A Facile and Efficient Synthesis of 4,5-Dihydro-1H-2,5-benzoxazocine-1,6(3H)-diones from 1,2-Cyclic Sulfamidates^[1]

Abstract

4,5-Dihydro-1H-2,5-benzoxazocine-1,6(3H)-diones have been synthesized by treatment of tert-butoxycarbonyl (Boc)-protected 1,2-cyclic sulfamidates with phthalic acid derivatives. Protection of one acid hydroxy group and the deprotection of the N-Boc group of the adducts, followed by cyclization, afforded the desired products in high yields. When derivatives of isophthalic acid were used in the synthetic sequence, nine-membered-ring analogues were formed. All the prepared compounds except one are novel.

Key words

benzoxazocines - nine-membered analogues - cyclization - sulfamidates

• References and Notes

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• 16 4,5-Dihydro-1H-2,5-benzoxazocine-1,6(3H)-diones 6a–k; General Procedure A solution of salt 5 (0.38 mmol) in MeCN (10 mL) was added slowly to a solution of DIPEA (0.1 mL, 0.57 mmol) in MeCN (30 mL) at 80 °C, and the mixture was kept at 80 °C for 2 h. The reaction was quenched with sat. aq NH₄Cl (10 mL) at 0 °C, and the mixture was diluted with EtOAc (30 mL) and washed sequentially with 1 M HCl (10 mL) and brine (10 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated, and the residue was purified by column chromatography [60–120 mesh silica gel, EtOAc–hexane (2:8)]. 4,5-Dihydro-1H-2,5-benzoxazocine-1,6(3H)-diones (6a); Alternative Procedure A solution of salt 7 (0.38 mmol) in CH₂Cl₂ (15 mL) was treated with HATU (295 mg, 0.77 mmol), HOAt (105 mg, 0.77 mmol), and DIPEA (0.2 mL, 1.15 mmol) at 0 °C. The mixture was stirred at r.t. for 36 h, diluted with H₂O (10 mL), and extracted with CH₂Cl₂ (15 mL). The organic phase was washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. The residue was purified by column chromatography [silica gel, EtOAc–hexane (2:8)] to give a white solid; yield: 43 mg (59%); mp 138–140 °C (Lit.^8a,b 139 °C). Selected analytical data: 8-Nitro-4,5-Dihydro-1H-2,5-benzoxazocine-1,6(3H)-dione (6b) Pale-yellow solid; yield: 72 mg (64%); mp 134–136 °C. IR (KBr): 3363, 2925, 1706, 1545, 1348 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.68 (d, J = 2.0 Hz, 1 H), 8.62 (dd, J = 8.0, 2.0 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 4.00–3.88 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.5, 166.3, 151.8, 136.4, 133.4, 129.3, 124.6, 118.9, 60.5, 41.2. ESI-MS: m/z = 237 [M + H]⁺. Anal. Calcd for C₁₀H₈N₂O₅: C, 50.85; H, 3.41. Found: C, 50.98; H, 3.37. (4R)-4-Phenyl-4,5-dihydro-1H-2,5-benzoxazocine-1,6(3H)-dione (6f) White solid; yield: 68 mg (67%); mp 86–88 °C; [α]_D ²⁵ +34.0 (c 2.2, CHCl₃). IR (KBr): 3444, 2925, 1771, 1714, 1391 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.84–7.77 (m, 2 H), 7.72–7.65 (m, 2 H), 7.48–7.42 (m, 2 H), 7.38–7.24 (m, 3 H), 5.47 (dd, J = 10.0, 5.0 Hz, 1 H), 4.65 (dd, J = 12.0, 10.0 Hz, 1 H), 4.22 (dd, J = 12.0, 5.0 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 168.8, 136.7, 134.1, 131.7, 128.7, 128.1, 127.8, 123.3, 62.2, 57.4. ESI-MS: m/z = 268 [M + H]⁺. Anal. Calcd for C₁₆H₁₃NO₃: C, 71.90; H, 4.90. Found: C, 72.10; H, 4.85.