Ethyl 2-(3-Methyl-5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepin-2-ylamino)benzoate

Abstract

A simple route for synthesis of ethyl 2-(3-methyl-5-oxo-4,5-dihydro-3H-benzo[e][1,4]diazepin-2-ylamino)benzoate is developed. The present work involves condensation of 2-(2-nitrobenzamido)propanoic acid with ethyl anthranillate followed by the H₂/Pd/C reduction to give the amino ester which upon heating in DMF in the presence of FeCl₃ affords the title compound. The structure of the title compound was established on the basis of ¹H-NMR, ¹³C-NMR and mass spectral data.

Introduction

The growing importance of substituted [1,4]benzodiazepines in the field of medicinal chemistry as potential chemotherapeutic agents have incited the organic synthetic community to devise efficient methodologies to construct these bicyclic hetero-compounds [1,2,3,4,5].

Little attention has been devoted to the structural perturbations caused by substitution at C-2 position in 1,4-diazepines possessing an imine bond (N1-C2) [6]. This fact, coupled with continuation of our work on the cyclization modes of tripeptide containing two units of anthranilic acid and an amino acid, prompted us to devise an efficient method of synthesis for benzo[e][1,4]diazepinone using transition metals [7,8,9]. The synthetic procedure described here can be protracted to prepare a wide range of derivatives for further biological evaluation.

Results and Discussion

(S)-2-(2-Nitrobenzamido)propanoic acid 1 [10] was coupled with ethyl 2-aminobenzoate using a standard procedure to afford 2 in good yield (70%, Scheme 1). The reduction of the nitro group was conducted under mild conditions (H₂/Pd/(C)) to furnish the corresponding amine 3. The ¹H-NMR spectrum of 3 indicated the presence of NH₂ group by displaying a broad D₂O exchangeable signal at δ 5.45. Furthermore, the methine proton was observed as doublet of quartet at δ 4.73, the ethyl group protons were observed as triplet and quartet at δ 1.31, 4.29, respectively.

The synthesis of the title compound 4 was accomplished by heating amine 3 in DMF at 110 °C in the presence of fused transition metal chlorides. Three transition metal chlorides (MgCl₂, ZnCl₂ and FeCl₃) were implemented. The cyclization of amine 3 was best achieved using fused FeCl₃ to afford the title benzodiazepinone compound in 75% yield.

The ¹H-NMR spectrum of the title compound displayed the methine proton attached to the stereogenic center at δ 4.23 as quartet. Moreover, and a doublet signal representing the methyl group next to stereogenic carbon was observed at 1.82 ppm. The ¹³C-NMR spectrum displayed a signal at 21.9 ppm for the methyl carbon next to the stereogenic center. The mass spectrum of 4 showed the M⁺ peak at m/z 337.9 attributed to the molecular formula C₁₉N₃O₃H₁₉ (M+H⁺).

Experimental

Amine 3 (400 mg, 1.13 mmol) was dissolved in DMF (30 mL) containing fused FeCl₃ (543.08 mg, 3.39 mmol). The resulting mixture was then heated with continuous stirring in oil bath for 24 h at 110 °C. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and then extraction with 40% EtoAc/hexane (2 × 100 mL). The combined organic layer was dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate in hexane to give the title compound 4 (285 mg, 75% yield) as a pale yellow oil. ¹H-NMR (400 MHz, CDCl₃): δ 1.28 (t, J = 7.1 Hz, 3H), 1.82 (d, J = 7.2 Hz, 3H) 4.23 (q, J = 7.0 Hz, 1H) 5.65 (q, J = 7.2 Hz, 2H) 7.05 (t, J = 4 Hz, 1H), 7.45 (m, 2H), 7.70 (m, 2H), 7.95 d, J = 5 Hz, 1H), 8.19 (s, 1H), 8.45 (m, 2H), 8.60 (d, J = 3 Hz, 1H), 11.5 (s, 1H); ¹³C-NMR (100 MHz, CDCl₃): δ 19.0, 21.9, 34.8, 58.7, 120.7, 125.3, 128.0, 131.9, 132.1, 132.4, 135.7, 139.3, 139.4, 145.6, 149.0, 152.6, 165.7, 173.0; ESI-MS m/z 337.9 (M⁺); Anal Calcd. for C₁₉H₁₉N₃O₃: C, 67.64; H, 5.68; N, 12.46; O, 14.23. Found: C, 67.69; H, 5.63; N, 12.52.