Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors

[eng] Radical reactions have been proven valuable tools in C-C bond generation because the initial radical can evolve to form additional C-C bonds until the new radical species is trapped. With the careful design of the substrates and the control of the reaction conditions, tandem radical reactions...

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Author: Puig Bosch, Jordi
Format: doctoral thesis
Status:Published version
Publication Date:2024
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/220600
Online Access:https://hdl.handle.net/2445/220600
http://hdl.handle.net/10803/694298
Access Level:Open access
Keyword:Reaccions químiques
Isonitrils
Chemical reactions
Isocyanides
id ES_e099e2a6d850e7ee6f87b0f2883fc113
oai_identifier_str oai:diposit.ub.edu:2445/220600
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
title Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
spellingShingle Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
Puig Bosch, Jordi
Reaccions químiques
Isonitrils
Chemical reactions
Isocyanides
title_short Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
title_full Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
title_fullStr Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
title_full_unstemmed Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
title_sort Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical Acceptors
dc.creator.none.fl_str_mv Puig Bosch, Jordi
author Puig Bosch, Jordi
author_facet Puig Bosch, Jordi
author_role author
dc.contributor.none.fl_str_mv Bradshaw, Ben
Bonjoch i Sesé, Josep
Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica
dc.subject.none.fl_str_mv Reaccions químiques
Isonitrils
Chemical reactions
Isocyanides
topic Reaccions químiques
Isonitrils
Chemical reactions
Isocyanides
description [eng] Radical reactions have been proven valuable tools in C-C bond generation because the initial radical can evolve to form additional C-C bonds until the new radical species is trapped. With the careful design of the substrates and the control of the reaction conditions, tandem radical reactions can be developed that allow the construction of complex structures starting from simple starting materials. Metal-catalyzed hydrogen atom transfer (MHAT) reactions are radical-based reactions that allow mild and non-toxic conditions, with high chemo- and site-selectivity and a wide functional group tolerance. Our group has developed several MHAT C-C bond-forming reactions of non-activated alkenes with a wide variety of acceptor groups such as aldehydes, ketones, Cbz hydrazones, and tosylhydrazones. Despite the many advantages presented by MHATbased radical reactions and their potential for developing new tandem reactions, few examples have yet been reported in the literature. In the present thesis, the aim was to expand the scope of radical acceptors that can be used in MHAT reactions as well as develop novel tandem reaction processes. First, isocyanides have been studied as radical acceptors to carry out a tandem reaction to obtain functionalized nitrogen heterocycles, highly valued compounds in medical chemistry (Scheme 2). The reaction uses MHAT conditions to generate a radical on an alkene that carries out a first radical addition step on the isocyanide, followed by subsequent intramolecular cyclization to give rise to the functionalized heterocycle. A wide range of different nitrogen-containing heterocycles can be synthesized using this methodology. In cases where the alkene substitution made it more challenging, combining HAT-Minisci conditions made the coupling possible. The reductive cyclization of these isocyanides has also been shown to be effective, in the absence of alkene, to give rise to the corresponding unfunctionalized heterocycles. Secondly, a cross-dehydrogenative coupling reaction has been developed from the initial serendipitously observed side reaction. Using conditions derived from MHAT and Minisci, it has been possible to generate radicals through C-H activation on the - position of ethers, amides, and alkanes to carry out the radical coupling on activated heterorenes. This reaction has the potential to be applied in medicinal chemistry for latestage functionalization under mild conditions. Thirdly, the use of tosylhydrazones as acceptor groups in MHAT reactions has been studied to carry out a tandem reaction that begins with intramolecular cyclization followed by in situ fragmentation of the tosylhydrazine and subsequent intermolecular trapping of the generated tertiary radical with a Michael acceptor in a Giese-type addition. This reaction allows the generation of two adjacent quaternary centers in a single reaction via the formation of two geminal C-C bonds. This methodology has been used to prepare functionalized derivatives of adamantane, a very interesting scaffold from the point of view of medicinal chemistry and other fields, using different Michael acceptors. Further transformations also allowed the preparation of adamantanesubstituted heterocycles.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/220600
http://hdl.handle.net/10803/694298
url https://hdl.handle.net/2445/220600
http://hdl.handle.net/10803/694298
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Puig Bosch, Jordi, 2025
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Puig Bosch, Jordi, 2025
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Departament - Farmacologia, Toxicologia i Química Terapèutica
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869422217254666240
spelling Development of Iron-Catalyzed Hydrogen Atom Transfer Driven Cross-Coupling and Cyclization Reactions: Use of Isocyanides, Heterocycles and Tosylhydrazones as Radical AcceptorsPuig Bosch, JordiReaccions químiquesIsonitrilsChemical reactionsIsocyanides[eng] Radical reactions have been proven valuable tools in C-C bond generation because the initial radical can evolve to form additional C-C bonds until the new radical species is trapped. With the careful design of the substrates and the control of the reaction conditions, tandem radical reactions can be developed that allow the construction of complex structures starting from simple starting materials. Metal-catalyzed hydrogen atom transfer (MHAT) reactions are radical-based reactions that allow mild and non-toxic conditions, with high chemo- and site-selectivity and a wide functional group tolerance. Our group has developed several MHAT C-C bond-forming reactions of non-activated alkenes with a wide variety of acceptor groups such as aldehydes, ketones, Cbz hydrazones, and tosylhydrazones. Despite the many advantages presented by MHATbased radical reactions and their potential for developing new tandem reactions, few examples have yet been reported in the literature. In the present thesis, the aim was to expand the scope of radical acceptors that can be used in MHAT reactions as well as develop novel tandem reaction processes. First, isocyanides have been studied as radical acceptors to carry out a tandem reaction to obtain functionalized nitrogen heterocycles, highly valued compounds in medical chemistry (Scheme 2). The reaction uses MHAT conditions to generate a radical on an alkene that carries out a first radical addition step on the isocyanide, followed by subsequent intramolecular cyclization to give rise to the functionalized heterocycle. A wide range of different nitrogen-containing heterocycles can be synthesized using this methodology. In cases where the alkene substitution made it more challenging, combining HAT-Minisci conditions made the coupling possible. The reductive cyclization of these isocyanides has also been shown to be effective, in the absence of alkene, to give rise to the corresponding unfunctionalized heterocycles. Secondly, a cross-dehydrogenative coupling reaction has been developed from the initial serendipitously observed side reaction. Using conditions derived from MHAT and Minisci, it has been possible to generate radicals through C-H activation on the - position of ethers, amides, and alkanes to carry out the radical coupling on activated heterorenes. This reaction has the potential to be applied in medicinal chemistry for latestage functionalization under mild conditions. Thirdly, the use of tosylhydrazones as acceptor groups in MHAT reactions has been studied to carry out a tandem reaction that begins with intramolecular cyclization followed by in situ fragmentation of the tosylhydrazine and subsequent intermolecular trapping of the generated tertiary radical with a Michael acceptor in a Giese-type addition. This reaction allows the generation of two adjacent quaternary centers in a single reaction via the formation of two geminal C-C bonds. This methodology has been used to prepare functionalized derivatives of adamantane, a very interesting scaffold from the point of view of medicinal chemistry and other fields, using different Michael acceptors. Further transformations also allowed the preparation of adamantanesubstituted heterocycles.[cat] Les reaccions radicalàries destaquen com una eina per a la generació d’enllaços C C. En aquest camp, les reaccions de transferència d’àtom d’hidrogen catalitzades per metall (MHAT) s’han erigit com un mètode molt eficient per la generació d’aquest tipus enllaç degut a que utilitzen condicions de reacció suaus i no tòxiques, presenten alta quimio i regioselectivitat així com àmplia tolerància de grups funcionals. En aquest camp, el nostre grup ha desenvolupat diverses reaccions MHAT per la generació d’enl laços C C utilitzant diversos acceptors radicalaris com aldehids, cetones, Cbz hidrazones i tosil hidrazones. Per expandir el nostre coneixement en les reaccions MHAT i ampliar l’espectre de grups acceptors, la present tesi s’ha centrat en la investigació d’aquests processos. En primer lloc, es van estudiar els isocianurs com a grups acceptors radicalaris per formar i funcionalitzar heterocicles nitrogenats utilitzant alquens com a donadors radicalaris sota condicions MHAT. Es va poder optimitzar el procés i s’han pogut utilitzar diferents isocianurs com a substrats per generar nuclis funcional itzats de fenantridines, isoquinolines i indoles a través d’una reacció tàndem que inclou un primer pas d’addició intermolecular entre l’alquè i l’isocianur, seguit d’una ciclació intramol ecular. En els casos en que el grau de substitució de l’alquè feia difícil la reacció, es van combinar les condicions MHAT amb la reacció de Minisci per fer ho possible. També es va dur a terme amb èxit la ciclació reductiva dels isocianurs en absència d’a lquè per obtenir els heterocicles sense funcionalitzar. En segon lloc, es va desenvolupar una reacció d’activació C H a partir d’una reacció secundaria observada casualment. Aquesta va permetre la funcionalització d’heteroarens utilitzant èters, amides i alcans com a grups donadors radicalaris. Per fer ho, es van utilitzar condicions derivades de les util itzades en reaccions MHAT i Minisci. Finalment, es va desenvolupar una reacció radicalària tàndem utilitzant condicions MHAT utilitzant tosilhidrazones. La reacció inclou una primera etapa de ciclació intramolecular seguida d’una alquilació i intermolecular utilitzant un acceptor de Michael i permet generar dos centres quaternaris adjacents en una sola reacció a través de la formació de dos enllaços C C geminals.Universitat de BarcelonaBradshaw, BenBonjoch i Sesé, JosepUniversitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica2024info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/220600http://hdl.handle.net/10803/694298Tesis Doctorals - Departament - Farmacologia, Toxicologia i Química Terapèuticareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Puig Bosch, Jordi, 2025info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2206002026-05-27T06:46:51Z
score 15.81155

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