Highly Reactive Hydrocarbon Soluble Alkylsodium Reagents for Benzylic Aroylation of Toluenes using Weinreb Amides

Abstract

Deaggregating the alkyl sodium NaCH2SiMe3 with polydentate nitrogen ligands enables the preparation and characterisation of new, hydrocarbon soluble chelated alkylsodium reagents. Equipped with significantly enhanced metalating power over their organolithium counterparts, these systems can promote controlled sodiation of weakly acidic benzylic C−H bonds from a series of toluene derivatives under mild stoichiometric conditions. This has been demonstrated through the benzylic aroylation of toluenes with Weinreb amides, that delivers a wide range of 2‐arylacetophenones in good to excellent yields. Success in isolating and determining the structures of key organometallic intermediates has provided useful mechanistic insight into these new sodium‐mediated transformations.

Li vs Na: Divergent Reaction Patterns between Organolithium and Organosodium Complexes and Ligand-Catalyzed Ketone/Aldehyde Methylenation

“…Colorless crystals of 1-Na suitable for single-crystal X-ray diffraction (SCXRD) analysis were obtained by storing its nhexane solution at −35 °C overnight. The solid-state molecular structure of 1-Na is shown in Figure 1a and is very similar to the structure very recently reported by Hevia and coworkers: 50 comparing the crystallographic cell parameters confirms that they are the same crystals. For comparison, the 1-Li structure from our previous report in 2022 51 is also displayed (Figure 1b).…”

“…However, to the best of our knowledge, such a strategy is still unknown. During the preparation of this manuscript, Hevia and co-workers reported that lower aggregates of NaCH 50 Herein, we report that a rare organosodium monomeric complex, [Na(CH 2 SiMe 3 )(Me 6 Tren)] (1-Na), which was simultaneously reported by Hevia and co-workers, 50 exhibits distinct reactivity patterns with organic carbonyl substrates, compared with our previously reported organolithium counterpart, i.e., [Li(CH 2 SiMe 3 )(Me 6 Tren)] (1-Li): 51 1-Na converts a C�O bond in ketone/aldehyde into a C�CH 2 bond, i.e., conducts ketone/aldehyde methylenation. In comparison, 1-Li reacts with such substrates following the conventional and predictable nucleophilic addition route.…”

“…However, to the best of our knowledge, such a strategy is still unknown. During the preparation of this manuscript, Hevia and co-workers reported that lower aggregates of NaCH 2 SiMe 3 , which were stabilized by Lewis bases N , N , N ′, N ″,N″ - pentamethyldiethylenetriamine (PMDTA) and tris­[2-(dimethylamino)­ethyl]­amine (Me 6 Tren), can facilitate benzylic C sp3 –H bond metalation and subsequent aroylation with Weinreb amides, where the corresponding organolithium complex (LiCH 2 SiMe 3 + PMDTA) failed to deliver such reactivity . It is interesting for us to note that the benzylic C sp3 –H bond metalation is concentration-dependent: while we reported in 2022 that the combination of LiCH 2 SiMe 3 + Me 6 Tren can deliver such metalation with neat toluene, Hevia and co-workers observed that LiCH 2 SiMe 3 + Me 6 Tren/PMDTA cannot activate toluene in hexane solution …”

“…Tren), can facilitate benzylic C sp3 −H bond metalation and subsequent aroylation with Weinreb amides, where the corresponding organolithium complex (LiCH 2 SiMe 3 + PMDTA) failed to deliver such reactivity 50. It is interesting for us to note that the benzylic C sp3 −H bond metalation is concentration-dependent: while we reported in 2022 that the combination of LiCH 2 SiMe 3 + Me 6 Tren can deliver such metalation with neat toluene,51 Hevia and co-workers observed that LiCH 2 SiMe 3 + Me 6 Tren/PMDTA cannot activate toluene in hexane solution.…”

“…Keith Izod, Roly Armstrong, and Matthew Hopkinson (all at Newcastle University) for insightful discussions. The authors thank Professor Eva Hevia (Universität Bern) for providing in-depth insight of the recent publication regarding 1 -Na from her group.…”