Ring expansion of indene by photoredox-enabled functionalized carbon-atom insertion

Abstract

Skeletal editing has received unprecedented attention as an emerging technology for the late-stage manipulation of molecular scaffolds. The direct achievement of functionalized carbon-atom insertion in aromatic rings is challenging. Despite ring-expanding carbon-atom insertion reactions, such as the Ciamician-Dennstedt re-arrangement, being performed for more than 140 years, only a few relevant examples of such transformations have been reported, with these limited to the installation of halogen, ester and phenyl groups. Here we describe a photoredox-enabled functionalized carbon-atom insertion reaction into indene. We disclose the utilization of a radical carbyne precursor that facilitates the insertion of carbon atoms bearing a variety of functional groups, including trifluoromethyl, ester, phosphate ester, sulfonate ester, sulfone, nitrile, amide, aryl ketone and aliphatic ketone fragments to access a library of 2-substituted naphthalenes. The application of this methodology to the skeletal editing of molecules of pharmaceutical relevance highlights its utility.

Fig. 1 |. Skeletal editing via single-atom insertion.

a, Ring expansion by single-atom insertion. b, Mechanism of previously reported carbon-atom insertion reaction. c, Carbon-atom insertion reagents. d, Possible reaction mechanisms and challenges for carbyne radical precursors. e, Indene ring expansion via functionalized carbon-atom insertion.

Fig. 2 |. Development of the functionalized carbon-atom insertion reaction.

a, Identification of carbyne reagent. Reaction conditions: indene (0.1 mmol), 2 (0.12 mmol), Ru(dtbbpy)₃(PF₆)₂ (1 mol%) and Na₂CO₃ (0.2 mmol) in CH₃CN (0.05 M), irradiation with a 30 W blue LED (λ_max = 450 nm) under an argon atmosphere at room temperature (r.t.) for 12 h. The yields were determined by GC-FID analysis using hexadecane as an internal standard. b, Control experiments. c, Sensitivity assessment of reaction conditions. GC-FID, gas chromatography-flame ionization detector; T, temperature; C, concentration; I, light intensity.

Fig. 3 |. Substrate scope for the functionalized carbon-atom insertion reaction.

Isolated yields on a 0.2 mmol scale unless stated otherwise. Reaction conditions: indene (0.2 mmol), 2d (0.24 mmol), Ru(dtbbpy)₃(PF₆)₂ (1 mol%) and Na₂CO₃ (0.4 mmol) in CH₃CN (4 ml, 0.05 M), irradiation with a 30 W blue LED (λ_max = 450 nm) under an argon atmosphere at room temperature (r.t.) for 12 h. ^a2f was used instead of 2d. Isolated after oxidation to alcohol. r.s.m., remaining starting material. ^bIsolated after oxidation to alcohol.

Fig. 4 |. α-Iodonium diazo compounds scope for the functionalized carbon-atom insertion reaction.

Isolated yields on a 0.2 mmol scale unless stated otherwise. Reaction conditions: indene (0.2 mmol), α-iodonium diazo reagent (0.24 mmol), Ru(dtbbpy)₃(PF₆)₂ (1 mol%) and Na₂CO₃ (0.4 mmol) in CH₃CN (4 ml, 0.05 M), irradiation with a 30 W blue LED (λ_max = 450 nm) under an argon atmosphere at room temperature (r.t.) for 12 h. ^aα-Iodonium diazomethylnitrile (0.3 mmol), stirred at room temperature for 1 h.

Fig. 5 |. Synthetic applications of the functionalized carbon-atom insertion reaction.

a, Functionalized carbon-atom insertion of biindene. b, Skeletal modification of aldosterone synthase inhibitor. c, Application to synthesis of adapalene derivative 5d.

Fig. 6 |. Mechanistic studies.

a, The ultraviolet–visible absorption spectrum of 1a (5 × 10⁻³ mol l⁻¹), 2d (6 × 10⁻³ mol l⁻¹) and Ru(dtbbpy)₃(PF₆)₂ (5 × 10⁻⁵ mol l⁻¹) in MeCN was collected, respectively. Accordingly, the photocatalyst Ru(dtbbpy)₃(PF₆)₂ and 2d were found to be absorbing species near the excitation wavelength (λ_max = 450 nm). b, Infeasibility of direct photosensitization excludes the possibility of an energy transfer pathway. c, Stern–Volmer quenching studies. Stern–Volmer analysis revealed that the luminescence emission of Ru(dtbbpy)₃(PF₆)₂ was quenched efficiently by α-iodonium diazo 2d, whereas no quenching was observed with indene. d, Cyclic voltammetry measurements of indene. e, Cyclic voltammetry measurements of 2d. f, Deuterium labelling experiments. g, Radical capture experiments. h. Deallylation in the carbon insertion of substrate 6g. i, Methyl migration in the carbon insertion of 1,1-dimethylindene 6i. r.t., room temperature. TEMPO, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl; 2,6-DTBP, butylhydroxytoluol.

Fig. 7 |. Proposed reaction mechanism and DFT calculations.

a, Computed Gibbs energy profiles for competing pathways for indene ring expansion from C-centred radical I• intermediate. Calculated Gibbs free energies (uB3LYP-D3/def2tzvpp//uB3LYP/def2svp–CPCM (acetonitrile)) are given in kcal mol−1. b, Energetics for the formation of intermediate• promoted by single electron transfer between the triplet [Ru^II] and reagent 2f. For computational details, see Supplementary Methods.