Mixed Mg/Li Amides of the Type R₂NMgCl⋅LiCl as Highly Efficient Bases for the Regioselective Generation of Functionalized Aryl and Heteroaryl Magnesium Compounds

Abstract

Two are better than one: Mixed lithium‐magnesium complexes of the type R2NMgCl⋅LiCl are kinetically highly active bases that convert a range of polyfunctional aromatic and heteroaromatic substrates into the corresponding magnesiated derivatives with high regioselectivity.

Metalated Heterocycles in Organic Synthesis: Recent Applications

“…196 The recently developed highly soluble mixed magnesium/lithium amide derived from 2,2,6,6-tetramethylpiperidine 97, which has high kinetic activity because of the presence on the lithium chloride salt (see above), has shown to be a quite efficient base for the regioselective generation of functionalized heteroaryl magnesium compounds. 197 For example, treatment of 2-chloropyrimidine (96) with this reagent 97 allowed the generation of the corresponding 4-magnesiated derivative 98 at -55 ºC which adds to p-bromobenzaldehyde to give the alcohol 99 (Scheme 29). When the isopropylmagnesium chloride/lithium chloride mixture was used, the bromo/magnesium exchange in 5-bromo-4-halogeno-2,6-dimethoxypyrimidines and also the successive one-pot bromo/magnesium exchange and difunctionalization on 4,5-dibromo-2,6-dimethoxypyrimidine, was regioselectively achieved.…”

Metalated N-heterocyclic reagents prepared by the frustrated Lewis pair TMPMgCl·BF3 and their addition to aromatic aldehydes and activated ketones

“…Metalated N-heterocyclic reagents prepared by the frustrated Lewis pair TMPMgClÁBF 3 and their addition to aromatic aldehydes and activated ketones † Sophia M. Manolikakes, Milica Jaric, Konstantin Karaghiosoff and Paul Knochel* Treatment of pyridines, quinoline and methylthiopyrazine with the frustrated Lewis pair TMPMgClÁBF 3 (1) leads to organotrifluoro borates which react readily with a variety of aromatic aldehydes in the absence of a transition metal catalyst.…”

“…1 Recently, we have shown that the frustrated Lewis pair 2 TMPMgClÁBF 3 (1, TMP = 2,2,6,6-tetramethylpiperidyl) made by mixing TMPMgClÁLiCl 3 with BF 3 ÁOEt 2 below À40 1C is able to metalate a range of pyridines and related N-heterocycles with excellent regioselectivity. 4 The organometallic reagent produced by the treatment of pyridine (2a) with the Lewis pair 1 is the pyridyl trifluoroborate 3a, as shown by a 2 J 19F-13C coupling of 14.7 Hz between C2 of 2a and the fluorine atoms (Table 1).…”

“…Then, we examined various 3-substituted pyridines (8a-d) and found that their treatment with TMPMgClÁBF 3 (1) at À40 1C or À78 1C affords metalated species of type 9 which react smoothly with several aromatic aldehydes (Table 2). Thus, the treatment of ethyl nicotinate (8a) with the Lewis pair 1 (1.1 equiv., À40 1C, 30 min) provides after the addition to 4-bromobenzaldehyde (5c, 0.8 equiv.…”

“…À40 1C to 25 1C, 4 h) and cyclization the lactone 10a in 72% yield ( Table 2, entry 1). Similarly, the 3-chloro and 3-fluoro substituted pyridines 8b and 8c are readily metalated by TMPMgClÁBF 3 (1, 1.1 equiv.) at À78 1C within 10 min and give after quenching with the aldehydes 5c and 5b, respectively, the alcohols 10b and 10c in 71-81% yield (Table 2, entries 2 and 3).…”