Enhancing Metalating Efficiency of the Sodium Amide NaTMP in Arene Borylation Applications

Abstract

Though LiTMP (TMP=2,2′,6,6′‐tetramethylpiperidide) is a commonly used amide, surprisingly the heavier NaTMP has hardly been utilised. Here, by mixing NaTMP with tridentate donor PMDETA (N,N,N′,N′′,N′′‐pentamethyldiethylenetriamine), we provide structural, and mechanistic insights into the sodiation of non‐activated arenes (e.g. anisole and benzene). While these reactions are low yielding, adding B(OiPr)3 has a profound effect, not only by intercepting the CAr‐Na bond, but also by driving the metalation reaction towards quantitative formation of more stabilized sodium aryl boronates. Demonstrating its metalating power, regioselective C2‐metalation/borylation of naphthalene has been accomplished contrasting with single‐metal based protocols which are unselective and low yielding. Extension to other arenes allows for in situ generation of aryl boronates which can then directly engage in Suzuki–Miyaura couplings, furnishing a range of biaryls in a selective and efficient manner.

Gram‐Scale Synthesis, Isolation and Characterisation of Sodium Organometallics:nBuNa and NaTMP

“…However, sodium bases, such as NaTMP, hold a great potential for accessing new synthetic landscape. Recently, our laboratory has reported the combination of this base with the tridentate donor PMDETA ( N , N , N ′, N ′′, N ′′‐pentamethyldiethylenetriamine) and B(O i Pr) 3 for the selective deprotonative borylation of inactivated arenes, [31] which could be cross‐coupled to give a new versatile route to the synthesis of biaryl motifs. Here, we illustrate this approach with 1‐methoxynaphthalene, which can be easily borylated and directly coupled with an aryl bromide to obtain the corresponding biaryl product in a 60 % isolated yield ( Scheme 3 ,a ).…”

Perdeuteration of Arenes via Hydrogen Isotope Exchange Catalyzed by the Superbasic Sodium Amide Donor Species NaTMP·PMDETA

“…Deuterated benzene was chosen for this purpose, as it is the cheapest commercially available deuterated arene molecule. It has been used previously as a deuterium source in transition-metal-catalyzed and acid-catalyzed HIE, ,, and it can undergo borylation by the previously mentioned NaTMP/B­(O i Pr) 3 combination . To test our hypothesis, we added a catalytic amount of NaTMP (10 mol %) and the donor molecule PMDETA ( N , N , N ′, N ″, N ″-pentamethyldiethylenetriamine) (10 mol %) to a solution of anisole ( 1a ) in C 6 D 6 .…”

“…Previous studies have shown that addition of TMEDA in hexane induces the deaggregation of NaTMP from a nonsolvated trimer to a dimer (Figure ), while addition of anisole to a mixture of NaTMP and TMEDA or PMDETA allows the isolation of mixed aggregates [(L) 2 Na 2 (TMP)­(C 6 H 4 –OMe)] (L = TMEDA, 3a ; L = PMDETA, 3b ) . These sodium mixed aggregates showed an incomplete metalation of anisole (36% after iodolysis), which was attributed to the equilibrium between the starting materials (L)­NaTMP and anisole with product 3 and TMP­(H) ( vide infra ).…”

“…To further prove the utility of NaTMP for synthetic purposes working on a higher scale, we proceeded to combine the HIE process with the deprotonative borylation that we have reported previously . Anisole (1 mmol) was dissolved in deuterated benzene (2.5 mL) with NaTMP, and PMDETA was added to the mixture.…”

“…These reactions are facilitated by the initial sodiation of the arene by NaTMP with concomitant formation of TMP­(H). While the metalation step is low yielding, due to the dynamic equilibrium between the products and starting materials, introduction of Lewis acidic B­(O i Pr) 3 shifts this equilibrium toward the quantitative formation of the desired C–B bond, achieving the borylation of unactivated arenes such as benzene, naphthalene, or anisole . Despite the popularity of alkali-metal amide bases, their use in HIE processes with less reactive substrates have been precluded by either their incompatibility with some deuterium sources (e.g., D 2 O, MeOD) or their lack of reactivity with others (e.g., C 6 D 6 , D 2 ).…”