The preparation of C-3 building blocks and their use in heterocyclic synthesis

Schofield, Stephen Robert (1996) The preparation of C-3 building blocks and their use in heterocyclic synthesis. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

This work concerns the investigation of new synthetic routes to heterocycles via a building block strategy. Three classes of heterocycle are targeted - pyrimidines, pyrazoles and isoxazoles. These classes cover both five- and six-membered ring systems and are representative of a much wider range of target molecules, having possible bioactivity. All three classes of heterocycle can also be produced from the same type of building block by altering the nature of the bisnucleophile used to close the ring (a 2- or 3-atom unit).

The building blocks employed contain a 1,3-dicarbonyl structure with a protected carbonyl group at the 2-position. The first building blocks prepared have a protected ester by way of a ketene dithioacetal. The reduction of this group (by dissolving metal) leads to a dithiane, equivalent to a formyl group. Both the ketene dithioacetals and the dithianes are subsequently cyclised to the five- and six-membered heterocycles. Ketene dithioacetal building blocks generate heterocycles that bear a novel mercapto thioether side chain. Building blocks based on dithianes show complex cyclisation patterns by offering multiple reaction sites.

The incorporation of fluorine into this class of building block proved to be troublesome so attention was focused on the use of vinyl ethers and enamines as masked formyl equivalents. By adapting the work of Schreiber and developing a novel procedure to form fluorinated building blocks, it is possible to isolate three heterocyclic precursors - a bis(trifluoroacetyl)-and mono)trifluoroacetyl)-enamine and an analogous compound containing a dithiane-masked formyl unit. These building blocks have then been converted into all three classes of heterocycle described earlier.

By comparing the data of molecules generated by this route with those in recent literature it is possible to gain a much more complete view of the cyclisation processes. For example, many of the building blocks used in this work contain more than two sites for reaction which lead to complex mechanistic possibilities which can be rationalised.

The initial objective of merging an intrinsically bioactive molecule (the classes of heterocycle chosen) with a bioactive enhancer (the inclusion of fluorine into these molecules) has proven successful.

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