학술논문
Amide Formation via Ni-Catalyzed Reductive Coupling Reactions with Isocyanates
Document Type
Dissertation/Thesis
Source
TDX (Tesis Doctorals en Xarxa)
Subject
Language
English
Abstract
Recientemente, las reacciones de acoplamiento cruzado entre electrófilos se han posicionado como potentes alternativas a las reacciones clásicas de acoplamiento cruzado entre electrófilos orgánicos y nucleófilos organometálicos. Dichos acoplamientos reductivos ofrecen numerosas ventajas, ya que utilizan compuestos de partida simples y fácilmente asequibles que evitan la necesidad de sintetizar especies organometálicas sensibles a la humedad y al oxígeno. Debido a ello, los protocolos experimentales son prácticos y las condiciones de reacción suaves. La ubiquidad de las amidas en moléculas biológicamente activas tales como péptidos, agroquímicos y productos farmacéuticos, así como en materiales sintéticos, impulsa continuamente el desarrollo de nuevos métodos para la síntesis eficiente de amidas. La presente Tesis Doctoral, se centra en el desarrollo de nuevos acoplamientos reductivos cruzados catalizados por níquel para la síntesis de amidas, utilizando isocianatos como el sintón correspondiente a la amida. Específicamente, se presenta un nuevo protocolo para la síntesis de amidas alifáticas a partir de bromuros de alquilo primarios, secundarios y terciarios en combinación con isocianatos de arilo y alquilo. Asimismo, se incluye el desarrollo de una metodología para la hidroamidación altamente diastereoselectiva de alquinos con isocianatos para la formación de acrilamidas. Dicho protocolo utiliza bromuros de alquilo como fuentes suaves para la formación de hidruros in situ. Finalmente, se discuten resultados preliminares sobre la amidación regiodivergente, retentiva y remota, de bromuros de alquilo secundarios inactivados. Las transformaciones desarrolladas aquí constituyen nuevos métodos para la síntesis de amidas mediante la formación de enlaces C-C catalizada por metales y se caracterizan por sus condiciones suaves, su amplio alcance de reacción, su excelente regioselectividad y alta tolerancia a diversos grupos funcionales.
Recently, cross-electrophile couplings have become powerful alternatives to classical cross-coupling reactions that are based on nucleophile/electrophile regimes. Starting from readily available building blocks, reductive couplings are practical and mild protocols that circumvent the use of moisture and air-sensitive organometallic species. The ubiquity of amides in biologically relevant molecules such as peptides, agrochemicals and pharmaceuticals, as well as in polymers, continually prompts the design of novel methods for amide synthesis. This Doctoral Thesis focuses on the development of novel nickel-catalyzed reductive protocols for the synthesis of amides using isocyanates as the amide synthon. Specifically, we have discovered a novel protocol for the synthesis of aliphatic amides from primary, secondary and tertiary alkyl bromides in combination with aryl and alkyl isocyanates. A methodology for the highly diastereoselective hydroamidation of alkynes with isocyanates to afford acrylamides has been developed, with alkyl bromides used as in situ and mild hydride sources. Finally, efforts towards the regiodivergent retentive and chain-walking amidation of unactivated acyclic secondary alkyl bromides are discussed. The transformations developed herein are characterized by their mild conditions, wide substrate scope and excellent chemo- and regioselectivity, and constitute novel methods for the formation of amides via metal-catalyzed C—C bond formation.
Recently, cross-electrophile couplings have become powerful alternatives to classical cross-coupling reactions that are based on nucleophile/electrophile regimes. Starting from readily available building blocks, reductive couplings are practical and mild protocols that circumvent the use of moisture and air-sensitive organometallic species. The ubiquity of amides in biologically relevant molecules such as peptides, agrochemicals and pharmaceuticals, as well as in polymers, continually prompts the design of novel methods for amide synthesis. This Doctoral Thesis focuses on the development of novel nickel-catalyzed reductive protocols for the synthesis of amides using isocyanates as the amide synthon. Specifically, we have discovered a novel protocol for the synthesis of aliphatic amides from primary, secondary and tertiary alkyl bromides in combination with aryl and alkyl isocyanates. A methodology for the highly diastereoselective hydroamidation of alkynes with isocyanates to afford acrylamides has been developed, with alkyl bromides used as in situ and mild hydride sources. Finally, efforts towards the regiodivergent retentive and chain-walking amidation of unactivated acyclic secondary alkyl bromides are discussed. The transformations developed herein are characterized by their mild conditions, wide substrate scope and excellent chemo- and regioselectivity, and constitute novel methods for the formation of amides via metal-catalyzed C—C bond formation.