Sonia Bruña

Haloarenes are core building blocks of modern organic synthesis, primarily due to their role as precursors for the synthesis of organometallic reagents (e.g., Grignards), for nucleophilic substitution reactions or for reagents in cross-coupling chemistry. Within this field, preparation of meta-substituted arenes is particularly desirable and challenging, as they cannot be easily obtained by conventional processes.

As a first approach to this challenge, our group has recently developed a strategy to create aromatic carbonhalogen bonds, in particular ortho-/meta-diiodoarenes (C), via the regioselective sodium magnesiate templated dimetallations of different functionalised aryl substrates (A). Initially the organometallic intermediate (B) was synthesised which was subsequently electrophilically quenched with iodine.¹

Polyfunctional arenes can also be prepared via halogen-metal exchange reactions. Elegant examples, dealing with the development of the so called turbo Grignard Reagents (TGR), for example, iPrMgCl.LiCl, have been reported by Knochel and co-workers, where the LiCl additive considerably improves the efficiency of Mg insertion into various aromatic and heterocyclic iodine-carbon and bromine-carbon bonds.² The high functional group tolerance revealed by TGR (and GR), together with the mild conditions in which these exchange reactions are performed, prompted us to investigate the single iodo/magnesium exchange reaction of the di-iodoarenes (C).

Different substrates and Mg reagents are currently being investigated. For instance, the aforementioned iPrMgCl.LiCl and its ‘conventional’ analogue iPrMgCl have shown promise in converting di-iodoarenes (C) into the corresponding mono-magnesiated arenes (D), in THF at -78°C, within seconds and in good yields. The functional group helps direct the exchange reaction to the ortho position. Subsequent addition of different electrophiles allows the preparation of polyfunctional organic compounds (E) (with three different substituents). Intriguingly, if water is used as the electrophile, a facile route to obtain meta-substituted arenes (F) is forthcoming. Both (E)– and (F)-type products are potentially important precursors for pharma, agricultural and materials applications.

References:
1. (a) A. J. Martínez-Martínez, A. R. Kennedy, R. E. Mulvey and C. T. O’Hara, Science 2014, 346, 834-837. (b) A. J. Martínez-Martínez, S. Justice, B. J. Fleming, A. R. Kennedy, I. D. H. Oswald and C. T. O’Hara, Sci. Adv. 2017, 3, e1700832.
2. For example see: (a) A. Krasovskiy and P. Knochel, Angew. Chem. Int. Ed. 2004, 43, 3333-3336. (b) C. Sämann, B. Haag and P. Knochel, Chem. Eur. J. 2012, 18, 16145-16152. (c) D. S. Ziegler, B. Wei and P. Knochel, Chem. Eur. J. 2019, 25, 2695-2703.