Regioselective Bromine/Magnesium Exchange for the Selective Functionalization of Polyhalogenated Arenes and Heterocycles

Abstract Using the bimetallic combination sBu2Mg⋅2 LiOR (R=2‐ethylhexyl) in toluene enables efficient and regioselective Br/Mg exchanges with various dibromo‐arenes and ‐heteroarenes under mild reaction conditions and provides bromo‐substituted magnesium reagents. Assessing the role of Lewis donor additives in these reactions revealed that N,N,N′,N′′,N′′‐pentamethyldiethylenetriamine (PMDTA) finely tunes the regioselectivity of the Br/Mg exchange on dibromo‐pyridines and quinolines. Combining spectroscopic with X‐ray crystallographic studies, light has been shed on the mixed Li/Mg constitution of the organometallic intermediates accomplishing these transformations. These systems reacted effectively with a broad range of electrophiles, including allyl bromides, ketones, aldehydes, and Weinreb amides in good yields.

Abstract: Using the bimetallic combination sBu 2 Mg·2 LiOR (R = 2-ethylhexyl) in toluene enables efficient and regioselective Br/Mg exchanges with various dibromo-arenes and -heteroarenes under mild reaction conditions and provides bromo-substituted magnesium reagents. Assessing the role of Lewis donor additives in these reactions revealed that N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDTA) finely tunes the regioselectivity of the Br/Mg exchange on dibromo-pyridines and quinolines. Combining spectroscopic with X-ray crystallographic studies, light has been shed on the mixed Li/Mg constitution of the organometallic intermediates accomplishing these transformations. These systems reacted effectively with a broad range of electrophiles, including allyl bromides, ketones, aldehydes, and Weinreb amides in good yields.
Functionalized halogenated arenes and heteroarenes are key tools for constructing pharmaceuticals, materials, and natural products. [1] Several metal-mediated approaches for the functionalization of polyhalogenated substrates have been developed to access these valuable molecules, [2] including regioselective zinc insertion in the presence of LiCl on dihalogenated (hetero)arenes. [3] Contrastingly, halogen/magnesium exchange, one of the most powerful methods to functionalize haloarenes, has shown limited success for this type of substrates in terms of versatility and regioselective tunability. Some exceptions include the use of iPrMgCl·LiCl (1 a, turbo-Grignard reagent), [4] which can promote selective Br/Mg exchanges in THF. [5] Improved regioselectivities have also been achieved using bulkier variations of 1 a containing mesityl or 2,4,6-triisopropylphenyl substituents. [6] Recently, it was shown by some of us that mixed-metal compositions sBuMgOR·LiOR (1 b) and to a greater extent the stoichiometric variant sBu 2 Mg·2 LiOR (R = 2-ethylhexyl, 1 c) can promote Br/Mg exchanges in toluene or other nonpolar solvents with an excellent substrate scope when operated at room temperature. [7,8] While formation of lithium magnesiates was postulated, the constitution of the organometallic intermediates involved has not yet been determined. Expanding further the synthetic utility of these alkyl/alkoxide s-block metal combinations, herein, we report fast and highly regioselective Br/Mg exchanges on various dibromo-arenes and -heterocycles using sBu 2 Mg·2 LiOR (R = 2-ethylhexyl, 1 c) in toluene. Interestingly, in some cases, the addition of Lewis donors such as PMDTA activates a regioselectivity switch, an operation that can be rationalized on consideration of the bimetallic constitution of the organometallic intermediates in these exchanges.
We commenced our studies assessing the regioselectivity of the Br/Mg exchange on 2,4-dibromoanisole (2 a) with several mixed Li/Mg combinations (Table 1).
Trapping of 7 a with 3-methoxybenzaldehyde afforded the alcohol 9 a in 80 % yield (Scheme 3). This donor effect was quite general and the same procedure was extended to other polyhalogenated (hetero)arenes. Thus, 6 b-6 d underwent complete Br/Mg exchange upon treatment with 1 c·PMDTA, leading to the less sterically hindered magnesium species. After allylation or addition to Michlers ketone, the polyfunctionalized products 9 b-9 d were isolated in 61-83 % yield.
Intrigued by this unique reactivity and the profound effect that Lewis donors cause on the regioselectivity of the Br/Mg exchange reactions, we next studied the constitution of these organometallic intermediates prior to electrophilic interception. Firstly, 1 c was prepared in situ and reacted with 2bromoanisole (15, 2.0 equiv, toluene, 25 8C, 30 min), affording a pale yellow solution which deposited colourless crystals of [Ar 2 (OR)MgLi] 2 (16, Ar= o-MeO-C 6 H 4 , R= 2-ethylhexyl, Figure 1).
X-ray crystallographic studies confirmed the bimetallic constitution of 16, which exists as a centrosymmetric contaction-pair dimer. Demonstrating that these reactions are genuine Br/Mg exchanges, the Mg is attached to two orthometalated anisole groups, occupying the position previously filled by Br atoms in 15. Alkoxide bridges complete the Mg coordination sphere. Contrastingly, the Li atom only binds to one OR ligand, achieving further coordinative stabilization via two OMe groups from the metalated anisole molecules. This special coordination of the Li atoms could be responsible for the marked Lewis donor effect observed in the regioselective control in these Br/Mg exchanges (see above). Thus, PMDTA could preferentially chelate the Li atoms, precluding their interaction with the donor substituents of the substrate, ultimately favoring the formation of solvent-separated ion pair species, which would suppress any possible Li/Mg communication. Notably, Mulvey has recently stressed that bimetallic cooperation in deprotonative metalation reactions  is key in order to achieve unique regioselectivities that cannot be replicated by single-metal reagents, [21] as illustrated by the meta-magnesiation of toluene using a sodium magnesiate base in hexane. [22] In these systems, Na acts as an intramolecular Lewis acid to engage the substrate, which, in turn, is deprotonated by the complexed magnesiate anion. Another significant feature of 16 is that only one equivalent of the lithium alkoxide is incorporated into the final molecular arrangement despite two being present in the exchange reagent sBu 2 Mg·2 LiOR (1 c). Further insight into the formation of 16 was gained by monitoring the reactions of 1 c with 15 (2.0 equiv) in [D 8 ]toluene (Figure 1), which showed that 16 is obtained quantitatively along with the concomitant formation of sBuBr and one equivalent of free LiOR. [17] 1 H-DOSY NMR supports that the solid state structure of 16 is retained in toluene solution. The activation of both sBu groups in 1 c contrasts with the sluggish reactivity of sBu 2 Mg or sBuMg(OR) towards 15, showcasing the mediating role of lithium through forming a contacted anionically activated magnesiate species of enhanced Br/Mg exchange ability. [17] Building on these findings we next assessed the reactivities of iPrMgCl·LiCl (1 a) and nBu 2 Mg·2 LiOR (1 d) towards 2-bromo-4-iodoanisole (17, Scheme 5). For this substrate, Li-directing effects should favor the Br/Mg exchange ortho to the donating OMe group, whereas considering purely the activation of the C À halogen bond, functionalization at the C(4) position via I/Mg exchange should be preferred. Unsurprisingly, turbo-Grignard 1 a in neat THF reacts with the most activated site of 17, undergoing exclusively I/Mg exchange, affording, after allylation, the anisole derivative 18 in 85 % yield. However, a completely different scenario plays out for 1 d in toluene, where coordination effects dominate, encouraging reactivity ortho to the directing OMe group and hence triggering a Br/Mg exchange with a selectivity of 4:1. Subsequent allylation and chromatographical separation furnished 19 in 65 % yield (Scheme 5). Supporting this interpretation, and demonstrating the importance of noncoordinating solvent toluene, addition of polydentate donor PMDTA which can chelate Li, switches off this Br/Mg exchange preference, offering an I/Mg exchange only. [17] Finally, NMR monitoring of the reaction of 2,5-dibromopyridine (10 a) with sBu 2 Mg·2 LiOR (1 c) in [D 8 ]toluene at À20 8C for 30 min revealed complete consumption of the starting material, as evidenced by the presence of sBuBr and a distinct set of new resonances which we can attribute to 12 a, the product of regioselective C(2) Br/Mg exchange. [17] The most informative signals are those for the C(2) and C(5) positions in the 13 C{ 1 H} NMR spectra which appear at 140.5 and 119.8 ppm, respectively for 10 a (Figure 2). After 30 min, complete disappearance of the signal assigned for C(2)ÀBr is accompanied by emergence of a new resonance in the aromatic region at 203.5 ppm, [23] which is assigned to C(2) À Mg in 12 a; whereas the chemical shift of the C(5) À Br hardly changes (118.5 ppm) with respect to the one observed for 10 a.
Additionally, 1 H-DOSY NMR displays co-diffusion of the three new aromatic resonances related to the metalated arene alongside the signals defined for 2-ethylhexanolate, consistent with them belonging to the same molecular entity in toluene solution with a mean diffusion coefficient of D = 4.349 10 À10 m 2 s À1 . [17] Final observations revealed a second set of alkoxide-related resonances in the aliphatic region of the 13 C{ 1 H} NMR, which did not belong to 12 a, but bore a striking  with displacement ellipsoids at 50 % probability, all hydrogen atoms omitted, and with C atoms in 2-ethylhexyl substituents and anisyl rings drawn as wire frames (except for C ipso and C ortho ) for clarity. [20] similarity to uncomplexed LiOR, as previously observed in the formation of 16.
While 12 a is thermally unstable, which precluded its crystallization, on the basis of these studies we can propose a structure similar to that of 16 (Scheme 6) but in this case the C(2) selectivity is driven by the coordination of Li to the pyridine N, guiding the Br/Mg exchange to the C(2) position. If a Lewis donor is added, this lithium-directing effect no longer operates and, as shown in Table 2 and Scheme 4, the selectivity of the Br/Mg exchange switches to the C(5) position.
In conclusion, we have reported regioselective Br/Mg exchanges of dibromo(hetero)arenes performed by reagents of the type R 2 Mg·2 LiOR 1 (R = sBu, nBu, R 1 = 2-ethylhexyl) in toluene. Addition of a chelating ligand such as PMDTA allowed in certain cases a regioselectivity switch of the exchange. This switch can be rationalized in terms of the bimetallic cooperation between Li and Mg. The preference of Li to coordinate to the Lewis basic sites of the substrate in toluene in the absence of any donor additives guides the Br/Mg exchange to the position adjacent to these basic sites, akin to the CIPE mechanism in metalation chemistry, thus enabling new regioselectivities not available using turbo-Grignard reagents.