Iodine-Magnesium Exchange on Unprotected Imidazoles in the Presence of LiCl

Abstract

The presence of LiCl allows the convenient preparation of magnesiated imidazoles starting from unprotected iodoimid­azoles. They react with various electrophiles in satisfactory yields.

Key words

magnesium - heterocycles - organometallic reagents - imidazole - exchange reaction

References and Notes

• 1 Newkome GR. Pandler WW. Contemporary Heterocyclic Chemistry   Wiley; New York: 1982. 
• 2 For a recent example, see: Kitbunnadaj R. Zuiderveld OP. Christophe B. Hulscher S. Menge WMPB. Gelens E. Snip E. Bakker RA. Celanire S. Gillard M. Talaga P. Timmerman H. Leurs R. J. Med. Chem.  2004,  47:  2414 
• 3 Seley KL. Salim S. Zhang L. O’Daniel PI. J. Org. Chem.  2005,  70:  1612 
• 4 Matsunaga N. Kaku T. Ojida A. Tasaka A. Tetrahedron: Asymmetry  2004,  15:  2021 
• 5 Kopp F. Krasovskiy A. Knochel P. Chem. Commun.  2004,  20:  2288 
• 6a Krasovskiy A. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  3333 
• 6b For the solubilization of lanthanide salts in the presence of LiCl, see: Krasovskiy A. Kopp F. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  497 
• 7 Knochel P. Yeh MCP. Berk SC. Talbert J. J. Org. Chem.  1988,  53:  2390 

8

Typical Procedure for the Synthesis of 4-Iodo-5-(methylsulfanyl)-1 H -imidazole ( 3i)
4,5-diiodo-1H-imidazole (1b, 640 mg, 2.00 mmol) was placed in a dry and argon-flushed Schlenk tube equipped with a magnetic stirring bar and a septum. A solution of LiCl in THF (0.5 M, 4.0 mL, 2.0 mmol, 1.0 equiv) was added and after stirring 5 min at r.t., the resulting slurry was cooled to -20 °C and MeMgCl (3.0 M in THF, 0.7 mL, 2.0 mmol, 1.0 equiv) was added dropwise. After completion of the addition, the mixture was stirred at -20 °C for further 20 min. Then, i-PrMgCl·LiCl (1.3 M in THF, 1.7 mL, 2.2 mmol, 1.1 equiv) was added slowly and the resulting mixture was allowed to warm to r.t. The exchange reaction was monitored by TLC (samples quenched with MeOH, silica plates; CH₂Cl₂-MeOH, 19:1) versus the starting material and was usually complete after 45 min. The resulting slurry was cooled to -20 °C and (S)-methyl methanesulfonothioate (610 mg, 2.40 mmol, 1.20 equiv) was added neat at this temperature, then the mixture was allowed to warm to r.t. After the completion of the reaction (TLC monitoring) the reaction mixture was poured on H₂O (20 mL) and sat. aq NH₄Cl (20 mL), and the aqueous layer was extracted with CH₂Cl₂ (3 × 40 mL). The combined CH₂Cl₂ layers were dried (Na₂SO₄) and evaporated in vacuo. Flash column chromatography (silica gel, CH₂Cl₂-MeOH, 19:1) afforded 4-iodo-5-(methylsulfanyl)-1H-imidazole (3i) as colorless solid (mp 126.1-128.4 °C).