Highly Diastereoselective NHC-Catalyzed [4+3] Annulation of Enals, Alde­hydes and N-Phenyl Urea/Thiourea for the Synthesis of Monocyclic trans-1,3-Diazepanes

Abstract

N-Heterocyclic carbene catalyzed synthesis of 1,3-diazepanes from α,β-unsaturated aldehydes, N-phenyl urea/thiourea and aromatic aldehydes has been developed. The reactive Breslow intermediate, formed by reaction of the enal with the NHC, attacks as a d³ nucleophile at the 1-arylidene-3-arylurea derivative, which is produced by simple reaction of N-phenyl urea/thiourea with an aromatic aldehyde. The resulting intermediate, on subsequent heterocyclization, forms the product with high yield. The reaction proceeded smoothly with high atom economy, producing a new C–C and a new C–N bond in a one-pot operation.

Key words

N-heterocyclic carbene - diastereoselective - 1,3-diazepane - multicomponent - one-pot reaction

• References and Notes

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• 13 Synthesis of 1,3-Diazepanes 5a–j; General Procedure: A flame-dried round-bottom flask was charged with imidazolium salt 4b (0.034 g, 0.1 mmol, 10 mol%), α,β-unsaturated aldehyde (1 mmol) and CH₂Cl₂ (4 mL) under a positive pressure of nitrogen, followed by addition of DBU (0.0152 g, 0.1 mmol, 10 mol%) by using a syringe, and the resulting orange solution was stirred for 30 min at room temperature. To this solution, aromatic aldehyde (1.0 mmol) and N-phenyl urea/thiourea (1.0 mmol) was added by using a syringe and the reaction mixture was stirred for a further 2.5 h (completion of reaction was confirmed by TLC analysis). Subsequently, water (5 mL) was added and the reaction mixture was extracted with EtOAc. The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography (silica gel; Merck, 60–120 mesh; EtOAc–hexane, 3:22) to afford the pure product. 6-(4-Methoxyphenyl)-7-(4-nitrophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5b);Yellow solid; mp 227–229 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.44 (dd, J _5Ha–5Hb = 14.4, J _5Ha–6H = 10.4 Hz, 1 H), 2.69 (dd, J _5Hb–5Ha = 14.4, J _5Hb–6H = 2.4 Hz, 1 H), 3.73 (s, 3 H), 4.05 (ddd, J _6H-5Ha = 10.4, J _6H-7H = 9.4, J _6H-5Hb = 2.4 Hz, 1 H), 5.30 (dd, J _7H-6H = 9.4, J _7H-NH = 2.1 Hz, 1 H), 6.36 (d, J _NH-7H = 2.1 Hz, 1 H), 6.69–7.02 (m, 4 H), 7.09–7.64 (m, 5 H), 7.38–8.14 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.8, 157.9, 155.4, 146.4, 145.5, 140.9, 135.7, 129.9, 129.0, 127.2, 124.7, 121.8, 121.3, 114.0, 57.6, 55.9, 40.5, 37.4. MS: m/z = 431.15 [M⁺]. Anal. Calcd for C₂₄H₂₁N₃O₅: C, 66.81; H, 4.91; N, 9.74. Found: C, 66.86; H, 4.87; N, 9.79. 6,7-Bis(4-nitrophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5d): Yellow solid; mp 231–233 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.78 (dd, J _5Ha-5Hb = 14.4, J _5Ha-6H =10.3 Hz, 1 H), 3.09 (dd, J _5Hb-5Ha = 14.4, J _5Hb-6H =2.3 Hz, 1 H), 4.35 (ddd, J _6H-5Ha = 10.3, J _6H-7H = 9.4, J _6H-5Hb = 2.3 Hz, 1 H), 5.63 (dd, J _7H-6H = 9.4, J _7H-NH = 2.3 Hz, 1 H), 6.76 (d, J _NH-7H = 2.3 Hz, 1 H), 7.09–7.78 (m, 5 H), 7.39–8.12 (m, 4 H), 7.45–8.24 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.4, 156.7, 154.6, 146.9, 146.2, 145.3, 135.9, 130.2, 129.4, 127.6, 124.6, 122.5, 121.8, 120.3, 58.3, 40.7, 38.5. MS: m/z = 446.12 [M⁺]. Anal. Calcd for C₂₃H₁₈N₄O₆:C, 61.88; H, 4.06; N, 12.55. Found: C, 61.83; H, 4.10; N, 12.49. 6,7-Bis(4-bromophenyl)-3-phenyl-1,3-diazepane-2,4-dione (5e): Yellow solid; mp 246–248 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.73 (dd, J _5Ha-5Hb = 14.4, J _5Ha-6H = 10.3 Hz, 1 H), 2.85 (dd, J _5Hb-5Ha = 14.4, J _5Hb-6H = 2.3 Hz, 1 H), 4.17 (ddd, J _6H-5Ha = 10.3, J _6H-7H = 9.3, J _6H-5Hb = 2.3 Hz, 1 H), 5.35 (dd, J _7H-6H = 9.3, J _7H-NH = 2.3 Hz, 1 H), 6.12 (d, J _NH-7H = 2.3 Hz, 1 H), 7.02–7.60 (m, 5 H), 7.05–7.40 (m, 4 H), 7.12–7.44 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 155.3, 147.2, 136.4, 135.8, 135.3, 131.6, 129.9, 129.0, 128.7, 128.1, 124.9, 121.5, 120.6, 57.6, 39.3, 36.5, 24.3. MS: m/z = 511.97 [M⁺]. Anal. Calcd for C₂₃H₁₈Br₂N₂O₂: C, 53.72; H, 3.53; N, 5.45. Found: C, 53.76; H, 3.59; N, 5.50.