Sc(OTf)₃-Catalyzed Addition of Bromomagnesium 2-Vinyloxy Ethoxide to Various Aldehydes Leading to Protected Aldol Products

Abstract

The addition of bromomagnesium 2-vinyloxy ethoxide to various aldehydes in the presence of 10 mol% Sc(OTf)₃ provides a broad range of functionalized protected aldol compounds. The enantioselective preparation of these aldols can be achieved via a Swern oxidation–CBS reduction sequence. Use of the dioxolane derived from 2-bromocyclohexanone provides the expected aldol product as the anti diastereoisomer (dr >99:1).

Key words

aldol - Grignard addition - scandium triflate - catalysis

• References and Notes

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• 17 General All reactions were carried out under an argon atmosphere in flame-dried glassware. Syringes which were used to transfer anhydrous solvents or reagents were purged with argon prior to use. THF was continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen, then stored over MS 4 Å. Et₂O was predried over CaH₂ and further dried with the solvent purification system SPS-400-2 from Innovative Technologies Inc. and stored over MS 4 Å. Yields refer to isolated yields of compounds estimated to be >95% pure as determined by ¹H NMR (25 °C) and capillary GC analysis. Chemical shifts are reported as δ values in ppm relative to the solvent peak. NMR spectra were recorded in a solution of CDCl₃ (residual chloroform: δ = 7.27 ppm for ¹H NMR and δ = 77.0 ppm for ¹³C NMR). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Column chromatography was performed using SiO₂ (0.040–0.063 mm, 230–400 mesh ASTM) from Merck. Typical Procedure for the Preparation of Alcohols of Type 4 (TP1) A dry and argon-flushed 10 mL Schlenk tube, equipped with a stirring bar and septum, was charged with 2-(vinyloxy)ethanol (5, 132 mg, 1.50 mmol, 1.50 equiv) in Et₂O (1.5 mL). Then, i-PrMgBr (1.55 mmol, 1.55 equiv) was added dropwise at 25 °C. After 5 min of stirring, Sc(OTf)₃ (49.2 mg, 0.10 mmol, 0.10 equiv) and aldehyde 6 (1.00 mmol, 1.00 equiv) were successively added, and the reaction mixture was stirred at 40 °C for the given time. After a full conversion was detected by GC analysis, sat. aq NH₄Cl (15 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over Na₂SO₄, filtered, and solvent was removed under reduced pressure. Purification via column chromatography (SiO₂) afforded expected products 4. 1-(2-Bromophenyl)-2-(1,3-dioxolan-2-yl)ethanol (4b) According to TP1, i-PrMgBr (1.91 mL, 1.55 mmol, 1.55 equiv) was added to a solution of 2-(vinyloxy)ethanol (5, 132 mg, 1.50 mmol, 1.50 equiv) in Et₂O (1.5 mL). Then, Sc(OTf)₃ (49.2 mg, 0.10 mmol, 0.10 equiv) and 2-bromobenzaldehyde (6b, 155 mg, 1.00 mmol, 1.00 equiv) were added. The reaction mixture was stirred for 3 h at 40 °C. Purification by flash column chromatography (SiO₂ loaded with i-hexane containing 2% Et₃N; eluent: i-hexane–EtOAc = 6:4) afforded the desired product 4b (235 mg, 86%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.65 (dd, J = 7.8, 1.8 Hz, 1 H), 7.51 (dd, J = 8.0, 1.4 Hz, 1 H), 7.34 (td, J = 7.6, 1.4 Hz, 1 H), 7.12 (td, J = 7.6, 1.8 Hz, 1 H), 5.33 (dt, J = 9.5, 2.1 Hz, 1 H), 5.12 (dd, J = 5.2, 3.8 Hz, 1 H), 4.14–4.01 (m, 2 H), 3.98–3.87 (m, 2 H), 3.59 (d, J = 2.2 Hz, 1 H), 2.25 (ddd, J = 14.6, 3.8, 2.2 Hz, 1 H), 1.95 (ddd, J = 14.6, 9.5, 5.2 Hz, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 142.6, 132.6, 128.7, 127.6, 127.4, 121.4, 103.3, 69.3, 65.0, 64.8, 40.5 ppm. IR (diamond ATR, neat): ν = 3457, 3060, 2957, 2884, 1736, 1590, 1567, 1466, 1438, 1409, 1360, 1308, 1270, 1192, 1119, 1076, 1019 cm^–1. MS (EI, 70 eV): m/z (%) = 44 (22), 73 (100), 77 (22), 87 (16), 116 (20), 181 (11), 183 (14), 184 (19), 186 (11), 274 (1). HRMS (EI): m/z [M⁺] for C₁₁H₁₃BrO₃: 274.0048; found: 274.0027. 2-(1,3-Dioxolan-2-yl)-1-(3-fluorophenyl)ethanol (4c) According to TP1, i-PrMgBr (1.91 mL, 1.55 mmol, 1.55 equiv) was added to a solution of 2-(vinyloxy)ethanol (5, 132 mg, 1.50 mmol, 1.50 equiv) in Et₂O (1.5 mL). Then, Sc(OTf)₃ (49.2 mg, 0.10 mmol, 0.10 equiv) and 3-fluorobenzaldehyde (6c, 124 mg, 1.00 mmol, 1.00 equiv) were added. The reaction mixture was stirred for 3 h at 40 °C. Purification by flash column chromatography (SiO₂ loaded with i-hexane containing 2% Et₃N; eluent: i-hexane–EtOAc = 7:3) afforded the desired product 4c (190 mg, 90%) as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.26 (m, 1 H), 7.16–7.10 (m, 2 H), 6.95 (dd, J = 8.2, 1.0 Hz, 1 H), 5.09–4.97 (m, 2 H), 4.12–4.02 (m, 2 H), 3.96–3.86 (m, 2 H), 3.42 (d, J = 2.4 Hz, 1 H), 2.10 (ddd, J = 5.5, 4.3, 1.6 Hz, 2 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 163.0 [d, ¹J(C,F) = 246 Hz], 146.6 [d, ³J(C,F) = 7 Hz], 129.9 [d, ³J(C,F) = 8 Hz], 121.2 [d, ⁴J(C,F) = 3 Hz], 114.2 [d, ²J(C,F) = 21 Hz], 112.7 [d, ²J(C,F) = 22 Hz], 103.1, 69.7 [d, ⁴J(C,F) = 2 Hz], 65.0, 64.9, 42.3 ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –113.1. IR (diamond ATR, neat): ν = 3451, 2959, 2888, 1615, 1590, 1484, 1449, 1411, 1362, 1244, 1091, 1060, 1024 cm^–1. MS (EI, 70 eV): m/z (%) = 43 (20), 44 (18), 45 (50), 73 (100), 87 (26), 95 (12), 97 (21), 194 (1). HRMS (EI): m/z [M⁺] for C₁₁H₁₃FO₃: 212.0849; found: 194.0768 [M – H₂O]⁺. 1-(2-Chloro-6-fluorophenyl)-2-(1,3-dioxolan-2-yl)ethanol (4d) According to TP1, i-PrMgBr (1.91 mL, 1.55 mmol, 1.55 equiv) was added to a solution of 2-(vinyloxy)ethanol (5, 132 mg, 1.50 mmol, 1.50 equiv) in Et₂O (1.5 mL). Then, Sc(OTf)₃ (49.2 mg, 0.10 mmol, 0.10 equiv) and 2-chloro-6-fluorobenzaldehyde (6d, 158 mg, 1.00 mmol, 1.00 equiv) were added. The reaction mixture was stirred for 2 h at 40 °C. Purification by flash column chromatography (SiO₂ loaded with i-hexane containing 2% Et₃N; eluent: i-hexane–EtOAc = 1:4) afforded the desired product 4d (215 mg, 87%) as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.23–7.13 (m, 2 H), 6.99 (ddd, J = 10.9, 7.1, 2.3 Hz, 1 H), 5.54 (ddd, J = 9.7, 6.0, 3.6 Hz, 1 H), 5.10 (t, J = 4.5 Hz, 1 H), 4.09–3.99 (m, 2 H), 3.96–3.84 (m, 2 H), 3.09 (dd, J = 6.1, 2.4 Hz, 1 H), 2.53 (dddd, J = 14.4, 9.7, 4.7, 1.7 Hz, 1 H), 2.12 (dt, J = 14.5, 4.0 Hz, 1 H) ppm. ¹⁹F NMR (282 MHz, CDCl₃): δ = –113.1 ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 161.9 [d, ¹J(C,F) = 240 Hz], 133.6 [d, ³J(C,F) = 7 Hz], 129.3 [d, ³J(C,F) = 11 Hz], 128.4 [d, ²J(C,F) = 13 Hz], 125. 8, 115.1 [d, ²J(C,F) = 15 Hz], 102.9, 66.1 [d, ³J(C,F) = 1 Hz], 65.0, 64.8, 39.3 [d, ⁴J(C,F) = 3 Hz]. IR (diamond ATR, neat): ν = 3452, 3083, 2963, 2886, 1604, 1575, 1454, 1411, 1360, 1317, 1239, 1189, 1174, 1132, 1067, 1024 cm^–1. MS (EI, 70 eV): m/z (%) = 45 (17), 73 (100), 159 (14), 228 (4). HRMS (EI): m/z [M⁺] for C₁₁H₁₂ClFO₃: 246.0459; found: 228.0349 [M – H₂O]⁺.