Extended Multicomponent Reactions with Indole Aldehydes: Access to Unprecedented Polyheterocyclic Scaffolds, Ligands of the Aryl Hydrocarbon Receptor

Article abstract of DOI:10.1002/anie.202011253

The participation of reactants undergoing a polarity inversion along a multicomponent reaction allows the continuation of the transformation with productive domino processes. Thus, indole aldehydes in Groebke–Blackburn–Bienaymé reactions lead to an initial adduct which spontaneously triggers a series of events leading to the discovery of novel reaction pathways together with direct access to a variety of linked, fused, and bridged polyheterocyclic scaffolds. Indole 3- and 4-carbaldehydes with suitable isocyanides and aminoazines afford fused adducts through oxidative Pictet–Spengler processes, whereas indole 2-carbaldehyde yields linked indolocarbazoles under mild conditions, and a bridged macrocycle at high temperature. These novel structures are potent activators of the human aryl hydrocarbon receptor signaling pathway.

Full text of DOI:10.1002/anie.202011253

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Extended Multicomponent Reactions with Indole Aldehydes.
Access to Unprecedented Polyheterocyclic Scaffolds, Ligands of
the Aryl Hydrocarbon Receptor
Authors: Rodolfo Lavilla, Ouldouz Ghashghaei, Marina Pedrola,
Francesca Seghetti, Victor V Martin, Ricardo Zavarce, Michal
Babiak, Jiri Novacek, Frederick Hartung, Katharina Rolfes,
and Thomas Haarmann-Stemmann
This manuscript has been accepted after peer review and appears as an
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202011253
Link to VoR: https://doi.org/10.1002/anie.202011253

10.1002/anie.202011253
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COMMUNICATION
Extended Multicomponent Reactions with Indole Aldehydes:
Access to Unprecedented Polyheterocyclic Scaffolds, Ligands of
the Aryl Hydrocarbon Receptor
Ouldouz Ghashghaei,[a]X Marina Pedrola,[a]X Francesca Seghetti,[a] Victor V. Martin,[a] Ricardo
Zavarce,[a] Michal Babiak,[b] Jiri Novacek,[b] Frederick Hartung,[c] Katharina M. Rolfes,[c] Thomas
Haarmann-Stemmann[c] and Rodolfo Lavilla*[a]
[a]
Dr. O. Ghashghaei, Ms. M. Pedrola, Dr. F. Seghetti, Mr. V. V. Martin, Mr. R. Zavarce, Prof. R. Lavilla
Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine (IBUB), Universitat de Barcelona
Av. Joan XXIII, 27-31, 08028, Barcelona, Spain
E-mail: rlavilla@ub.edu
[b]
[c]
Mr. M. Babiak, Dr. J. Novacek
CEITEC, Masaryk University
University Campus Bohunice, Brno 62500, Czech Republic.
Mr. F. Hartung, Ms. K. M. Rolfes, Dr. T. Haarmann-Stemmann
IUF Leibniz Research Institute for Environmental Medicine.
40225 Düsseldorf, Germany
X
Both authors contributed equally to this work
Supporting information for this article is given via a link at the end of the document.
Abstract: The participation of reactants undergoing a polarity
inversion along a multicomponent reaction, allows the continuation
of the transformation with productive domino processes. Thus,
indole aldehydes in Groebke-Blackburn-Bienaymé reactions lead to
an initial adduct which spontaneously triggers a series of events
leading to the discovery of novel reaction pathways together with a
to a polarity inversion, following the initial MCR. Relevant reports
in the literature include related processes where this concept is
implicit.[6–9]
We particularly focused on electrophilic indolealdehydes that
render nucleophilic moieties after the MCR and promote
subsequent reactions within the adduct, or with other species
present in the medium (Figure 1). This situation is found in
several MCRs involving aromatic aldehydes and remains
unexplored. Indoles are common scaffolds in drugs and
bioactive compounds. Furthermore, they are influential motifs in
the design of domino processes [10–12] and indole carbaldehydes
direct access to
a
variety of linked, fused and bridged
polyheterocyclic scaffolds. Indole 3- and 4-carbaldehydes with
suitable isocyanides and aminoazines afford fused adducts through
oxidative Pictet-Spengler processes, whereas indole 2-carbaldehyde
yields linked indolocarbazoles under mild conditions, and a bridged
macrocycle at high temperature. These novel structures are potent
activators of the human aryl hydrocarbon receptor signaling pathway. have already displayed a rich reactivity in this endeavor.[13–15]
Indoles are also present in a variety of MCRs. However, they
often appear as mere substituents of the reactive groups on the
Multicomponent reactions (MCRs) are transformations involving
inputs.[16,17]
three or more reactants that yield a unified adduct in a single
step. MCRs are among the strategies of choice to achieve high
diversity and complexity levels, offering significant exploratory
potential in a simple experimental framework. Accordingly, they
have an impressive impact on modern organic synthesis,
medicinal chemistry, materials science, etc.[1–3]
Another way to rapidly reach molecular complexity deals with
domino processes, where an initial reaction triggers a series of
consecutive transformations to generate intermediates that
interact with other functionalities present in the substrate.[4,5]
Domino reactions are, however, highly dependent on the
specific arrangement of the substrates, which usually need to be
previously prepared through multistep synthesis. Therefore,
these reactions are challenging to generalize, and their use is
somewhat restricted. Incidentally, MCRs can be described as
intermolecular domino reactions featuring simple starting
materials.
Here we present the concept of extended MCRs, as an
alternative approach to tackle the aforesaid limitations of classic
domino reactions. Extended MCRs involve reactants that trigger
an ensuing cascade of inter/intramolecular transformations due
Figure 1. The concept of extended MCRs with indolealdehydes.
1
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We focused on the Groebke-Blackburn-Bienaymé MCR (GBB):
the interaction of α-aminoazines, aldehydes and isocyanides to
analogous conditions.[21] Moreover, the detection of the imine 5a
and the intermediate dihydropyridine 6a supports the
mechanistic hypothesis [See Supporting Information (SI)]. The
reaction was repeated in the presence of several acid/oxidant
combinations in one-pot and stepwise protocols. The GBB went
smoothly with Yb(OTf)3 as the catalyst. In terms of the external
oxidant, the performance of CoBr2 particularly stood out from
yield imidazoazines,
chemistry.[18–20]
a
privileged scaffold in medicinal
Thus, we performed a GBB with -aminopyridine 1a, indole-3-
carbaldehyde 2a and ethyl isocyanoacetate 3a in open air and
observed the formation of the fused adduct 7a (25%, Scheme
1A). Likely, the initial GBB adduct 4a was oxidized to the
corresponding imine 5a by atmospheric O2, which underwent an
acid-catalyzed Pictet-Spengler (PS) cyclization upon the indole
C2 position to give the dihydropyridine 6a, that subsequently
oxidized to the final product 7a (structure confirmed by X-Ray
crystallography, Scheme 1B). The imine generation can be
related to the auto-oxidation of glycine derivatives under
FeCl3, CuI, IBX and blue-LED-promoted photocatalytic
2+ [22–24]
oxidations using Eosin Y, Rose Bengal and Ru(bpy)3
.
Although the final product is directly achievable from the 1a, 2a
and 3a mixture, higher yields (41%) and cleaner crudes were
obtained when the GBB adduct 4a was isolated in a prior step,
possibly due to the sensitivity of isocyanides in the presence of
particular oxidizing agents.
A)
B)
Pictet-Spengler
Indole C2
N
N
N
N
OHC
Oxidation
N
HN
EtO2C
GBB
Oxidation
N
NH2
N
EtO2C
N
H
N
H
Acid Cat.
Oxidant
H
N
N
N
1a
N
2a
6a
7a
7a
HN
EtO2C
CH3CN
80 ºC
N
N
C
EtO2C
3a
EtO2C
N
H
N
H
N
Oxidation
N
N
(iodine)
N
4a
5a
N
HN
EtO2C
Pictet-Spengler
Indole C4
NH
EtO2C
NH
Acid Catalysts
: Yb(OTf)3, TFA, BF3.Et2O
Oxidants: Air, O2, CoBr2, I2, Photocatalysts/LED
6'a
8a
8a
C)
A = I
Cyclization
upon Indole C4
Cyclization
N
N
N
A
A
N
C2
upon Indole
Key Domino Bond Formed
A
A
8a
N
N
7a
A = Yb3+
H, BF3,..
,
NH
N
EtO2C
EtO2C
H
5a
5a
D)
NH2
N
NH2
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
EtO2C
N
H
N
H
(EtO)2OP
N
H
EtO2C
N
H
N
H
(EtO)2OP
(EtO)2OP
N
N
H
H
7c (14%)
7b (10%)
GBB:
7a
7f
7g
(11%)
(41%)
GBB: 50%
(26%)
7d (36%)
7e (37%)
GBB:
44%
[ox]: 23%
47%
[ox]: 30%
[ox]:
81%
NH2
N
N
MeO
MeO
N
N
N
N
N
N
N
N
O
N
S
N
N
N
N
N
N
Br
N
NH
NH
OMe
EtO2C
(EtO)2OP
N
EtO2C
EtO2C
EtO2C
N
H
EtO2C
7h
N
H
8a (28%)
GBB: 50%
8b (9%)
GBB: 44%
7i (43%)
GBB: 95%
[ox]: 43%
7j
(20%)
7k (32%)
GBB: 66%
[ox]: 48%
GBB: 71%
[ox]:
(31%)
[ox]:
[ox]:
21%
28%
33%
NH2
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
N
OMe
OMe
O
EtO2C
Br
EtO2C
MeO
EtO2C
Me
EtO2C
EtO2C
MeO
EtO2C
MeO2C
O
N
N
H
)
10a (30%
GBB: 84%
[ox]: 36%
8d
(44%)
8c (10%)
GBB: 95%
[ox]: 10%
8e (17%)
GBB: 37%
[ox]: 30%
10b (19%)
GBB:
[ox]:
H
GBB: 66%
[ox]: 67%
96%
20%
9a (40%)
9b
(5%)
Scheme 1. Extended oxidative GBBs featuring indole-3(4)-aldehydes: A) Reaction conditions and mechanism. B) X-ray and microED structures of
compounds 7a and 8a. C) Hypothesis for the regioselective PS. D) Scope and variations. For sequential processes, the yield of each step is reported.
2
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Remarkably, the use of iodine brought a dramatic modification in
the connectivity pattern of the domino process, as it promoted
an unconventional cyclization upon the indole C4, in the
presence of the free C2 position, yielding adduct 8a (28%).
Compound 8a features a complex fused seven-membered ring
and, not being able to obtain suitable crystals, its structure was
secured by microcrystal Electron Diffraction[25] (Scheme 1B).
This cyclization mode is unprecedented in unbiased indole
systems, as PS and other electrophilic processes prefer position
C2,[26] whereas reactions on position C4 only occur under
enzymatic catalysis.[27] Presumably, the coordination with one
imidazole N atom in the imine 5a favors the later cyclization by
increasing the steric bulk around C2. This hypothesis was
further supported as a standard PS reaction between 4-
chlorobenzaldehyde and tryptamine in the presence of iodine[28]
yields common C2 products (Scheme 1C and SI).
performing the reaction with three equivalents of the aldehyde
input, the unoptimized yield rose to 25%. As the new domino
process should, in principle, proceed with any isocyanide, we
switched to cyclohexyl isocyanide 3f and repeated the reaction
with the modified stoichiometry, to yield adduct 11b (33%) in an
unprecedented ABC3 domino fashion (Scheme 2A and SI).
Similar reactions involving 5-bromo-1-aminopyridine, tert-butyl
isocyanide, and 4-methoxyphenyl isocyanide also led to the
corresponding adducts 11c (28%), 11d (17%) and 11e (15%)
(Scheme 2C). The latter’s structure was secured by X-Ray
crystallography (Scheme 2D). These results displayed the
usefulness of the new intermolecular domino as a remarkably
convenient one-pot access to the valuable indolocarbazole
scaffold.[31,32]
Astonishingly, when we promoted the reaction with cyclohexyl
isocyanide by microwave irradiation (90 minutes at 110 °C), we
isolated small amounts of compound 11b (9%), whereas the
major component was its complex isomer 12 (28%), whose
structure was elucidated by X-Ray crystallography (Scheme 2D).
Compound 12 features a spiroazabicyclo[4.3.1]decane core
fused with one benzimidazole, and two indole rings. We
detected traces of compound 12 at 80 ºC but not at rt. Moreover,
the two isomers 11b and 12 did not interconvert under acidic
and thermal conditions.
Next, we studied the scope of this extended MCR. Regarding
the isocyanide input, only those capable of yielding conjugated
imines (5) undergo the domino process. PhosMIC and benzyl
isocyanide proceeded in a similar manner to yield adducts 7b
(10%), 8b (9%) and 7c (14%). TOSMIC did not yield the
expected GBB adduct, likely due to its low nucleophilicity. In
agreement with this hypothesis, 4-fluorophenetyl-, 4-
methoxyphenyl- and cyclohexyl isocyanide did not evolve
beyond their respective GBB adducts (Scheme 1D and SI).
With respect to aminoazines, 1-aminoisoquinoline and 2-
aminoquinoline afforded the expected compounds 7d (36%) and
7e (37%) respectively in the presence of CoBr2 (Scheme 1D).
These adducts display interesting S- and C-shape topologies.
2,4-Diaminopyrimidine yielded the adducts 7f (26%) and 7g
The generation of indolocarbazoles 11 and the bicyclic adduct
12 may be explained through a unified mechanism (Scheme 2B).
The proposed reaction mechanism involves the formation of the
GBB adduct 4t featuring a highly nucleophilic 2-subsituted indole
moiety that attacks a second aldehyde unit to form the
intermediate alcohol M1. A similar nucleophilic addition takes
place between this intermediate and a third aldehyde unit to
generate diol M2, which cyclizes to afford alcohol M3. This
intermediate undergoes a dehydration/aromatization step to give
the indolocarbazole 11b (Scheme 2B). At high temperature,
however, M2 may evolve through the generation of intermediate
M4 resulting from the hydroxyl displacement by the amino group
and similarly, the quaternary ammonium salt M5 would arise.
This intermediate may undergo a [1,2] Stevens rearrangement[33]
justifying the connectivity found in compound 12. Although
several alternative Stevens rearrangements can, in principle,
take place, the illustrated pathway presumably leads to the most
stable adduct likely involving a reasonably favored intermediate
(See SI for a discussion).
(11%) in
a regioselective manner, following the protocol
developed by the group.[29] The antibiotic trimethoprim suitably
reacted likewise to give adduct 7h (31%).[30] Interestingly, 2,4-
diaminopyrimidine adducts react smoothly in air, not requiring
other oxidants, probably due to their higher electron density.
As for the scope of the aldehyde component, activated
(hetero)aromatic aldehydes should react, facilitating the PS step.
Accordingly,
5-bromoindole-3-carbaldehyde
yielded
the
expected adducts 7i (43%) and 8c (10%) in the presence of
CoBr2 and I2, respectively. 5-Methoxy-3-carbaldehyde and 1-
methyl indole 3-carbaldehyde provided adducts 8d (44%) and
8e (17%) in the presence of I2. Furan 3- and thiophene 3-
carbaldehyde gave the corresponding adducts 7j (20%) and 7k
(32%) respectively. The incorporation of indole 4-
carboxaldehyde afforded adducts 9a (40%) and 9b (5%) through
PS cyclization upon indole C3 position, featuring an alternative
connectivity of the fused seven-membered ring (Scheme 1D).
Electron-rich benzaldehydes, such as 3,4,5-trimethoxy
benzaldehyde and piperonal, provided the expected adducts
10a (30%) and 10b (19%). Consistently, pyridine aldehydes only
yielded GBB adducts (See SI). In general, the processes lead
quite cleanly to the oxidized compounds 7-10 with relatively few
side reactions (imine oxidation, isocyanide hydrolysis) given the
mild conditions used.
Overall, the extended MCRs reach remarkable bond-forming
indexes and structural diversity/complexity levels in one-pot
operations with modest overall yields, which, however, can be
specifically optimized attending to their particular input
combinations. For representative examples, see the tuning of
conditions leading to compounds 7a and 7f in SI.
Having an exclusive access to a variety of novel heteroaromatic
scaffolds, we intended to determine their bioactivity profile. We
focused on the aryl hydrocarbon receptor (AHR), as
indolocarbazoles and related structures are listed among its
ligands.[34,35] Upon binding of a ligand in the cytoplasm, AHR
translocates to the nucleus and binds to xenobiotic-responsive
elements (XRE) in the enhancer of target genes, e.g. encoding
cytochrome P450 (CYP) 1A1, to induce their expression.
Next, we reacted equimolar quantities of indole 2-carbaldehyde
2l, 2-aminopyridine 1a, and ethyl isocyanoacetate 3a in the
presence of Yb(OTf)3, to presumably obtain the adduct 7l,
following the expected oxidative domino process (Scheme 2A).
Yet surprisingly, indolocarbazole 11a was isolated instead, when
3
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Scheme 2. Extended non-oxidative GBBs with indole 2-carbaldehyde: A) Domino adducts with ethyl isocyanoacetate. B) Unified mechanistic hypothesis. C)
Scope of indolocarbazoles. D) X-Ray structures of compounds 11e and 12.
AHR regulates multiple physiological and pathophysiological
processes, including xenobiotic metabolism, immune responses,
inflammation, and carcinogenesis.[34–36] Recent studies,
particularly assessing AHR’s function in the context of skin and
gut diseases, have unmasked the Janus-faced nature of
AHR.[37,38] Depending on cell-type, tissue, microenvironment,
and presence of ligand(s), either activation or inhibition of AHR
may be beneficial. The AHR binding pocket is still not well
described, and although computational studies have shed some
light, the generation of potent AHR ligands still relies mostly on
stimulated XRE-driven reporter gene activity in hepatoma cells
(Figure 2C).
Taken together, these results strongly indicate that extended
MCRs enable the production of a variety of AHR-activating
compounds. The tested compounds are almost as potent as the
positive control (6-formylindolo[3,2-b]carbazole, FICZ). The
described modular access to these scaffolds will facilitate further
studies to prove their bonding to the AHR and to assess their
pharmacokinetic and safety profiles, facilitating a drug discovery
appropriate synthesis and screening.[39,40] As shown in Figure 2A, program.
exposure to compounds 8a, 11b-e and 12 (but not 7a) resulted
in a dose-dependent induction of CYP1A enzyme activity in
AHR-proficient but not AHR-knockdown HaCaT keratinocytes.
At the highest test concentration, 8a interfered with CYP1A
enzyme activity, suggesting that this compound is metabolized
by CYP1A isoforms and thus competing with the deethylation of
7-ethoxyresorufin. All compounds, except 7a, increased the
CYP1A1 and CYP1B1 copy numbers in HaCaT cells in an AHR-
dependent manner (Figure 2B). Aside 7a and 8a, all compounds
To conclude, we have described several domino-prolonged
GBBs with indole carbaldehydes that directly yield
unprecedented polyheteroaromatic systems. We believe that the
concept of extended MCRs may have a positive impact in the
exploration of the chemical and reactivity spaces, taking into
account that similar polarity changes could take place in many
MCRs.
4
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Figure 2. Effect of test compounds on AHR-driven gene expression and CYP1A enzyme activity. A) AHR-proficient HaCaT-EV and AHR-knockdown
HaCaT-shAHR keratinocytes were treated with 0.1% DMSO, 100 nM of the AHR agonist FICZ and increasing concentrations of the compounds (100 nM, 1 µM,
10 µM). After 6 h, CYP1A-mediated deethylation of 7-ethoxyresorufin was determined. B) HaCaT-EV and HaCaT-shAHR cells were treated for 6 h with 0.1%
DMSO, 100 nM FICZ, and 10 µM of each test compound. After 6 h, total RNA was isolated, reverse transcribed, and copy numbers of CYP1A1 and CYP1B1 were
determined by quantitative real-time PCR. C) XRE-HepG2 cells were treated with 0.1% DMSO, 100 nM FICZ, and 10 µM of each compound. After 24 h,
AHR/XRE-dependent luciferase activity was determined. * p ≤ 0.05.
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10.1002/anie.202011253
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Extend your MCR! By engaging indolealdehydes in an isocyanide Multicomponent Reaction, the polarity inversion of the indole
moiety along the transformation triggers an extension of the domino process, leading to a variety of unprecedented fused, linked and
bridged scaffolds. The processes are parallelizable and the adducts display remarkable bioactivity as potent ligands of the aryl
hydrocarbon receptor.
Institute and/or researcher Twitter usernames: @RLavillaGroup, @IBUB_UB
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