Catalytic Enantioselective Addition of Indoles to Activated N-Benzylpyridinium Salts: Nucleophilic Dearomatization of Pyridines with Unusual C-4 Regioselectivity

Abstract

The catalytic enantioselective dearomatization of pyridines with nucleophiles represents a direct and convenient access to highly valuable dihydropyridines. Available methods, mostly based on N-acylpyridinium salts, give addition to the C-2/C-6 of the pyridine nucleus, rendering 1,2-/1,6-dihydropyridines. Herein, we present an alternative approach to this type of dearomatization reaction, employing activated N-benzylpyridinium salts in combination with a bifunctional organic catalyst. Optically active 1,4-dihydropyridines resulting from the addition of the nucleophile (indole) to the C-4 of the pyridine nucleus are obtained as major products, rendering this method for nucleophilic dearomatization of pyridines complementary to previous approaches.

Nucleophilic Dearomatization of Activated Pyridines

“…Finally, some experimental investigations led us to propose a reaction pathway showing the catalyst involved in the double (covalent and H-bond) activation of both of the reaction partners. In 2016, our group disclosed the first example of organocatalytic enantioselective dearomatization of N-alkylpyridinium salts [60]. Overcoming the poor reactivity (and dearomatized product instability) by placing an EWG group (such as nitro or cyano) at the 3-position, thus enhancing the electrophilicity of the cation, we were able to productively engage N-alkylpyridinium salts in nucleophilic dearomatizations, using indoles as reaction partners (Scheme 20).…”

Heterocyclic Group Transfer Reactions with I(III) N-HVI Reagents: Access to N-Alkyl (Heteroaryl)onium Salts via Olefin Aminolactonization

“…In organic chemistry, they serve as ionic liquids 5 (2) and phase transfer catalysts 6 , exhibit a diverse range of biological activities (3,4) (Figure 1a), and have a long history as synthetic intermediates, an area that has seen a recent surge of new advancements. Representative of their versatile reactivity, pyridinium and related salts can undergo full or partial reductions [7][8][9] , cycloadditions 10,11 , photochemical isomerizations 12 , cross couplings 13 , addition of one-or two-electron heteroatom or carbon nucleophiles 8,14 , and facile C-H metalations 15 , and many of these include asymmetric variants [16][17][18] (Figure 1b). The breadth of available transformations make pyridinium salts valuable templates for accessing functionalized 6-membered aza-heterocyclic scaffolds, which are prevalent in agrochemicals, alkaloid natural products, and are the most commonly encountered heterocyclic motif in FDA approved small molecule drugs 19 .…”

Origin of Regio‐ and Stereoselectivity in the NHC‐catalyzed Reaction of Alkyl Pyridinium with Aliphatic Enal

“…[4] Recently, the organocatalysts were introduced to more demanding N-alkylpyridinium salts, which provided an alternative platform with opportunities in the enantioselective dearomatization of pyridine compared with the N-acyl analogues (Scheme 1b). [5] A regioselectivity issue arises from the two different positions prone to nucleophilic attack present on the pyridine nucleus. This results in either a variable C2/C6 or C4 selectivity depending on the substitution pattern at the pyridine ring.…”

“…Only the reactions involving the C4 nucleophilic sites were observed preferentially in organocatalytic dearomatization reactions. [5] To the best of our knowledge, the origin of the regioselectivity of these kinds of reactions is still unclear. Our previous studies demonstrated that the reactivity of the active sites strongly influences regioselectivity.…”