Catalytic, Enantioselective Hydrogenation of Heteroaromatic Compounds

Abstract

Enantioselective catalytic hydrogenation of heteroarenes provides straightforward, atom‐economical access to the corresponding cyclic heterocycles, which are found as common structural motifs in many important biologically active reagents and alkaloids. This enantioselective transformation has developed only recently due to the high stability of these aromatic compounds and the poisoning effects of nitrogen or sulfur atoms to chiral catalysts. Moreover, heteroarenes comprise a very large family with diverse structural features and each type of heteroarene substrate shows distinct reactivity in hydrogenation. Various heteroarenes, including quinolines, isoquinolines, quinoxalines, pyridines, indoles, pyrroles, imidazoles, oxazoles, and furans, can be smoothly hydrogenated with good to excellent enantioselectivity under proper reaction conditions. Transition‐metal catalysts, based on iridium, ruthenium, rhodium, and palladium complexes, play an important role in this field, and organocatalysts have also shown high efficiency for hydrogenation of certain heteroarenes. This chapter provides a comprehensive analysis that includes the advantages of a given catalyst system for each type of substrate. Some total syntheses that feature enantioselective hydrogenation of heteroaromatics as key steps are also described in this chapter.

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

“…2 Major efforts in this realm have been invested in asymmetric reductions, resulting in numerous highly enantioselective methods that provide solutions for many heteroaromatic substrates. 35 However, the enantioselective reduction of aromatic hydrocarbons is virtually nonexistent, such that only one report involves the highly enantioselective hydrogenation of substituted naphthalenes (e.g., 66 / 67) based on a Ru catalyst. 36 Nevertheless, this indicates that perhaps soon we will see more of these transformations, especially with elusive benzene derivatives that could unlock complementary access to enantioenriched cyclohexane derivatives.…”

Reducing Challenges in Organic Synthesis with Stereoselective Hydrogenation and Tandem Catalysis

“…For strongly stabilized rings, such as benzene derivatives, few catalysts are able to overcome the activation barrier for de-aromatization, resulting in adverse side reactions such as hydro-defunctionalization. 74 Despite these challenges, recent years have seen breakthroughs in arene hydrogenation. For example, Glorius has reported the hydrogenation of fluorinated benzenes and pyridines.…”

“…With an array of biological activities from anti-microbial to anti-cancer, alkaloids comprise a large class of structurally diverse natural products. , Their most distinguishing feature is the presence of a basic nitrogen atom that often poses synthetic challenges. Heteroarene reduction by cascade hydrogenation has shown potential for piecing together these intricate frameworks from achiral substrates. − Multiple stereocenters can be generated in one step by global reduction of a simple, highly oxidized aromatic substrate. This strategy has had an impact on the production of fine chemicals, with large multi-thousand-ton scale industrial processes developed.…”

“…This disparity requires a level of reactivity to overcome issues of chemo­selectivity. For strongly stabilized rings, such as benzene derivatives, few catalysts are able to overcome the activation barrier for de-aromatization, resulting in adverse side reactions such as hydro-defunctionalization …”

“…AH methods have been developed for approximately three dozen heteroarenes, with quinolines, quinoxalines, indoles, and isoquinolines being the most common. − General strategies employ chiral auxiliaries, organocatalysis, and transition metal catalysis, the latter being the most frequently used, with many recent applications to the synthesis of complex alkaloids. For example, Zhao used a hydrogen-borrowing approach ( vide infra ) to effect an asymmetric reductive amination cascade for the synthesis of tetrahydroquinolines .…”