Skeletally Tunable Seven-Membered-Ring Fused Pyrroles

Article abstract of DOI:10.1021/acs.orglett.1c02251

We describe a copper-mediated method that enables the synthesis of seven-membered-ring fused pyrroles (7-mrFPs). The protocol proceeds via an in situ spiro-intermediate ring expansion and tolerates a library of 7-mrFP derivatives with a broad range of functional groups in a simple step with tangible parameters and substrate adaptations. These rare 7-mrFPs are now accessible on a millimolar scale, and selected examples exhibit high antioxidant activity.

Full text of DOI:10.1021/acs.orglett.1c02251

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Letter
Skeletally Tunable Seven-Membered-Ring Fused Pyrroles
Dimitrios Andreou, Nsikak B. Essien, Cristina Pubill-Ulldemolins, Michael A. Terzidis,
Athanasios N. Papadopoulos, George E. Kostakis,* and Ioannis N. Lykakis*
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ABSTRACT: We describe a copper-mediated method that
enables the synthesis of seven-membered-ring fused pyrroles (7-
mrFPs). The protocol proceeds via an in situ spiro-intermediate
ring expansion and tolerates a library of 7-mrFP derivatives with a
broad range of functional groups in a simple step with tangible
parameters and substrate adaptations. These rare 7-mrFPs are now
accessible on a millimolar scale, and selected examples exhibit high
antioxidant activity.
We recently described a synthetic protocol29 that incorpo-
aturally occurring and interesting biological N-hetero-
Ncycles can be synthesized from abundant resources rates readily available nitroalkenes, amines, and α-substituted
incorporating similar synthetic principles.1 The possibilities for
aldehydes and yields a library of skeletally tunable substituted
pyrroles via a Cu-promoted 1,2-migration process.30−32 We
combining readily available resources are endless; however,
hypothesized that its slight modification should represent a
reliable synthetic path to easily access 7-mrFPs and with
tangible parameters and substrate alterations to afford a
comprehensive library of these unknown species. We grounded
our hypothesis on the use of the commercially available
cyclohexanecarbaldehyde (1), a component whose use toward
the synthesis of 7-mrFPs is unknown, amines, and nitro-
styrenes (Scheme 1B). This triadic combination could
generate 7-mrFPs through a controllable cyclization and 1,2-
migration ring expansion process.31,33−37 In our previous
study,29 we identified a one order of magnitude difference in
the use of coordination polymers (CPs) (1 mol %) and metal
salts (10 mol %) as precatalysts; therefore, we adopted this
protocol in the current study (Table S1).
when aiming for a specific heterocycle containing five-, six-, or
seven-membered fused rings, the starting material choice and
the synthetic process have to be modular and selective. In
particular, the formation of the fused seven-membered N-
heterocycles is challenging due to ring strain,2 and thus only a
limited number of methods are available, and their applicability
is narrow.3−6
Pyrrole and its derivatives dominate synthetic and medicinal
chemistry because of their bioactive and therapeutic proper-
ties.7,8 The traditional Paal−Knorr and Hantzsch reactions and
the more recent synthetic approaches tolerate various
functionalized and substituted pyrroles through different
starting materials.9−15 However, the chemistry and applications
of several pyrrole derivatives are underdeveloped because
reliable synthetic protocols are not in place. Specifically, seven-
membered-ring fused pyrroles (7-mrFPs) are a subclass of
pyrroles that have received less attention, and only sporadic
examples are known.16,17 This limited number of 7-mrFPs can
be synthesized via metal-catalyzed18−25 or microwave- or
thermal-assisted processes.26,27 The former method encom-
passes the multistep formation of a structurally complex
molecule, which, in turn, transforms to the fused derivative
(Scheme 1A). From a biological and synthetic perspective,
Pietruszka et al.28 reported an enzymatic catalytic process that
converts 7-mrFPs to the corresponding natural product,
prodiginines, thus setting the stage for opening new research
directions in 7-mrFP chemistry.
The reaction of 1, butylamine (2), and (E)-1-methyl-4-(2-
nitrovinyl)benzene (3) in a 1/1/1 ratio (0.2 mmol) in 1 mL of
MeOH in a sealed tube at 80 °C in the absence of a catalyst
yielded the desired product 4 in 32% yield (Figure 1, entry 1).
The salts were used in 10 mol %, and the CPs were used in 1
1
mol %. Yields were determined by H NMR of the crude
Received: July 6, 2021
https://doi.org/10.1021/acs.orglett.1c02251
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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[Cu(II)(L)2(CH3CN)2]·2(ClO4)·2MeCN (Cu-1), [Cu(II)-
(L)2(NO3)2] (Cu-2), [Cu(II)-(L)2(MeCN)2]·2BF4 (Cu-3),
and [Cu(II)(L)2(OTf)2] (Cu-4), where L is 1-{2-[(1H-
benzo[d][1,2,3]triazol-1-yl)methyl]-benzyl}1H-benzo-[d]-
[1,2,3]triazole, were prepared following previous protocols (for
CP structures, see Figure S3).39,40 However, in the case of Cu-
4, we modified the synthetic protocol to improve its yield. The
pairs Cu-2/Cu-3 and Cu-1/Cu-4 favor the formation of 4a
and 4, respectively (Figure 1, entries 2−5). The majority of
copper salts (10 mol %) give similar total yields (4 + 4a),
eradicating the appearance of 3c but favoring the formation of
4a (Figure 1, entries 7−16). However, CuI outperformed and
afforded the anticipated 7-mrFP 4 in 68% yield (Figure 1, entry
6). From this screening, it is evident that the pair of salts, CuI
and Cu(NO3)2, and the pairs of precatalysts have an opposite
preference but a similar performance, thus giving us the
opportunity to isolate both the desired 7-mrFP, 4, and the
unexpected 7-mrFP, 4a, in good yield. These preliminary
screenings established the necessity of a Cu source to improve
the yield, and thus we decided to continue our study using the
metal salts CuI and Cu(NO3)2. Part of our future studies will
focus on developing precatalyst(s) that will eliminate the
formation of the desired or unexpected 7-mrFPs.
Scheme 1. Synthetic Procedures for 7-mrFPs
Then, we screened various solvents in the absence of a
catalyst (Table S2) or the presence of CuI (Table S3). In the
former case, imine 2a (the product of the reaction between 1
and 2) was the main product. In the presence of CuI, the
reactions in MeOH, EtOH, and CH3CN provided 4 in good
yield (Table S3, entries 1−3), but reactions in other solvents,
that is, tetrahydrofuran (THF), toluene, 1,2-dichloroethane
(1,2-DCE), and hexane, were less efficient (Table S3, entries
4−7). Reactions in MeOH at lower temperatures favored 2a,
whereas reactions with a smaller amount of nitroalkene yielded
4 in lower yield (Table S4, entries 1 and 2). Then, we extended
our study to different times (2, 3, and 18 h) and observed that
the total yields of 4 and 4a remained unaltered (Table S4,
entries 3−6), with the best results obtained within 6 h. In
addition, reactions with other Lewis acids favored the
formation of 4a (Table S5).
We explored the substrate scope with the optimized
conditions in hand and incorporated a commercially available
range, substituted in various positions, of amines and 2-
nitroalkenes. All reactions afforded a mixture of the desired and
the unexpected 7-mrFPs; however, by altering CuI or
Cu(NO3)2 salts, we could isolate both species in good yields
and obtain a comprehensive library of, in total, 28 7-mrFPs
(Scheme 2). Irrespective of the electron-donating (Me) or
-withdrawing (Cl, Br, COOMe, NO2) group at the o, m, or p
position, the character of the 2-nitroalkene component, or the
nature of the amines (aliphatic, benzylamine, and substituted
anilines), 7-mrFPs (4−19) were formed in good isolated yields
(45−67%). Then, to expand the applicability of our method,
we performed the following four sets of reactions. First, we
synthesized (E)-1-nitro-4-(2-nitro-2-phenylvinyl)benzene (see
the SI) and used it instead of 3. On this occasion, we were able
to eliminate the formation of the unexpected product 4a and
obtain the corresponding penta-substituted 7-mrFPs (20−23)
in moderate yields (55−64%). Then, we performed the
reactions with Cu(NO3)2, and selected homo-penta-substi-
tuted 7-mrFPs 4a−7a, 17a, and 18a were isolated in good
yields (37−43%, Scheme 2). To access the N−H derivative 7-
mrFPs, we incorporated amines with simple leaving groups
(MeSO2NH2, BocNH2, NH3-MeOH (7N)), but the nitro-
Figure 1. Catalyst evaluation for the synthesis of the 7-mrFP 4.
mixture, and in all cases, a 100% consumption of 3 was
observed (Table S1). However, we observed the formation of
four other products. Compounds 3a, 3b, and 3c were
byproducts (Figure S1). However, interestingly, compound
4a (18%) was the outcome of a Michael addition reaction of 4
and the unreactive starting nitrostyrene 3 (Figure S2, Table
S1); therefore, the total yield of the 7mrFPs was ∼50%.38 The
use of the well-characterized Cu(II)−benzotriazole-based
precatalysts (1% loading) (Cu-1, Cu-2, Cu-3, and Cu-4)39,40
improved the yield of total 7mrFPs (4 + 4a ∼90%) and
minimized the byproduct formation (<10%). Compounds
B
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Scheme 2. Synthesis of the 7-mrFPs 4−23, 4a−7a, 17a and
18a in the Presence of CuI or Cu(NO3)2 in MeOH
Scheme 3. Substrate Evaluation for the Cu-Mediated
Synthesis of Fused Pyrroles
heteroaromatic 2-(2-thiophenyl)-1-nitroethylene provided the
penta-substituted 7mrFP in 38% yield (see Figure S5).
Lastly, to assess this process’s potential, we also carried out
the synthesis of 13 on a 1 mmol scale with 10% mol of CuI and
5 mL of MeOH at 70 °C in a 15 mL sealed tube. After reaction
completion, the desired pyrrole 13 was isolated in 48% yield
(Scheme 2). Similarly, with 10% mol of Cu(NO3)2, the
corresponding homo-penta-substituted 7-mrFP 4a was isolated
in 39% yield (Scheme 2).
We carried out targeted trials and density functional theory
(DFT) studies to shed light on the plausible mechanism. The
use of 2-phenylcyclopropyl aldehyde (1′) in place of 1 failed to
afford the expected four-membered fused pyrrole (4′);
however, the reaction of cyclopentanecarbaldehyde 1′′ yielded
the corresponding six-membered fused pyrrole 4′′ in 60% yield
(Scheme 3). The use of cyclohexanone in place of 1 afforded
the fused pyrrole 4′′ in a low 26% yield (Scheme 3). These
observations disfavor the use of ketones as the starting
carbonyl component in our protocol. Then, electron-with-
drawing substituted styrenes, that is, −CN and −COOMe, as
well as styrene and β-Br-substituted styrene (Figure S6)
discarded the 7-mrFP formation. Similar results were observed
using other conjugated compounds, such as methylpropiolate
or phenylacetylene, in place of β-nitrostyrene 3. Still, the use of
methyl propiolate or dimethyl acetylene dicarboxylate
(DMAD) yielded a mixture of unidentified products (Figure
S6). These results indicate the necessity of conjugated
nitroalkene in our protocol. Reactions in the presence of
TEMPO, with or without CuI, yielded a mixture of
unidentified products, aldehyde 3b, as the primary product,
and the desired 7-mrFPs 4 (ca. 5−10%) (results not shown).
On the basis of NMR analysis, imine 2a reacted with TEMPO,
alkene remained intact, or a mixture of unidentified products
was observed (Scheme 3). The reactions with p-toluidine lead
to the corresponding 7-mrFPs in ca. 60% yield; however, in the
absence of a catalyst, they failed to produce the desired pyrrole
(Scheme 3). This result enhances the necessity of a Cu-
mediated pathway. To further expand the scope, we used 2-
cyclohexyl-1-nitroethylene, which gave the corresponding
7mrFP in low yield (10%, see Figure S4), whereas the
C
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yielding a mixture of unidentified oxidizing products.41 Lastly,
the reaction of ethanolamine instead of BuNH2 lead to the
formation of the desired pyrrole 19 in an almost 1:1 ratio with
the spiro-pyrrolo-oxazol derivative 19′ (Scheme 3). On the
basis of this experimental evidence (Figure 1 and Scheme 3)
and the preliminary theoretical studies (Figures S7), this
organic transformation is a cooperative outcome of the Cu
entity and the MeOH solvent. The desired 7-mrFPs are
formed via an in situ spiro-intermediate ring expansion,
however, further experiments and calculations are necessary
to fully elucidate the mechanism.
Given the limited biological and pharmacological evidence
of 7-mFPs28 and motivated by Barclay’s successful demon-
stration of pyrroles as antioxidants to scavenge radicals,42 we
explored the antioxidant behavior of selected molecules. On
the basis of the literature,43 we chose the hydrophobic 4, 9,
and 18 and the nitro-substituted 8, 14, and 15 derivatives. The
antioxidant activity was evaluated via their ability to scavenge
in vitro free radicals such as 1,1-diphenyl-picrylhydrazyl
(DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic
acid) (ABTS), and hydroxyl (HO•) compared with the
common antioxidant agents nordihydroguaiaretic acid
(NDGA), butylated hydroxytoluene (BHT), and trolox
(Table S6). On average, all pyrroles showed higher activity
against HO• and a low to moderate ability to scavenge ABTS
and DPPH. Furthermore, the ability of pyrroles to scavenge
HO• is higher than that of the reference compound trolox.
Specifically, the hydrophobic pyrroles 4, 9, and 18 show higher
activity, and 18 outperforms the others (Figure 2). Moreover,
using the SwissADME web tool,44 we theoretically evaluate the
pharmacokinetics, drug-likeness and medicinal chemistry
friendliness of all of the small molecules produced with our
method (Figure S8). This predictive tool suggests that
compounds 13 and 16 are good candidates to passively
permeate the blood−brain barrier and the effluent from the
central nervous system. In contrast, compounds 8, 14, and 19
may passively permeate the blood−brain barrier but not the
effluent from the central nervous system. Both experimental
and theoretical data determine the biological importance of
this class of previously unknown 7-mrFPs, giving rise to a
plausible approach for a series of pro-drug molecules and
opening new research biological avenues.
To the best of our knowledge, we report the first
methodology that yields a comprehensive library of 7-mrFPs,
in one step, from readily available resources in good yields in a
clean manner. We can tune the skeletal substitution with
tangible parameters and substrate alterations and easily obtain
previously inaccessible molecules. Biological studies of selected
examples reveal high antioxidant activity, certifying our choice
to invest and extend this family of pyrrole derivatives. Work to
expand this methodology into other products, further optimize
the precatalysts and protocol, and study these components’
biological activity are under investigation.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02251.
General procedures, experimental section, mechanistic
studies, antioxidant activity, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Ioannis N. Lykakis − Department of Chemistry, Aristotle
University of Thessaloniki, 54124 Thessaloniki, Greece;
orcid.org/0000-0001-8165-5604; Email: lykakis@
chem.auth.gr
George E. Kostakis − Department of Chemistry, School of Life
Sciences, University of Sussex, Brighton BN19QJ, United
Kingdom; orcid.org/0000-0002-4316-4369;
Email: G.Kostakis@sussex.ac.uk
Authors
Dimitrios Andreou − Department of Chemistry, Aristotle
University of Thessaloniki, 54124 Thessaloniki, Greece
Nsikak B. Essien − Department of Chemistry, School of Life
Sciences, University of Sussex, Brighton BN19QJ, United
Kingdom
Cristina Pubill-Ulldemolins − Department of Chemistry,
School of Life Sciences, University of Sussex, Brighton
BN19QJ, United Kingdom
Michael A. Terzidis − Department of Nutritional Sciences &
Dietetics, International Hellenic University, 57400
Thessaloniki, Greece
Athanasios N. Papadopoulos − Department of Nutritional
Sciences & Dietetics, International Hellenic University, 57400
Thessaloniki, Greece
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02251
Author Contributions
All authors contributed to writing the manuscript and
approved its final version. I.N.L. devised the project with
critical input and comments from G.E.K. D.A., with I.N.L.,
performed and evaluated the catalytic experiments. N.B.E.
Figure 2. % DPPH scavenging ability (RA%), % superoxide radical
scavenging activity (ABTS%), and competition % with DMSO for the
hydroxyl radical (HO• %) for pyrroles 4, 8, 9, 14, 15, and 18.
D
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biological studies. C.P.-U. performed the theoretical calcu-
lations
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research work was supported by the Hellenic Foundation
for Research and Innovation (HFRI) and the General
Secretariat for Research and Technology (GSRT) under the
HFRI Ph.D. Fellowship grant to D.A. (GA. 2355). I.N.L.
acknowledges the project “An Open-Access Research Infra-
structure of Chemical Biology and Target-Based Screening
Technologies for Human and Animal Health, Agriculture and
the Environment (OPENSCREEN-GR)” (MIS 5002691),
implemented under the Action “Reinforcement of the
Research and Innovation Infrastructure”, funded by NSRF
2014-2020 and cofinanced by the Greece and the European
Union. N.B.E. acknowledges TETFUND for a Ph.D. fellow-
ship. C.P.-U. thanks the Wellcome Trust and the School of Life
Sciences for funding support.
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