Directed functionalization of 1,2-dihydropyridines: stereoselective synthesis of 2,6-disubstituted piperidines

Abstract

A practical and highly stereoselective approach to access 2,6-disubstituted piperidines using an amidine auxiliary is reported. Following the diastereoselective addition of Grignard reagents at the 2-position of an activated pyridinium salt, the amidine group directs a regioselective metalation at the 6-position, enabling further functionalization. A subsequent electrophilic quench or a Negishi cross-coupling could be performed, resulting in 2,6-disubstituted dihydropyridines. These were reduced to the saturated piperidine rings with high diastereoselectivity.

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

“…In this context, the advantage of direct C-H fluorination over traditional fluorination methods is that it does not require the introduction of other functional groups. Although many methods have been developed for fluorination reactions [3,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46], including the addition of electrophilic fluorine to alkenes [1,28,32], the fluorination of aryl triflates [29] and arylpalladium complexes [2,47], few permit a one-step transformation of unactivated C(sp 3 )-H bonds to C(sp 3 )-F bonds [1,3,36,38,48]. Such a transformation would be highly valuable for the late-stage functionalization (LSF) of complex molecules, such as those in Scheme 1.…”

Brønsted‐Acid‐Catalyzed Multicomponent One‐Pot Reaction: Efficient Synthesis of Polysubstituted 1,2‐Dihydropyridines

“…[10] In 2014, Charette et al showeda ne fficient and stereoselective synthetic method leading to functionalized 1,2-dihydropyridines by using an amidine auxiliary. [11] In 2015, Liu et al developed ag old-catalyzed highly regioselective oxidative ring expansiono f2 -alkynyl-1,2dihydropyridine and its analogues, using pyridine-N-oxide as the oxidant. [12] The Trost group reported aphosphine-catalyzed synthesis of 1,2-dihydropyridines via an alkyne isomerization/ electrocyclization sequence with propargylidene carbamates as materials.…”

Sequential Pyridine Dearomatization–Mizoroki–Heck Cyclization for the Construction of Fused (Dihydropyrido)isoindolinone Ring Systems

“…8 Related stereoselective transformations that entail application of chiral auxiliaries or catalytic asymmetric transformations have been reported as well. [9][10][11] In addition to enhanced pyridine electrophilicity, α and γ benzylic C-H groups of N-alkyl/acyl pyridinium salts also exhibit markedly increased acidity. This results in conversion of appropriately substituted alkylpyridines into the corresponding anhydrobases (or alkylidene dihydropyridines) as indicated in Scheme 1, b.…”