UC Riverside

Despite the plethora of synthetic and catalysis methodologies developed for the direct activation of carbon–carbon (C–C) bonds, its direct insertion by carbene or carbenoid intermediates is unprecedented. This is intriguing provided the versatility of carbene and carbenoid intermediates in inserting into strong C–H, O–H, N–H, Si–H, and B–H bonds. The approach detailed in this chapter entails targeting metal carbenoid insertion into strained C–C bonds. Synthesis routes to generate substrates for metal-carbene-mediated C–C insertions were developed. Initial studies with the diazo compounds synthesized thus far have led to cyclization and C–H insertion products, suggesting a high barrier to C–C insertion despite attempts to disfavor C–H insertion.Dual Brønsted/Lewis acid catalysis involving environmentally benign, readily accessible protic acid and iron promotes site-selective tert-butylation of electron-rich arenes using di-tert-butylperoxide. This transformation inspired the development of a synergistic Brønsted/Lewis acid catalyzed aromatic alkylation that fills a gap in the Friedel–Crafts reaction literature by employing unactivated tertiary alcohols as alkylating agents, leading to new quaternary carbon centers. Corroborated by DFT calculations, the Lewis acid serves a role in enhancing the acidity of the Brønsted acid. The use of non-allylic, non-benzylic, and non-propargylic tertiary alcohols represents an underexplored area in Friedel–Crafts reactivity. The intermolecular Friedel–Crafts alkylation represents a straightforward approach to synthesizing C(sp2)–C(sp3) bonds. When readily accessible alcohols are utilized directly as the alkylating agents, the sole byproduct generated is water. Traditional Friedel–Crafts alkylation reactions are typically limited to alkyl (pseudo)halides and activated alcohols that form stabilized carbocations. However, by using inexpensive and abundant ZnCl2 and camphorsulfonic acid (CSA) as catalysts, we present a site-selective Friedel–Crafts alkylation of phenolic derivatives with unactivated secondary alcohols. This catalytic process favors ortho-selectivity, even in the absence of steric influence. Mechanistic studies served to elucidate the origin of site-selectivity, favoring an SN1 pathway in which zinc and CSA function to scaffold both the phenolic and alcohol reactants for ortho-functionalization. This work highlights the efficacy of simple catalysts for achieving C(sp2)–C(sp3) bond synthesis, departing from conventional transition-metal-catalyzed cross-coupling methods.