LiHMDS‐Mediated Deprotonative Coupling of Toluenes with Ketones

Abstract

We demonstrate that lithium hexamethyldisilazide (LiHMDS) acts as an effective base for deprotonative coupling reactions of toluenes with ketones to afford stilbenes. Various functionalities (halogen, OCF 3 , amide, Me, aryl, alkenyl, alkynyl, SMe, and SPh) are allowed on the toluenes. Notably, this system proved successful with low-reactive toluenes bearing a large pKa value compared to that of the conjugate acid of LiHMDS (hexamethyldisilazane, 25.8, THF), as demonstrated by 4-phenyltoluene (38.57, THF) and toluene itself ( 43, DMSO).

Dual Basicity and Nucleophilicity of Organosodium Reagents in Benzylic C−H Additions of Toluenes to Diarylethenes and Ketones

“…Emphasising the efficiency on the substrate metalation and the strong nucleophilic character of the in situ generated NaCH 2 Ar ⋅ PMDETA intermediates, it was seen that the relevant tertiary alcohols, formed prior to the dehydration step, were obtained in almost quantitative yields (see SI). Related to these findings it should be noted that Kondo has recently reported the ability of LiHMDS to mediate deprotonative coupling of toluenes with ketones [23] . Showcasing a clear alkali‐metal effect, this study is performed using strongly polar solvent DMI, 40 °C, and an excess of ketone and lithium amide (4 and 3 equivalents respectively) is required, The authors propose these conditions are required to favour lithiation of the toluene derivative and it was also noted that using NaHMDS or KHMDS significantly lower conversions were observed.…”

Masters of Mediation: MN(SiMe3)2 in Functionalization of C(sp3)−H Latent Nucleophiles

“…To overcome this drawback, later on the same group in 2023 reported an updated protocol for deprotonative coupling of benzylic C−H bonds with ketones to afford stilbenes 50 (Scheme 25). [72] This protocol operates with stoichiometric amount of LiN(SiMe 3 ) 2 and applicable to low reactive toluene derivatives with high pKa value and compatible to wide variety of functionalities. In contrast, its counterparts NaN(SiMe 3 ) 2 and KN(SiMe 3 ) 2 were ineffective in this transformation.…”

Process Development and Manufacture of the Core Starting Material of Adagrasib (MRTX849)

“…Despite similar basicity values, sodium bis­(trimethylsilyl)­amide [NaHMDS] was much less effective and did not achieve nearly similar level of conversion to 1 (entry 2). The contrasting reactivity of the sodium and lithium cation has been extensively discussed in the literature and is usually a complex combination of factors such as solvation and coordination effects highly dependent on the unique chemical system at play. , The desired product was not observed when sodium hydride [NaH] or potassium tert -butoxide [KO t Bu] was employed. Lithium bis­(trimethylsilyl)­amide [LiHMDS] exhibited the best reaction profile and was further investigated.…”