Cation−π Interactions in the Benzylic Arylation of Toluenes with Bimetallic Catalysts

Abstract

A method to directly arylate toluene derivatives with aryl bromides to generate diarylmethanes, which are important building blocks in drug discovery, is described. In this method, KN(SiMe) in combination with a (NIXANTPHOS)Pd catalyst accomplished the deprotonative activation of toluene derivatives to permit cross-coupling with aryl bromides. Good to excellent yields are obtained with a range of electron-rich to neutral aryl bromides. Both electron-rich and electron-poor toluene derivatives are well tolerated, and even 2-chlorotoluene performs well, providing a platform for introduction of additional functionalization. This discovery hinges on the use of a main group metal to activate toluene for deprotonation by means of a cation-π interaction, which is secured by a bimetallic K(NIXANTPHOS)Pd assembly. Mechanistic and computational studies support acidification of toluene derivatives by the K-cation- π interaction, which may prove pertinent in the development of other, new reaction systems.

Transition-metal-free formal cross-coupling of aryl methyl sulfoxides and alcohols via nucleophilic activation of C-S bond

“…In a subsequent study, 2.0 equivalents of potassium fluoride added to the reactions with LiO t Bu or NaO t Bu restored the reactivity providing 63% and 27% yield, respectively ( Table 3, entries 4-5). These control experiments support a pivotal role of potassium cation in the transition-metal-free cross-coupling 49,50 . Hence, a computational study was conducted to fully understand this unusual C-S bond activation mode for methyl sulfoxides that does not require a transition metal catalyst.…”

Efficient Synthesis of Bulky 2,2’‐Bipyridine and (S)‐Pyridine‐Oxazoline Ligands

“…Reaction development and optimization . Based on our previous work [6a,b,7a,b,10] involving van Leeuwen's NIXANTPHOS ligand [2,11] (see Table 1 for structure), we began to study coupling of 6,6′‐dimethyl‐2,2′‐bipyridine ( 1 a , 1 equiv.) and bromobenzene ( 2 a , 3 equiv.)…”

Synthesis of Indoles through Domino Reactions of 2‐Fluorotoluenes and Nitriles

“…Although the equilibrium presumably lies very far to the left, the benzylic organometallic was efficiently trapped by the imine,p roviding biologically important 1,2diarylethylamine derivatives upon workup (36 examples,56-98 %y ield). [17] Our ongoing interest in the synthesis of biologically active compounds inspired us to ask if other electrophiles would undergo selective reactions with the transiently generated benzyl organometallic intermediates in as imilar fashion to Scheme 2a.F rom our past experience,w ek new that MN-(SiMe 3 ) 2 bases add to nitriles with arelatively high barrier, [17a] and thus we envisioned the benzylation of benzonitriles as apath forward. Further,wedesired to exploit the reactivity of the metalated imine intermediate to form an NÀCb ond.…”