From Hünig's Base to Bis([1,2]dithiolo)-[1,4]thiazines in One Pot: Scorpionine

Charles W. Rees, Carlos F. Marcos, Cecilia Polo, Oleg A. Rakitin, Tomás Torroba, Andrew White and David J. Williams

Department of Chemistry, Imperial College

How can you add structural value, in a one-pot reaction, by mixing two simple commercially available compounds, breaking 14 and making 12 bonds, in high yield under mild conditions, to produce a new heterocyclic system by an entirely new method?

Answer:

scorpionine with link to pdb file

In a complex sequence of about 15 reaction steps, N-ethyl di-isopropylamine (Hünig's base) reacts with disulfur dichloride (sulfur monochloride) to give the bis([1,2]dithiolo)-[1,4]thiazine (Scorpionine) in an overall yield of 40%.

Remarkable features of this reaction are

  1. its selectivity (only the iso-propyl groups react, and they react completely, whilst the ethyl group is entirely inert)
  2. its overall yield, which requires an average yield of 94% for each of the 15 reactions
  3. the mild conditions compared to those of other 1,2-dithiole syntheses
  4. the structure, properties and stability of the black metallic product
The reaction is best performed with an excess of S2Cl2 in 1,2-dichloroethane in the presence of another (inert!) base such as 1,4-diazabicyclo-[2.2.2]octane (DABCO) for three days at room temperature, followed by brief heating at reflux. After chromatographic purificaton the product C8H5NS7, m.p. 202-203°C, is obtained as black needles with a striking metallic lustre. The symmetrical structure followed from mass spectrometry, and 1H and 13C NMR, which showed that the N-ethyl group was intact, but that all the 14 C-H bonds of the iso-propyl groups had disappeared, in a striking demonstration of the difference in reactivity of primary and secondary alkyl groups.

If the carbon connectivity of Hünig's base is retained, only a few reasonable structures are possible for such a stable compound, and spectroscopy indicated the structure shown for Scorpionine (below), which was confirmed by X-ray crystallography.

packing of scorpionine The extended packing of this molecule in the crystal lattice can be see here.

If the reaction is run in the presence of an oxygen source (e.g. formic acid or THF!), two other products are also formed, with one or both of the thione sulfur atoms replaced by oxygen. All three products (which have been interconverted) have very similar shapes and conformations in the crystal lattice. The delocalised dithiole rings are planar, with the fused ring system folded about the thiazine N...S axis, and with the N-ethyl group folder back, scorpion-like, towards the thiazine ring sulphur.

Details can be found in Angew. Chemie, 1997, 36, 281 where a mechanism is proposed for the reaction. This compound and its analogues are displaying some very interesting chemistry.