Abstract
Nucleophilic dearomatization of azaarenium salts is a powerful strategy to access 3D scaffolds of interest from easily accessible planar aromatic azaarene compounds. Moreover, this approach yields complex dihydroazaarenes by allowing the functionalization of the scaffold simultaneously to the dearomatization step. On the other side, organocatalysis is nowadays recognized as one of the pillars of the asymmetric catalysis field of research and is well-known to afford a high level of enantioselectivity for a myriad of transformations thanks to well-organized transition states resulting from low-energy interactions (electrostatic and/or H-bonding interactions…). Consequently, in the last fifteen years, organocatalysis has met great success in nucleophilic dearomatization of azaarenium salts. This review summarizes the work achieved up to date in the field of organocatalyzed nucleophilic dearomatization of azaarenium salts (mainly pyridinium, quinolinium, quinolinium and acridinium salts). A classification by organocatalytic mode of activation will be disclosed by shedding light on their related advantages and drawbacks. The versatility of the dearomatization approach will also be demonstrated by discussing several chemical transformations of the resulting dihydroazaarenes towards the synthesis of structurally complex compounds.
Highlights
Dihydropyridines and their azaarene counterparts like dihydroisoquinolines, dihydroquinolines and dihydroacridines are widespread backbones in naturally occurring products or drugs and are interesting building blocks for the construction of complex architectures (Figure 1a) [1]
From a mechanistic point of view, the reaction proceeds through the formation of a C(1)-ammonium point of view, the reaction proceeds through the formation of a C(1)-ammonium enolate enolate intermediate resulting from the nucleophilic addition of the catalyst C25 to the intermediate resulting from the nucleophilic addition of the catalyst C25 to the aryl ester aryl ester 105 followed by deprotonation by the DABCO used as a Brønsted base
Nucleophilic dearomatization of azaarenium salts has emerged as a versatile choice
Summary
Dihydropyridines and their azaarene counterparts like dihydroisoquinolines, dihydroquinolines and dihydroacridines are widespread backbones in naturally occurring products or drugs and are interesting building blocks for the construction of complex architectures (Figure 1a) [1]. 1,2-dihydropyridines were reported as useful reactive building blocks, for example in the synthesis of (−)-Oseltamivir (Tamiflu® ), a drug used in the treatment of influenza [2]. The second one involves the dearomatization of azaarenes by nucleophilic addition or reduction (addition of hydride) to the corresponding azaarenium salt. Whereas enantioselective hydride addition requires the use of pre-functionalized azaarenes (introduction of Nu prior to the addition of the hydride) and leads to tetrahydro products (and will not be discussed ) [7,8,9], nucleophilic dearomatization (Nu 6= H) offers the advantage of introducing chemical diversity simultaneously to the dearomatization step. The azaarenes suffer from poor electrophilicity and generally require an activation step to undergo a nucleophilic addition (Figure 1c).
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