Synthesis of Three-Dimensional Benzophenone Analogues Based on a [2.2]Paracyclophane Scaffold

Abstract

Herein, we report the synthesis of functionalized three-dimensional benzophenone analogues derived from [2.2]paracyclophane (pCp). The potential use of these compounds as photocatalysts is disclosed. Benzophenone and its derivatives are well-known photoactive compounds that have been extensively employed over the years as catalysts to promote a variety of transformations activated by light. The development of differently substituted three-dimensional versions of such compounds may significantly expand the range of their applications in photocatalysis. Exploitation of the planar chirality of substituted paracyclophanes may also lead to significant innovations in different fields. [2.2]Paracyclophane-based benzophenone derivatives incorporating reactive ester or amide functions at their pseudo-gem position are successfully prepared in a selective manner. Examples of both racemic and enantiopure compounds are reported. As a proof of concept, the catalytic activities of the newly synthesized molecules are compared to that of benzophenone in a known photooxidation reaction.

Key words

[2.2]paracyclophanes - planar chirality - benzophenone analogues - esters - primary amides

Publication History

Received: 16 February 2024

Accepted after revision: 10 March 2024

Accepted Manuscript online:
10 March 2024

Article published online:
26 March 2024

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• 23 Compound (±)-1 In a 50 mL flask, [2.2]paracyclophane (1 equiv., 2 g, 9.6 mmol) was dissolved in CH₂Cl₂ (20 mL) and cooled to –10 °C. A solution of benzoyl chloride (2 equiv., 2.7 g, 2.2 mL, 19.2 mmol) and AlCl₃ (1.75 equiv., 2.24 g, 0.92 mL, 16.8 mmol) in CH₂Cl₂ (10 mL) was added and the reaction was stirred at –10 °C for 1 h. The mixture was then filtered and hydrolyzed with ice. The resulting aqueous solution was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were washed with aqueous NaHCO₃ solution and brine, then dried over Na₂SO₄. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel column chromatography (Cy/EtOAc = 30:1) to yield (±)-1 (2.4 g, 7.68 mmol, 80%) as a white solid. ¹H NMR (600 MHz, CDCl₃): δ = 7.72–7.68 (m, 2 H), 7.54 (td, J = 7.4, 1.4 Hz, 1 H), 7.41 (t, J = 7.7 Hz, 2 H), 6.75 (dd, J = 8.0, 1.3 Hz, 1 H), 6.72–6.68 (m, 2 H), 6.57 (t, J = 1.1 Hz, 2 H), 6.56 (d, J = 7.6 Hz, 1 H), 6.35 (d, J = 7.9 Hz, 1 H), 3.37–3.31 (m, 1 H), 3.28–3.22 (m, 1 H), 3.21–3.05 (m, 3 H), 3.04–2.92 (m, 2 H), 2.86 (ddd, J = 12.8, 10.4, 5.4 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 196.6 (C), 141.6 (C), 139.9 (C), 139.3 (C), 139.3 (C), 138.9 (C), 136.3 (C), 136.0 (CH), 135.7 (CH), 134.3 (CH), 132.7 (CH), 132.7 (CH), 132.4 (CH), 132.4 (CH), 131.1 (CH), 129.9 (2 CH), 128.2 (2 CH), 35.6 (CH₂), 35.3 (CH₂), 35.2 (CH₂), 35.1 (CH₂). The spectroscopic data are consistent with the literature data for this compound (see Ref. 13).
• 24 Compound (±)-5 Anhydrous AlCl₃ (1.9 equiv., 1.21 g, 9.09 mmol) was suspended in dry CH₂Cl₂ (50 mL) in a 100 mL round-bottomed flask. The mixture was cooled to –10 °C, and (COCl)₂ (1.9 equiv., 1.18 g, 0.80 mL, 9.11 mmol) was added dropwise (pale yellow solution). The resulting suspension was stirred at –10 °C for 5 min, then [2.2]paracyclophane (1 equiv., 1 g, 4.8 mmol) was slowly added portionwise, turning the solution dark red. The reaction mixture was stirred at –10 °C for 30 min. About 50 g of ice was then added, turning the mixture yellow. The two immiscible layers were separated, and the aqueous phase was extracted with cold CH₂Cl₂ (–20 °C, 3 × 50 mL). The combined organic phases were kept at –20 °C, dried over MgSO₄, and concentrated under reduced pressure in a cold bath. The resulting yellow solid (1 equiv., 1.43 g, 4.8 mmol) was suspended in dry chlorobenzene (40 mL). The solution was heated at reflux and stirred for 3 d. The mixture was then concentrated under reduced pressure. The resulting brown solid (1 equiv., 1.3 g, 4.8 mmol) was dissolved in a mixture of methanol (20 mL) and CH₂Cl₂ (6 mL). The solution was heated at reflux and stirred for 3 d. The mixture was then concentrated under vacuum. The crude product was purified by silica gel column chromatography (Cy/EtOAc = 30:1) to afford (±)-5 (823 mg, 3.09 mmol, 64%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 7.14 (d, J = 1.9 Hz, 1 H), 6.66 (dd, J = 7.7, 2.0 Hz, 1 H), 6.59–6.53 (m, 2 H), 6.52–6.43 (m, 3 H), 4.10 (ddd, J = 12.9, 9.8, 1.8 Hz, 1 H), 3.92 (s, 3 H), 3.26–2.94 (m, 6 H), 2.87 (ddd, J = 12.9, 10.1, 6.9 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 167.5 (C), 142.6 (C), 139.9 (C), 139.8 (C), 139.3 (C), 136.4 (CH), 136.1 (CH), 135.3 (CH), 133.1 (CH), 132.7 (CH), 132.2 (CH), 131.5 (CH), 130.7 (C), 51.7 (CH₃), 36.1 (CH₂), 35.2 (CH₂), 35.1 (CH₂), 34.9 (CH₂). The synthesis of this compound was replicated several times. The spectroscopic data are consistent with the literature data for this compound (see Ref. 15).
• 25 Compound (±)-6 A solution of (±)-5 (1 equiv., 1 g, 3.75 mmol) in anhydrous CH₂Cl₂ (30 mL) was cooled to –10 °C. TiCl₄ (1 M solution in CH₂Cl₂, 3.5 equiv., 26 mL, 13.1 mmol) was added portionwise, followed by 1,1-dichlorodimethyl ether (3.5 equiv., 1.51 g, 1.19 mL, 13.1 mmol). The mixture was allowed to warm to room temperature and stirred under argon for 16 h. The reaction was then quenched by the addition of ice. The aqueous phase was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with saturated aqueous NaHCO₃ solution, water, and brine, then dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Cy/EtOAc = 20:1) to afford (±)-6 (0.68 g, 2.31 mmol, 62%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 9.91 (s, 1 H), 7.07 (t, J = 1.8 Hz, 2 H), 6.72–6.67 (m, 2 H), 6.65–6.60 (m, 2 H), 4.29–4.05 (m, 2 H), 3.81 (s, 3 H), 3.21–3.05 (m, 5 H), 3.05–2.93 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 190.6 (CH), 167.0 (C), 143.5 (C), 142.1 (C), 140.1 (C), 139.7 (C), 138.2 (CH), 136.6 (C), 136.2 (CH), 136.0 (CH), 135.7 (CH), 134.5 (CH), 133.8 (CH), 130.8 (C), 51.9 (CH₃), 35.0 (CH₂), 34.8 (CH₂), 34.6 (CH₂), 31.2 (CH₂). The spectroscopic data are consistent with the literature data for this compound (see Ref. 18).
• 26 Grignard Reaction for the Synthesis of Intermediate (±)-7a; Representative Procedure A Compound (±)-6 (1 equiv., 500 mg, 1.7 mmol) was dissolved in dry THF (10 mL) under an argon atmosphere. PhMgBr (1.2 equiv., 1 M in THF, 2.0 mL, 2.0 mmol) was added dropwise, and the resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of saturated aqueous NH₄Cl solution. THF was removed under vacuum, and the resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (Cy/EtOAc = 25:1) to yield product (±)-7a (520 mg, 1.4 mmol, 82%) as a white solid. IR (neat): 3498, 2949, 1711, 1594, 1492, 1436, 1274, 1199, 1096, 1077, 1033, 919, 872, 793, 764, 730 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.21–7.16 (m, 4 H), 7.15–7.08 (m, 3 H), 6.98 (s, 1 H), 6.72 (d, J = 7.7 Hz, 1 H), 6.62 (d, J = 7.7 Hz, 1 H), 6.50 (d, J = 7.2 Hz, 1 H), 6.46 (d, J = 7.6 Hz, 1 H), 5.65 (d, J = 3.7 Hz, 1 H), 4.05 (ddd, J = 13.7, 10.0, 3.7 Hz, 1 H), 3.98 (d, J = 1.2 Hz, 3 H), 3.39 (dd, J = 3.8, 1.2 Hz, 1 H), 3.32 (ddd, J = 13.8, 9.9, 4.3 Hz, 1 H), 3.21–3.03 (m, 4 H), 2.89 (ddd, J = 13.8, 10.5, 3.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 169.6 (C), 143.5 (C), 143.3 (C), 141.8 (C), 139.9 (C), 139.8 (C), 137.1 (CH), 136.1 (CH), 135.4 (C), 134.9 (CH), 134.4 (CH), 131.9 (CH), 129.3 (C), 128.3 (2 CH), 127.7 (CH), 127.2 (CH), 127.0 (2 CH), 72.6 (CH), 52.4 (CH₃), 35.0 (CH₂), 34.9 (CH₂), 34.1 (CH₂), 32.3 (CH₂). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₂₄O₃Na: 395.1618; found: 395.1618.
• 27 Oxidation Reaction for the Synthesis of Compound (±)-3a; Representative Procedure B In a round-bottomed flask under an argon atmosphere, compound (±)-7a (1 equiv., 420 mg, 1.13 mmol) was dissolved in CH₂Cl₂ (9 mL). Dess–Martin periodinane (DMP, 1.25 equiv., 599 mg, 1.41 mmol) was then added to the reaction mixture. The resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO₃ solution. The immiscible phases were separated, and the aqueous layer was extracted with CH₂Cl₂ (×2). The combined organic phases were washed with water and brine, dried over MgSO₄, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (Cy/EtOAc = 35:1) to yield product (±)-3a (386 mg, 1.04 mmol, 92%) as a white solid. IR (neat): 1716, 1657, 1596, 1556, 1435, 1275, 1196, 1076, 953, 861, 800, 764, 750, 720 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.67–7.64 (m, 2 H), 7.53–7.49 (m, 1 H), 7.42–7.37 (m, 2 H), 7.19 (d, J = 2.1 Hz, 1 H), 6.89 (d, J = 1.9 Hz, 1 H), 6.72 (ddd, J = 7.8, 5.6, 2.0 Hz, 2 H), 6.66 (d, J = 7.9 Hz, 1 H), 6.61 (d, J = 7.8 Hz, 1 H), 4.14 (t, J = 10.0 Hz, 1 H), 3.96 (s, 3 H), 3.33–3.23 (m, 1 H), 3.19–3.05 (m, 4 H), 2.94–2.86 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 196.0 (C), 167.2 (C), 142.5 (C), 141.9 (C), 139.5 (C), 139.3 (C), 139.2 (C), 137.0 (C), 136.2 (CH), 136.1 (CH), 135.9 (CH), 135.1 (CH), 134.5 (CH), 133.6 (CH), 132.1 (CH), 129.8 (2 CH), 129.6 (C), 128.1 (2 CH), 51.9 (CH₃), 35.7 (CH₂), 34.8 (CH₂), 34.8 (CH₂), 34.7 (CH₂). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₃O₃: 371.1642; found: 371.1641.
• 28 Synthesis of Primary Amide (±)-4a; Representative Procedure C To a solution of compound (±)-3a (1 equiv., 200 mg, 0.54 mmol) in EtOH (5.5 mL) was added a solution of KOH (10 equiv., 2 M in H₂O, 2.7 mL, 5.4 mmol). The resulting mixture was heated at reflux and stirred for 5 h. The reaction was then cooled to room temperature and acidified to pH 5 with an aqueous HCl solution (2 M). The resulting mixture was extracted with CH₂Cl₂, dried over MgSO₄, and concentrated under reduced pressure to afford the carboxylic acid (±)-8a (190 mg, 0.533 mmol, 99%) as a white solid. To a suspension of this compound (1 equiv.) in CH₂Cl₂ (5.5 mL), oxalyl chloride (1.2 equiv., 81 mg, 55 μL, 0.64 mmol) was added, followed by a few drops of DMF (10 mol%, 5 μL, 0.05 mmol). The solution was stirred overnight at room temperature. The solvent was then removed under reduced pressure to afford the desired acyl chloride derivative (198 mg, 0.528 mmol, quant.) as a yellow solid. This product (1 equiv.) was dissolved in dry acetone (4.5 mL). NH₄OH (32 equiv., 2.4 mL, 16.9 mmol) was added at 5 °C, and the solution was stirred for 1 h. Water was then added, and the acetone was evaporated under reduced pressure. The resulting aqueous solution was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with saturated aqueous Na₂CO₃ solution and water, dried over Na₂SO₄, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (Cy/EtOAc = 2:1) to afford (±)-4a (160 mg, 0.45 mmol, 85%) as a white solid. IR (neat): 3005, 1657, 1596, 1555, 1447, 1371, 1322, 1276, 1075, 839, 802, 742, 720 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.66 (d, J = 7.8 Hz, 2 H), 7.50 (t, J = 7.3 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 2 H), 6.99 (s, 1 H), 6.86 (s, 1 H), 6.77 (dd, J = 7.7, 1.4 Hz, 1 H), 6.69 (d, J = 7.9 Hz, 2 H), 6.63 (d, J = 7.7 Hz, 1 H), 5.62 (s, 2 H), 4.01–3.83 (m, 1 H), 3.37–3.25 (m, 1 H), 3.23–2.98 (m, 4 H), 2.97–2.86 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 196.1 (C), 170.3 (C), 142.2 (C), 139.9 (C), 139.7 (C), 139.5 (C), 139.1 (C), 136.4 (C), 136.3 (CH), 136.1 (CH), 135.2 (CH), 135.2 (CH), 134.1 (CH), 133.2 (C), 132.0 (CH), 131.7 (CH), 129.9 (2 CH), 128.1 (2 CH), 36.0 (CH₂), 35.2 (CH₂), 34.8 (CH₂), 34.7 (CH₂). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₂O₂N: 356.1645; found: 356.1644.
• 29 Photooxidation of Benzylic Alcohol in the Presence of Catalyst (±)-1; Representative Procedure D In a glass vial, (±)-1 (0.2 equiv., 14 mg, 0.046 mmol) was dissolved in DMSO-d ₆ (0.6 mL). Benzyl alcohol (9) (1 equiv., 22 mg, 21 μL, 0.2 mmol) was added to the mixture. The vial was then placed in a Rayonet photoreactor, and the reaction was irradiated at 300–350 nm under air for 55 h (Temp = 29 °C). Water (10 mL) and CH₂Cl₂ (10 mL) were then added. The phases were separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic phases were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The conversion (unreacted starting material vs desired product) was determined by ¹H NMR analysis of the crude reaction mixture.