Tunable [3+2] and [4+2] annulations for pyrrolidine and piperidine synthesis

Abstract

N-heterocycles are privileged pharmaceutical scaffolds in drug discovery and development. We disclose here divergent intermolecular coupling strategies that can access diverse N-heterocycles directly from olefins. The radical-to-polar mechanistic switching is key for the divergent cyclization processes. These distinctive annulations result in the coupling of alkenes with simple bifunctional reagents for divergent N-heterocycle syntheses.

Scheme 1.

Background and proposed divergent annulations.

Scheme 2.

Reaction optimization studies.^{[a] [a]}Standard reaction conditions: for pyrrolidine, 2 (0.25 mmol), 1 (200 mol%), NIS (110 mol%), DCM (4.0 mL), CFL light, N₂, 16 h. For piperidine, 2 (0.25 mmol), 1 (200 mol%), NBS (110 mol%), DCM (0.25 mL), CFL light, N₂, 1 h, then HFIP (0.5 mL), 36 h. ^[b]under an atmosphere of N₂. ^[c]1 h under light before addition of HFIP. ^[d]Yields in parenthesis were isolated yields. The pyrrolidine 4a was isolated as an exocyclic olefin 4 after being treated to these conditions: NaH (1.25 mmol), THF (0.5 mL), 0 °C to rt, 18 h.

Scheme 3.

Pyrrolidine substrate scope studies.^{[a] [a]}Standard reaction conditions were used and for the detailed procedure, please refer to the Supporting Information. ^[b]These exocyclic olefins were obtained after subjecting the isolated iodo-pyrrolidine products to the following conditions: NaH (1.25 mmol), THF (0.5 mL), 0 °C to rt, 18 h.

Scheme 4.

Piperidine substrate scope studies.^{[a] [a]}For detailed information, please refer to the Supporting Information. ^[b]yield for the bromo-intermediate. ^[c]yield for the cyclization from the bromo-intermediate. ^[d]AlBr₃. ^[e]Zn(OTf)₂.

Scheme 5.

Mechanistic studies and synthetic utilities.