An Expedient Synthesis of 2-Aryl-1,4-benzoxazin-3-ones via Tandem Anionic Cyclisation/Alkylation Reactions of N-Boc-O-benzyl-2-aminophenols

Abstract

A one-pot, tandem anionic cyclization/alkylation reaction of N-Boc-O-benzylated-2-aminophenols to give 2-aryl-1,4-benzoxazin-3-ones is described. The Boc protecting group plays a crucial role in the process, as the tert-butoxide liberated in the cyclisation step facilitates the benzylic deprotonation necessary for the subsequent alkylation. The reaction gives expedient access to a range of substitution patterns in 1,4-benzoxazin-3-ones of potential biological relevance.

Key words

1,4-benzoxazin-3-one - cyclization - alkylation - reagent recycling - DIBOA

• References and Notes

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• 18 General Procedure; Anionic Cyclisation/Alkylation Reaction: To a solution of the appropriate N-Boc-O-benzyl-2-aminophenol (0.3 mmol) in anhyd THF (1 mL) under nitrogen atmosphere cooled at –78 °C, a solution of t-BuLi was added dropwise (1.7 M in pentane, 0.39 mL, 0.66 mmol). The solution immediately turned orange. It was stirred at –78 °C for 10 min, then 2 h at –20 °C. Then the corresponding electrophile was added (0.6 mmol) and the resulting mixture was stirred for an additional 2 h at 20 °C before being quenched with H₂O (5 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL) and the combined organic extracts washed with H₂O (20 mL) and brine (20 mL), dried over MgSO₄ and filtered. The product was purified by flash chromatography eluting with hexane–EtOAc (9:1 → 8:2). Data for selected products (for all data, see Supporting Information) follows. 2a: mp 110–111 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.88 (br s, 1 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.20–7.35 (m, 3 H), 7.09–7.18 (m, 1 H), 7.00 (td, J = 7.8, 1.5 Hz, 1 H), 6.90 (td, J = 7.7, 1.3 Hz, 1 H), 6.73 (dq, J = 7.9, 1.4 Hz, 1 H), 4.65–5.13 (m, 2 H), 3.21 (d, J = 14.7 Hz, 1 H), 2.84 (d, J = 14.7 Hz, 1 H), 1.81 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 167.3, 142.9, 140.5, 139.0, 128.3, 128.0, 126.1, 125.6, 124.1, 122.4, 120.7, 117.5, 115.5, 115.4, 84.7, 46.8, 28.7, 28.3, 24.5. HRMS (ES): m/z [M + H⁺] calcd for C₁₈H₁₈NO₂: 280.13318; found: 280.1335. IR: 1680, 1502, 1448, 1370, 1155, 1057 cm^–1. 2g: mp 150–155 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.56 (s, 1 H), 7.56 (d, J = 6.8 Hz, 2 H), 7.22–7.36 (m, 3 H), 7.17 (d, J = 7.9 Hz, 1 H), 7.02 (td, J = 7.8, 1.4 Hz, 1 H), 6.91 (td, J = 7.8, 1.4 Hz, 1 H), 6.81 (dd, J = 7.8, 1.4 Hz, 1 H), 2.38 (dd, J = 14.5, 6.8 Hz, 1 H), 2.12 (dd, J = 14.5, 6.8 Hz, 1 H), 0.98–1.08 (m, 1 H), 0.35–0.57 (m, 2 H), 0.19–0.33 (m, 1 H), 0.00–0.08 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 168.2, 143.3, 139.3, 128.3, 127.9, 126.3, 125.7, 124.4, 122.2, 117.3, 115.6, 84.9, 44.6, 6.0, 4.6, 4.4. HRMS (ES): m/z [M + H⁺] calcd for C₁₈H₁₈NO₂: 280.1338; found: 280.1345, IR: 1688, 1502, 1428, 1368, 1124, 1045 cm^–1. 2h: mp 123–126 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.35 (s, 1 H), 8.54 (s, 1 H), 8.40–8.50 (m, 1 H), 7.58 (d, J = 12 Hz, 1 H), 7.46 (dd, J = 6.1, 1.8 Hz, 2 H), 7.22–7.35 (m, 3 H), 7.06–7.18 (m, 2 H), 6.97 (ddd, J = 7.9, 6.1, 1.8 Hz, 1 H), 6.88 (ddd, J = 7.9, 6.1, 1.8 Hz, 1 H), 6.72 (dt, J = 7.9, 1.8 Hz, 1 H), 3.72 (dd, J = 14.1, 1.6 Hz, 1 H), 3.40 (dd, J = 14.1, 1.6 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 166.6, 152.1, 147.9, 142.7, 138.7, 138.0, 131.3, 128.5, 128.4, 126.1, 125.7, 124.1, 122.8, 122.6, 117.5, 115.5, 84.1, 43.0, 28.2. HRMS (ES): m/z [M + H⁺] calcd for C₂₀H₁₇N₂O₂: 317.1290; found: 317.1302. IR: 1682, 1502, 1448, 1372, 1128, 1031 cm^–1.