Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines

Abstract

The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1′-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.

An interrupted Corey–Chaykovsky reaction of designed azaarenium salts: synthesis of complex polycyclic spiro- and fused cyclopropanoids

“…But, the synthesis of spirocarbocyclic piperidines by this means is quite rarely accomplished. 6,7 Interestingly, Eisch 6 a and Fraenkel 6 c achieved this synthetic feat through an intramolecular addition of hard nucleophiles such as organolithiums and Grignard reagents, although the C-4 position in pyridinium salts is soft. On the other hand, the synthetic utility of bis-enamine functionality of the so-formed dihydropyridines has also been underutilized.…”

3-[N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses

“…Spiroheterocyclic motifs are present in a number of approved drugs and natural compounds [ 1 , 2 , 3 , 4 ] ( Figure 1 ). Such an interest in spirocyclic structures echoed in the field of synthetic organic chemistry, giving rise to a number of elegant preparative approaches to compounds of this type [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”

Brook Rearrangement as Trigger for Dearomatization Reaction: Synthesis of Non‐Aromatic N‐Heterocycles**

“…Additionally, the semi‐pinacol rearrangement of activated pyridines facilitated the generation of spirocyclic piperidine derivatives through subsequent hydrogenation reaction [13c] . Notably, a broader approach to the semi‐pinacol rearrangement process has recently been established, enabling the creation of dihydropyridine spirocycles with remarkable efficiency [13d] . It is important to note that these studies produce valuable scaffolds that could be subjected to downstream transformations.…”