Microwave-Accelerated Alkylation of Arenes/Heteroarenes with Benzylic Alcohols Using Antimony(III) Chloride as Catalyst: Synthesis of O-Heterocycles

Abstract

An efficient protocol for alkylation of electron-rich arenes/heteroarenes with benzylic alcohols under microwave irradiation using antimony(III) chloride as catalyst has been developed. The mild reaction conditions, high yields, operational simplicity, and applicability to various substrates render the approach a useful route for the synthesis of diaryl/triarylalkane. In addition, a new route for the conversion of ortho-alkenylated phenols into functionalized O-heterocycles has been accomplished.

antimony(III) chloride - alkylation - arenes - microwave - oxygen heterocycles

References and Notes

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Typical Procedure for the Alkylation of 1,3-Dimethoxy-benzene (1) with 1-Phenylethanol (2a) Followed by Demethylation
1,3-Dimethoxybenzene (1, 0.276 g, 2 mmol), 1-phenyl-ethanol (2a, 0.268 g, 2.2 mmol), and SbCl₃ (0.068 g, 0.30 mmol) were mixed with dry MeCN (2 mL) in an Anton Paar microwave vessel and sealed with a cap. The resulting mixture was irradiated with microwave (400 W) for 25 min when 2a was fully consumed (checked by TLC). The reaction mixture was quenched with sat. aq NaHCO₃ solution (1 mL), and the viscous mass thus obtained was dissolved in EtOAc and passed through Celite to remove metal salts. The Celite bed was thoroughly washed with EtOAc, and the filtrate was washed with H₂O, brine, and dried (MgSO₄). Removal of solvent yielded the crude product which was dried under vacuo and then dissolved in dry CH₂Cl₂ (5 mL). The solution was cooled (-20 ˚C), and BBr₃ (0.5 mL, 5 mmol) was added. The solution was slowly brought to 0 ˚C. The dark brown reaction mixture was stirred at 0 ˚C for 2 h when TLC showed complete disappearance of the starting compound. The reaction mixture was quenched with ice-water, and the product was extracted with CH₂Cl₂. The organic layer was washed with brine and dried (Na₂SO₄). The solvent was removed under vacuo, and the residue was purified by chromatography (silica, eluant: CHCl₃-MeOH) to get pure monoalkylated and dialkylated products 3a and 3b, respectively. 4-(1-Phenylethyl)benzene-1,3-diol (3a)
Yield 65%; thick oil. IR (neat): ν = 3400, 3025, 2968, 2932, 1605, 1517, 1451, 1215, 1113, 972, 909, 758, 735, 701 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.11-7.25 (m, 5 H), 6.98 (d, 1 H, J = 8.3 Hz), 6.32 (dd, 1 H, J = 8.3, 2.4 Hz), 6.17 (d, 1 H, J = 2.4 Hz), 4.61 (br s, 2 H), 4.20 (q, 1 H, J = 7.1 Hz), 1.50 (d, 3 H, J = 7.1 Hz). ^¹³C NMR (50 MHz, CDCl₃): δ = 154.7, 154.0, 145.8, 128.7, 128.6, 127.4, 126.3, 124.8, 107.8, 103.5, 38.0, 21.1. Anal. Calcd for C₁₄H₁₄O₂: C, 78.48; H, 6.59. Found: 78.11; H, 6.38.
4,6-Bis(1-phenylethyl)benzene-1,3-diol (3b)
Yield 14%; thick oil. IR (neat): ν = 3522, 3025, 2968, 2932, 1605, 1517, 1506, 1451, 1215, 1113, 972, 909, 759, 735, 703 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.10-7.28 (m, 10 H), 7.05 (s, 1 H), 6.11 (s, 1 H), 4.20 (q, 2 H, J = 7.2 Hz), 1.54 (d, 6 H, J = 7.2 Hz). ^¹³C NMR (50 MHz, CDCl₃): δ = 152.4, 145.7, 128.6, 127.4, 127.2, 127.0, 126.3, 124.1, 104.3, 38.5, 21.2. Anal. Calcd for C₂₂H₂₂O₂: C, 82.99; H, 6.96. Found: 82.64; H, 6.68.
4- tert -Butyl-2-(1,3-diphenylallyl)phenol (29)
Yield 67%; thick oil. IR (neat): ν = 3447, 2963, 2928, 1491, 1261, 752, 698 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.10-7.37 (m, 12 H), 6.64-6.75 (m, 2 H), 6.35 (d, 1 H, J = 16.0 Hz), 5.07 (d, 1 H, J = 7.1 Hz), 1.23 (s, 9 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 151.2, 143.7, 142.2, 137.2, 131.8, 131.5, 128.7, 127.4, 126.7, 126.4, 124.7, 115.9, 114.8, 49.1, 34.2, 31.5. Anal. Calcd for C₂₅H₂₆O: C, 87.68; H, 7.65. Found: 87.31; H, 7.41.
5-Methoxy-2-(1-phenylbut-3-enyl)phenol (32)
Yield 68%; thick oil. IR (neat): ν = 3420, 3026, 1614, 1597, 1200, 1150, 698 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.19-7.37 (m, 5 H), 7.16 (d, 1 H, J = 8.5 Hz), 6.50 (dd, 1 H, J = 8.5, 2.5 Hz), 6.34 (d, 1 H, J = 2.5 Hz), 5.70-5.78 (m, 1 H), 4.95-5.09 (m, 2 H), 4.21 (t, 1 H, J = 7.8 Hz), 3.76 (s, 3 H), 2.74-2.84 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 158.9, 154.2, 144.1, 136.9, 128.7, 128.4, 127.9, 126.2, 123.2, 116.1, 105.9, 102.3, 55.1, 43.7, 39.1. Anal. Calcd for C₁₇H₁₈O₂: C, 80.28; H, 7.13. Found: 79.91; H, 6.87.
Typical Procedure for the Intramolecular Cyclization of 4- tert -Butyl-2-(1,3-diphenylallyl)phenol (29) with Copper(II) Bromide To a solution of 29 (0.342 g, 1 mmol) in dry MeCN (5 mL), was added CuBr₂ (0.536 g, 2.4 mmol) and stirred at ambient temperature. After completion of the reaction (5 min, checked by TLC) MeCN was removed under vacuo, and the crude product was quenched with H₂O, dissolved in EtOAc, and the suspension was passed through Celite. The organic layer was washed with brine and dried (Na₂SO₄). The solvent was removed under vacuo, and the residue was purified by chromatography (silica, eluant: hexane-EtOAc) to get pure 33.
6- tert -Butyl-3-bromo-2,4-diphenyl chroman (33)
Single diastereomer; yield 96%; colorless solid; mp 240-241 ˚C. IR (neat): ν = 2955, 1497, 1238, 1005, 696 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.26-7.49 (m, 11 H), 6.86 (d, 1 H, J = 8.6 Hz), 6.67 (d, 1 H, J = 1.8 Hz), 5.17 (d, 1 H, J = 9.8 Hz), 4.44-4.63 (m, 2 H), 1.14 (s, 9 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 152.4, 144.4, 141.9, 138.7, 129.3, 128.9, 128.5, 128.4, 127.9, 127.4, 126.7, 125.2, 124.1, 116.2, 82.6, 57.4, 53.9, 34.1, 31.3. ESI-MS: m/z = 421 [M⁺]. Anal. Calcd for C₂₅H₂₅BrO: C, 71.26; H, 5.98. Found: 70.98; H, 5.73.
2-(Bromomethyl)-3,4-dihydro-7-methoxy-4-phenyl-2 H -chromene (34)
Mixture of syn and anti isomers; yield 86%; thick oil. IR (neat): ν = 2930, 1609, 1504, 1491, 1206, 1051, 752 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 7.13-7.34 (m, 7 H), 6.31 and 6.28 (2 s, 1 H), 4.36-4.48 (m, 1 H), 3.53-3.83 (m, 6 H), 2.85-2.98 (m, 1 H), 2.16-2.26 (m, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 155.3, 155.1, 154.0, 153.4, 142.8, 141.0, 132.6, 131.4, 128.9, 128.7, 128.1, 127.5, 127.2, 126.8, 124.1, 121.7, 102.5, 102.3, 101.7, 101.3, 56.3, 56.2, 50.9, 42.1, 41.8, 41.2, 41.1, 36.6, 36.5, 29.6. ESI-MS: m/z = 333 [M⁺]. Anal. Calcd for C₁₇H₁₇BrO₂: C, 61.28; H, 5.14. Found: 60.91; H, 4.87.

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