Oxidative C-C, C-O and C-N bond formation at the benzylic position of cyclic ethers

Abstract

The direct coupling of seemingly unreactive sp3 carbon centres under oxidative conditions, known as “cross–dehydrogenative couplings” (CDCs), has stimulated a great deal of synthetic interest in recent years, owing to the promise of such reactions as efficient one–pot methods for C–C and C–N bond formation. This thesis describes the development of two novel CDC based methodologies for C–C and C–N bond formation at the benzylic positions of cyclic ethers. The thesis opens with a survey of the relevant background literature. The first reaction developed, the oxidative arylation of cyclic ethers, allows C–C bond formation at benzylic centres with a previously intractable nucleophile, anisole (Scheme A.1). Copper catalysis was required for the reaction to proceed efficiently, and the reaction was found to be highly sensitive to modification of either coupling partner, but is able to produce a range of novel compounds via what is a synthetic alternative to the oxa–Pictet Spengler reaction. The examples described herein support a mechanism involving the facile synthesis of an intermediate oxonium ion that is subsequently attacked by anisole in the presence of copper (II). Scheme A.1 Oxidative Arylation of Isochroman There are no examples in the literature of oxidative one-pot access to C–N bond formation at the benzylic positions of cyclic ethers using free amines as the nucleophiles. Such a method was the second procedure developed in this thesis. It was achieved via trapping the intermediate oxonium ion with ethanol, to give a C–O bonded transient intermediate, followed by nucleophilic attack of a free amine to afford the products in one pot (Scheme A.2). This method does not require any metal catalysts. The reaction is able to tolerate modification of either coupling partner, offering access to a range of novel small molecules. The results described in this section support the mechanism mentioned above: initial formation of a transient intermediate that is subsequently attacked by aniline at an elevated temperature. However, the results imply the reaction mechanisms are very different for the C–C and C–N bond forming reactions. Scheme A.2 A Novel Oxidative C–N Bond Forming Reaction between Isochromans and Free Amines