Chloroacetamides as Valuable Synthetic Tools to Access Nitrogen-Containing Heterocycles Using Both Radical and Non-Radical Processes
[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...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/106936 |
| Acceso en línea: | https://hdl.handle.net/2445/106936 http://hdl.handle.net/10803/400290 |
| Access Level: | acceso abierto |
| Palabra clave: | Compostos heterocíclics Heterocyclic compounds |
| Sumario: | [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. |
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