ratio of the reagents
indolylacetic acid 1a and indole 2a. At first, we
increased the amount of 1a from 0.57 mmol to 1.14
mmol and reacted it with 2a (0.57 mmol). This led to
an acceleration of the reaction, which was completed
within 2 h as compared to 8 h with equimolar amounts
of the reaction partners; however, the formation of the
desired product was reduced from 60 to 40% (entry 24).
3h
3j
2
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10.1002/adsc.201900688
Advanced Synthesis & Catalysis
[a] All reaction was carried out an a 0.57 mmol (1a) in 5 mL
of solvent in presence of 1 eq. Cu(OAc)2·H2O at 115 oC for
2h;[b]All isolated products were characterized by 1H and
13C NMR spectra. For 3h and 3j X-ray crystal structures
were additionally obtained.[15] In addition, HPLC
analysis coupled to electrospray ionization mass
spectrometry (LC-ESI-MS) was performed; [c]Isolated
yields; [d]Purity was determined by HPLC coupled to a
UV diode array detector (DAD) at 220-400 nm.
[a] All reaction was carried out an a 0.57 mmol (1b-g) in 5
mL of solvent in presence of 1 eq. Cu(OAc)2·H2O at 115 oC
for 2h; [b] isolated yield.
Next, we investigated a variety of substituted
indole-3-acetic acid derivatives (1b-g) for the
preparation of DIMs (3p-z, 3aa-ae). Different
functional groups, including Cl, OMe, and F in
different positions of the indole ring were tolerated,
and the desired products were generally obtained in
good to excellent yields (59-85%).
Both
electron-donating
and
electron-
withdrawing groups were tolerated. Electron-
donating substituents as in 5-methoxyindole (2a),
4-methylindole (2b), 6-methoxyindole (2h), 6-
ethoxyindole (2i) resulted in excellent yields (3a-
It was noticed that electron-withdrawing
substituents such as Cl or F on the phenyl ring of
indoleacetic acid (1b
efficient reactions as compared with indole
derivatives bearing electron-donating groups (2a
, 1d, 1e, 1f) led to more
b, 3h-i: 79-83%). Compound 3a had previously
been reported to be a potent agonist of the
immunostimulatory receptor GPR84.[8] The
coupling of indoles substituted with electron-
withdrawing groups such as 4-fluoroindole (2c),
,
2b) providing the desired products in excellent
yields ranging from 77-83%. On the other hand,
the coupling reaction of indoleacetic acids
substituted with electron-withdrawing groups such
bromoindoles
carboxaldehydes (2e
with carboxylic acid 1a delivered the desired
products in good to excellent yields (3c-g 3j 3k
67-77%). Indoles substituted with carboxylic acid
esters or phenyl groups at position 2 (2l 2m and
(
2d
,
2g
,
2j), indole-4-/5
/
2f) and 6-cyanoindole (2k
)
as Cl or F (1b
bearing electron-withdrawing groups, including F
2c), Br (2d), CHO (2e), or Cl (2q), led to the
desired products but in lower, still in good yields
3r 3w 3z 3ab 3ad: 59-74%). Reaction of 5-
methoxyindoleacetic acid 1c with 4-
, 1d, 1e, 1f) with indole derivatives
,
,
:
(
,
(
-
s
,
,
,
,
2n) yielded the desired products 3l-n, in somewhat
lower yields (55-68%) probably due to steric
hindrance. Reaction of 1a with the tricyclic 1H-
benzo[g]indole (2o) or N-protected indole 2p
provided 3o (67%) or 3p (71%) in good yields.
(
)
methoxyindole (2r), or 4-fluoroindole (2c),
respectively, delivered the corresponding products
in excellent yields (3t: 85%, 3u: 73%). Moreover,
the coupling of N1-methyl-3-indoleacetic acid
(
1g) with 4-methylindole (2b) proceeded well
Table 3. Reactions of differently substituted 2-(1H-
indol-3-yl)acetic acid derivatives with substituted
indoles[a,b]
yielding 84% of product 3ae. In addition, the
reaction of 5-chloroindoleacetic acid with 1H-
benzo[g]indole provided the product 3x (78%) in
very good yield.
Next, we investigated this protocol for preparing
(un)symmetrical DIMs at a larger scale as required for
biological studies. We performed gram scale reactions
of indole-3-acetic acid (1a, 5.7 mmol) with 5-
fluoroindole (2s, 11.4 mmol), of 5-methoxy-3-
indoleacetic acid (1c, 4.8 mmol) with 5-
methoxyindole (1a, 9.7 mmol), and of 5-fluoro-3-
indoleacetic acid (1h, 5.2 mmol), with 5-fluoroindole
(2s, 10.4 mmol) (Scheme 1). In all reactions, we
obtained the desired products in very good yields (3af:
72%, 3ag: 83% and 3ah: 76%). Compounds 3af-ah
had previously been reported as potent agonists of the
immunostimulatory receptor GPR84 and these
compounds are of importance as pharmacological
tools.[8]
3
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10.1002/adsc.201900688
Advanced Synthesis & Catalysis
depicted in Scheme 4, the reaction of 1a or 1d with
1H-indazoles 8a-b yielded mixtures of N1- (9a: 57%,
9b: 54%) and N2-subsitututed indazoles (10a: 30%,
10b: 27%). We observed that the N1-substituted
products were obtained in higher yields as they are
thermodynamically favoured; the combined overall
yields of 9 and 10 were excellent. Compound 9a had
previously been prepared by reaction of 3-
hydroxymethylindole with 1H-indazole in the
presence of metallic sodium at 100 °C for 9 h.
However, the yield of 9a obtained in that reaction was
significantly lower (13.8%) when compared to the
present method (57%).[16]
Scheme 1. Gram-scale synthesis of (un)symmetrical DIMs
3af-ah, which are potent agonists of the orphan G protein-
coupled receptor GPR84.
It is worth noting that the reactions are highly
regioselective as the decarboxylative alkylation occurs
exclusively in the 3-position of indoles as confirmed
1
by H, and 13C NMR spectroscopy. Additionally, X-
ray analysis of representative examples, including 3h
and 3j, unambiguously confirmed that the coupling
reaction had occurred at the 3-position of the indole
ring. Many functional groups including chloro and
bromo substituents as well as carboxaldehyde and
carboxylic acid ester groups remained intact,
providing opportunities for further derivatization.
Next, the protocol was applied to prepare azaindole
derivatives. We observed that the coupling reaction of
1a with 4-, 5- or 6-azaindole (4a-c), yielded the N1-
alkylated products (5a-c, Scheme 2), whereas reaction
Scheme 4. Decarboxylative coupling reaction of 1a and 1d
with 1H-indazole derivatives (8a-b).
Finally, we applied the developed protocol to
reactions of 2-(1-benzofuran-3-yl)acetic acid, and
benzo[b]thiophene-3-acetic acid, respectively, with 5-
methoxyindole (2a). However, no desired products
were formed although many spots appeared on TLC.
These results suggest that the presence of the N-atom
is important for reactivity, which may stabilize the
indolinium-copper(II) complex (e.g. see intermediate
B in Scheme 5) through 1,3-conjugation during the
reaction. We also studied the reaction of 3-
indolepropionic acid with 5-methoxyindole (2a) under
the same reaction conditions, but no reaction took
place. In a further attempt, we performed the reaction
of indole-3-glyoxalic acid with 2a under
decarboxylative coupling conditions, but the desired
product was not obtained. These observations suggest
that upon decarboxylation, the formation of a benzylic
type intermediate complex with Cu(II) is important for
reactivity (e.g. see intermediate B in Scheme 5), which
cannot be formed in case of the reaction of 3-
indolepropionic acid and indole-3-glyoxalic acid.
with 7-azaindole (4d) afforded the 3,3-̕ coupled
product 5d in good yields. Compound 5d was
previously reported to possess anticancer activity.[16]
Scheme 2. Decarboxylative coupling reaction of 1a with
azaindoles 4a-d.
The coupling reaction of 1a with 1H-
benzimidazole (6a) afforded 7a in an excellent yield
of 80% (Scheme 3). The structure of the product was
confirmed by X-ray crystallography.[15] Compound 7a
was previously reported to possess anti-fungal and
anti-convulsant activities.[17]
Although the exact mechanism of the
decarboxylative coupling reaction is not completely
clear, a plausible mechanism is proposed for the
synthesis of 3a in Scheme 5. In order to understand if
this reaction was mediated via a radical mechanism,
we performed control experiments in the presence of
2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). As
depicted in Scheme 5a, reaction of indole-3-acetic acid
(1a) and indole (2t) was carried out in the absence or
in the presence of TEMPO. Under both conditions, the
product DIM (3ai) was produced in excellent yields
(74% and 70%) suggesting that radicals did not play a
role in this reaction. Based on literature,[17] indole-3-
acetic acid (1a) reacts with Cu(OAc)2 affording a
Cu(II) carboxylate species (A). Elimination of CO2 (B)
followed by nucleophilic substitution of 5-
7a
Scheme 3. Decarboxylative coupling of 1a with 1H-
benzimidazole (6a).
We further studied the coupling reaction of indole-
3-acetic acid derivatives with 1H-indazoles. As
4
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10.1002/adsc.201900688
Advanced Synthesis & Catalysis
methoxyindole (2a) affords intermediate C. Re-
and extracted with ethyl acetate (2 X 25 mL). The combined
aromatization of C via C-H bond cleavage generates D, organic layers were washed with brine solution (25 mL),
which then undergoes reductive elimination to
produce the desired coupling product 3a along with
elemental copper.
dried over Na2SO4, and evaporated under reduced pressure
to the dryness. The crude product was purified by either
recrystallization or column chromatography.
Acknowledgements
T.P. is grateful to the Alexander von Humboldt (AvH) foundation
and to Bayer Pharma for a postdoctoral fellowship. C.E.M., M.U.
and S.U. were supported by the DAAD (Projekt-ID 57143280:
International Master of Science in Drug Research). G.S. thanks
Prof. A. C. Filippou for providing X-ray infrastructure.
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In conclusion, we developed an efficient copper(II)-
promoted decarboxylative coupling reaction of indole-
2-(1H-indol-3-yl)acetic acids and indoles for the
preparation of (un)symmetrical 3,3’-DIMs, which are
of significant interest due to their biological activities,
especially in inflammation, immunity and cancer. The
developed new synthetic method for (un)symmetrical
3,3’-DIMs employs mild reaction conditions, is
operationally simple, and provides these valuable
products in high yields. The reaction has a broad
substrate scope with good functional groups tolerance
and proceeds with high regioselectivity. Reactions of
indole-2-(1H-indol-3-yl)acetic acids with azaindoles
produced different N-substituted products depending
on the position of the N-atom in the ring, which
governs the electron densities in the ring system. The
target molecules obtained in gram scale will allow
comprehensive biological studies.
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General procedures for the synthesis of 3a-z, 3aa-ai, 5a-
d, 7a, 9a-b, 10a-b. To the solution of 2-(1H-indol-3-
yl)acetic acids (1a-h, 0.57 mmol) in ACN (5 mL) in a 50
mL sealed tube, indole derivatives, azaindoles,
benzimidazoles, or indazoles (1.14 mmol) and
Cu(OAc)2·H2O (0.57 mmol) was charged. The reaction
mixture was stirred at 115 °C for 2 h. After completion of
the reaction (monitored by TLC), the mixture was cooled to
room temperature. Reaction mixture was poured into water
5
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10.1002/adsc.201900688
Advanced Synthesis & Catalysis
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1100, 129-136.
6
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10.1002/adsc.201900688
Advanced Synthesis & Catalysis
FULL PAPER
Decarboxylative coupling reaction of 2-(1H-indol-
3-yl)acetic acids with indole, azaindole,
benzimidazole and indazole derivatives
Adv. Synth. Catal., 2019, Volume, Page – Page
Thanigaimalai Pillaiyar,a,* Muhammed Uzair,a Saif
Ullah,a Gregor Schnakenburg,b and Christa E.
Müllera
[Practical & mild conditions] [Broad scope, good
functional group tolerance, high regioselectivity
& atom economy] [55-85% yield, gram scale
synthesis possible] [44 examples, 29 new
compounds]
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This article is protected by copyright. All rights reserved.