Ring Expansion of 3‐Oxetanone‐Derived Spirocycles: Facile Synthesis of Saturated Nitrogen Heterocycles

Abstract

One ring to bring them all: 4,5‐Spirocycles derived from 3‐oxetanone and β‐heteroatom‐substituted amino compounds undergo a Lewis acid mediated reaction cascade to form saturated nitrogen heterocycles. The unique reactivity of 3‐oxetanone facilitates access to biologically important morpholines, piperazines, and thiomorpholines with an otherwise difficult‐to‐access substitution pattern from readily available starting materials.

Recent Applications of Oxetanes in the Synthesis of Heterocyclic Compounds

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 With their on-going efforts in examining reactivity profiles of oxetanes derived from 3-oxetanones, Carreira and coworkers also developed a facile synthesis of highly functionalized morpholines, piperazines and thiomorpholines by utilizing an indium catalyzed ring opening of spirooxazolidine oxetanes with subsequent ring expansion of the oxazolidine (Scheme 9b). 32 The cascade reaction is believed to involve indium catalyzed Strecker reaction of the spirocyclic oxetanes with trimethylsilyl cyanide to afford oxetane nitriles. Lewis acid activation of the oxetanes promotes an intramolecular 6-exo cyclization, leading to the formation of densely functionalized morpholines and related heterocycles with excellent diastereoselectivities.…”

Ring Expansions of Oxiranes and Oxetanes

“…The reaction proceeds at room temperature in DCM, affording the products in moderate to high yields. Professor Carreira has reported a second novel ring expansion of 3-oxetanones to heterocycles (Scheme 46) [57]. This two-step process, which starts by converting the ketone into a chiral spirocyclic mixed heteroatom ketal (N/N, N/O or N/S), results in the formation of useful chiral nitrogen heterocycles.…”

A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds

“…Indeed, 13 of the 200 best-selling small molecule drugs in 2012 contain a piperazine ring (for examples, see Figure 1). 9 However, in the vast majority of these molecules, the piperazine ring is isolated (i.e. not fused to another ring) and is not substituted on any of its carbon atoms.…”