Derivatives of 5-chromenone are common among natural products, particularly in medicinal plants ^[1-4]. For example, tomentodiones H and J, which are two syncarpic acid-conjugated terpenoids (SACTs) isolated from the traditional Chinese medicinal plant Rhodomyrtus tomentosa, contain multi-substituted 5-chromenone scaffolds (Scheme 1) ^[5]. Perhydro-tetrahydrocannabinol (THC) and -cannabichromene (CBC), constituents of marijuana (Cannabis sativa), also possess such important cores ^[6]. Owing to their occurrence in medicinal compounds, intense efforts have focused on the synthesis of 5-chromenone derivatives.

The synthesis of 5-chromenone derivatives is generally achieved using the cost-effective and commercially available 1, 3-cyclohexanedione as the starting material (Scheme 2). Only a two-step procedure is required to prepare 5-chromenone derivatives from 1, 3-cyclohexanedione and either prenyl bromide ^[7-9] or bromo-substituted benzyl bromide ^[10]. Owing to its atom- and step-economy, the [3+3] annulation of 1, 3-cyclohexanedione with unsaturated precursors represents a more convenient and straightforward strategy. In the presence of acids or water, α, β-unsaturated aldehydes ^[11-15] and propargylic alcohols ^[16-21] are suitable coupling partners in this process. Despite these advances, exploiting new [3+3] annulation reactions to access 5-chromenone frameworks from other easily accessible and low-cost chemicals is still in high demand.

Isoprene is an important bulk chemical in industry with an annual capacity of up to 800, 000 metric tons. Expanding on our continuing interest in exploring the diverse reactivity of isoprene ^[22-25], we have developed an efficient alternative for the synthesis of 5-chromenone derivatives 3 via [3+3] annulation of isoprene 2a and 1, 3-cyclohexanediones 1 using the solid acid Nafion as a catalyst (Scheme 2, this work). The pathway for this process involves a domino C-prenylation and intramolecular cyclization. Using prenol 4a as the coupling partner in the presence of AlCl₃ catalyst resulted in the chemoselectivity of the reaction switching exclusively to O-prenylation ^[26-33]. Notably, both products 3 and 5 could be aromatized to the corresponding prenylated resorcinols that are otherwise difficult to synthesize ^[34-39].

Reagents were purchased from commercial sources and used without further purification. Solvents were treated prior to use following standard procedures. Unless otherwise stated, all reactions were conducted under inert conditions. All reactions were monitored by TLC, GC-FID, or NMR analysis. Flash column chromatography was performed on silica gel (200–300 mesh) using a forced flow of eluent at 0.3–0.5 bar pressure. Silica gel GF254 was used for TLC analysis and products were visualized by fluorescence quenching under UV light. ¹H NMR and ¹³C NMR spectra were recorded on a 400 MHz instrument at room temperature in CDCl₃ using tetramethylsilane (TMS) as an internal standard. HRMS data were obtained with a Micromass HPLC-Q-TOF mass spectrometer (ESI) or Agilent 6540 Accurate-MS spectrometer (Q-TOF).

Isoprene (120 μL, 1.20 mmol) was added to a mixture of cyclic 1, 3-diketones 1 (0.40 mmol) and Nafion (10 wt%) in 1, 2-dichloroethane (DCE, 1.0 mL) in a sealed tube and stirred at 110 ℃ for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel using petroleum ether and ethyl acetate to give the desired 5-chromenones 3.

2, 2-Dimethyl-7-phenyl-2, 3, 4, 6, 7, 8-hexahydro-5H-chromen-5-one (3a). Light yellow solid, mp 60–61 ℃, 84.1 mg, 82% yield, R_f = 0.60 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.29 (m, 2H), 7.27–7.21 (m, 3H), 3.39–3.27 (m, 1H), 2.74–2.49 (m, 4H), 2.40–2.14 (m, 2H), 1.75–1.62 (m, 2H), 1.34 (s, 3H), 1.25 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 197.2, 169.7, 143.1, 128.7, 126.9, 126.7, 109.8, 77.5, 43.8, 39.1, 36.6, 32.2, 27.7, 25.5, 15.7. HRMS calculated for C₁₇H₂₁O₂ [M+H]⁺ 257.1536, found 257.1543.

2, 2-Dimethyl-2, 3, 4, 6, 7, 8-hexahydro-5H-chromen-5-one (3b). Colorless oil, 53.1 mg, 74% yield, R_f = 0.60 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 2.33–2.24 (m, 4H), 2.20–2.16 (m, 2H), 1.92–1.85 (m, 2H), 1.62–1.58 (m, 2H), 1.22 (s, 3H), 1.21 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 198.2, 170.6, 110.0, 77.0, 36.7, 32.3, 29.2, 26.6, 21.0, 15.7. HRMS calculated for C₁₁H₁₇O₂ [M+H]⁺ 181.1223, found 181.1225.

2, 2, 7-Trimethyl-2, 3, 4, 6, 7, 8-hexahydro-5H-chromen-5-one (3c). White solid, mp 68–69 ℃, 62.9 mg, 81% yield, R_f = 0.60 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 2.43–2.33 (m, 1H), 2.36–2.25 (m, 1H), 2.26–2.10 (m, 3H), 2.10–1.96 (m, 2H), 1.69–1.55 (m, 2H), 1.28 (s, 3H), 1.21 (s, 3H), 1.02 (d, J = 6.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 198.2, 170.0, 109.5, 77.1, 45.1, 37.3, 32.2, 28.6, 27.5, 25.7, 21.1, 15.6. HRMS calculated for C₁₂H₁₉O₂ [M+H]⁺ 195.1380, found 195.1385.

2, 2, 7, 7-Tetramethyl-2, 3, 4, 6, 7, 8-hexahydro-5H-chromen-5-one (3d). White solid, mp 70–71 ℃, 69.6 mg, 84% yield, R_f = 0.70 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 2.23–2.13 (m, 6H), 1.60 (t, J = 6.6 Hz, 2H), 1.22 (s, 6H), 0.99 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 197.9, 168.9, 108.7, 77.1, 50.7, 43.0, 32.3, 32.2, 28.4, 26.6, 15.5. HRMS calculated for C₁₃H₂₁O₂ [M+H]⁺ 209.1536, found 209.1531.

2, 2, 6, 6-Tetramethyl-2, 3, 4, 6, 7, 8-hexahydro-5H-chromen-5-one (3e). Colorless oil, 25.7 mg, 31% yield, R_f = 0.70 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 2.33 (tt, J = 6.4, 1.7 Hz, 2H), 2.20 (tt, J = 6.6, 1.8 Hz, 2H), 1.77 (q, J = 6.4 Hz, 2H), 1.63 (t, J = 6.6 Hz, 2H), 1.25 (s, 6H), 1.09 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 203.1, 168.4, 108.1, 76.7, 39.9, 34.8, 32.4, 26.7, 26.2, 25.0, 16.2. HRMS calculated for C₁₃H₂₁O₂ [M+H]⁺ 209.1536, found 209.1538.

2, 2, 8, 8-Tetramethyl-2, 3, 4, 6, 7, 8-hexahydro-5H-chromen-5-one (3e'). Colorless oil, 41.8 mg, 50% yield, R_f = 0.60 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 2.40–2.34 (m, 2H), 2.19 (t, J = 6.7 Hz, 2H), 1.78–1.72 (m, 2H), 1.59 (t, J = 6.7 Hz, 2H), 1.22 (s, 6H), 1.12 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 198.0, 175.8, 108.4, 76.4, 35.7, 35.2, 33.6, 32.0, 26.4, 25.6, 16.1. HRMS calculated for C₁₃H₂₁O₂ [M+H]⁺ 209.1536, found 209.1538.

2, 2, 6, 6, 8, 8-Hexamethyl-2, 3, 4, 8-tetrahydro-5H-chromene-5, 7(6H)-dione (3f). Light yellow solid, mp 58–59 ℃, 32.0 mg, 32% yield, R_f = 0.70 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 2.33 (t, J = 6.7 Hz, 2H), 1.69 (t, J = 6.7 Hz, 2H), 1.34 (s, 6H), 1.31 (s, 6H), 1.30 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 213.9, 198.3, 170.9, 106.7, 77.7, 55.1, 47.7, 31.9, 26.5, 25.1, 24.7, 16.7. HRMS calculated for C₁₅H₂₃O₃ [M+H]⁺ 251.1642, found 251.1646.

2, 2-Dimethyl-3, 4, 6, 7-tetrahydrocyclopenta[b]pyran-5(2H)-one (3g). Light yellow oil, 30.7 mg, 46% yield, R_f = 0.30 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 2.53–2.50 (m, 2H), 2.43–2.40 (m, 2H), 2.24–2.18 (tt, J = 6.5, 2.0 Hz, 2H), 1.67 (t, J = 6.5 Hz, 2H), 1.35 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 204.0, 183.8, 113.1, 80.5, 33.2, 31.8, 26.8, 26.4, 14.5. HRMS calculated for C₁₀H₁₅O₂ [M+H]⁺ 167.1067, found 167.1065.

2, 2-Dimethyl-3, 4, 6, 7, 8, 9-hexahydrocyclohepta[b]pyran-5(2H)-one (3h). Light yellow oil, 10.3 mg, 13% yield, R_f = 0.60 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 2.63–2.55 (m, 2H), 2.52–2.46 (m, 2H), 2.27 (t, J = 6.8 Hz, 2H), 1.80–1.73 (m, 4H), 1.59 (t, J = 6.8 Hz, 2H), 1.25 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 201.9, 170.6, 112.4, 76.5, 41.4, 33.0, 32.2, 26.5, 23.4, 21.2, 18.4. HRMS calculated for C₁₂H₁₉O₂ [M+H]⁺ 195.1380, found 195.1373.

1, 3, 7, 7-Tetramethyl-1, 5, 6, 7-tetrahydro-2H-pyrano[2, 3-d]pyrimidine-2, 4(3H)-dione (3i). Light yellow solid, mp 126–127 ℃, 26.0 mg, 29% yield, R_f = 0.30 (petroleum ether/EtOAc 2/1). ¹H NMR (400 MHz, CDCl₃) δ 3.33 (d, J = 9.5 Hz, 6H), 2.47 (t, J = 6.6 Hz, 2H), 1.78 (t, J = 6.6 Hz, 2H), 1.40 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 163.2, 155.1, 151.3, 85.5, 81.3, 31.9, 28.4, 27.9, 26.5, 16.0. HRMS calculated for C₁₁H₁₇N₂O₃ [M+H]⁺ 225.1234, found 225.1232.

2, 2, 7-Trimethyl-3, 4-dihydro-2H, 5H-pyrano[4, 3-b]pyran-5-one (3j). Light yellow oil, 36.2 mg, 47% yield, R_f = 0.40 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 5.66 (s, 1H), 2.39 (t, J = 6.6 Hz, 2H), 2.13 (s, 3H), 1.72 (d, J = 13.3 Hz, 2H), 1.29 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 165.2, 164.1, 159.8, 100.8, 96.9, 77.6, 32.0, 26.5, 19.7, 16.6. HRMS calculated for C₁₁H₁₅O₃ [M+H]⁺ 195.1016, found 195.1018.

Prenol (125 μL, 1.20 mmol) was added to a mixture of cyclic 1, 3-diketones 1 (0.40 mmol) and AlCl₃ (5.4 mg, 10 mol%) in DCE (1.0 mL) in a sealed tube and stirred at 70 ℃ for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel using petroleum ether and ethyl acetate to give the desired O-prenylated cyclohexenones 5.

5-((3-Methylbut-2-en-1-yl)oxy)-1, 6-dihydro-[1, 1'-biphenyl]-3(2H)-one (5a). Light yellow oil, 65.2 mg, 64% yield, R_f = 0.50 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.30 (m, 2H), 7.28–7.21 (m, 3H), 5.47 (s, 1H), 5.44–5.35 (m, 1H), 4.49–4.35 (m, 2H), 3.40–3.32 (m, 1H), 2.76–2.49 (m, 4H), 1.79 (d, J = 1.4 Hz, 3H), 1.71 (d, J = 1.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 198.8, 176.9, 142.8, 139.8, 128.8, 127.0, 126.7, 117.9, 102.8, 65.8, 43.9, 39.4, 36.7, 25.8, 18.3. HRMS calculated for C₁₇H₂₁O₂ [M+H]⁺ 257.1536, found 257.1541.

3-((3-Methylbut-2-en-1-yl)oxy)cyclohex-2-en-1-one (5b). Light yellow oil, 55. mg, 77% yield, R_f = 0.40 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 5.40–5.29 (m, 2H), 4.33 (d, J = 6.9 Hz, 2H), 2.36 (t, J = 6.3 Hz, 2H), 2.32–2.27 (m, 2H), 1.93 (p, J = 6.5 Hz, 2H), 1.74 (s, 3H), 1.66 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 199.9, 177.9, 139.6, 117.9, 103.0, 65.4, 36.7, 29.2, 25.8, 21.3, 18.2. HRMS calculated for C₁₁H₁₇O₂ [M+H]⁺ 181.1223, found 181.1227.

5-Methyl-3-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-en-1-one (5c). Colorless oil, 53.5 mg, 69% yield, R_f = 0.50 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 5.38–5.30 (m, 2H), 4.33 (d, J = 6.9 Hz, 2H), 2.44–2.32 (m, 2H), 2.25–2.06 (m, 2H), 2.04–1.94 (m, 1H), 1.74 (s, 3H), 1.66 (s, 3H), 1.03 (d, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 199.8, 177.3, 139.6, 118.0, 102.6, 65.5, 45.1, 37.3, 28.9, 25.8, 20.9, 18.2. HRMS calculated for C₁₂H₁₉O₂ [M+H]⁺ 195.1380, found 195.1382.

5, 5-Dimethyl-3-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-en-1-one (5d). Colorless oil, 36.5 mg, 44% yield, R_f = 0.50 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 5.42–5.30 (m, 2H), 4.35 (d, J = 6.8 Hz, 2H), 2.25 (s, 2H), 2.18 (s, 2H), 1.76 (s, 3H), 1.67 (s, 3H), 1.04 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 199.7, 176.2, 139.6, 118.0, 101.8, 65.6, 50.8, 43.0, 32.6, 28.4, 25.9, 18.3. HRMS calculated for C₁₃H₂₁O₂ [M+H]⁺ 209.1536, found 209.1541.

6, 6-Dimethyl-3-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-en-1-one (5e). Colorless oil, 47.9 mg, 58% yield, R_f = 0.70 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 5.39–5.34 (m, 1H), 5.24 (s, 1H), 4.32 (d, J = 6.9 Hz, 2H), 2.40 (t, J = 6.4 Hz, 2H), 1.81–1.73 (m, 5H), 1.67 (s, 3H), 1.08 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 204.6, 175.8, 139.5, 118.1, 101.3, 65.5, 40.2, 35.1, 26.4, 25.8, 24.6, 18.2. HRMS calculated for C₁₃H₂₁O₂ [M+H]⁺ 209.1536, found 209.1530.

2, 2, 6, 6-Tetramethyl-5-((3-methylbut-2-en-1-yl)oxy)cyclohex-4-ene-1, 3-dione (5f). Light yellow solid, mp 56–57 ℃, 13.2 mg, 25% yield, R_f = 0.70 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 5.49 (s, 1H), 5.43–5.35 (m, 1H), 4.45 (d, J = 6.7 Hz, 2H), 1.79 (s, 3H), 1.71 (s, 3H), 1.39 (s, 6H), 1.34 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 213.7, 199.5, 177.7, 140.0, 117.8, 99.9, 66.2, 55.3, 48.4, 25.9, 25.2, 24.5, 18.4. HRMS calculated for C₁₅H₂₃O₃ [M+H]⁺ 251.1642, found 251.1644.

3-((3-Methylbut-2-en-1-yl)oxy)cyclopent-2-en-1-one (5g). Light yellow oil, 32.7 mg, 49% yield, R_f = 0.30 (petroleum ether/EtOAc 4/1). ¹H NMR (400 MHz, CDCl₃) δ 5.42–5.36 (m, 1H), 5.28 (d, J = 1.2 Hz, 1H), 4.48 (d, J = 7.1 Hz, 2H), 2.62–2.55 (m, 2H), 2.44–2.38 (m, 2H), 1.77 (s, 3H), 1.70 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 206.2, 190.2, 140.6, 117.6, 105.0, 68.7, 34.1, 28.7, 25.8, 18.3. HRMS calculated for C₁₀H₁₅O₂ [M+H]⁺ 167.1067, found 167.1070.

3-((3-Methylbut-2-en-1-yl)oxy)cyclohept-2-en-1-one (5h). Colorless oil, 10.7 mg, 28% yield (0.2 mmol scale), R_f = 0.60 (EtOAc). ¹H NMR (400 MHz, CDCl₃) δ 5.41 (s, 1H), 5.40–5.36 (m, 1H), 4.27 (d, J = 6.8 Hz, 2H), 2.61–2.54 (m, 4H), 1.89–1.79 (m, 4H), 1.78 (s, 3H), 1.68 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 202.6, 176.4, 139.3, 118.3, 106.2, 65.7, 41.8, 33.2, 25.9, 23.7, 21.4, 18.3. HRMS calculated for C₁₂H₁₉O₂ [M+H]⁺ 195.1380, found 195.1377.

In a sealed Schlenk tube (25 mL), Nafion (10 wt%, 37.7 mg), 5-phenyl-1, 3-cyclohexanedione 1a (2.00 mmol, 376.5 mg), DCE (5.0 mL), and isoprene (0.60 mL, 6.00 mmol) were added in sequence. The resulting mixture was stirred at 110 ℃ for 24 h. Upon completion, Nafion was filtered, washed with ethyl acetate, and dried by vacuum pump for 1 h prior to use in the next cycle. The collected solution was analyzed by GC-FID using 1, 3, 5-trimethoxybenzene as an internal standard.

An oven-dried Schlenk flask equipped with a magnetic stirrer was sealed with a rubber plug and then evacuated and back-filled with nitrogen. The flask was charged with a solution of LiHMDS (1.0 mol/L in THF, 1.5 mL, 3.0 equiv), dry THF (1.0 mL), and dry pentane (2.0 mL) and cooled to –78 ℃. After stirring for 10 min, a solution of substrate 3a or 5a (128.1 mg, 0.5 mmol, 1.0 equiv) in THF (1.0 mL) was added dropwise over 3 min and stirred at –78 ℃ for an additional 30 min. A solution of tosyl chloride (209.7 mg, 1.1 mmol, 2.1 equiv) in THF (1.5 mL) was then added dropwise over 10 min and further stirred at –78 ℃ for 30 min. A solution of LiHMDS (1.0 mol/L in THF, 0.5 mL, 1.0 equiv) was then added dropwise over 1 min. The mixture was subsequently warmed to room temperature over 20 min and then stirred at room temperature for an additional 30 min. The reaction was quenched by 1.0 mol/L HCl (aq, 5 mL) and diluted with EtOAc (20 mL). The aqueous phase was then extracted with EtOAc and the combined organic phases were washed with brine (1 × 10 mL), dried over anhydrous Na₂SO₄, filtered through Celite, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired aromatized product 6a or 7a.

6-Chloro-2, 2-dimethyl-7-phenylchroman-5-ol (6a). Brown oil, 120.5 mg, 83% yield, R_f = 0.50 (petroleum ether/EtOAc 8/1). ¹H NMR (400 MHz, CDCl₃) δ 7.46–7.35 (m, 5H), 6.47 (s, 1H), 5.85 (s, 1H), 2.78 (t, J = 6.8 Hz, 2H), 1.84 (t, J = 6.8 Hz, 2H), 1.36 (s, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 153.3, 149.7, 139.3, 138.8, 129.4, 128.1, 127.7, 111.8, 109.0, 108.8, 74.6, 32.1, 26.8, 17.8. HRMS calculated for C₁₇H₁₈ClO₂ [M+H]⁺ 289.0990, found 289.0986.

2-Chloro-5-((3-methylbut-2-en-1-yl)oxy)-[1, 1'-biphenyl]-3-ol (7a). Yellow oil, 111.5 mg, 77% yield, R_f = 0.30 (petroleum ether/EtOAc 30/1). ¹H NMR (400 MHz, CDCl₃) δ 7.50–7.34 (m, 5H), 6.64 (d, J = 2.8 Hz, 1H), 6.53 (d, J = 2.9 Hz, 1H), 5.78 (s, 1H), 5.49 (t, J = 7.0 Hz, 1H), 4.50 (d, J = 6.8 Hz, 2H), 1.81 (s, 3H), 1.74 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 158.3, 152.5, 141.5, 139.3, 138.7, 129.3, 128.2, 127.9, 119.3, 110.5, 110.1, 101.5, 65.2, 25.9, 18.3. HRMS calculated for C₁₇H₁₈ClO₂ [M+H]⁺ 289.0990, found 289.0999.

In previous works, the annulations of 1, 3-cyclohexanediones were often performed in the presence of various homogeneous acids. In comparison, we began our investigation by employing solid acids to catalyze the [3+3] annulation of 5-phenyl-1, 3-cyclohexanedione 1a and isoprene 2a (Table 1). To our delight, when Nafion was subjected to the mixture of 1a, 2a, and dioxane at 110 ℃, the anticipated [3+3] adduct 3a was afforded in 76% yield (entry 1). Other heterogeneous acids, such as H-MOR (Si/Al = 24) and H-USY (Si/Al = 3), showed no catalytic activity, while Amberlyst-15 was able to promote the annulation, albeit with decreased yield (entries 2–4). Temperature-programmed desorption of ammonia (NH₃-TPD) experiments revealed the sequence of acid amount of the catalysts as Amberlyst-15 (3.397 mmol/g) > H-USY (1.318 mmol/g) > H-MOR (0.876 mmol/g), which is consistent with their catalytic performances ^[40]. An exception to this sequence was Nafion (2.123 mmol/g), which gave the highest yield of 3a (entry 1), presumably due to the strong, electron-deficient polyfluoro-substituted sulfonic group on Nafion making it more acidic than Amberlyst-15. These results suggested that both acid amount and strength of the catalyst contribute to its reactivity. A survey of the solvents demonstrated that the annulation in DCE furnished the product 3a in 92% yield, while the non-polar solvent toluene gave an inferior result (entries 5 and 6). The temperature exerted a remarkable influence on the reaction outcome. The yield of 3a increased dramatically with increasing temperatures in the range of 80 to 110 ℃, at which temperature the productivity plateaued (entries 7–10).

It is worthwhile to mention that prenol 4a and 1, 3-cyclohexanedione 1a could also undergo the [3+3] annulation efficiently under the standard conditions (Table 2, entry 1). Surprisingly, when this reaction was performed at 70 ℃, a small amount of 5a was detected along with 3a (entry 2). Compound 3a was the cyclized C-prenylated product, while 5a was formed by O-prenylation of 1a. Considering that direct O-prenylation of 1, 3-cyclohexanedione is rare ^[41], additional efforts were devoted to increasing the selectivity of 5a. Happily, O-prenylated product 5a was afforded exclusively using Lewis acid AlCl₃ (entry 4). Other Lewis acids, such as InCl₃, GaCl₃, and Zn(OTf)₂, furnished 3a as the main product, while in the presence of YCl₃, 5a predominated, but with a lower yield (entries 5–8). Utilizing dioxane/toluene as the solvent diminished the yield of 5a (entries 9 and 10). Increasing the temperature increased the formation of 3a (entry 12).

Having established the optimal conditions, we next explored the generality of the [3+3] annulation of cyclic 1, 3-diketones with isoprene. The expected adduct 3a was isolated in 82% yield after subjecting 5-phenyl-1, 3-cyclohexanedione 1a to the standard conditions (Table 3). Using this procedure, 1, 3-cyclohexanedione 1b was readily converted to 5-chromenone 3b in 74% yield. Other suitable substrates for the reaction were 5-methyl- and 5, 5-dimethyl-substituted 1, 3-cyclohexanediones, which provided the corresponding products 3c and 3d in 81% and 84% yield, respectively. In the case of 4, 4-dimethyl-1, 3-cyclohexanedione 1e, the reaction gave a mixture of 5-chromenones 3e and 3e' in 81% yield with moderate regioselectivity. Gratifyingly, sterically hindered, tetramethyl-substituted 1, 3, 5-cyclohexanetrione 1f (syncarpic acid) ^[42-44] was also tolerated in this process, providing the target product 3f in an acceptable yield. The structure of 3f was unambiguously confirmed by X-ray crystallography ^[45]. Notably, the transformation could be successfully extended to 1, 3-cyclopentanedione 1g and 1, 3-cycloheptanedione 1h, albeit with decreased yields. Moreover, this protocol was also applicable to heterocyclic 1, 3-dicarbonyls, such as N-methyl barbituric acid 1i and 4-hydroxy-6-methyl-2H-pyran-2-one 1j.

The scope of cyclic 1, 3-diketone O-prenylation was further examined (Table 4). In the presence of AlCl₃, the coupling of 5-phenyl-1, 3-cyclohexanedione 1a and prenol 4a furnished the desired product 5a in 64% isolated yield. The simple 1, 3-cyclohexanedione 1b underwent the process efficiently to produce O-prenylated cyclohexenone 5b in 77% yield. The 5-methyl-substituted 1, 3-cyclohexanediones 1c and 1d were compatible with the transformation, producing the target O-prenylated products 5c and 5d in acceptable yields. Surprisingly, when 4, 4-dimethyl-1, 3-cyclohexanedione 1e was employed as the substrate, the reaction afforded 5e in high selectivity. O-prenylation of syncarpic acid 1f generated 5f in a decreased yield, which is likely due to its large steric hindrance. Five- and seven-membered cyclic 1, 3-ketones 1g and 1h could also be employed in this process.

To demonstrate the potential applications of this methodology in organic synthesis, gram-scale experiments and derivatizations of the resulting products were performed (Scheme 3). Both transformations could be easily scaled up to 5.0 mmol, leading to the formation of cyclized C-prenylated product 3a and O-prenylated cyclohexenone 5a in 70% and 68% yield, respectively. Treatment of 3a with lithium hexamethyldisilazide (LiHMDS) and tosyl chloride (TsCl) provided the aromatized chloro-substituted resorcinol 6a product in 83% yield ^[46]. Following the same procedure, 5a could be converted to O-prenylated resorcinol 7a in 77% yield. It should be noted that prenylated resorcinols are also important scaffolds that can be found in diverse natural products ^[47-52]. However, conventional catalytic prenylation of resorcinols often displays poor selectivity and does not yield the O-prenylated product ^[34-39]. Thus, our approach provides an expedient alternative to construct C- and O-prenylated resorcinols with high selectivity.

The reusability of the Nafion catalyst for the [3+3] annulation of 5-phenyl-1, 3-cyclohexanedione 1a and isoprene 2a was examined (Fig. 1). Unfortunately, the yield of 3a gradually decreased after each cycle. The polymerization of isoprene could not be avoided in the presence of the strong acid at high temperatures ^[53-57]. Thus, after several runs under the optimized conditions, the accumulated coke on the surface of Nafion led to its diminished catalytic activity.

The coupling of 1, 3-cyclohexanedione 1b with isoprene/prenol was used to illustrate the mechanism for the two catalytic processes (Scheme 4). Initially, 1, 3-cyclohexanedione 1b can tautomerize into its enol form 1b'. In the presence of the solid acid Nafion, isoprene 2a is protonated to yield the active isopentenyl cation A. The subsequent nucleophilic attack by the enol moiety of 1b' furnishes the C-prenylated diketone B, which further undergoes acid-catalyzed intramolecular cyclization to afford [3+3] adduct 3b. For Lewis acid catalysis, prenol 4a is activated by AlCl₃ to give intermediate D, followed by the nucleophilic S_N2 substitution of the hydroxyl group of enol isomer 1b to generate O-prenylated product 5b.

We have developed an efficient strategy for achieving C- and O-prenylation of cyclic 1, 3-diketones. Using the solid acid Nafion as a catalyst, 1, 3-cyclohexanediones and isoprene could undergo [3+3] annulation to yield cyclized C-prenylated 5-chromenone products. Alternatively, the AlCl₃-catalyzed coupling of 1, 3-cyclohexanediones and prenol exclusively resulted in the formation of O-prenylated cyclohexenones. Notably, both products could be easily transformed into the corresponding prenylated resorcinols that are otherwise difficult to prepare. The advantages of our methodology include excellent selectivity, high atom-economy, simple operation, and easy scale-up. These attributes impart great potential for its use in organic synthesis.