Polysubstituted Thiazole Derivatives via the Halogen-Dance Reaction

Abstract

A short and efficient method for the synthesis of a series of 5-functionalized 4-bromo-2-chlorothiazole derivatives has been developed by application of the halogen-dance reaction.

halogen dance - metalation - lithiation - thiazole

References and Notes

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<A NAME="RD28207ST-9">9</A>

General Procedure for the HD Reaction and Quenching with Electrophiles to Compounds 2a-h:
To a solution of 5-bromo-2-chlorothiazole (1, 199 mg, 1 mmol, 1 equiv) in anhydrous THF under argon atmosphere a freshly prepared solution of LDA (1.2 equiv) in anhydrous THF was added at -80 °C and the mixture stirred at that temperature until TLC analysis showed complete HD reaction (15-20 min). Then the corresponding electrophile (1.5 equiv) was added at -80 °C and the reaction was allowed to warm to r.t. The reaction mixture was poured into 2 N HCl and the aqueous phase was extracted with Et₂O. The organic layer was washed with 2 N HCl (2×), H₂O (2×) and brine (2×), dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified either by column chromatography or by Kugelrohr distillation.

<A NAME="RD28207ST-10">10</A>

4-Bromo-2-chloro-5-iodothiazole (2d) Light yellow solid (76%); mp 60-61 °C; bp 150 °C (2 mbar). ¹³C NMR (50 MHz, CDCl₃): δ = 72.9 (s, C5), 132.6 (s, C4), 156.3 (s, C2).

<A NAME="RD28207ST-11">11</A>

4-Bromo-2-chlorothiazole-5-carbaldehyde (2g) Light yellow crystals (56%); mp 83-84 °C; bp 100 °C (0.35 mbar). ¹H NMR (200 MHz, CDCl₃): δ = 9.88 (s, 1 H, CHO). ¹³C NMR (50 MHz, CDCl₃): δ = 132.1 (s), 134.9 (s), 160.1 (s, C2), 181.9 (d, CHO).