CuI/l-Proline-Catalyzed Intramolecular Aryl Amination: An Efficient Route for the Synthesis of 1,4-Benzodiazepinones

Abstract

An effective protocol for the synthesis of potentially bioactive benzo[e]chromeno[6,5-b][1,4]diazepine-3,8(7H,13H)-dione and dibenzo[b,e][1,4]diazepin-11(10H)-one derivatives in good to excellent yields has been achieved by CuI/l-Proline catalyzed coupling reaction as the key step. The methodology offers clean reaction conditions and easy isolation of the products in 61-92% yields.

Key words

CuI - l-proline - 1,4-benzodiazepinones - intramolecular cyclization

References and Notes

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22

Procedure for the Synthesis of Compound 8a
To a solution of the compound 6a (160 mg, 0.50 mmol) in DMSO (5 mL), CuI (9.5 mg, 0.05 mmol), l-proline (12 mg, 0.1 mmol), and Cs₂CO₃ (325.8 mg, 1 mmol) were added. The reaction mixture was stirred at 120 ˚C for 8 h. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with CH₂Cl₂ (3 × 15 mL) and washed with H₂O (3 × 15 mL). The combined organic layer was filtered and dried over Na₂SO₄. The solvent was distilled off, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using PE and EtOAc (4:1) as eluent to give a white solid product 8a. Analytical Data of Compound 8a
Yield 72%, solid; mp 156-158 ˚C. IR (KBr): ν_max = 1609, 3328 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.28 (s, 3 H), 3.51 (s, 3 H), 5.27 (s, 1 H), 6.72 (s, 1 H), 6.77 (d, 1 H, J = 7.6 Hz), 6.91 (s, 1 H), 7.01-7.07 (m, 2 H), 7.29 (d, 1 H, J = 8.8 Hz), 7.87 (d, 1 H, J = 7.6 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 20.61, 38.06, 118.39, 120.73, 122.59, 123.04, 124.85, 124.97, 132.45, 132.90, 135.76, 143.01, 150.60, 168.57. HRMS: m/z calcd for C₁₅H₁₄N₂O [M⁺ + Na]: 261.1004; found: 261.1029.

23

Procedure for the Synthesis of Compound 8e To a solution of the compound 7f (0.50 mmol) in DMSO-H₂O (4:1; 5 mL), CuI (0.05 mmol), l-proline (0.1 mmol), and DABCO (3 mmol) were added. The reaction mixture was stirred at 120 ˚C for 9 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with CH₂Cl₂ (3 × 15 mL) and washed with H₂O (3 × 15 mL). The combined organic layer was filtered and dried over Na₂SO₄. The solvent was distilled off, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using PE and EtOAc (1:1) as eluent to give a white solid product 8e.
Analytical Data of Compound 8e Yield 88%, white solid; mp 240-242 ˚C. IR (KBr): ν_max = 1162, 1600, 1644, 1659 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.35 (t, 3 H, J = 6.4 Hz), 2.43 (s, 3 H), 3.28 (q, 1 H, J = 6.4 Hz), 3.46 (q, 1 H, J = 6.8 Hz), 3.71 (s, 3 H), 6.90 (d, 1 H, J = 10.0 Hz), 7.24 (s, 2 H), 7.35-7.50 (m, 5 H), 7.56-7.61 (m, 2 H), 7.78 (d, 1 H, J = 7.6 Hz), 8.42 (d, 1 H, J = 9.6 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.14, 21.65, 29.79, 45.92, 115.58, 120.57, 123.65, 124.12, 127.39, 128.90, 129.29, 129.84, 132.22, 132.56, 132.83, 134.77, 135.74, 136.41, 138.52, 141.10, 144.42, 161.54, 165.17. HRMS: m/z calcd for C₂₆H₂₃N₃O₄S [M⁺ + Na]: 496.1307; found: 496.1311.