Shaping Molecular Landscapes: Recent Advances, Opportunities, and Challenges in Dearomatization

Abstract

Dearomatization is a fundamental chemical transformation, and it underlies some of the most efficient tactics for generating threedimensional complexity from basic two-dimensional precursors. The dearomative toolbox, once restricted to only a handful of reactions, has begun to grow more sophisticated as novel methods are added, introducing more functionality under milder conditions and with more control over chemo-, regio-, and stereoselectivity than ever before. Over the past two decades, major developments in dearomative processes have bolstered significant total-synthesis endeavors and greatly expanded the scope and complexity of chemical building blocks accessible from feedstock arenes. In this Perspective, we highlight some of the recent advances and key challenges that remain in this vibrant area of organic chemistry.

Single point activation of pyridines enables reductive hydroxymethylation

“…4 In particular dearomative methods that form both C-H and C-C bonds represent an important class of reaction that are particularly versatile and efficient. However, despite their importance, [5][6][7][8][9][10][11][12] these types of reactions continue to be underrepresented in the literature.…”

trans-Selective and Switchable Arene Hydrogenation of Phenol Derivatives

“…Arene hydrogenation is a powerful tool to transform simple, two-dimensional precursors into more complex, three-dimensional scaffolds. 1 A plethora of readily available arenes and heteroarenes provided by established transformations (e.g., cross-coupling, aromatic substitution), offer potential access to a wide array of cyclic saturated motifs. The strategic importance of arene hydrogenation is exemplified by the industrial synthesis of cyclohexane 2 and cyclohexene 3 from benzene on multi-ton scale.…”

“…In general, the transition-metal catalyzed hydrogenation of arenes favors the corresponding all- cis configuration of the saturated analogues ( Scheme 1 a, path I). 1 , 4 The cis -selectivity results from a fast, continuous hydrogenation of the substrate through a non-interrupted coordination to the catalyst. The corresponding trans -isomers require a π-facial exchange of the dearomatized diene or olefin intermediate via substrate desorption and readsorption to the catalyst, which is associated with binding to the sterically more hindered π-face.…”

“…For this reason, the corresponding trans -isomers remain minor side products during arene hydrogenation. 1 , 4 However, trans -isomers of multisubstituted saturated carbo- and heterocycles are desirable product motifs, and their synthesis starting from the corresponding cis -isomers is often limited, rendering a direct trans -selective hydrogenation of arenes desirable ( Scheme 1 a, path II).…”

“…The chemoselective hydrogenation of phenols to cyclohexanones showed no significant influence caused by the substitution pattern, giving access to the volatile methylcyclohexanones 4a – 4ac in good yields. The catalytic system based on rhodium provides products generated by the all- cis addition 1 , 4 of hydrogen atoms to the substrates, whereas the catalytic system based on palladium gives access to the thermodynamically more stable diastereomers.…”