Base-Induced Cyclisation of ortho-Substituted 2-Phenyloxazolines to Give 3-Aminobenzofurans and Related Heterocycles

Published as part of the ISHC Conference Special Section

Abstract

Treatment of ortho-benzyloxyphenyloxazolines with butyllithium and potassium tert-butoxide results in cyclisation with ring opening of the oxazoline to give 2-aryl-3-aminobenzofurans. The reaction also occurs with the corresponding benzylthio and benzylamino compounds to give benzothiophenes and indoles, respectively. Use of an ortho-allyloxyphenyloxazoline gives the corresponding 2-vinylbenzofuran, while both α-methylbenzyloxy and benzylsulfonyl compounds form stable spirooxazolidine products. The X-ray structure of an aminobenzothiophene product has been determined.

Key words

cyclisation - oxazoline - benzofuran - benzothiophene - indole - Schlosser’s base - spiro heterocycle

• References and Notes

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• 4 Typical Experimental Procedures A solution of 2-(benzyloxy)benzoic acid (10.00 g, 43.8 mmol) and thionyl chloride (6.4 mL, 10.44 g, 87.7 mmol) in toluene (90 mL) was heated under reflux for 3 h and then cooled and evaporated to give 2-(benzyloxy)benzoyl chloride (10.80 g, 100%) as a pale yellow oil which was used without further purification. This was dissolved in CH₂Cl₂ (40 mL) and added dropwise to a solution of 2-amino-2-methylpropan-1-ol (7.81 g, 87.6 mmol) in CH₂Cl₂ (50 mL) stirred at 0 °C. Once the addition was complete, the reaction mixture was allowed to warm to r.t. for 18 h before being poured into water. The two layers were separated and the aqueous layer was re-extracted with CH₂Cl₂ (2×). The combined organic layers were washed successively with 2 M HCl, 2 M NaOH, and water before being dried and evaporated to give the amide (12.68 g, 97%) as a colourless solid, mp 115–117 °C, which was used without further purification. SOCl₂ (3.7 mL, 6.03 g, 50.7 mmol) was added to a solution of 2-(benzyloxy)-N-(1-hydroxy-2-methylpropan-2-yl)benzamide (12.68 g, 42.4 mmol) in CH₂Cl₂ (210 mL), and the reaction mixture was stirred at r.t. for 18 h. The mixture was washed with 2 M NaOH and water before being dried and evaporated to give, after purification by Kugelrohr distillation (185 °C/9.2 Torr), 1 (10.14 g, 85%) as a colourless oil which formed a low-melting solid on standing. IR: 1718, 1645, 1038, 967, 871, 848, 751, 733, 695 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.72 (dd, J = 7.5, 2.0 Hz, 1 H), 7.52 (d, J = 7.5 Hz, 2 H), 7.38–7.35 (m, 3 H), 7.29 (t, J = 7.3 Hz, 1 H), 7.01–6.97 (m, 2 H), 5.18 (s, 2 H, OCH₂Ar), 4.11 (s, 2 H, oxazoline CH₂), 1.41 (s, 6 H, CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 161.2 (C=N), 157.3 (C–O), 137.0 (C), 131.9 (CH), 131.1 (CH), 128.2 (2 CH), 127.5 (CH), 126.7 (2 CH), 120.6 (CH), 118.6 (C), 113.5 (CH), 78.8 (oxazoline CH₂), 70.5 (OCH₂Ar), 67.5 (C), 28.4 (CH₃). HRMS (ESI⁺): m/z calcd for C₁₈H₂₀NO₂ [M + H]⁺: 282.1489; found: 282.1478. Under a nitrogen atmosphere, n-BuLi (2.5 M in hexane, 6.6 mL, 16.5 mmol) was added to a stirred mixture of 2-[2-(benzyl­oxy)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1, 1.41 g, 5.01 mmol) and t-BuOK (1.88 g, 16.8 mmol) in dry THF (50 mL). The reaction mixture was stirred at r.t. for 2 h before being quenched by addition of sat. aq NH₄Cl and extracted with Et₂O (3×). The combined organic layers were dried and evaporated to give, after purification by column chromatography (Al₂O₃, gradient elution, Et₂O/hexane 3:2 to EtOAc), 3 (1.13 g, 80%) as orange crystals, mp 59–63 °C. IR: 3325, 2974, 2933, 1605, 1452, 1362, 1256, 1043, 1026, 739, 694 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.08–8.05 (m, 2 H), 7.64–7.62 (m, 1 H), 7.46–7.41 (m, 3 H), 7.34–7.30 (m, 1 H), 7.29–7.25 (m, 1 H), 7.24–7.20 (m, 1 H), 3.42 (s, 2 H, CH₂), 2.65 (br s, 2 H, NH and OH), 1.07 (s, 6 H, CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 153.0 (C), 148.5 (C), 131.1 (C), 129.5 (C), 128.5 (2 CH), 128.0 (CH), 126.5 (2 CH), 124.4 (CH), 122.5 (CH), 122.2 (C), 119.6 (CH), 111.2 (CH), 70.3 (CH₂), 58.1 (C), 24.7 (CH₃). HRMS (ESI⁺): m/z calcd for C₁₈H₂₀NO₂ [M + H]⁺: 282.1489; found: 282.1482.
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