Diversity-Oriented Approach to Macrocyclic Cyclophane Derivatives via Ring-Closing Metathesis^{[ 1 ]}

Dedicated to Professor Mariappan Periasamy on the occasion of his 60th birthday.

Abstract

A short synthetic approach to the macrocyclic framework of longithorone C is described via ring-closing metathesis using the Grubbs 2nd generation catalyst.

Keywords

paracyclophane - macrocycles - ring-closing metathesis - oxidation - alkylation

• References and Notes

• 1 A portion of this work has been presented at the 19th International Symposium on Olefin Metathesis and Related Chemistry (ISOM XIX), July 10, 2011, Rennes, France.
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• 17 We have determined the E/Z ratio of RCM products 16–19 (Figure 2), based on ¹H NMR spectral data. In most of the cases, we observed E-configured compounds as the major product; this assumption was based on our earlier experience on cyclophane derivatives. See reference 11i.
• 18 Alkene Derivatives of Malonate Ester; General Procedure: To a suspension of NaH (3 equiv) in THF was added 3 (1 equiv) dropwise at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. Bromide 5c (1.1 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under nitrogen. At the conclusion of the reaction (TLC monitoring), the reaction mixture was quenched with H₂O and extracted with diethyl ether. The organic layer was washed with brine, dried with Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 4%) to afford 6c (67%) as a liquid. ¹H NMR (400 MHz, CDCl₃): δ = 1.18–1.22 (m, 6 H), 1.35–1.40 (m, 2 H), 1.81–1.90 (m, 2 H), 2.01–2.05 (m, 2 H), 3.26 (t, J = 7.2 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 4 H), 4.88–4.97 (m, 2 H), 5.66–5.70 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.90, 26.38, 28.02, 33.14, 51.69, 61.05, 114.83, 137.77, 169.23. IR (neat): 2929, 2859, 1741, 1640, 1464, 1368, 1183 cm^–1. HRMS (Q-Tof): m/z [M + Na] calcd for C₁₂H₂₀O₄Na: 251.1259; found: 251.1265. Alkylation of Ethyl Acetoacetate; General Procedure: In a 100 mL round-bottomed flask equipped with a nitrogen gas inlet, ethyl acetoacetate 4 (1 equiv) was added dropwise at r.t. to K₂CO₃ (4 equiv) in acetonitrile and the mixture was stirred for 1 h. Bromide 5c (1.1 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under a nitrogen atmosphere. At the conclusion of the reaction (TLC monitoring), the crude mixture was filtered through a Celite pad and extracted with diethyl ether. The organic layer was washed with brine and dried with Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 4%) to afford alkylated ethyl acetoacetate derivative 8c (68%) as a liquid. ¹H NMR (400 MHz, CDCl₃): δ = 1.28 (t, J = 7.2 Hz, 3 H), 1.32–1.44 (m, 2 H), 1.80–1.92 (m, 2 H), 2.00–2.10 (m, 2 H), 2.22 (s, 3 H), 3.41 (t, J = 7.4 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.94–5.04 (m, 2 H), 5.72–5.82 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.16, 26.64, 27.62, 28.82, 33.41, 59.77, 61.37, 115.13, 137.96, 169.88, 203.24. IR (neat): 2991, 2934, 1742, 1716, 1641, 1448, 1360, 1216 cm^–1. HRMS (Q-Tof): m/z [M + H] calcd for C₁₁H₁₉O₃: 199.1334; found: 199.1334. General Procedure for 10c: To a suspension of NaH (3 equiv) in THF was added alkylated malonate ester 6c (1 equiv) dropwise at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. Dibromide 1 (0.5 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under nitrogen. The organic layer was washed with brine, dried with Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 8%) to afford bis-alkene malonate derivative 10c (65%) as a white solid material. Mp 60–65 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.22 (t, J = 7.1 Hz, 12 H), 1.34–1.41 (m, 4 H), 1.70–1.74 (m, 4 H), 1.99 (q, J = 7.1 Hz, 4 H), 3.24 (s, 4 H), 3.64 (s, 6 H), 4.08–4.23 (m, 8 H), 4.89–5.00 (m, 4 H), 5.70–5.81 (m, 2 H), 6.52 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.21, 23.87, 31.73, 31.97, 34.18, 55.68, 58.72, 61.13, 114.04, 114.76, 124.20, 138.52, 151.87, 171.76. IR (neat): 3054, 2989, 1729, 1641, 1422, 1266 cm^–1. HRMS (Q-Tof): m/z [M + H] calcd for C₃₄H₅₁O₁₀: 619.3482; found: 619.3499. General Procedure for 11c: To a suspension of NaH (3 equiv) in THF was added alkylated malonate ester 6c (1 equiv) dropwise at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. p-Xylylene dibromide 2 (0.5 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under nitrogen. At the conclusion of the reaction (TLC monitoring), the reaction was quenched with H₂O and extracted with diethyl ether. The organic layer was washed with brine, dried with Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 8%) to afford bis-alkene malonate ester derivative 11c (62%) as a white solid material. Mp 60–65 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.23 (t, J = 7.2 Hz, 12 H), 1.34–1.40 (m, 4 H), 1.73–1.77 (m, 4 H), 2.04 (q, J = 7.2 Hz, 4 H), 3.19 (s, 4 H), 4.10–4.22 (m, 8 H), 4.97–5.03 (m, 4 H), 5.78–5.80 (m, 2 H), 6.95 (s, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.22, 23.72, 31.54, 33.90, 37.87, 58.90, 61.33, 115.16, 129.92, 134.97, 138.21, 171.45. IR (neat): 3054, 2989, 1729, 1641, 1422, 1266 cm^–1. HRMS (Q-Tof): m/z [M + H] calcd for C₃₂H₄₇O₈: 559.3271; found: 559.3286. General Procedure for 12c: In a 100 mL round-bottomed flask equipped with a nitrogen gas inlet, K₂CO₃ (4 equiv) in acetonitrile was added to alkylated ethyl acetoacetate 8c (1 equiv) dropwise at r.t. and stirred for 1 h. Dibromo compound 1 (0.5 equiv) was added and the reaction mixture was stirred at r.t. for 12 h under nitrogen. At the conclusion of the reaction (TLC monitoring), the crude mixture was filtered through a Celite pad and extracted with diethyl ether. The organic layer was washed with brine, dried with Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 6%) to afford the alkylated ethyl acetoacetate derivative 12c (72%) as a solid. Mp 60–65 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.23–1.25 (m, 6 H), 1.29–1.37 (m, 4 H), 1.64–1.76 (m, 4 H), 2.03 (q, J = 7.0 Hz, 4 H), 2.11 (s, 6 H), 3.06–3.31 (m, 4 H), 3.62 (s, 6 H), 4.09–4.26 (m, 4 H), 4.91–5.01 (m, 4 H), 5.69–5.80 (m, 2 H), 6.50 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.20, 23.76, 27.15, 31.30, 31.66, 34.22, 55.53, 61.32, 64.32, 114.29, 115.05, 124.30, 138.28, 151.66, 172.61, 205.10. IR (neat): 2979, 2911, 1739, 1717, 1531, 1212 cm^–1. HRMS (Q-Tof): m/z [M + Na] calcd for C₃₂H₄₆O₈Na: 581.3090; found: 581.3105. General procedure for 13c: To a suspension of NaH (3 equiv) in THF was added alkylated ethyl acetoacetate 8c (1 equiv) dropwise at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. Dibromide 1 (0.5equiv) was added to the reaction mixture, which was stirred at r.t. for 12 h under nitrogen. At the conclusion of the reaction (TLC monitoring), the reaction was quenched with H₂O and extracted with diethyl ether. The organic layer was washed with brine, dried with Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 10%) to afford bis-alkylated derivative 13c (66%) as a white solid. Mp 60–65 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.12–1.15 (m, 6 H), 1.33–1.45 (m, 4 H), 1.45–1.54 (m, 2 H), 1.59–1.70 (m, 2 H), 2.00–2.07 (m, 4 H), 2.65–2.75 (m, 2 H), 2.75–2.85 (m, 4 H), 3.74 (s, 6 H), 4.00–4.08 (m, 4 H), 4.90–5.00 (m, 4 H), 5.71–5.82 (m, 2 H), 6.59 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.43, 26.71, 32.01, 33.48, 33.75, 45.83, 56.11, 60.15, 113.64, 114.74, 126.60, 138.70, 151.36, 176.23. IR (neat): 2931, 2860, 1726, 1506, 1211 cm^–1. HRMS (Q-Tof): m/z calcd: for C₂₈H₄₃O₆ [M + H]: 475.3060; found 475.3060. General Procedure for 14c and 15c: To a degassed solution of bis-alkylated derivative 10c or 11c in anhydrous toluene (5 mL) was added Grubbs 2nd generation catalyst (5 mol%) at r.t., and reaction mixture was heated at reflux overnight. At the conclusion of the reaction (TLC monitoring), the crude reaction mixture was filtered through a Celite pad (washed with CH₂Cl₂) and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 5%) to afford cyclophane derivatives 14c and 15c. Compound 14c: Yield: 78%. ¹H NMR (400 MHz, CDCl₃): δ = 1.01–1.14 (m, 4 H), 1.23–1.30 (m, 12 H), 1.44 (td, J = 13.4, 4.4 Hz, 2 H), 1.59 (td, J = 13.4, 4.4 Hz, 2 H), 1.76–1.77 (m, 2 H), 1.92–1.95 (m, 2 H), 3.13 (s, 1 H), 3.17 (s, 1 H), 3.62 (s, 1 H), 3.66 (s, 1 H), 3.67 (s, 6 H), 4.14–4.30 (m, 8 H), 5.06 (t, J = 3.9 Hz, 2 H), 6.63 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.26, 23.50, 31.27, 32.43, 33.27, 55.78, 57.63, 61.13, 114.36, 124.43, 130.34, 151.71, 172.40. IR (neat): 2931, 2860, 1730, 1510, 1212 cm^–1. HRMS (Q-Tof): m/z [M + H] calcd for C₃₂H₄₇O₁₀: 591.3169; found: 591.3160. Compound 15c: Yield: 80%. ¹H NMR (400 MHz, CDCl₃): δ = 1.10 (m, 4 H), 1.28 (m, 12 H), 1.46–1.48 (m, 4 H), 1.83–1.88 (m, 4 H), 3.30 (s, 4 H), 4.25 (m, 8 H), 5.07–5.09 (m, 2 H), 7.02 (s, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.27, 23.49, 31.53, 32.49, 39.06, 58.15, 61.50, 129.75, 130.53, 135.36, 172.06. IR (neat): 2982, 2940, 1732, 1446, 1266 cm^–1. HRMS (Q-Tof): m/z [M + H] calcd for C₃₀H₄₃O₈: 531.2958; found: 531.2957. General Procedure for 18: In a 100 mL round-bottomed flask was charged flash chromatographic-grade silica gel (6 g). A solution of CAN (5 mol%) in water (2.5 mL) was added dropwise until a free-flowing yellow solid was obtained. CH₂Cl₂ (25 mL) was added and the bis-alkylated derivative 13c dissolved in CH₂Cl₂ (2 mL) was added dropwise. At the conclusion of the reaction (TLC monitoring), the crude mixture was filtered through a Celite pad (washed with CH₂Cl₂) and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc–petroleum ether, 5%) to afford bis-alkylated quinone derivative 18 (67%) as a liquid. ¹H NMR (400 MHz, CDCl₃): δ = 1.19–1.22 (m, 6 H), 1.37–1.45 (m, 4 H), 1.49–1.56 (m, 2 H), 1.63–1.70 (m, 2 H), 2.06 (q, J = 7.0 Hz, 4 H), 2.59–2.65 (m, 6 H), 4.07–4.12 (m, 4 H), 4.94–5.02 (m, 4 H), 5.71–5.81 (m, 2 H), 6.54 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.42, 26.40, 31.75, 32.22, 33.52, 44.24, 60.67, 115.10, 133.89, 138.24, 146.68, 174.78, 187.40. IR (neat): 2931, 2858, 1728, 1464, 1266 cm^–1. HRMS (Q-Tof): m/z [M + H] calcd for C₂₆H₃₇O₆: 445.2590; found: 445.2601.