Complex-induced proximity effect CIPE

Directed remote metalation (DreM) of biaryl amides and O-carbamates, conceptually based on the complex-induced proximity effect (CIPE) [15] provides, especially in view of their link to transition metal-catalyzed cross coupling regimens [16], general and versatile routes to fluorenones (16 —> 15, Scheme 4) [5,17] and biaryl amides (16 —> 17) [18] whose features are overriding Friedel-Crafts reactivity and yield enhancement in comparison to Suzuki-Miyaura coupling routes for highly hindered biaryls, respectively. Additional features of the O-carbamate DreM result is potential further DoM of 17 with appropriate phenol protection and cyclization to dibenzopyranones [18]. 

The status, detailed in the excellent comprehensive review by Clayden [5a], and supplemented by coverage of the complex-induced proximity effect (CIPE) [15] may be summarized by the following, at times conflicting, points. 

The directed ortho metalation is fundamentally a complex-induced proximity effect (CIPE) in which the formation of a pre-metalation complex brings reactive groups into proximity for directed deprotonation. 

Whisler, M. C., MacNeil, S., Snieckus, V., Beak, P. Beyond thermodynamic acidity A perspective on the complex-induced proximity effect (CIPE) in deprotonation reactions. Angew. Chem., Int. Ed. Engl. 2004, 43, 2206-2225. 

An insight into the deprotonation reaction of 1 with rert-butyllithium can be gained by computational methods [9]. In the experiment, this reaction is effected at very low temperatures (-70 to -90 °C) under kinetically controlled conditions. Under these conditions, the reaction will proceed via the energetically more stable transition state. Two reaction paths are plausible, resulting in the formation of the two possible epimers (R,S)-2 and (SJS)-2. Each of these reaction paths will be considered separately. With the implication of the complex induced proximity effect (CIPE) [10], the reaction is believed to start with a pre-coordinated te/t-butyllithium molecule, whose lithium... 

SCHEME 26.2 Complex-induced proximity effect (CIPE) process. 

Deprotonation of -amidobenzene and /3-amidophospho-nates may be achieved using j-BuLi. The resulting species may be alkylated, e.g., with phosphorus or silicon electrophiles (eq 43), in a reaction that is mediated by a complex-induced proximity effect (CIPE). ... 

A basic three-step mechanism has been proposed to explain the DoM reaction (Scheme 11.2). This invokes the complex-induced proximity effect (CIPE) wherein the allq l lithium aggregate (RLi) coordinates to the DMG through an equilibrium process, and the complex thus formed places the base in close proximity to the ortho proton leading to a coordinated ortho-lithiated species, which then reacts with the electrophile to form the 1,2-disubstituted arene. ... 

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