Iodine-Catalyzed Nucleophilic Substitution Reactions of Benzylic Alcohols

Abstract

Molecular iodine efficiently catalyzes the direct nucleophilic substitution of the hydroxy group of benzylic alcohols with carbon and oxygen nucleophiles.

nucleophilic substitution - benzyl alcohols - carbocation - Lewis acid

References and Notes

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General Experimental Procedure
To a solution of the benzylic alcohol (1 mmol) and nucleophile (1.2 mmol) in MeCN (3 mL) was added I₂ (5 mol%) and the mixture was stirred at 0 °C to r.t. After completion of the reaction (monitored by TLC), the reaction mixture was washed with sat. aq Na₂S₂O₃ solution and extracted with EtOAc. The organic layer was separated and washed with brine, dried over anhyd Na₂SO₄, and the solvent was evaporated under vacuum. The resulting crude product was purified by silica gel column chromatography (EtOAc-hexane as the eluents).
Spectroscopic Data of Representative Examples
Compound 4c: yellow liquid. IR (neat): 3061, 3029, 2924, 2859, 1952, 1601, 1493, 1452, 1094, 1028, 739, 698 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.91 (p, J = 6.1 Hz, 2 H), 3.53 (t, J = 6.1 Hz, 2 H), 3.58 (t, J = 6.2 Hz, 2 H), 4.44 (s, 2 H), 5.26 (s, 1 H), 7.13-7.30 (m, 15 H). ¹³C NMR (100 MHz, CDCl₃): δ = 142.0, 138.1, 127.8, 127.1, 127.0, 126.8, 126.7, 126.5, 83.2, 72.5, 66.9, 65.5, 29.8. MS (EI): m/z = 355 [M⁺ + Na]. HRMS: m/z calcd for C₂₃H₂₄O₂Na: 355.1673; found: 355.1683.
Compound 5a: solid; mp 110-112 °C.^16a IR (KBr): 3491, 3057, 2924, 1616, 1593, 1490, 1387, 1200, 1135, 812, 740, 701 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.97 (d, 1 H, J = 8.7 Hz), 7.76 (dd, 1 H, J = 7.8 Hz), 7.72 (d, 1 H, J = 8.7 Hz), 7.20-7.42 (m, 12 H), 7.06 (d, 1 H, J = 8.7 Hz), 6.41 (s, 1 H), 5.27-5.40 (br s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.9, 141.8, 133.5, 129.8, 129.7, 129.3, 129.2, 128.9, 127.3, 126.9, 123.3, 123.0, 120.3, 119.9, 48.6. MS (EI): m/z = 310 [M⁺]. Anal. Calcd (%) for C₂₃H₁₈O: C, 89.03; H, 5.80. Found: C, 89.4; H, 5.64.
Compound 5e: white solid; mp 86-88 °C. IR (KBr): 3444, 2964, 3024, 2964, 2855, 2372, 1876, 1599, 1509, 1444, 1331, 1254, 1090, 823, 743 cm^-1. ¹H NMR (200 MHz, CDCl₃ + DMSO): δ = 1.62 (d, J = 7.0 Hz, 3 H), 4.20 (q, J = 7.0 Hz, 1 H), 6.62 (d, J = 8.6 Hz, 2 H), 7.02 (d, J = 8.6 Hz, 2 H), 6.83 (dt, J = 1.1, 8.9 Hz, 2 H), 6.93-7.06 (m, 2 H), 7.21-7.30 (m, 1 H), 8.57 (br s, 1 H, NH), 10.13 (s, 1 H, OH). ¹³C NMR (100 MHz, CDCl₃): δ = 153.9, 136.4, 135.5, 126.7, 125.4, 119.7, 119.3, 117.9, 116.9, 113.8, 113.7, 110.0, 34.6, 21.4. MS (EI): m/z = 238 [M⁺ + H]. HRMS: m/z calcd for C₁₆H₁₆NO: 238.1231; found: 238.1239.

Only a single product was obtained in all these cases. For regioselectivity purpose, the analytical data of the products 5a and 5i were compared with the data obtained from the earlier literature and was found to be in accordance, see:

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<A NAME="RD35607ST-17">17</A>

Optically active p-methoxy α-phenyl ethanol was obtained from the corresponding ketone following the standard reduction procedure using CBS catalyst; ee was calculated using chiral HPLC.