BF₃×OEt₂-Catalyzed Unusual Formation of cis-2,3-Disubstituted
Tetrahydrofuran Scaffolds

Abstract

Aldehydes undergo smooth cyclization with 4-(phenylthio)but-3-en-1-ol in the presence of BF₃˙OEt₂ in dichloromethane at room temperature to afford a novel class of 2,3-disubstitued tetrahydrofurans in good yields with all-cis-selectivity. This method is simple, selective, and convenient for the synthesis of tetrahydrofuran scaffolds in a single step.

Keywords

Lewis acid - aldehydes - 4-(phenylthio)but-3-en-1-ol - tetrahydrofuran scaffolds

References and Notes

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13

General Procedure
To a mixture of aldehyde (1.0 mmol) and (E)-4-(phenylthio)-but-3-en-1-ol (2.1 mmol) in dry CH₂Cl₂ (3 mL) was added BF₃˙OEt₂ (0.2 mmol), and the mixture was stirred for the time specified. After complete consumption of alcohol as indicated by TLC, the reaction mixture was quenched with sat. aq NaHCO₃ and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried over anhyd Na₂SO₄. Removal of solvent under reduced pressure, followed by purification over silica gel (Merck, 100-200 mesh, hexane) gave pure product. The products thus obtained were characterized by NMR and IR spectroscopy.
3-[Bis(phenylthio)methyl]-2-(4-bromophenyl)-tetrahydrofuran (3c) IR (neat): ν_max = 3445, 3020, 2920, 2852, 1902, 1724, 1595, 1486, 1447, 1403, 1254, 1208, 1182, 1060, 1008, 983, 811, 754, 495 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.41-7.67 (m, 4 H), 7.35 (d, J = 8.3 Hz, 2 H), 7.17-7.30 (m, 6 H), 6.97 (d, J = 8.3 Hz, 2 H), 4.89 (d, J = 7.5 Hz, 1 H), 4.37 (d, J = 4.5 Hz, 1 H), 3.98-4.11 (m, 2 H), 2.50-2.59 (m, 1 H), 2.15-2.32 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 140.6, 138.2, 138.1, 133.1, 132.9, 131.3, 130.5, 129.9, 129.7, 128.2, 121.4, 82.5, 68.1, 61.7, 52.7, 29.4. ESI-MS: m/z = 479 [M + Na].
3-[Bis( p -tolylthio)methyl]-2-(4-bromophenyl)-tetrahydrofuran (3h) IR (neat): ν_max = 3447, 3021, 2922, 2856, 1901, 1722, 1593, 1489, 1449, 1402, 1252, 1208, 1180, 1066, 1010, 981, 810, 756, 498 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.37 (d, J = 8.3 Hz, 2 H), 7.19-7.22 (m, 4 H), 7.01-7.08 (m, 6 H), 4.9 (d, J = 6.9 Hz, 1 H), 4.24 (d, J = 4.7 Hz, 1 H), 3.96-4.09 (m, 2 H), 2.45-2.55 (m, 1 H), 2.33 (d, J = 2.8 Hz, 6 H), 2.14-2.28 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 140.6, 138.2, 138.1, 133.1, 132.9, 131.3, 130.5, 129.9, 129.7, 128.2, 121.4, 82.5, 68.1, 61.7, 52.7, 29.4, 21.1. ESI-MS: m/z = 507 [M + Na]. HRMS: m/z calcd for C₂₅H₂₅OS₂BrNa: 507.0427; found: 507.0410.
3-[Bis( p -tolylthio)methyl]tetrahydro-2-propylfuran (3j) IR (neat): ν_max = 3449, 3021, 2924, 2864, 1727, 1642, 1490, 1455, 1375, 1180, 1101, 1038, 946, 807, 749, 499 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.36 (t, J = 7.9 Hz, 4 H), 7.11 (t, J = 7.9 Hz, 4 H), 4.13 (d, J = 9.9 Hz, 1 H), 3.97-4.02 (m, 1 H), 3.88-3.92 (m, 1 H), 3.69-3.74 (m, 1 H), 2.46-2.53 (m, 1 H), 2.38 (d, J = 3.9 Hz, 6 H), 2.17-2.24 (m, 1 H), 1.85-1.93 (m, 1 H), 1.53-1.60 (m, 2 H), 1.33-1.45 (m, 2 H), 0.97 (t, J = 6.9 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 133.8, 133.4, 129.7, 129.6, 79.8, 65.9, 60.6, 47.1, 30.6, 30.2, 21.1, 19.4, 14.0. ESI-MS: m/z = 390 [M + NH₄].
3,3a,4,9b-Tetrahydro-4-(phenylthio)-2 H -furo[3,2- c ]-chromene (4)
IR (neat): ν_max = 3061, 2926, 1726, 1586, 1483, 1452, 1368, 1305, 1225, 1107, 1075, 1039, 949, 848, 749, 695, 480 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.30-7.42 (m, 5 H), 7.19 (t, J = 8.3 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 6.83-6.89 (m, 2 H), 5.81 (d, J = 5.2 Hz, 1 H), 4.41 (d, J = 2.1 Hz, 1 H), 4.01-4.06 (m, 1 H), 3.89-3.94 (dd, J = 16.7, 8.3 Hz, 1 H), 2.81-2.87 (m, 1 H), 1.96-2.04 (m, 1 H), 1.58-1.67 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 152.7, 133.4, 130.0, 129.5, 129.1, 128.1, 120.9, 117.1, 99.2, 67.7, 45.6, 43.1, 27.7. ESI-MS: m/z = 307 [M + Na]. HRMS: m/z calcd for C₁₇H₁₆O₂SNa: 307.0768; found: 307.0752.