Facile Access to Hetero-poly-functional Arenes and meta-Substituted Arenes via Two-Step Dimetalation and Mg/Halogen-Exchange Protocol

The Grignard reagent, iPrMgCl and its lithium chloride-enhanced 'turbo' derivative iPrMgCl.LiCl have been employed to investigate the single iodo/magnesium exchange reactions of the trisubstituted arenes, 2,5-diiodo-N,N-diisopropylbenzamide 1, 1,4-diiodo-2-methoxybenzene 2, and 1,4-diiodo-2-(trifluoromethyl)benzene 3. These three arenes themselves were initially prepared by a double ortho-, meta '-deprotonation of N,N-diisopropylbenzamide, anisole and (trifluoromethyl)benzene, respectively, using the sodium magnesiate reagent [Na4Mg2(TMP)(6)(nBu)(2)] (where TMP is 2,2,6,6-tetramethylpiperidide), and subsequent electrophilic quenching with iodine/THF solution. Thus, by following a combined deprotonation and magnesium/halogen exchange strategy, the simple monosubstituted arenes can be converted to trisubstituted diiodoarenes, which can ultimately be transformed into the corresponding mono-magnesiated arenes, in THF at -40 degrees C, within seconds in good yields. The other functional group (OMe, NiPr2 or CF3 respectively) present on the di-iodoarenes helps direct the exchange reaction to the ortho position, whereas subsequent addition of different electrophiles permits the preparation of hetero-poly-functional-arenes, with three different substituents in their structure. Intriguingly, if water is used as the electrophile, a new and facile route to prepare meta-substituted arenes, which cannot be easily obtained by conventional processes, is forthcoming. In contrast to directed ortho-metalation (DoM) chemistry, this reaction sequence can be thought of as InDirect meta-Metalation (IDmM). The scope of the chemistry has been tested further by exposing the initial unreacted iodo-functionality at the meta-position to a second Mg/I-exchange reaction and subsequent functionalization.

Automated summary

The Grignard reagent and lithium chloride-enhanced derivative have been used for single iodine/magnesium exchange reactions to produce trisubstituted arenes, allowing for the preparation of poly-functional arenes and a new route for meta-substituted arenes using water as the electrophile. This reaction can be viewed as an InDirect meta-Metalation process and shows potential for further functionalization of the initial unreacted iodine functionality.