Nucleophilic Addition of Ethyl 3-Bromodifluoromethyl-3-benzyloxyacrylate to Imines: An Effective Entry to Novel gem-Difluorinated Amino Esters and their Derivatives

Abstract

Zinc- or tetrakis(dimethylamino)ethylene (TDAE)-mediated nucleophilic addition of ethyl 3-bromodifluoromethyl-3-benzyloxyacrylate to imines afforded gem-difluorovinyl substituted β-amino esters (α-addition product) and gem-difluorinated δ-amino esters (γ-addition product) or their cyclized derivatives, depending on the mediator and the nature of substituents on the imines.

Key words

nucleophilic addition - amino esters - bromodifluoro­methylated acrylate - imines - gem-difluorinated

References and Notes

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1

Current address: Department of Medicinal Chemistry and The Center for Protein Structure and Function, The University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 4070, Lawrence, KS 66045-7562, USA.

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Zinc Powder Mediated Reaction of Acrylate 1 with Imines 2; General Procedure To a suspension of activated zinc powder (100 mg, 1.5 mmol) and sulfonimine 2 (1 mmol) in THF (4 mL) was added acrylate 1 (335 mg, 1 mmol) dropwise over 5 minutes at 60 °C. The mixture was stirred continuously at 60 °C for the time specified in Table [1] . The reaction was quenched by the addition of a sat. aq solution of NH₄Cl (5 mL) and extracted with Et₂O (3 × 10 mL). The combined organic extracts were washed with brine (30 mL), dried (Na₂SO₄), and the solvent was removed. The residue was purified by chromatography on silica gel (n-hexane-EtOAc, 3:1 or 5:1) to give α-difluorovinyl substituted β-amino esters 3 as two diasteromers. syn-3b White solid; mp 80-82 °C. IR (film): 3232, 3033, 2988, 1739, 1597, 1493, 1445, 1368, 1323, 1284, 1256, 1237, 1174, 1155, 1091, 1066, 1012, 961, 900, 813, 738, 724, 697, 673, 569, 542 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.22 (3 H, t, J = 7.2 Hz), 2.33 (3 H, s), 3.53-3.56 (1 H, m), 4.07-4.12 (2 H, m), 4.96 (2 H, AB system, J = 10.2 Hz), 5.17 (1 H, dd, J = 8.7, 6.3 Hz), 5.82 (1 H, d, J = 8.7 Hz), 6.96-7.46 (13 H, m). ¹⁹F NMR (282 MHz, CDCl₃): δ = -96.5 (1 F, d, J = 68.3 Hz), -110.9 (1 F, d, J = 68.3 Hz). MS: m/z (%) = 367 (1), 366 (1), 296 (5), 294 (14), 255 (1), 230 (1), 174 (2), 155 (14), 140 (1), 92 (8), 91 (100), 65(8), 51 (1). Anal. calcd for C₂₇H₂₆ClF₂NO₅S: C, 58.96; H, 4.76; N, 2.55. Found: C, 58.99; H, 4.88; N, 2.54.

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TDAE-Mediated Reaction of Acrylate 1 with Imines 2; General Procedure To a solution of acrylate 1 (335 mg 1 mmol) and sulfonimine 2 (1 mmol) in anhyd DMF (4 mL) cooled in an ice-salt bath under argon was added TDAE (239 mg, 0.29 mL, 1.2 mmol) dropwise via syringe over 0.5 h. A red color developed immediately with the formation of a fine white precipitate. The mixture was stirred vigorously for 1 h under cooling and then warmed to r.t. When the reaction was complete the orange red turbid solution was filtered and quenched by the addition of a sat. aq solution of NH₄Cl (8 mL). The mixture was extracted with EtOAc (3 × 20 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na₂SO₄), and concentrated in vacuo to give a residue, which was purified by flash chromatography (n-hexane-EtOAc, 20:1Æ3:1) to give the expected δ-amino ester 4 and the novel difluorovinyl substituted acrylate 5 as the by product. 4a White solid; mp 138-139 °C. IR (film): 3406, 3257, 2986, 1720, 1662, 1600, 1498, 1458, 1447, 1409, 1369, 1334, 1320, 1246, 1203, 1161, 1115, 1095, 1064, 1028, 929, 852, 816, 751, 698, 564 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.24 (3 H, t, J = 7.3 Hz), 2.31 (3 H, s), 4.13 (2 H, q, J = 7.3 Hz), 4.96 (1 H, ddd, J = 12.6, 12.6, 10.2 Hz), 5.21 (2 H, AB system, J = 11.7 Hz), 5.56 (1 H, s), 5.64 (1 H, d, J = 10.2 Hz), 7.03-7.48 (14 H, m). ¹⁹F NMR (282 MHz, CDCl₃): δ = -110.2. MS: m/z (%) = 486 (1, M⁺ - Et), 470 (1), 424 (2), 380 (9), 350 (7), 314 (2), 261 (5), 260 (32), 181 (3), 155 (16), 140 (2), 92 (8), 91 (100), 65 (6). Anal. calcd for C₂₇H₂₇F₂NO₅S: C, 62.90; H, 5.28; N, 2.72. Found: C, 62.97; H, 5.32; N, 2.81.

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The general procedure for zinc powder mediated reactions was applied to imine 6. 7f Yellowish oil; R _f 0.2-0.3 (n-hexane-EtOAc, 10:1). IR (film): 3064, 3032, 2923, 1763, 1496, 1455, 1398, 1361, 1282, 1137, 1084, 743, 699 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.75 (1 H, d, J = 15.3 Hz), 3.85-3.88 (1 H, m), 4.42 (1 H, d, J = 3.0 Hz), 4.84-4.94 (3 H, m), 7.02-7.43 (15 H, m). ¹⁹F NMR (282 MHz, CDCl₃): δ = -95.7 (1 F, d, J = 65.7 Hz), -109.8 (1 F, d, J = 65.7 Hz). MS: m/z (%) = 405 (1), 380 (1), 350 (1), 333 (1), 315 (9), 314 (12), 273 (1), 253 (1), 194 (1), 181 (2), 162 (3), 140 (1), 131 (11), 106 (5), 91 (100), 77 (3), 65 (8), 51 (1). HRMS: m/z calcd for C₂₅H₂₁F₂NO₂ (M⁺), 405.15404; found, 405.15897. 8f Yellowish oil; R _f 0.3-0.4 (n-hexane-EtOAc, 5:1). IR (film): 3032, 2981, 2904, 1695, 1666, 1496, 1456, 1370, 1350, 1280, 1194, 1150, 1109, 1060, 699 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.26 (3 H, t J = 7.1 Hz), 4.10 (1 H, d, J = 15.0 Hz), 4.17 (2 H, q, J = 7.1 Hz), 4.42 (1 H, d, J = 15.0 Hz), 4.85 (1 H, s), 5.09 (1 H, dd, J = 9.6, 3.9 Hz), 7.13-7.43 (10 H, m). ¹⁹F NMR (282 MHz, CDCl₃): δ = -103.8 (1 F, dd, J = 216.3, 9.6 Hz), -114.0 (1 F, dd, J = 216.3, 3.9 Hz). MS: m/z (%) = 343 (3), 314 (3), 298 (13), 271 (4), 250(72), 224 (2), 172 (2), 156 (2), 147 (3), 129 (7), 105 (6), 91 (100), 77 (3), 65 (11), 51 (2). Anal. calcd for C₂₀H₁₉F₂NO₂: C, 69.96; H, 5.58; N, 4.08. Found: C, 70.14; H, 5.75; N, 3.83. 9f Yellowish heavy oil; R _f 0.3-0.4 (n-hexane-EtOAc, 3:1). IR (film): 3461, 3064, 3032, 2922, 1711, 1665, 1632, 1496, 1452, 1431, 1396, 1365, 1238, 1199, 1138, 1096, 1063, 1029, 962, 849, 745, 701 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.49 (1 H, d, J = 15.3 Hz), 4.67 (1 H, dd, J = 16.5, 2.1 Hz), 4.98 (2 H, AB system, J = 12.0 Hz), 5.54-5.60 (2 H, m), 7.17-7.40 (15 H, m). ¹⁹F NMR (282 MHz, CDCl₃): δ = -89.1 (1 F, dd, J = 270.4, 16.5 Hz), -120.0 (1 F, dd, J = 270.4, 2.1 Hz). MS: m/z (%) = 405 (4), 386 (1), 314 (56), 288 (1), 250 (1), 226 (1), 196 (2), 174 (11), 140 (2), 118 (1), 106 (31), 92 (8), 91 (100), 79 (3), 77 (3), 65 (11), 51 (2). Anal. calcd for C₂₅H₂₁F₂NO₂: C, 74.06; H, 5.22; N, 3.45. Found: C, 73.84; H, 5.63; N, 3.21. HRMS: m/z calcd for C₂₅H₂₁F₂NO₂ (M⁺): 405.15404; found: 405.15448