N,N'-1,2-Phenylenebis[4-(chloromethyl)benzamide]

Abstract

N,N'-1,2-Phenylenebis[4-(chloromethyl)benzamide] (3) was obtained in 61% yield by nucleophilic acyl substitution of 4-(chloromethyl)benzoyl chloride (2) with 1,2-phenylenediamine (1) under basic conditions. The title compound was characterized by FT-IR, ¹H NMR, ¹³C NMR, low- and high-resolution EI-MS, and melting point.

Substituted benzamides have been in clinical use for many years as anti-emetics, anti-arrhythmics, neuroleptics, and/or anti-psychotics in the treatment of various disorders [1]. They also constitute versatile intermediates for the synthesis of anti-tumor and anti-inflammatory agents [2], protease inhibitors [3], dyes [4], and have been extensively used as sensitizers for radio- or chemotherapies [5]. On the other hand, benzyl chloride derivatives are widely used as synthetic building blocks. They constitute, for instance, the precursors to benzyl esters, which are commonly employed in industry as plasticizers, flavorants, and perfumes [6]. Hence, organic molecules bearing both functionalities may be of practical interest.

We report here the synthesis of N,N'-1,2-phenylenebis[4-(chloromethyl)benzamide] (3) by nucleophilic acyl substitution of 4-(chloromethyl)benzoyl chloride (2) with 1,2-phenylenediamine (1) in the presence of Et₃N (Scheme 1) [7].

Experimental Section

General

¹H and ¹³C NMR spectra were recorded at 25 °C on a Bruker 400 spectrometer in DMSO-d₆ as solvent, and chemical shifts are reported relative to residual solvent peaks [8]. The low-resolution mass spectrum was obtained using a Varian MAT 311A spectrometer. The infrared spectrum was recorded using a Diamond ATR (attenuated total reflection) accessory (Golden Gate) on a Bio-Rad Excalibur FTS 3000 MX spectrophotometer. The melting point (mp) was measured in an Opti Melt MPA 100 instrument and is uncorrected. Thin-layer chromatography was carried out on Merck aluminium sheets coated with silica gel 60 F₂₅₄. Compounds were visualized by use of 254 nm UV light and/or phosphomolybdic acid 20% (wt.) solution in ethanol with heating. All solvents were of p.a. grade or were purified by standard techniques [9]. Anhydrous sodium sulfate was used for drying solutions. 1,2-Phenylenediamine (1) and 4-(chloromethyl)benzoyl chloride (2) were purchased from commercial suppliers and used as received without further purification.

Synthesis of N,N'-1,2-phenylenebis[4-(chloromethyl)benzamide] (3)

To a stirred solution of 1,2-phenylenediamine (1) (500 mg, 4.55 mmol) and Et₃N (1.59 mL, 11.4 mmol) in CH₂Cl₂ (20 mL) kept at 0 °C was added dropwise (using a pressure-compensated addition funnel) a solution of 4-(chloromethyl)benzoyl chloride (2) (1.75 g, 9.09 mmol) in CH₂Cl₂ (20 mL). The reaction mixture was allowed to stir for 5 h at room temperature, after which time TLC analysis showed full conversion of the starting materials. The organic phase was washed with H₂O (15 mL × 2) and brine (15 mL × 2), dried (Na₂SO₄), filtered, and concentrated. The solid residue was recrystallized from CH₂Cl₂/pentane, affording product 3 (1.1 g, 61% yield [10]) as a white crystalline solid: TLC R_f (AcOEt/hexane 1:1) 0.40; mp = 191–193 °C; ¹H NMR (400 MHz, DMSO-d₆) δ/ppm = 4.83 (s, 4H), 7.31 (dd, J = 6.0, 3.6 Hz, 2H), 7.59 (d, J = 8.4 Hz, 4H), 7.67 (dd, J = 6.0, 3.6 Hz, 2H), 7.96 (d, J = 8.4 Hz, 4H), 10.08 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ/ppm = 45.23 (2C), 125.51 (2C), 125.80 (2C), 127.81 (4C), 128.83 (4C), 131.19 (2C), 133.97 (2C), 141.22 (2C), 164.92 (2C); FT-IR (ATR) ν_max (cm⁻¹) 3287 (N-H stretching), 1644 (C=O stretching, amide I band), 1514 (N-H bending, amide II band), 1305, 1267 (C-H stretching, CH₂Cl), 672, 476; MS (ESI) m/z 412 [M⁺]. HRMS calculated for C₂₂H₁₈Cl₂N₂O₂ 412.07453; found 412.07426.