Base catalysed halogen dance reactions

Halogen-dance (HD) reactions on heteroaromatic systems led - via treatment of halogenated starting compounds with LDA - to rearranged lithiated intermediates. They were thoroughly studied within our research group and proved to be a versatile synthetic route to multisubstituted heterocycles. Up to now, no efforts have been made to adopt this approach to thiophene-spacer-thiophene compounds. Consequently we were mainly interested in double-rearranged lithium intermediates which - after treatment with TMSCl - should yield disubstituted Dibromo(spacer)bithienylsilanes.

Mechanism of Halogen Dance Reactions

Scheme 6

After initial metalation of 1 by LDA (Step {1}) via halogen-metal exchange reactions a series of rearrangement steps occur resulting in the formation of rearranged target I3. Two equations are mainly responsible for a complete turnover: {3} regenerates starting compounds 1 thus promoting continuous transbromination in {2}, whereas {4} - in an auto-catalytic sense - permanently forms the transbrominating dibromothienyl catalyst I4 under concomitant production of the target HD product I3. This auto-catalytic compound I4 - firstly emerging in {2}, is prominently responsible for a successful migration via its role in {3} and{4}. All compounds considered within this scheme are symmetric and - as having two reactive sites for HD available - we therefore aimed at double halogen migrations: this fact has been neglected in the above scheme for graphical simplification.

The driving force for all these HD reactions is the formation of the finally most stable Li-intermediate, with the Li atom residing at the most acidic C-H position. We have undertaken first preliminary ab initio calculations with the best available and most appropriate basis set for these purposes (all results have been checked by frequency analysis after DFT calculation).

Ab initio calculations in the HD area

Scheme 7

ab initio Calculations with GAUSSIAN94
basis set: g 6-311+g(2d,p), method: b3lyp
Hardware: SGI PowerChallenge RISC computer
Computing CPU time per molecule: up to 26 hrs

At the beginning we have been restricting ourselves to furans and to maximum dibromo substrates for CPU time reasons. It can be seen from the calculation results that a lithium atom adjacent to the furan oxygens is much more stable as compared to the 3-position of the hetero aromatic moiety (c). Moreover, an unambiguous, stabilizing influence of a bromine atome (i.e. an electron withdrawing substituent, probably in connection with some participation of a lone-pair directing effect) can be observed (in calculations as well as in the experiment): (a) and (b) are striking examples - rationalizing the exclusive formation of a 2-lithiofuran species under thermodynamic equilibrium conditions. An electronically not supporting substituent does not force o-lithiation - compare (d) versus (c): quite in contrast, the o-lithiomethyl derivative seems to be somewhat less stable as compared to the meta-intermediate, possible via the +I influence of the methyl substituent in combination with some steric influence. This theoretical result soundly proofs the experimental observation: upon metalation of 3-methylfuran with LDA ca. 45% ortho- versus 55% meta-lithiation occurs. As all results obtained were in excellent agreement with our experimental data and observations in the thiophene and furan field [6],[7], we are encouraged to undertake further efforts aiming at the enthalpy calculation of a whole HD cycle, which additionally will require the (CPU-time consuming) ab initio investigation of dibromo lithio-intermediates.

Experimental Realisation

Preliminary studies on a model-compound comprising an acetylene group were undertaken, to ensure its neglecting effect to potential ortho-litiation (which indeed would be a strongly limiting factor to complete halogen migrations):

Scheme 8

In a rough non optimized experiment only HD and HD-retained product accompanied by some unconverted material, but no substitution adjacent to the acetylene group was observed.

Halogen dance reaction on 1a:

Scheme 9

Halogen dance reaction on 1d:
The usually applied amount of 2.5 equ. LDA yielded only mono-rearranged product and left starting material. Increase of both the amounts of LDA and of the solvent led to the desired product in good yields. This can be explained with the low solubility of the starting product (1d) in THF and its low rate for lithiation:

Scheme 10