Metal Mediated Synthesis. Synthetic and Mechanistic Investigations of Conjugate Addition and Reductive Amination

Abstract: The thesis is divided into two separate parts, one treating conjugate addition and the other reductive aminations.

The first part of the thesis is concerned with organocopper promoted conjugate addition to .alfa.,.beta.-unsaturated compounds. Mechanistic investigations of iodotrimethylsilane (TMSI) promoted mono-organocopper reagents using 2-cyclohexenone and butylcopper(LiI) show that TMSI activates organocopper reagents in two ways: either by quenching a .pi.-complex by coordinating to the carbonyl oxygen or by acting as a nucleophile towards copper in the .pi.-complex. The dominating role is determined by the solvent used. Furthermore, it is shown that a .pi.-complex without activation of the carbonyl carbon has a low reactivity, both for cuprates and for mono-organocopper compounds. The kinetic behaviour of these mono-organocopper reagents indicates that the reactive species contains two copper atoms, suggestedly a dimeric organoiodocuprate (RCuILi)₂. The role of LiI as an inseparable part of the reagent is emphasized.

A highly asymmetric synthesis of (S)-geranylcitronellol a using a TMSI-promoted homoallylic mono-organocopper reagent is also included. The asymmetry is derived from chiral camphor-based crotonates, which are used as recyclable chiral auxuliaries. Almost complete stereocontrol (>98% d.e.) is observed. In addition, a synthesis of all-trans-geranylgeraniol is described.

The second part of the thesis describes a simple method for reductive amination of ketones. A simple method for reductive amination of ketones with gaseous ammonia to primary amines is reported. By treating a mixture of a ketone and ammonia with Ti(O-iPr)₄ followed by TiCl₄ an iminium salt is formed which is reduced with borane dimethylsulfide complex. Furthermore, the synthesis of secondary and tertiary amines is discussed. The presence of the iminium salt has been confirmed with NMR. Some easily available asymmetric borane reducing agents are examined to probe the potential of preparing optically active amines in one step.