Dearomatization reactions provide a synthetic connection between readily available, simple aromatic starting materials and more saturated intermediates of greater molecular complexity and synthetic utility. The last decade has witnessed a steady increase in the development of dearomative methods, providing new synthetic approaches to high-value building blocks and natural products. This review highlights advances both in the area of dearomatization methodologies for the most chemically inert arenes and in synthetic applications of such strategies.
Direct
epoxidation of aromatic nuclei by cytochrome P450 monooxygenases
is one of the major metabolic pathways of arenes in eukaryotes. The
resulting arene oxides serve as versatile precursors to phenols, oxepines,
or trans-dihydrodiol-based metabolites. Although
such compounds have an important biological and chemical relevance,
the lack of methods for their production has hampered access to their
utility. Herein, we report a general arenophile-based strategy for
the dearomative synthesis of arene oxides. The mildness of this method
permits access to sensitive monocyclic arene oxides without any noticeable
decomposition to phenols. Moreover, this method enables direct conversion
of polycyclic arenes and heteroarenes into the corresponding oxepines.
Finally, these studies provided direct connection between simple aromatic
precursors and complex small organic molecules via arene oxides and
oxepines.
A nickel(0)-catalyzed method for the synthesis of quinazolinediones from isatoic anhydrides and isocyanates is described. High-throughput ligand screening revealed that XANTPHOS was the optimal ligand for this transformation. Subsequent optimization studies, supported by kinetic analysis, significantly expanded the reaction scope. The reaction exhibits a case of substrate inhibition kinetics with respect to the isocyanate. Preliminary results on an asymmetric synthesis of atropisomeric quinazolinediones are reported.
The development of an intramolecular arylation of sp3 C–H bonds adjacent to nitrogen using aryl halides is described. Arylation was accomplished using either Ni(COD)2 or 1,10-phenanthroline in sub-stoichiometric amounts and the reaction conditions were applied to a variety of electronically differentiated benzamide substrates. Preliminary studies suggest a mechanism involving aryl and alkyl radical intermediates.
Herein we report a dearomative syn-1,4-diamination protocol using simple nonactivated arenes and amines. This one-pot method utilizes arene–arenophile para-cycloadducts, formed via visible-lightmediated [4+2]-photocycloaddition that undergoes formal allylic substitution with amine nucleophiles under Pdcatalysis. The products are obtained with exclusive syn-1,4-selectivity; the method permits enantioselective desymmetrization of naphthalene, as well as elaborations of amine-containing drug molecules. Furthermore, the resulting unsaturated products are amenable to numerous options for diversification. Overall, this novel dearomative functionalization strategy offers rapid and straightforward access to complex building blocks, which are difficult to prepare otherwise, from simple arenes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.