Synthesis of Fluorinated 2-Benzylphthalazin-1(2H)-one, 1-Phthalazinamine, and 1-Alkoxy/Benzyloxyphthalazine Derivatives by an Ultrasonication Method

Abstract

Fluorinated heterocyclic compounds have been proven to exhibit interesting potential biological activities. Therefore, various fluorinated 2-benzylphthalazine-1(2H)-one and phthalazine-1-amine derivatives and nonfluorinated 1-alkoxy/benzyloxyphthalazines derivatives have been synthesized by an ultrasonication method. This protocol is more efficient than the conventional method in terms of its product yield and reaction handling and timelines.

Key words

ultrasound - sonochemistry - fluorinated heterocycles - benzylphthalazinones - phthalazinamines - phthalazines

Publication History

Received: 17 February 2022

Accepted after revision: 08 May 2022

Accepted Manuscript online:
08 May 2022

Article published online:
09 June 2022

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• 31 4-(4-Chlorobenzyl)-2-[4-(trifluoromethoxy)benzyl]phthalazin-1(2H)-one (3a): Typical Procedure A mixture of 4-(4-chlorobenzyl)phthalazin-1(2H)-one (1; 0.37 mmol, 1.0 equiv), 4-(trifluoromethoxy)benzyl bromide (2a; 0.5 mmol, 1.5 equiv), Cs₂CO₃ (0.74 mmol, 2.0 equiv), and KI (0.1 equiv) in MeCN (3 mL) was stirred at RT for 60–90 min in a laboratory ultrasonic bath (LABMAN Digital Ultrasonic Cleaner LMUC-6; 40 kHz ultrasound). The bath temperature was maintained by adding cold water from time to time when the temperature exceeded 28 °C. When the reaction was complete (TLC), the solvent was removed under a low vacuum and the solid residue was washed with H₂O. The product was extracted with CH₂Cl₂ and the extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, EtOAc–hexane) to give a pale yellow solid; yield: 78%; mp 110–112 °C. IR (ATR): 2926, 2853, 1666, 1649, 1490, 1278, 1154, 1099, 1017, 749 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.52–8.28 (m, 1 H), 7.84–7.63 (m, 3 H), 7.50 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 9.2 Hz, 2 H), 7.16 (dd, J = 8.1, 2.8 Hz, 4 H), 5.39 (s, 2 H), 4.25 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.2, 148.8, 145.1, 136.1, 135.7, 133.1, 132.7, 131.4, 130.3 (2 C), 129.8 (2 C), 129.1, 128.8 (2 C), 128.4, 127.5, 124.9, 121.7, 121.0, 120.5 (q, J = 257.1 Hz), 53.8, 38.2. ¹⁹F NMR (377 MHz, CDCl₃): δ = –57.68. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₁₇ClF₃N₂O₂: 445.0931; found: 445.0932.