Enantioselective Synthesis of Alkyl Azaarenes

Abstract

This Minireview covers reports on the enantioselective synthesis of alkyl azaarenes since 2014. It deals with the latest achievements on the reactivity of alkyl azaarenes aiming at the preparation of more complex azaarenes containing chiral centers. They rely on the activating properties of the nitrogen atom when opportunely coordinated with a metal complex or Brønsted acid and possibly containing chiral ligands. In addition, conveniently located electron-withdrawing activating functional groups help increase the reactivity of the azaarenes. The same concepts operate in the case of vinyl azaarenes.[a] Dr. Scheme 1. Modes of activationScheme 2. Early example by Lam. 2 3 4 5 6 7 8

Iron-catalyzed radical intermolecular addition of unactivated alkenes to alkenyl N-heteroarenes

“…Among such reactions, many elegant ways for obtaining structurally complex azaarenes have been established. 3 Surprisingly, radical type reactions of alkenyl N-heteroarenes have not been widely studied. The groups of Knowles, 4 a Melchiorre, 4 b Ley, 4 c Ravelli, 4 d Ngai, 4 e Zhu, 4 f Liu 4 g and Jiang 4 h – n have developed conjugate addition reactions of distinct radical species to alkenyl N-heteroarenes.…”

Direct C(sp3)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

“…Although transitionmental-catalyzed allylic substitution reactions employing various nucleophilic or electrophilic allylic precursors have been extensively studied [8][9][10], limited strategies were reported for their application in the C(sp 3 )-H allylic functionalization of 2-alkylazaarenes. Due to the high pK a value of alkyl azaarenes, the functionalization of benzylic C(sp 3 )-H was challengeable and pre-activation of the benzylic proton with suitable Lewis acids was often required prior to deprotonation of the alkyl chain by a stoichiometric base (Scheme 1a) [11][12][13][14][15][16][17]. In most cases, super stoichiometric amounts of strong bases, such as n-BuLi or LiHMDS, would be used, which severely limited their applications.…”

Asymmetric α-Functionalization of 2-Alkyl Azaarenes: Synthesis of Tertiary Fluorides Having Vicinal Stereogenic Centers

“…α-Stereogenic centers containing ortho -substituted pyridines or azaarenes are frequently found motifs in natural products and pharmaceuticals . Despite its usefulness, enantioselective functionalization of azaarenes has gained less consideration and there is demand for new methodologies for synthesizing such compounds.…”