Mechanism

Mechanism of Halogen Dance

The following scheme shows an overview of the mechanism of halogen migration on a 5-substituted 2-bromofuran based on research carried out within the field of bromothiophenes [2-4]. A very similar sequence takes place in the case of a 3-substituted 2-bromofuran as starting compound.

The sequence starts with lithiation of the starting compound 1 at the most acidic site (eqn. 1), followed by a key step common to all halogen migration reactions (eqn. 2): if the initial lithiation product 2 comes into contact with unreacted 1, a lithium-halogen exchange reaction leading to the dibrominated furan 3 takes place. A polybromo compound of this type is a prerequisite in all halogen dance examples known to us, serving as a co-catalyst for the two possible ensuing transmetalation steps (eqns. 3 and 4) which complete the migration. In eqn. 3 the transbrominating agent 3 is consumed under formation of scrambling product 5, but above all also under regeneration of starting compound 1, which according to eqn. 2 is responsible for 3 being formed again. In addition the initial lithiation product 2 and dibromide 3 produce the migration target 5 via an autocatalytic step as revealed by eqn. 4 - by these means to the advantage of a total rearrangement at least small amounts of 3 are sustained during the whole reaction time. Apparently reactive bromo-intermediates (and not bases) play the catalytic role - therefore we proposed the term aryl bromide catalysed dance (ABCD) reaction for such LDA-induced halogen migrations and prefer it over the term base-catalysed halogen dance (BCHD) reaction. Both processes represented by eqns. 3 and 4 give rise to the formation of the most stable, "final" lithium intermediate 5 with the Li-atom at the most acidic site.

Although the equilibrium positions of eqns. 2-4 do have some influence on the overall reaction rate, the main factor for a migration to occur is the simultaneous presence of 1 and 2 and their potential to react. These preconditions are mainly influenced by the sequence of addition and by the ratio of starting compounds:

reacting the educt with a slightly less than equimolar amount of base or by adding LDA to the starting compound (inverse addition) provide the optimum conditions for a rearrangement,
whereas slow addition of 1 to an excess of base (thus enabling immediate and complete metalation and therefore preventing the formation of transbrominating species like 3) is the method of choice for retaining the halogen dance.

Other factors that influence the reaction rate of the initial lithiation (eqn. 1) are the type of solvent (more polar solvents have been found to accelerate the metalation rate and are therefore helpful in preventing HD) and, to some extent, the temperature.

Influence of the electrophile

When quenching reactions under halogen dance prevention conditions with certain electrophiles (dimethylformamide or alkyl halides), by-products with rearranged patterns have been obtained in varying amounts. We assume this effect to be attributed to the weaker electrophilic properties of those electrophiles as compared to the others used: slower reaction of e.g. DMF with 2 enables, via simultaneous presence of HD prevention product 6, the formation of transbromination catalyst 3. Subsequently, the same reaction sequence via interaction between 2 and 3 leads to the rearrangement by-product 5.

For this reason the successful completion of a prevention reaction is only possible using strong electrophiles (reacting with the primary lithiated species immediately) like aldehydes, ketones or chlorotrimethylsilane.