Amide formation via ni-catalyzed reductive coupling reactions with isocyanates

• Autores: Eloísa Sofia Serrano Robledo
• Directores de la Tesis: Ruben Martin Romo (dir. tes.)
• Lectura: En la Universitat Rovira i Virgili ( España ) en 2018
• Idioma: español
• Tribunal Calificador de la Tesis: Miquel Costas Salgueiro (presid.), Pablo Mauleón Pérez (secret.), Clement Mazet (voc.)
• Programa de doctorado: Programa de Doctorado en Ciencia y Tecnología Química por la Universidad Rovira i Virgili
• Materias:
  • Ciencias tecnológicas
    • Ingeniería y tecnología químicas
      • Tecnología de catálisis
• Enlaces
  • Tesis en acceso abierto en:  hdl.handle.net  TDX 
• Resumen

  • Recently, reductive cross-electrophile couplings have become powerful alternatives to classical cross-coupling reactions that are based on nucleophile/electrophile regimes.(1-3) Starting from readily available building blocks, reductive couplings are practical and mild protocols that circumvent the use of moisture and air-sensitive organometallic species. In line with the Martin group’s interest in developing strategies that use heteroallenes to access value-added compounds,(4, 5) the current Doctoral Thesis focuses on the development of novel nickel-catalyzed reductive protocols for the synthesis of amides from isocyanates. The ubiquity of amides in biologically relevant molecules such as peptides, proteins, agrochemicals and pharmaceuticals, as well as in synthetic materials, continually prompts the development of novel methods for amide synthesis. The transformations developed herein contribute to the formation of amides via metal-catalyzed C—C bond formation.

    Our first strategy aimed to synthesize aliphatic amides from unactivated alkyl bromides using isocyanates as amide synthons.(6) This required overcoming two main challenges. Firstly, alkyl halides are in general challenging substrates due to their propensity to undergo unproductive reduction, homodimerization and β-hydride elimination reactions.(7) Secondly, isocyanates pose a challenge in catalytic protocols due to their high reactivity and ability to bind strongly to low-valent transition metal complexes, as well as their ease to undergo dimerization and trimerization reactions.(8) Optimized reaction conditions used a cheap Ni(II) source in combination with bipyridine-type ligands and Mn as the reducing agent. The transformation allowed primary, secondary and tertiary alkyl bromides to be coupled with aryl and alkyl isocyanates. Furthermore, tertiary N-substituted amides could be accessed via the sequential addition of a third electrophile in a one-pot protocol.

    Our second strategy focused on the synthesis of acrylamides via the hydroamidation of alkynes using isocyanates.(9) One of the primary challenges at the outset of these studies was the sensitivity of isocyanates to nucleophiles, including hydride sources. In this project, we took advantage of the propensity of alkyl bromides to undergo β-hydride elimination to generate catalytic amounts of Ni—H species that could perform the hydrometallation step. Using a catalytic system based on a Ni(II) source, phenanthroline-type ligands, Mn as the reducing agent, and isopropyl bromide as the hydride source, a broad range of aryl-, alkyl-, silyl- and boryl-substituted acetylenes could be combined with aryl and alkyl isocyanates to give the desired acrylamides with high levels of diastereoselectivity. For both of the above-mentioned transformations, preliminary mechanistic studies and stoichiometric experiments with Ni(0) and Ni(II)-complexes have pointed towards reaction mechanisms involving the intermediacy of Ni(I) species.

    Our last venture aimed to develop a divergent synthesis of branched and linear amides from unactivated secondary acyclic alkyl halides by means of a retentive and a chain-walking amidation, respectively.(10) The key to the successful retentive amidation was to supress β-hydride elimination by using low reaction temperatures and fine-tuned bipyridine ligands. The optimization of the chain-walking amidation is challenging, as contrary to the project developed previously by our group using CO₂,(11) the secondary alkyl positions present in the chain can be readily amidated, posing selectivity issues. The optimization of the reaction temperature and the π–acceptor bipyridine ligand will be the key to reaching high levels of regioselectivity towards the linear amide product. This project is still ongoing in our laboratories.