Aluminum Iodide Promoted Highly Z-Stereoselective Synthesis of β-Iodo Morita-Baylis-Hillman Esters with Ketones as Aldol Acceptors

 

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Abstract

Aluminum iodide has been found to promote the ­efficient and highly stereoselective synthesis of (Z)-β-iodo-α-­(hydroxyalkyl)acrylates via one-pot three-component coupling ­reactions. This new system has made it possible to utilize various ketones as the electrophiles, in order to react with an aluminum ­allenoate intermediate for the synthesis of β-iodo Morita-Baylis-Hillman adducts with high yield and excellent Z-stereoselectivity (>99%).

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AlI₃ appeared superior to other metal iodides, such as MgI₂ (79% yield, Z/E = 91:9) or TiI₄ (<10% yield) in terms of Z/E selectivity and chemical yield when using benzaldehyde as the electrophilic acceptor.

The formation of allenoate was expected from the isolation of β-iodo ethyl acrylate after aqueous work-up without adding electrophilic acceptors.

Experimental Procedure: CH₂Cl₂ (2.0 mL) was slowly added to an aluminum iodide (0.22 mmol) at -78 °C under N₂. Ethyl propiolate (0.24 mmol) and the ketone (0.20 mmol) were added sequentially. The reaction was monitored by TLC. After the reaction time indicated in Table [1] , it was quenched with H₂O (2.0 mL) and an aqueous layer was extracted with CH₂Cl₂. The combined organic phase was dried over Na₂SO₄ and the solvent was removed under vacuum. The crude product was purified by column chromatography (CH₂Cl₂-hexane 3:1) to provide a pure product.
( Z )-Ethyl 3-[4-(Trifluoromethyl)phenyl]-3-hydroxy-2-(iodomethylene)butanoate (Entry 13).
IR: 3476, 2983, 1718, 1327, 1124, 845 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.60 (2 H, d, J = 8.0 Hz), 7.54 (2 H, d, J = 8.5 Hz), 7.24 (1 H, s), 4.17 (2 H, m), 4.08 (1 H, br s), 1.70 (3 H, s), 1.16 (3 H, t, J = 7.5 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 167.74, 149.20, 148.92, 129.95 (q, J = 129.5 Hz), 125.71, 125.53, 124.26 (q, J = 540.8 Hz), 84.81, 77.89, 62.05, 28.94, 13.98. MS: m/e (relative intensity) = 414 (0.2) [M⁺], 399 (48), 354 (12), 271 (100), 244 (24), 175 (6).
( Z )-Ethyl 3-Hydroxy-2-(iodomethylene)-3-(4-methoxy-phenyl)butanoate (Entry 14).
IR: 3464, 2920, 1719, 1509, 1027, 505 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.22 (2 H, d, J = 8.7 Hz), 7.03 (1 H, s), 6.86 (2 H, d, J = 8.7 Hz), 4.12 (2 H, q, J = 6.9 Hz), 3.66 (1 H, s), 1.70 (3 H, s), 1.53 (3 H, s) 1.19 (3 H, t, J = 7.2 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 168.04, 159.13, 150.59, 136.97, 130.58, 113.82, 83.26, 77.80, 61.78, 55.47, 28.94, 14.09. MS: m/e (relative intensity) = 377 (0.3) [M⁺], 361 (15), 232 (30), 203 (100), 152 (43).
( Z )-Ethyl 3-Hydroxy-2-(iodomethylene)-3- p -tolyl-butanoate (Entry 15).
IR: 3490, 2980, 1722, 1298, 1184, 1028, 820 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.29 (2 H, d, J = 8.4 Hz), 7.13 (2 H, d, J = 8.4 Hz), 7.04 (1 H, s), 4.16 (2 H, m), 3.74 (1 H, s), 2.33 (3 H, s), 1.69 (3 H, s), 1.18 (3 H, t, J = 7.2 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 167.95, 150.39, 141.96, 137.38, 129.19, 125.26, 83.48, 77.96, 61.76, 28.91, 21.21, 14.04. MS: m/e (relative intensity) = 360 (0.005) [M⁺], 344 (10), 216 (100), 188 (36), 120 (10).
( Z )-Ethyl 3-Hydroxy-2-(iodomethylene)-3- o -tolyl-butanoate (Entry 16).
IR: 3498, 2980, 1722, 1295, 1182, 1027, 483 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.52 (1 H, m), 7.17 (3 H, m), 6.82 (1 H, s), 4.15 (2 H, m), 3.39 (1 H, br s), 2.39 (3 H, s), 1.82 (3 H, s), 1.14 (3 H, t, J = 7.2 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 167.78, 150.96, 141.63, 136.15, 132.49, 128.82, 126.05, 125.96, 81.78, 78.22, 61.52, 28.69, 21.95, 14.12. MS: m/e (relative intensity) = 359 (0.0015) [M⁺], 216 (100), 144 (33), 120 (13). ( Z )-Ethyl 3-Hydroxy-2-(iodomethylene)-3,4,4-trimethylpentanoate (Entry 18).
IR: 3520, 2958, 1723, 1289, 1180, 503 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.79 (1 H, s) 4.30 (2 H, m), 2.44 (1 H, br s) 1.45 (1 H, s), 1.37 (3 H, t, J = 7.0 Hz), 0.98 (9 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 169.14, 152.41, 81.92, 81.08, 61.68, 38.98, 25.81, 24.71, 14.10. MS: m/e (relative intensity) = 326 (0.15) [M⁺], 309 (100), 272 (30), 226 (13), 146 (10).
( Z )-Ethyl 3-Hydroxy-2-(iodomethylene)-3-phenyl-pentanoate (Entry 19).
IR: 3489, 2978, 1721, 1299, 1185, 701 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.33 (5 H, m) 7.00 (1 H, s), 4.14 (2 H, q, J = 7.2 Hz), 3.58 (1 H, s), 2.06 (2 H, m), 1.14 (3 H, t, J = 5.8 Hz), 0.82 (3 H, t, J = 7.2 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 168.20, 150.37, 142.72, 128.89, 127.62, 126.14, 83.15, 80.31, 61.77, 32.70, 14.04, 7.95. MS: m/e (relative intensity) = 360 (0.01) [M⁺], 331 (30), 216 (100), 108 (8).