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’s 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[10–12] . 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’- and 3,3’- biindole backbone 3 Inherently chiral materials based on 2,2’-biindole are characterized by an atropoisomeric backbone of two 2,2’ interconnected indole rings bearing 3,3’ substituents usually constituted by 2,2’-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’-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’-substituents. Introduction of a π 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’-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’-diaryl/heteroaryl 2,2’-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’-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’-diheteroaryl-3,3’-biindole 3,3’-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’-Ind2T4 (up); chiral HPLC profiles at different temperatures (bottom). Computational studies indicated possibility to achieve configurational stability for 3,3’-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, 491–502. [3] T. C. Barden, Peptides 2011, 26, 31–46. [4] A. Penoni, K. M. Nicholas, Chem. Commun. 2002, 2, 484–485. [5] A. Penoni, J. Volkmann, K. M. Nicholas, Org. Lett. 2002, 4, 699–701. [6] F. Tibiletti, M. Simonetti, K. M. Nicholas, G. Palmisano, M. Parravicini, F. Imbesi, S. Tollari, A. Penoni, 6 Tetrahedron 2010, 66, 1280–1288. [7] A. Penoni, G. Palmisano, Y. Zhao, K. N. Houk, J. Volkman, K. M. Nicholas, J. Am. Chem. Soc. 2009, 131, 653–661. [8] D. G. Zhao, J. Chen, Y. R. Du, Y. Y. Ma, Y. X. Chen, K. Gao, B. R. Hu, J. Med. Chem. 2013, 56, 1467– 1477. [9] S. J. Yao, Z. H. Ren, Z. H. Guan, Tetrahedron Lett. 2016, 57, 3892–3901. [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, 6853–6859. [11] L. Scapinello, A. Maspero, S. Tollari, G. Palmisano, K. M. Nicholas, A. Penoni, J. Vis. Exp. 2020, 155, 1– 12. [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, 2708–2717. [14] G. Abbiati, A. Arcadi, E. Beccalli, G. Bianchi, F. Marinelli, E. Rossi, Tetrahedron 2006, 62, 3033–3039

Indoles and Biindoles: Synthesis of Powerful Tools for Pharmaceutical and Materials Sciences / Luca Scapinello - : . , 2021. ((33. ciclo, Anno Accademico 2019/2020.

Indoles and Biindoles: Synthesis of Powerful Tools for Pharmaceutical and Materials Sciences

SCAPINELLO luca
2021-01-01

Abstract

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’s 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[10–12] . 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’- and 3,3’- biindole backbone 3 Inherently chiral materials based on 2,2’-biindole are characterized by an atropoisomeric backbone of two 2,2’ interconnected indole rings bearing 3,3’ substituents usually constituted by 2,2’-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’-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’-substituents. Introduction of a π 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’-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’-diaryl/heteroaryl 2,2’-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’-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’-diheteroaryl-3,3’-biindole 3,3’-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’-Ind2T4 (up); chiral HPLC profiles at different temperatures (bottom). Computational studies indicated possibility to achieve configurational stability for 3,3’-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, 491–502. [3] T. C. Barden, Peptides 2011, 26, 31–46. [4] A. Penoni, K. M. Nicholas, Chem. Commun. 2002, 2, 484–485. [5] A. Penoni, J. Volkmann, K. M. Nicholas, Org. Lett. 2002, 4, 699–701. [6] F. Tibiletti, M. Simonetti, K. M. Nicholas, G. Palmisano, M. Parravicini, F. Imbesi, S. Tollari, A. Penoni, 6 Tetrahedron 2010, 66, 1280–1288. [7] A. Penoni, G. Palmisano, Y. Zhao, K. N. Houk, J. Volkman, K. M. Nicholas, J. Am. Chem. Soc. 2009, 131, 653–661. [8] D. G. Zhao, J. Chen, Y. R. Du, Y. Y. Ma, Y. X. Chen, K. Gao, B. R. Hu, J. Med. Chem. 2013, 56, 1467– 1477. [9] S. J. Yao, Z. H. Ren, Z. H. Guan, Tetrahedron Lett. 2016, 57, 3892–3901. [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, 6853–6859. [11] L. Scapinello, A. Maspero, S. Tollari, G. Palmisano, K. M. Nicholas, A. Penoni, J. Vis. Exp. 2020, 155, 1– 12. [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, 2708–2717. [14] G. Abbiati, A. Arcadi, E. Beccalli, G. Bianchi, F. Marinelli, E. Rossi, Tetrahedron 2006, 62, 3033–3039
indoles, biiindoles, nitrosoarenes, alkynes, chiral electrodes, inherently chiral materials
Indoles and Biindoles: Synthesis of Powerful Tools for Pharmaceutical and Materials Sciences / Luca Scapinello - : . , 2021. ((33. ciclo, Anno Accademico 2019/2020.
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