An Efficient Protocol for the Synthesis of Pyrazolo[1,5-c]quinazolines by a Staudinger–Aza-Wittig–Dehydroaromatization Sequence

Abstract

The one-pot synthesis of azide-substituted dihydropyrazoles in isopropanol was performed by using chalcones, hydrazine hydrate, and an acyl chloride at 0 ℃. Subsequent Staudinger–aza-Wittig–dehydroaromatization reactions of the products with methyl(diphenyl)phosphine were also investigated for further application in the construction of pyrazolo[1,5-c]quinazolines.

Key words

azidodihydropyrazoles - aza-Wittig reaction - Staudinger reaction - cascade reaction - dehydroaromatization - pyrazoloquinazolines

• References and Notes

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• 23 1-Acyl-5-(2-azidophenyl)-4,5-dihydropyrazoles 4a–p: General Procedure Hydrazine hydrate (2; 3 mmol) was added to a stirred solution of the appropriate azidochalcone 1 (3 mmol) in i-PrOH (10 mL) at 0 °C, and the mixture was vigorously stirred until the reaction was complete (TLC). Acyl chloride 3 (3.3 mmol) was then added dropwise and the mixture was allowed to warm to r.t. The precipitated solid was collected, washed with EtOH, and crystallized from CH₂Cl₂–PE. 5-(2-Azidophenyl)-1-(4-chlorobenzoyl)-3-phenyl-4,5-dihydro-1H-pyrazole (4a) White crystals; yield: 1095 mg (91%); mp 164–165 ℃. IR (KBr): 3387, 2927, 2858, 2129, 1639, 1597, 1489, 1423, 1284, 1087, 748 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 8.4 Hz, 2 H, Ar-H), 7.70–7.68 (m, 2 H, Ar-H), 7.44–7.39 (m, 5 H, Ar-H), 7.34–7.30 (m, 1 H, Ar-H), 7.22–7.17 (m, 2 H, Ar-H), 7.11–7.07 (m, 1 H, Ar-H), 5.98 (q, J = 5.6 Hz, 1 H, Ar-CH), 3.79 (dd, J₁ = 11.6, J₂ = 17.6 Hz, 1 H, CH), 3.08 (dd, J₁ = 5.6, J₂ = 17.6 Hz, 1 H, CH). ¹³C NMR (100 MHz, CDCl₃): δ = 165.1, 155.4, 137.2, 136.7, 132.5, 132.0, 131.7, 131.1, 130.5, 128.9, 128.7, 127.9, 126.7, 126.2, 125.2, 118.6, 57.2, 40.8. LC-MS: m/z = 401. Anal. Calcd for C₂₂H₁₆ClN₅O: C, 65.76; H, 4.01; N, 17.43. Found: C, 65.79; H, 4.05; N, 17.40.
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• 25 Pyrazolo[1,5-c]quinazolines 8; General Procedure A solution of methyl(diphenyl)phosphine (0.20 g, 1 mmol) in toluene (5 mL) was added dropwise to a stirred solution of the appropriate 1-acyl-5-(2-azidophenyl)-4,5-dihydropyrazole 4 (1 mmol) in toluene (5 mL) at r.t. The mixture was stirred at r.t. for 2 h and then refluxed for 1–6 h until the reaction was complete (TLC). The solvent was then removed under reduced pressure, and the residue was crystallized from CH₂Cl₂–PE. 2-(4-Chlorophenyl)-5-phenylpyrazolo[1,5-c]quinazoline (8a) White crystals; yield: 305 mg (86%); mp 171–172 ℃. IR (KBr): 3431, 1618, 1610, 1490, 1436, 1402, 1367, 1282, 1180, 1091, 943, 825, 746, 682, 597, 557 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.56–8.54 (m, 2 H, Ar-H), 8.10–7.99 (m, 4 H, Ar-H), 7.70–7.41 (m, 7 H, Ar-H), 7.36 (s, 1 H, Ar-H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.8, 146.3, 141.9, 139.9, 137.1, 132.3, 132.1, 131.2, 129.9, 129.2, 128.8, 128.7, 128.4, 127.8, 126.8, 123.0, 119.5, 95.3. LC-MS: m/z = 355. Anal. Calcd for C₂₂H₁₄ClN₃: C, 74.26; H, 3.97; N, 11.81. Found: C, 74.29; H, 3.91; N, 11.88.