Palladium-Catalyzed Asymmetric [3+2] Cycloaddition Reaction of Vinyl Cyclopropane with Electron-Deficient Dienes

Abstract

Palladium-catalyzed asymmetric [3+2] cycloaddition reaction of vinyl cyclopropane and electron-deficient dienes was realized. The cycloaddition reaction proceeded regioselectively on the distant C=C double bond of electron-deficient dienes, and was mainly controlled by the steric hindrance of the 5-substituent of electron-deficient dienes. Chiral multi-substituted cyclopentanes bearing three functional groups (monosubstituted alkene, conjugated ester, and cyano) and three continuous stereocenters were obtained in moderate to high yields, diastereoselectivities, and enantioselectivities.

Key words

palladium - [3+2] cycloaddition - vinyl cyclopropane - asymmetric catalysis - electron-deficient diene

Publication History

Received: 06 January 2024

Accepted after revision: 18 March 2024

Accepted Manuscript online:
18 March 2024

Article published online:
03 April 2024

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• 13 Synthesis of Products 3; General Procedure: To a flame-dried Schlenk tube, Pd₂(dba)₃ (0.005 mmol, 4.28 mg), L4 (0.012 mmol, 7.33 mg), and anhydrous THF (2.0 mL) were added. The resulting mixture was allowed to stir for 30 min, then vinyl cyclopropane 1 (0.24 mmol) and 2,4-diene 2 (0.2 mmol) were added subsequently. The resulting reaction mixture was stirred at room temperature until the raw material disappeared (monitored by TLC). After the volatiles were removed in vacuo, the resulting residue was purified by flash chromatography on silica gel with petroleum ether and ethyl acetate as eluent to give the product 3. Compound 3a: Yield: 36.8 mg (61%); colorless oil; ee: 93%. HPLC (Chiralcel NQ(2), 4.6 mm × 250 mm, hexane/isopropanol = 98:2, 0.7 mL/min, 217 nm): t _major = 32.79 min, t _minor = 35.37 min. [α]_D ¹⁹ +28.90 (c 1.0, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 6.70 (d, J = 10.9 Hz, 1 H), 5.69 (ddd, J = 17.0, 10.3, 8.1 Hz, 1 H), 5.20–4.99 (m, 2 H), 3.83 (s, 3 H), 3.78 (s, 3 H), 3.23 (dq, J = 9.7, 8.2 Hz, 1 H), 2.96 (td, J = 10.8, 9.6 Hz, 1 H), 2.79 (dd, J = 13.9, 7.5 Hz, 1 H), 2.47 (dq, J = 10.7, 6.7 Hz, 1 H), 2.39 (dd, J = 13.9, 8.4 Hz, 1 H), 1.30 (d, J = 6.8 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 165.04, 163.63, 145.81, 134.60, 130.84, 118.48, 115.40, 114.05, 52.77, 52.72, 50.07, 47.83, 44.79, 42.46, 40.14, 14.20. IR (KBr): 3441, 2838, 2960, 2250, 1730, 1607, 1445, 1363, 1254, 1066, 930, 770, 536 cm^–1. MS (DART): m/z = 303.1 [M + H]⁺. HRMS (DART): m/z [M + H]⁺ calcd for C₁₆H₁₉N₂O₄: 303.1339; found: 303.1336. Compound 3b: Yield: 26.1 mg (39%); colorless oil; ee: 65%. HPLC (Chiralcel ND(2), 4.6 mm × 250 mm, hexane/isopropanol = 98:2, 0.7 mL/min, 217 nm): t _major = 20.96 min, t _minor = 23.06 min. [α]_D ¹⁹ +26.8 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.72 (d, J = 11.1 Hz, 1 H), 5.68 (ddd, J = 16.9, 10.3, 7.7 Hz, 1 H), 5.20–5.07 (m, 2 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.27–3.14 (m, 1 H), 2.98 (dt, J = 11.1, 9.5 Hz, 1 H), 2.78 (dd, J = 13.7, 7.0 Hz, 1 H), 2.48–2.39 (m, 2 H), 1.76–1.61 (m, 2 H), 1.61–1.40 (m, 2 H), 0.97 (t, J = 7.1 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.15, 163.74, 146.86, 134.26, 130.09, 118.52, 116.10, 114.19, 54.81, 52.84, 52.78, 47.58, 45.37, 43.03, 38.49, 33.57, 20.98, 14.14. IR (KBr): 2955, 2832, 2718, 2321, 1724, 1605, 1437, 1363, 1250, 1069, 1069, 927, 776, 478 cm^–1. MS (DART): m/z = 331.2 [M + H]⁺. HRMS (DART): m/z [M + H]⁺ calcd for C₁₈H₂₃N₂O₄: 331.1652; found: 331.1650. Compound 3c: Yield: 32.7 mg (42%); colorless oil; ee: 73%. HPLC (Chiralcel NQ(2), 4.6 mm × 250 mm, hexane/isopropanol = 98:2, 0.7 mL/min, 217 nm): t _major = 18.23 min, t _minor = 19.85 min. [α]_D ¹⁹ +23.40 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.72 (d, J = 11.1 Hz, 1 H), 5.68 (ddd, J = 17.1, 10.3, 7.7 Hz, 1 H), 5.21–5.07 (m, 2 H), 3.84 (s, 3 H), 3.79 (s, 3 H), 3.21 (tt, J = 9.1, 7.6 Hz, 1 H), 2.98 (dt, J = 11.1, 9.4 Hz, 1 H), 2.77 (dd, J = 13.7, 7.0 Hz, 1 H), 2.48–2.38 (m, 2 H), 1.74–1.60 (m, 2 H), 1.54–1.38 (m, 2 H), 1.32–1.22 (m, 9 H), 0.90–0.80 (t, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.11, 163.71, 146.86, 134.25, 130.03, 118.46, 116.10, 114.19, 54.95, 52.80, 52.74, 47.59, 45.35, 43.01, 38.49, 31.74, 31.48, 29.53, 28.94, 27.54, 22.66, 14.14. IR (KBr): 3446, 2932, 2835, 2249, 1726, 1605, 1363, 1251, 1071, 988, 772 cm^–1. MS (DART): m/z = 387.2 [M + H]⁺. HRMS (DART): m/z [M + H]⁺ calcd for C₂₂H₃₁N₂O₄: 387.2278; found: 387.2274. Compound 3d: Yield: 33.9 mg (47%); colorless oil; ee: 67%. HPLC (Chiralcel ND(2), 4.6 mm × 250 mm, hexane/isopropanol = 98:2, 0.7 mL/min, 217 nm): t _major = 20.93 min, t _minor = 22.33 min. [α]_D ¹⁶ +16.70 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.72 (d, J = 11.1 Hz, 1 H), 5.68 (ddd, J = 17.0, 10.4, 7.7 Hz, 1 H), 5.23–5.03 (m, 2 H), 3.84 (s, 3 H), 3.79 (s, 3 H), 3.26–3.16 (m, 1 H), 2.98 (dt, J = 11.1, 9.4 Hz, 1 H), 2.77 (dd, J = 13.7, 6.9 Hz, 1 H), 2.47–2.36 (m, 2 H), 1.74–1.61 (m, 2 H), 1.57 (dt, J = 13.2, 6.6 Hz, 1 H), 1.44–1.27 (m, 2 H), 0.90 (d, J = 6.6, 0.9 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 165.11, 163.72, 146.77, 134.21, 130.06, 118.49, 116.15, 114.18, 55.14, 52.81, 52.73, 47.68, 45.37, 43.04, 38.52, 36.44, 29.38, 28.14, 22.48, 22.23. IR (KBr): 3443, 2956, 2865, 2250, 1728, 1606, 1443, 1365, 1254, 1129, 1070, 929, 743 cm^–1. MS (DART): m/z = 359.2 [M + H]⁺. HRMS (DART): m/z [M + H]⁺ calcd for C₂₀H₂₇N₂O₄: 359.1965; found: 359.1964. Compound 3e: Yield: 37.5 mg (51%); colorless oil; ee: 91%. HPLC (Chiralcel NQ(2), 4.6 mm × 250 mm, hexane/isopropanol = 99:1, 0.7 mL/min, 217 nm): t _major = 43.75 min, t _minor = 52.15 min. [α]_D ¹⁹ +28.90 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 6.72 (d, J = 11.1 Hz, 1 H), 5.68 (ddd, J = 17.0, 10.3, 7.7 Hz, 1 H), 5.48–5.40 (m, 1 H), 5.31–5.22 (m, 1 H), 5.21–5.07 (m, 2 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.28–3.17 (m, 1 H), 3.01 (dt, J = 11.1, 9.5 Hz, 1 H), 2.78 (dd, J = 13.7, 6.9 Hz, 1 H), 2.50–2.39 (m, 2 H), 2.30–2.13 (m, 2 H), 2.03 (pd, J = 7.6, 1.7 Hz, 2 H), 1.85–1.66 (m, 2 H), 0.96 (t, J = 7.5 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 165.09, 163.69, 146.75, 134.21, 133.98, 130.15, 126.47, 118.56, 115.98, 114.19, 54.43, 52.81, 52.77, 47.58, 45.45, 43.02, 38.65, 31.61, 25.09, 20.72, 14.31. IR (KBr): 3441, 2959, 2250, 1728, 1606, 1444, 1365, 1252, 1068, 989, 928, 771, 729 cm^–1. MS (DART): m/z = 371.2 [M + H]⁺. HRMS (DART): m/z [M + H]⁺ calcd for C₂₁H₂₇N₂O₄: 371.1965; found: 371.1963. Compound 3f: Yield: 30.6 mg (45%); colorless oil; ee: 78%. HPLC (Chiralcel NQ(2), 4.6 mm × 250 mm, hexane/isopropanol = 98:2, 0.7 mL/min, 217 nm): t _major = 35.11 min, t _minor = 37.16 min. [α]_D ¹⁹ +16.60 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 6.77 (d, J = 11.1 Hz, 1 H), 5.67 (ddd, J = 17.0, 10.3, 7.9 Hz, 1 H), 5.22–5.06 (m, 2 H), 3.84 (s, 3 H), 3.79 (s, 3 H), 3.28–3.18 (m, 1 H), 3.03 (dt, J = 11.1, 9.7 Hz, 1 H), 2.79 (dd, J = 13.7, 7.0 Hz, 1 H), 2.72 (dt, J = 9.8, 7.1 Hz, 1 H), 2.48–2.37 (m, 3 H), 2.06 (t, J = 2.6 Hz, 1 H), 1.99 (dq, J = 14.3, 7.2 Hz, 1 H), 1.88 (dq, J = 14.1, 7.0 Hz, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 165.08, 163.59, 146.61, 134.09, 130.20, 118.67, 115.45, 114.03, 81.69, 70.88, 53.12, 52.82, 52.79, 46.91, 45.35, 42.91, 38.61, 29.85, 16.64. IR (KBr): 3292, 2835, 2250, 1701, 1617, 1363, 1256, 1078, 931, 785 cm^–1. MS (ESI): m/z = 341.1 [M + H]⁺. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₁N₂O₄: 341.1496; found: 341.1491.