Part 1: synthesis of indoles as potential bioactive compounds
Indole and related derivatives play a strong relevant role in heterocyclic chemistry. They are diffused in a
huge array of different natural products[1], many of them with intriguing biological activity.[2] Other
applications spread uncountable fields: material science, fragrances, agrochemicals, pigments and dyes and
many more.[3] It\u2019s not surprising then that many efforts are made by organic chemists to find not only
synthetic methods to achieve indole fragments but also new functionalization protocols to afford with ease
complex targets.
Recently, Penoni group afforded a novel regioselective indole synthesis via annulation of variously
substituted nitrosoarenes and alkynes[4,5] (Figure 1). Main feature of this reaction is possibility to directly
prepare N-hydroxyindoles derivatives, when 4-nitronitrosobenzene is employed as reaction partner. High
efficiency on nitrosoarene-alkyne cycloaddition was noticed by trapping the formed unstable N-OH indole
product by methylation or interception with other electrophiles. Concerning other alkyne reactions with
other substituted nitrosobenzenes, indoles were detected as products; this feature was exploited to prepare
marine alkaloids meridianins and some modified aminoacids[6] (Figure 1). Reaction is supposed to pass
through a radical mechanism[7]
.
Figure 1: annulation reaction between alkynes and nitrosoarenes
3-Acylindoles(e.g. pravadoline, SCB01A, BPR0L075) are known to be bioactive compounds and recent studies
highlighted their interesting properties[8] and various synthetic approaches[9]. However, not many
indolization protocols are known to afford directly 3-acylindoles starting from easily available reactants.
Research topic was therefore focused on applying and optimizing nitrosoarene-alkyne one pot annulation
2
approach for the preparation of highly functionalizable compounds and/or biologically active products having
the 3-aroylindole fragment (Figure 2). Noticeably, after careful reaction optimization, unprotected Nhydroxy-3-aroylindoles were regioselectively detected as main products in most cases and recovered as
perfectly stable solid after precipitation with no need of protecting groups[10\u201312]
. Internal alkynes gave poor
reactivity.
Figure 2: annulation reaction between alkynones and nitrosoarenes.
Interestingly, reaction between 4-nitronitrosobenzene and 3-bromo-1-phenylprop-2-yn-1-one gave
regioselectively a 2-brominated indole compound. It is set as an objective for the near future a wide substrate
scope for synthesis of different 2-brominated indoles (Figure 3). Studies of reactivity of the latter compounds
towards classical cross coupling reactions is expected as well (Figure 3).
Figure 3: synthesis of a N-hydroxy-3-aroyl-2-bromo-indole (left); reactivity of the latter to classic cross
coupling reactions (right).
Part 2: synthesis of new organic semiconductors based on 2,2\u2019- and 3,3\u2019- biindole backbone
3
Inherently chiral materials based on 2,2\u2019-biindole are characterized by an atropoisomeric backbone of two
2,2\u2019 interconnected indole rings bearing 3,3\u2019 substituents usually constituted by 2,2\u2019-bitiophene units(Ind2T4,
Figure 4). Those substituents play the double role of hindering rotation around the interannular bond and
endowing system with specific properties. Main application of inherently chiral 2,2\u2019-biindoles is as starting
materials to obtain enantiopure oligomeric selectors in chiral electrochemistry[13]
. Monomer oligomerization
is usually performed in electrochemical cell by many repeating anodic voltametric cycles to afford an
oligomeric coating directly on working electrode. Our interest in the chemistry of indoles led us to explore
the opportunity to get some analogous structure by structural modification of 3,3\u2019-substituents. Introduction
of a \u3c0 spacer (Ind2Ph2T4, Ind2T6, Figure 4) was performed to study its influence on chiral properties of resulting
oligomers, whilst introduction of a benzochalchogenodiazole subunit allows to achieve a donor-acceptor
moiety with interesting optical properties (Ind2BTD2T4, Ind2BSeD2T4, Figure 4).
Figure 4: enantiomers of Ind2T4 (left); target 2,2\u2019-biindoles (right). R = alkyl.
Key core for synthesis of these compounds is a Larock-type 5-endo-dig double indole ring closure starting
from compound 1 (Scheme 1), as published by Abbiati in 2006[14]. This protocol shows good versatility as by
variation of aryl- or heteroaryl halide reaction partner is possible to prepare different 3,3\u2019-diaryl/heteroaryl
2,2\u2019-biindoles although in good to mediocre yield. Only racemate compounds are afforded due to lack of any
chiral catalyst. Subsequent nitrogen alkylation step is fundamental to ensure good solubility for processing.
Scheme 1: synthesis of 2,2\u2019-biindoles starting from 1 and an aryl/heteroaryl halide.
4
All new compounds have been deeply characterized either monomeric or oligomeric. Separation of Ind2Ph2T4,
Ind2T6 in their two enantiomers was performed through semipreparative chiral HPLC, as up to now synthetic
method allows only to afford targets as racemate mixtures. After electrodeposition, Ind2Ph2T4 and Ind2T6
enantiopure oligomeric films showed great enantioselectivity towards both enantiomers of a chiral
ferrocenylamine (Figure 5).
Figure 5: cyclic voltammetry graphs showing different oxidation peaks for enantiopure oligo N-Pr-Ind2Ph2T4
(left) and N-Pr-Ind2T6 (right) towards two enantiomers of a chiral ferrocenylamine (bottom).
Concerning Ind2BTD2T4 and Ind2BSeD2T4, full characterization of monomers and electroactive films has been
carried out. Enantiorecognition tests are planned for next future.
Since Larock-type ring closure reaction has been proved very useful although mediocre yielding, a new and
more performant synthetic plan to afford Ind2T4 has been optimized (Scheme 2). Key step is high yield SuzukiMiyaura cross coupling reaction starting from compound 5. Future developments concern on use of different
boronic pinacol esters to afford Ind2Ph2T4, Ind2T6, Ind2BTD2T4 and Ind2BSeD2T4 in better yields as well.
5
Scheme 2: synthesis of Ind2T4 passing through a Suzuki cross coupling step.
Structural analogue 2,2\u2019-diheteroaryl-3,3\u2019-biindole 3,3\u2019-Ind2T4 (Figure 6) was synthetized as well with the aim
to investigate its ability as chiral selectors. Unfortunately, when trying to separate them with chiral HPLC,
enantiomers peaks coalescence was noticed even at room temperature, suggesting configurational
instability.
Figure 6: synthesis of 3,3\u2019-Ind2T4 (up); chiral HPLC profiles at different temperatures (bottom).
Computational studies indicated possibility to achieve configurational stability for 3,3\u2019-biindoles by nitrogen
alkylation with very bulky tertbutyl group. Experiments in this direction are currently ongoing.
References:
[1] R. J. Sundberg, The Chemistry of Indoles, New York, 1970.
[2] V. Sharma, P. Kumar, D. Pathak, J. Heterocycl. Chem. 2010, 47, 491\u2013502.
[3] T. C. Barden, Peptides 2011, 26, 31\u201346.
[4] A. Penoni, K. M. Nicholas, Chem. Commun. 2002, 2, 484\u2013485.
[5] A. Penoni, J. Volkmann, K. M. Nicholas, Org. Lett. 2002, 4, 699\u2013701.
[6] F. Tibiletti, M. Simonetti, K. M. Nicholas, G. Palmisano, M. Parravicini, F. Imbesi, S. Tollari, A. Penoni,
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Tetrahedron 2010, 66, 1280\u20131288.
[7] A. Penoni, G. Palmisano, Y. Zhao, K. N. Houk, J. Volkman, K. M. Nicholas, J. Am. Chem. Soc. 2009,
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[10] G. Ieronimo, G. Palmisano, A. Maspero, A. Marzorati, L. Scapinello, N. Masciocchi, G. Cravotto, A.
Barge, M. Simonetti, K. L. Ameta, et al., Org. Biomol. Chem. 2018, 16, 6853\u20136859.
[11] L. Scapinello, A. Maspero, S. Tollari, G. Palmisano, K. M. Nicholas, A. Penoni, J. Vis. Exp. 2020, 155, 1\u2013
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[12] L. Scapinello, F. Vavassori, G. Ieronimo, K. L. Ameta, G. Cravotto, M. Simonetti, S. Tollari, G.
Palmisano, A. Maspero, K. M. Nicholas, et al., Manuscript in Preparation, 2020.
[13] S. Arnaboldi, T. Benincori, A. Penoni, L. Vaghi, R. Cirilli, S. Abbate, G. Longhi, G. Mazzeo, S. Grecchi,
M. Panigati, et al., Chem. Sci. 2019, 10, 2708\u20132717.
[14] G. Abbiati, A. Arcadi, E. Beccalli, G. Bianchi, F. Marinelli, E. Rossi, Tetrahedron 2006, 62, 3033\u2013303