# name
Chloroacetamides as Valuable Synthetic Tools to Access Nitrogen-Containing Heterocycles Using Both Radical and Non-Radical Processes

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Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica

# metadata.dc.description.abstract[].value
[eng] During this PhD work we have demonstrated that chloroacetamides are valuable and versatile intermediates for the synthesis of different nitrogen containing heterocycles using either radical or non-radical processes. Thus, we reported the first dearomative spirocyclization under ATRC conditions using a Cu(I) catalyst to access 2-azaspiro[4.5]decanes by treatment of benzyltrichloroacetamides with CuCl, in acetonitrile and with microwave activation. The results obtained with the different trichloroacetamides used in this study show the importance of having a bulky group on the nitrogen to achieve the cyclization process. When N-(-methylbenzyl)trichloroacetamides were submitted to the ATRC conditions described previously for the synthesis of morphans, the radical course of the reaction followed two main pathways. The first one, provided morphans through an ATRC from the 1-(carbamoyl)dichloromethyl radical with the amide Z-conformation, which underwent cyclization upon the ,-unsaturated nitrile followed by a diastereoselective chlorine atom transfer. In the second, as observed under reductive conditions, the same radical in its E conformation underwent a 1,4-hydrogen transfer generating a benzylic radical that reacts with the unsaturated ,-nitrile with configurational inversion at the quaternary stereogenic center involving memory of chirality (MOC). Additionally, as a result of an investigation aimed at the preparation of enamines from 4-trichloroacetamidocyclohexanones and pyrrolidine, we discovered a new route for the synthesis of 6-azabicyclo[3.2.1]octane ring (normorphan) present in many natural and non-natural compounds. The 5 min reaction was achieved under solvent-free conditions or using microwave activation in toluene. The process involves an unprecedented intramolecular -carbamoylation of ketones or an intramolecular haloform-type reaction of trichloroacetamides promoted by enamine (generated in situ) as counter-reagents. The methodology was applied to enantiopure N-(-methylbenzyl)trichloroacetamidocyclohexanone providing the expected normorphans which were separated and converted to the corresponding amino alcohols for their future use as organocatalysts. The methodology was successfully extended to additional substrates to provide the azatricyclic structure that constitutes the ring core of the pentacyclic natural product cephalocyclidin A. Additionally, enlargement of the side chain bearing the trichloroacetamide had a significant impact on the course of the reaction since it provided the anti-Bredt seven-membered ring alone. The structure of this unprecedented type of anti-Bredt ring (3-azabicyclo[4.3.1]dec-5-ene) is present in many natural compounds with few reported methodologies for its preparation. The results previously obtained with trichloroacetamides led us to use dichloroacetamides instead to achieve the radical process. Thus a new route for the synthesis of 2-azabicyclo[3.3.1]nonanes was reported using a radical cyclization of dichloroacetamide-tethered ketones in the presence of pyrrolidine, AIBN and TTMSS and under microwave activation. In a five-minute one-pot process, after the generation of an enamine, intramolecular addition of a chloromethylcarbamoyl radical, and oxidation of the -aminoalkyl radical intermediate, the resulting iminium salt evolved to the corresponding enamine and, after a workup, to the alkylated ketone. The methodology was successfully applied to the synthesis of the tricyclic core of immunosuppressant FR901483 and also to the preparation of the 3-azabicyclo[4.3.1]decane structure through formation of the seven membered ring. Finally, the synthesis of functionalized pyrrolidines and piperidines from linear monochloro- and dichloroacetamides using non-radical chemistry was investigated. These chloroacetamides were easily prepared from methyl vinyl ketone and the corresponding amine followed by treatment with dichloro or chloroacetyl chloride in a one-pot reaction. Here also, the t-butyl group on the nitrogen allowed the reaction to go further providing the corresponding polyfunctionalized piperidine with an acceptable yield. The cyclization process was also achieved using Darzens conditions in the presence of sodium methoxide or potassium t-butoxide to afford the above mentioned epoxides with good yields. Application of the methodology to monochloroacetamides provided the piperidine or the pyrrolidine ring depending on the nature of the substituent on the nitrogen atom.

# metadata.dc.description.abstract[].value
[spa] Durante este trabajo de tesis doctoral se ha demostrado que las cloroacetamidas son intermedios de gran utilidad para la síntesis de heterociclos nitrogenados a través de procesos radicalarios o no radicalarios. En este trabajo, hemos descrito por primera vez la espirociclación desaromatizante en bencenos no activados utilizando ciclación radicalaria con transferencia de átomo, a partir de benciltricloroacetamidas por tratamiento con CuCl en acetonitrilo y activación por microondas. Mientras que las N-(-metilbencil)tricloroacetamidas sometidas a condiciones radicalarias tenía dos rutas principales, la formación de morfanos y la generación de normorfanos a través de una transferencia 1,4 de hidrógeno y ciclación radicalaria con inversión de configuración en el centro bencílico y con memoria de quiralidad. Asimismo, como resultado de una investigación enfocada a la preparación de enaminas, a partir de 4-tricloroacetamidociclohexanona y pirrolidina, hemos descrito una nueva ruta para la síntesis de 6-azabiciclo[3.2.1]octanos (normorfanos). La reacción se llevó a cabo en 5 minutos ya sea sin disolvente o bien en tolueno y bajo activación por microondas. El proceso de carbamoilación o reacción tipo haloformo intramolecular a partir de cetonas no tenía precedentes en la literatura. Esta metodología fue aplicada a la síntesis del sistema tricíclico presente en el producto natural cephalocyclidin A. Los resultados anteriormente obtenidos con las tricloroacetamidas propiciaron el uso de dicloroacetamidas en su lugar para conseguir el proceso radicalario. De este modo, se logró desarrollar una nueva ruta de síntesis de 2-azabiciclo[3.3.1]nonanos a través de la ciclación radicalaria de cetonas enlazadas a dicloroacetamidas en presencia de pirrolidina, AIBN y TTMSS bajo activación por microondas durante cinco minutos. Esta metodología fue aplicada con éxito a la síntesis del núcleo tricíclico del inmunosupresor FR901483. Asimismo, se investigó la síntesis de pirrolidinonas y piperidinonas funcionalizadas a partir de dicloro- y monocloroacetamidas lineales utilizando química no radicalaria. Estas cloroacetamidas fueron fácilmente preparadas por reacción de las aminas correspondientes con metilvinilcetona y posterior tratamiento con cloruro de dicloro- o cloroacetilo en un proceso one-pot. Mientras que el derivado con el ter-butilo sobre el nitrógeno experimenta una ciclación espontánea, la ciclación de las cloroacetamidas lineales fue lograda a través de una condensación de Darzens.

# metadata.dc.source[].value
Tesis Doctorals - Departament - Farmacologia, Toxicologia i Química Terapèutica

# metadata.dc.title[].value
Chloroacetamides as Valuable Synthetic Tools to Access Nitrogen-Containing Heterocycles Using Both Radical and Non-Radical Processes