Activation of Michael Acceptors by Halogen-Bond Donors

Published as part of the Special Section 9^th EuCheMS Organic Division Young Investigator Workshop

In memoriam Professor J. Peter Guthrie

Abstract

Extending earlier studies on iodine catalysis, experimental investigations show that various halogen-bond donors can also be employed to accelerate the Michael addition between trans-crotonophenone and indole. Solvent as well as counteranion effects have been analyzed, and kinetic and computational investigations provide additional insights into the mode of activation.

Key words

catalysis - DFT calculations - halogen bonding - kinetics - solvent effects

• References and Notes

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• 12 C1–OTf was synthesized from 2-iodo-1-octlybenzimidazole (1.0 equiv) and methyl triflate (1.2 equiv) as described in the Supporting Information. ¹H NMR (CDCl₃, 300 MHz): δ = 0.86 (t, ³ J _HH = 6.3 Hz, 3 H), 1.26–1.43 (m, 10 H), 1.90 (quint, ³ J _HH = 7.5 Hz, 2 H), 4.16 (s, 3 H), 4.49 (t, ³ J _HH = 7.6 Hz, 2 H), 7.56–7.63(m, 2 H), 7.70–7.75 (m, 1 H), 7.82–7.87 (m, 1 H). ¹³C{apt} NMR (CDCl₃, 75 MHz): δ = 14.1 (s), 22.6 (s), 26.7 (s), 29.1 (s), 29.2 (s), 29.3 (s), 31.7 (s), 36.9 (s), 50.6 (s), 112.0 (s), 112.7 (s), 13.4 (s), 120.6 (d, ¹ J _CF = 320.4 Hz), 127.3 (s), 127.4 (s), 133.2 (s), 134.2 (s). IR (neat, ATR): ṽ = 2928 (w), 2857 (w), 1479 (w), 1028 (s), 747 (m), 637 (s) cm^–1. ESI-HRMS: m/z [M]⁺ calcd for C₁₆H₂₄N₂I⁺: 371.0979; found: 371.0976. Anal. Calcd for C₁₇H₂₄F₃IN2O₃S: C, 39.24; H, 4.65; N, 5.38. Found: C, 39.31; H, 4.91; N, 5.16.C5–OTf was obtained from 2-iodo-3-methyl-1-octylimidazolium bromide (1.0 equiv) by anion metathesis with NaOTf (1.5 equiv) in CH₂Cl₂/H₂O. ¹H NMR (CDCl₃, 400 MHz): δ = 0.88 (t, ³ J _HH = 6.8 Hz, 3 H), 1.23–1.39 (m, 10 H), 1.84 (quint, ³ J _HH = 7.2 Hz), 3.95 (s, 3 H), 4.17 (t, ³ J _HH = 7.5 Hz, 2 H), 7.57 (d, ³ J _HH = 2.0 Hz, 1 H), 7.73 (d, ³ J _HH = 2.0 Hz, 1 H). ¹³C{apt} NMR (CDCl₃, 125 MHz): δ = 14.2 (s), 22.7 (s), 26.4 (s), 29.1 (s), 29.1 (s), 31.8 (s), 30.5 (s), 39.9 (s), 53.1 (s), 103.1 (s), 120.8 (q, ¹ J _CF = 320 Hz), 124.9 (s), 126.7 (s). ¹⁹F{¹H} NMR (CDCl₃, 376 MHz) δ = –78.2 (s), –78.4 (d, ¹ J _F13C = 320 MHz). IR (neat, ATR): ṽ = 3107 (w), 2926 (w), 2857 (w), 1568 (w), 1497 (w), 1456 (w), 1246 (s), 1223 (m), 1153 (s), 1028 (s), 756 (w), 665 (w), 637 (s) cm^–1. ESI-LRMS: m/z (%) = 321.0 (100) [C5]⁺ 320.8 (20) [Na(OTf)₂]^–, 148.9 (100) [OTf]^–. ESI-HRMS [C5]⁺: m/z calcd for C₁₂H₂₂N₂I⁺: 321.0822; found: 321.0821.
• 13 Typical Experimental ProcedureA stock solution (1.00 mL) containing the reactants 1 and 2 as well as the internal standard SiEt₄ was added to the pure catalyst in an NMR tube. This resulted in approximate concentration of 50 mM in the catalyst, 500 mM in the reactants, and 125 mM in the standard. The course of the reaction was followed by ¹H NMR spectroscopy. If a reasonable amount of product was observed in the final NMR spectrum, the reaction was deactivated with 100 μL DMSO. Within 2 h, all volatile residues were removed under reduced pressure, and the product was isolated by column chromatography (SiO₂, cyclohexane/EtOAc = 9:1 (v/v), R_f = 0.11) as an off-white solid.Analytical Data for Compound 3103–104 °C. ¹H NMR (CD₂Cl₂, 300 MHz): δ = 1.42 (d, ³ J = 6.9 Hz), 3.23 (dd, ³ J = 8.5 Hz, ² J = 16.5 Hz, 1 H), 3.44 (dd, ³ J = 5.4 Hz, ² J = 16.4 Hz, 1 H), 3.73–3.84 (m, 1 H), 6.97 (d, ³ J = 2.2 Hz, 1 H), 7.04–7.16 (m, 2 H), 7.31 (d, ³ J = 8.0 Hz, 1 H), 7.41 (t, ³ J = 7.5 Hz, 2 H), 7.52 (t, ³ J = 7.4 Hz 1 H), 7.63 (d, ³ J = 7.8 Hz, 1 H), 7.91–7.93 (m, 2 H), 8.12 (br s, 1 H). ¹³C{¹H} NMR (CD₂Cl₂, 75.5 MHz): δ = 21.4 (s), 27.5 (s), 46.8 (s), 111.7 (s), 119.5 (s), 119.5 (s), 120.7 (s), 121.7 (s), 122.2 (s), 126.8 (s), 128.4 (s), 128.9 (s), 133.3 (s), 137.0 (s), 137.8 (s), 200.0 (s). IR (neat, ATR): ṽ = 3352 (m), 3057 (w), 2982 (w), 2961 (w), 2872 (w), 1667 (s), 1618 (w), 1593 (w), 1489 (w), 1445 (m), 1339 (m) 1215 (s), 999 (m), 745 (s), 60 (m) cm^–1. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₈H₁₈NO⁺: 264.1383; found: 264.1384.
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