Mills, M.R.; (2010) The development of a one-pot 1,4-addition/nitro-Mannich reaction. Doctoral thesis , UCL (University College London).

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Abstract

The introduction of this thesis reviews the three areas of importance to the research carried out. These are the nitro-Mannich reaction, the conjugate addition of nucleophiles to nitro-alkenes and the diastereoselectivity of electrophilic additions to substrates bearing an α-stereocentre. The Results and Discussion details the research carried out into the development of a one-pot 1,4-addition/nitro-Mannich reaction. Initially the research focused on triggering the reaction using a cyanide nucleophile. Three cyanide sources were investigated, trimethylsilylcyanide, potassium ferrous cyanide and acetone cyanohydrin. Although the desired one-pot reaction was not achieved using any of these reagents, a new method for the addition of cyanide to nitro-alkenes was successfully developed, and the use of these unusual but highly versatile synthetic building blocks was briefly demonstrated. More success was achieved with alkyl nucleophiles from dialkylzinc reagents. A one-pot 1,4-addition/nitro-Mannich sequence was discovered and optimised using diethylzinc. During the optimisation it was realised that the diastereoselectivity of the reaction was tuneable by the choice of solvent, using THF as the solvent provides the syn/anti-diastereoisomer as the major product, whist reactions in Et2O provide the syn/syn-diastereoisomer as the major product. The reaction scope was explored, and the reaction was rendered asymmetric via the employment of chiral additives. The reaction scope was determined to be very general, providing high levels of relative and absolute control across three contiguous stereocentres for a wide range of nitro alkenes and imines, and was also applicable to dimethylzinc and diphenylzinc. Finally a model was proposed for the resulting, solvent dependent stereochemistry. Conclusions regarding the research carried out are presented, along with suggested future studies to be undertaken. These include reactions to further probe the mechanism and stereochemical model, as well as to increase the utility of the reaction further. The experimental section provides procedures and data for all novel compounds, X-ray crystallographic data and a comprehensive list of references.

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