Highly congested spiro-compounds via photoredox-mediated dearomative annulation cascade

Abstract

Photo-mediated radical dearomatization involving 5-exo-trig cyclizations has proven to be an important route to accessing spirocyclic compounds, whereas 6-exo-trig spirocyclization has been much less explored. In this work, a dearomative annulation cascade is realized through photoredox-mediated C-O bond activation of aromatic carboxylic acids to produce two kinds of spirocyclic frameworks. Mechanistically, the acyl radical is formed through oxidation of triphenylphosphine and subsequent C-O bond cleavage, followed by a 6-exo-trig cyclization/SET/protonation sequence to generate the spiro-chromanone products in an intramolecular manner. Furthermore, the protocol was extended to more challenging intermolecular tandem sequences consisting of C-O bond cleavage, radical addition to an alkene substrate, and 5-exo-trig cyclization to yield complex spirocyclic lactams.

Fig. 1. Photocatalytic construction of spiro-compounds via radical dearomatization.

a Examples of spiro-containing pharmaceuticals. b Different strategies for light-mediated dearomative radical spirocyclization. c This work: spirocyclization via C–O bond activation of carboxylic acids.

Fig. 2. Reaction design.

Proposed photocatalytic cycle for intramolecular (Path A) and intermolecular (Path B) construction of spiro-compounds.

Fig. 3. Scope for the radical-based intramolecular dearomative spirocyclization.

Reaction conditions: carboxylic acid (0.3 mmol, 1 equiv.), triphenylphosphine (1.5 equiv.), K₃PO₄ (1 equiv.), [Ir(dF(CF₃)ppy)₂(dtbbpy)](PF₆), (1 mol%) CH₃CN/H₂O (85:15 vol%, 6 mL), N₂, blue LEDs (440 nm), 36 h, fan cooling (35–40 °C). Further derivatization of products 5a and 5s were performed under the following conditions: (i) NaBH₄, MeOH, 0 °C, 2 h; (ii) MeMgBr, THF, 0 °C, 16 h; (iii) H₂, Pd/C, MeOH, 12 h; (iv) H₂, Pd/C, MeOH, 60 h; (v) TFA, CH₂Cl₂, 16 h.

Fig. 4. Mechanistic studies.

a Fluorescence quenching of [Ir(dF(CF₃)ppy)₂(dtbbpy)](PF₆) (15 µM) by PPh₃ and other reaction components (1a, deprotonated 1a, 5a, and Ph₃PO) in MeCN/H₂O (85:15 vol%). b Control experiments with substrate 1a with radical traps (TEMPO and 1,1-diphenylethylene) and different deuterated solvents.

Fig. 5. The scope for intermolecular radical dearomative spirocyclization.

Reaction conditions: carboxylic acid (0.2 mmol, 1 equiv.), acrylamide acceptor (2 equiv.), triphenylphosphine (2 equiv.) K₃PO₄ (1 equiv.), [Ir(dF(CF₃)ppy)₂(dtbbpy)](PF₆) (1 mol%), CH₃CN/H₂O (85:15 vol%, 4 mL), N₂, blue LEDs (440 nm), 48 h, fan cooling (35–40 °C). ^acarboxylic acid (2 equiv.), acrylamide acceptor (0.2 mmol, 1 equiv.).

Fig. 6. Mechanistic studies.

DFT-investigation of the dearomatization mechanism at the B3LYP/6-311+G(d,p)–D3–CPCM(acetonitrile, UFF) level of theory.