Visible-Light-Mediated Organophotocatalyzed C(sp³)–H Activation and Intramolecular Cyclization

Abstract

A metal-free approach for C(sp³)–H activation followed by an intramolecular Giese reaction to construct a wide range of cyclic ether scaffolds of various ring sizes under environmentally benign and straightforward conditions is reported. An easily prepared pyrylium salt is employed as an organophotocatalyst for this visible-light-driven, highly atom-economical (PMI = 64.34 g/g for a 0.2 mmol scale), cost-effective, and chemoselective transformation. The reported method has a broad functional-group tolerance, resulting in good-quality products. Furthermore, downstream functionalizations of a product and a gram-scale synthesis (PMI = 17.41 g/g for a 10 mmol scale) are demonstrated, highlighting our method’s advantages.

Key words

pyrylium salts - C(sp³)–H bond activation - cyclization - cyclic ethers - organophotocatalysis

Publication History

Received: 17 June 2022

Accepted after revision: 27 September 2022

Accepted Manuscript online:
28 September 2022

Article published online:
27 October 2022

• References and Notes

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• 13 Substrates 1a–z; General Procedure All the substrates were prepared by following the previously reported method² with the necessary modifications. An oven-dried, 100 mL, two-necked, round-bottomed flask equipped with a magnetic stirrer was charged with NaH (1.1 equiv) in anhyd THF (30 mL) under argon. 2,2-Dimethylpropane-1,3-diol (10 mmol, 1.0 equiv) was separately dissolved in anhyd THF (20 mL) and the solution was slowly added to the stirred solution of NaH at 0 °C. The mixture was allowed to warm to rt, then the appropriate benzyl bromide (1.2 equiv) was added dropwise with stirring and the reaction mixture was left overnight. Next, the reaction was quenched by dropwise addition of sat. aq NH₄Cl (30 mL), and the organic layer was extracted with EtOAc (3 × 30 mL) and dried (Na₂SO₄₎ . The solvent was evaporated in a rotary evaporator, and the 3-(benzyloxy)-2,2-dimethylpropan-1-ol product was purified by flash column chromatography (silica gel). In the next step, the appropriate 3-(benzyloxy)-2,2-dimethylpropan-1-ol (1.0 equiv) and 100% Celite were added to a 100 mL round-bottomed flask equipped with a magnetic stirrer bar. PCC (1.2 equiv) and anhyd CH₂Cl₂ (50 mL) were then added under argon at room temperature. The mixture was stirred for 4 h and then filtered through a pad of Celite. The Celite bed was washed with CH₂Cl₂ (3 × 15 mL), and the filtrate was collected, washed successively with water, aq Na₂CO₃, and brine. The organic layer was dried (Na₂SO₄) and concentrated under a vacuum. The resulting crude product was purified by flash column chromatography to give the pure 3-(benzyloxy)-2,2-dimethylpropanal derivative. The final starting 2-[3-(benzyloxy)-2,2-dimethylpropylidene]malononitrile derivatives were obtained by the reaction between the appropriate 3-(benzyloxy)-2,2-dimethylpropanal (1.0 equiv) and malononitrile (1.1 equiv) in EtOH (30 mL) containing a catalytic amount of piperidine at rt with stirring. When the aldehyde was consumed (TLC), the solvent was removed in a rotary evaporator and the crude product was purified by flash column chromatography (silica gel). [3-(Benzyloxy)-2,2-dimethylpropylidene]malononitrile (1a) Colorless oil; yield 1.27 g (53%); R_f = 0.3 (silica gel, EtOAc–hexane, 0.5:9.5). ¹H NMR (500 MHz, CDCl₃): δ = 7.43–7.36 (m, 2 H), 7.33 (d, J = 9.9 Hz, 4 H), 4.55 (s, 2 H), 3.37 (s, 2 H), 1.33 (s, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 175.1, 137.5, 128.6, 128.0, 127.7, 113.2, 111.3, 88.1, 73.3, 41.3, 23.6.
• 14 Cyclic Ethers 2a–v: General Procedure A oven-dried 20 mL reaction tube equipped with a magnetic stirrer bar was charged with the appropriate substrate 1 (0.2 mmol, 1 equiv) and PC-IV (0.01 mmol, 0.05 equiv) was added. The tube was evacuated for 5 min an then backfilled with N₂; this cycle was repeated another four times before the tube was sealed with a rubber septum with a continuous flow of N₂. Freshly dried CH₂Cl₂ (2 mL) and TFA (0.4 mmol, 2 equiv) were added through needles, and the tube was placed on a magnetic stirrer and irradiated by a Kessil 40 W, 456 nm blue LED, at a distance of ~3 cm. A cooling fan approximately 1 ft away was used to maintain the system at about rt. After 24 h, the tube was removed from the setup and the mixture was diluted sequentially with CH₂Cl₂ (5 mL) and brine (10 mL), then extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layer was dried (Na₂SO₄) and the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography [silica gel (230–400 mesh), EtOAc-hexane/CH₂Cl₂-hexane]. 2-(4,4-Dimethyl-2-phenyltetrahydrofuran-3-yl)malononitrile (2a) Colorless oil; yield: 42.8 mg (89%; dr = 1:1). Isomer 2a′: colorless oil; R_f = 0.3 (CH₂Cl₂/hexane, 3:7); ¹H NMR (500 MHz, CDCl₃): δ = 7.45–7.33 (m, 5 H), 4.86 (d, J = 9.1 Hz, 1 H), 3.95 (d, J = 8.8 Hz, 1 H), 3.82 (d, J = 8.7 Hz, 1 H), 3.74 (d, J = 5.6 Hz, 1 H), 2.25 (dd, J = 9.1, 5.7 Hz, 1 H), 1.38 (s, 3 H), 1.34 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 139.0, 129.3, 129.2, 126.6, 111.8, 111.5, 84.1, 81.6, 56.3, 42.2, 27.3, 21.5, 20.8. Isomer 2a′′: colorless oil; R_f = 0.4 (CH₂Cl₂–hexane, 3:7); ¹H NMR (500 MHz, CDCl₃): δ = 7.52–7.32 (m, 5 H), 5.40 (d, J = 6.3 Hz, 1 H), 4.17 (d, J = 8.7 Hz, 1 H), 3.79 (d, J = 8.7 Hz, 1 H), 3.27 (d, J = 4.9 Hz, 1 H), 2.53 (dd, J = 6.1, 5.2 Hz, 1 H), 1.48 (s, 3 H), 1.42 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 136.5, 129.3, 129.0, 126.7, 113.2, 112.4, 82.2, 80.0, 54.7, 42.9, 29.5, 22.2, 21.0. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₆N₂NaO: 263.1155; found: 263.1155.
• 15 Zhou R, Liu H, Tao H, Yu X, Wu J. Chem. Sci. 2017; 8: 4654