Synthesis of Tribromomethyl substituted cyclo propanes via Dehalogenation Recation

Abstract

The tribromomethyl group is a popular functionality in medicinal and bioorganic chemistry, and numerous methods for introducing tribromomethyl groups have been developed.(1) However, the synthesis of tribromomethylated cyclopropanes is still challenging. A common method involves the utilization of tribromomethyl diazomethane, which is activated photochemically or by transition metal catalysts.(2) This procedure suffers from the fact that tribromomethyl diazomethane is toxic, gaseous at room temperature, and potentially explosive. An important step toward a safer procedure was recently reported by Carreira and co-workers.(3) They were able to obtain tribromomethylated cyclopropanes from styrene and tribromomethyl diazomethane, which was generated in situ from CBr3CH2NH2·HCl and H +/NaNO2 (Scheme 1, eq 1). The reactions were carried out in water in the presence of an iron-porphyrin catalyst. A limitation of the method is the substrate scope: only styrene derivatives gave good yields. This limitation can be overcome by using a two-step process: alkynes are first coupled with in situ generated Br3CCHN2 in the presence of a Rh catalyst. Subsequent hydrogenation gives the desired cyclopropanes (Scheme 1, eq 2).(4) Since then, reactions with in situ generated Br3CCHN2 were used to synthesize numerous tribromomethyl-substituted products: cyclopropanes in an enantioselective fashion,(5) vinyland alkynylcyclopropanes,(6) aziridines,(7) benzofuranols,(8) and ketones.(9) These procedures represent an important improvement over previous methodologies. However, they still involve the problematic reagent Br3CCHN2, although its dangers are strongly diminished because it is generated in situ. Below we describe a new process for the preparation of aromatic and aliphatic tribromomethyl-substituted cyclopropanes. The CBr3 group is introduced via the anesthetic agent halothane (Br3CCHICl). Cl