Asymmetric synthesis of 2-substituted oxetan-3-ones via metalated SAMP/RAMP hydrazones

2-Substituted oxetan-3-ones can be prepared in good yields and enantioselectivities (up to 84% ee) by the metalation of the SAMP/RAMP hydrazones of oxetan-3-one, followed by reaction with a range of electrophiles that include alkyl, allyl, and benzyl halides. Additionally, both chiral 2,2- and 2,4-disubstituted oxetan-3-ones can be made in high ee (86–90%) by repetition of this lithiation/alkylation sequence under appropriately controlled conditions. Hydrolysis of the resultant hydrazones with aqueous oxalic acid provides the 2-substituted oxetan-3-ones without detectable racemization

Copper (I) mediated radical cyclisation novel approaches to nitrogen heterocycles

This thesis describes novel catalysts and methods for the synthesis of nitrogen heterocycles using copper (I) mediated atom transfer radical cyclisation (A TRC). It is divided into six chapters. The first chapter provides a short review on the use of copper (I) salts In radical cyclisation chemistry. The second chapter describes the synthesis and copper (I) mediated A TRC of novel a-halo dienamides derived from a,B-unsaturated ketones. A range of multifunctional heterocyclic building blocks were prepared including pyrrolidinones, tetrahydroisoquinolinones and p-Iactams by 5-exo, 6-endo and 4-exo cyclisation. The third chapter extends the methodology discussed in chapter two to the synthesis and cyclisation of further a-halo dienamides derived from a,B-unsaturated aldehydes. This class of radical precursor was found to cyclise exclusively in the 4-exo mode to give B-lactam products. The fourth chapter looks at the copper (I) mediated 5-endo cyclisation of a-halo keto enamides as a potential route to the synthesis of the heterocyclic ring fragment of natural product ZG-1494a. The fifth chapter describes the synthesis of novel solid supported copper (I) catalysts and their application to the atom transfer radical cyclisation of a-halo amides. A comparison of the activity of these catalysts to solution ligand/copper (I) halide mixtures is made. The reusability of polystyrene supported catalysts in the cyclisation of one radical precursor is discussed. The sixth chapter gives the detailed preparative methods and analytical data for the compounds described in chapters two, three, four and five

Copper (I) mediated radical cyclisation : novel approaches to nitrogen heterocycles

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Regiochemistry of copper(I)-mediated cyclization reactions of halo-dienamides

Reaction of 2-substituted dienamides with catalytic amounts of copper halide/tripyridylamine (TPA) furnishes either 5-exo or 6-endo products with the outcome dependent upon the radical initiating unit. Reaction of 3-substituted dienamides produces beta-lactams via a 4-exo cyclization with termination of the reaction occurring via either halogen atom transfer, trapping with oxygen, elimination, or radical-radical coupling depending upon the diene

Palladium-Catalyzed Multicomponent Synthesis of 2‑Aryl-2-imidazolines from Aryl Halides and Diamines

An efficient palladium-catalyzed three-component reaction that combines aryl halides, isocyanides, and diamines provides access to 2-aryl-2-imidazolines in yields up to 96%. Through variation of the diamine component, the reaction can be extended to the synthesis of 2-aryl-1<i>H</i>-benzimidazoles and 2-aryl-1,4,5,6-tetrahydropyrimidines

Palladium-Catalyzed Multicomponent Synthesis of 2‑Aryl-2-imidazolines from Aryl Halides and Diamines

An efficient palladium-catalyzed three-component reaction that combines aryl halides, isocyanides, and diamines provides access to 2-aryl-2-imidazolines in yields up to 96%. Through variation of the diamine component, the reaction can be extended to the synthesis of 2-aryl-1<i>H</i>-benzimidazoles and 2-aryl-1,4,5,6-tetrahydropyrimidines

Bond rotation dynamics of enamides : the effect of the acyl group and potential for chirality transfer during 5-endo trig radical cyclizations

Barriers to rotation of the N-alkenyl bond in a series of N-cycloalkenyl-N-benzyl acetamide derivatives have been measured in different solvents by variable-temperature NMR experiments. The barriers range from 9.7 to 14.2 kcal/mol, depending on substituents on the acetamide acyl group. Polar solvents such as chloroform and methanol increase the barrier to rotation compared to nonpolar solvents such as toluene. The barrier to rotation of “mimics” for acetamide-based radicals are estimated. The relative order of the values of krot for different acyl groups parallels their reported Taft Es paramaters. For successful chirality transfer in 5-endo trig radical cyclization, it is evident that rotations would need to be significantly slower than those reported here