Synthesis of Spirocyclic Piperidines by Radical Hydroarylation

Abstract

Reported here are conditions for the construction of spirocyclic piperidines from linear aryl halide precursors. These conditions employ a strongly reducing organic photoredox catalyst in combination with a trialkylamine reductant to achieve formation of aryl radical species. Regioselective cyclization followed by hydrogen-atom transfer affords a range of complex spiropiperidines. This system operates efficiently under mild conditions without the need for toxic reagents or precious metals.

Key words

photoredox catalysis - spirocyclization - piperidines - ­hydroarylation - radicals

Publication History

Received: 25 October 2020

Accepted after revision: 19 November 2020

Accepted Manuscript online:
19 November 2020

Article published online:
18 December 2020

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• 18 Spiropiperidines 1–12; General Procedure A 16 mL screw-top test tube was charged with the appropriate aryl halide precursor (0.3 mmol, 1.0 equiv) and photocatalyst P1 (3DPAFIPN; 0.015 mmol, 5 mol%). The tube was then equipped with a stirrer bar and sealed with a PTFE/silicone septum. The atmosphere in the tube was exchanged by applying vacuum and backfilling with N₂, and solvent was added along with DIPEA (1.5 mmol, 5.0 equiv). The resulting mixture was stirred at 800 rpm for 16 h with irradiation by commercial blue LEDs. The reaction mixture was then diluted with H₂O and extracted with EtOAc (3 × 20 mL). The combined organic layer was dried (Na₂SO₄), filtered, and concentrated by rotary evaporation, and the residue was purified by chromatography (silica gel).