A new and efficient synthesis of unsaturated benzoxazepines using sodium metabisulfite and potassium permanganate as oxidative reagents

A mild oxidation of 1,2,3,5,6,11b-hexahydroimidazo[1,2-d ][1,4]benzoxazepines using KMnO 4 in DMF at room temperature produces a mixture of unsaturated and partially unsaturated [1,4]benzoxazepines in very good yields. Condensation of 2-(2-bromoethoxy)benzaldehydes with either o-phenylenediamine or ethylenediamine in the presence of oxidative reagents such as sodium metabisulfite in acetonitrile at reflux temperature produces a series of [1,4]benzoxazepines


Results and Discussion
Recently, we reported new and a convenient synthetic methods for synthesis of [1,4]benzoxazepines. 22,23 In continuation of our research program regarding the synthesis of biologically active nitrogen heterocycles, herein we describe development of new and straightforward approaches for preparation of 5,6dihydroimidazobenzoxazepines 20-26 and 6,7-dihydrobenzo[f]benzimidazoloxazepines 35-39, in good yields (Figure 2).The synthetic pathway for preparation of targeted compounds 20-26, is shown in Scheme 1.It starts from the condensation of 2-(2-bromoethoxy)benzaldehydes 6-12 with ethylene diamine in the presence of anhydrous K 2 CO 3 and acetonitrile at reflux temperature to give the corresponding saturated oxazepines 13-19. 22,23In addition to its 1 H, 13 C NMR and mass spectra, the structure of compound 16 was confirmed by X-ray analysis as shown in Figure 3. Oxidation of 13-19 with potassium permanganate in DMF at room temperature produced the targeted unsaturated benzoxazepines 20-26 in addition to the partially unsaturated benzoxazepines 27-33 in very good yields.Several experimental trials were carried out such as increasing the equivalents of KMnO 4 and/or increasing the reaction temperature to 65 o C in attempts to produce only unsaturated oxazepines 20-26, failed.The unsaturated oxazepine 40 (where X = Y = H) was not detected in the crude products.The compounds 20-26 and 27-33 were characterized by 1 H, 13 C NMR and high resolution mass spectroscopy.The mass spectra of prepared compounds displayed the correct molecular ion peaks for which the measured high resolution (HRMS) data were in good agreement with the calculated values.Spectral data, detailed in the experimental part, are consistent with the suggested structures.The structures of compounds 27-33 were confirmed by disappearance of CHNN and the secondary amine proton signals that usually show up as a sharp singlet and broad signals at around δ = 5 and 2.4 ppm, respectively, in their corresponding saturated oxazepines 13-19.Additionally, structure of compound 29 was confirmed by X-ray analysis as shown in Figure 4.
In a similar manner, several experimental trials were carried out to condense 2-(2bromoethoxy)benzaldehyde 6 with ortho-phenylenediamine as an example, failed and only a complex inseparable mixture of products was formed.Usually, one of the methods that is used in preparation of 2arylbenzimidazoles is the condensation of ortho-phenylenediamines with aldehydes in the presence of oxidative reagents such as sodium metabisulfite. 24Accordingly, when K 2 CO 3 was replaced with sodium metabisulfite, compound 35 was formed straightforwardly and as a unique product in a one-pot process.We believe that the condensation of phenylenediamine with aldehyde 6 under oxidative condition generates first the benzimidazole core followed by intramolecular nucleophilic substitution between nitrogen of the benzimidazole ring and 2-(2-bromoethoxy) unit.Using this strategy, a series of 6,7-dihydrobenzo[f]-4,5imidazo[1,2-d] [1,4]oxazepines 35-39 were prepared in easily and in good yields (Scheme 2). 1 H NMR spectra of compounds 35-39 in CDCl 3 show two multiplets centered at about 4.5 and 4.6 ppm corresponding to the two methylene protons of the benzoxazepine ring.Their 13 C NMR spectra in CDCl 3 , displayed two signals at about 47 and 69 ppm which also corresponding to the carbon atoms of the oxazepine ring.Additionally, the structure of compound 36 was confirmed by X-ray analysis as shown in Figure 5. Inspired by these results, we turned our attention again to the condensation of aldehydes 6 and 8, as examples, with ethylenediamine in the presence of sodium metabisulfite.Indeed, when aldehydes 6 or 8 were condensed with ethylenediamine in the presence of sodium metabisulfite in acetonitrile at reflux temperature, products whose physical and spectroscopic properties (mp, NMR and HRMS) were identical to those of 27 and 29, in yields of 52% and 49% respectively, were obtained.The seven-memebered ring is nonplanar in the three compounds (16, 29 and 36).The mean deviations of the atoms (N1, C2, C6, C7, O8, C9 and C10) from the average plane are 0.2654 Å, 0.1470 Å 0.1757Å, for 16, 29 and 36, respectively.The degree of non-planarity is the highest in 16 and due to that, the five-membered ring is nonplanar, whereas it is planar in 29 and 36.The average deviation of the atoms N1, C2, N3, C4 and C5 are 0.1584 Å , 0.0029 Å and 0.0386 Å for 16, 29 and 36, respectively.This is due to the fact that C2 is sp 2 hybridized in 29 and 36 while it is sp 3

Experimental Section
General.Silica gel 60 for column chromatography was obtained from Fluka.The progress of reactions was monitored by means of thin-layer chromatography (TLC), carried out on TLC sheets that were visualized under UV light (where appropriate).On the other hand, preparative thick layer (0.25 mm) chromatography was performed on silica gel glass plates (60 F-254, 20 cm × 20 cm, Fluka).Melting points were determined on a Stuart scientific melting point apparatus in open capillary tubes and are uncorrected. 1H NMR and 13 C NMR spectra were recorded on a 500 MHz spectrometer (Bruker DPX-500) with TMS as the internal standard.Chemical shifts expressed in (δ) are given in ppm, whereas J-values for 1 H-1 H coupling constants are given in Hertz.High-resolution mass spectra (HRMS) were obtained (in positive/or negative ion mode) using electron spray ion trap (ESI) technique with a Bruker APEX-4 (7 Tesla) instrument.Samples were dissolved in acetonitrile, diluted in spray solution (methanol/water 1:1 v/v + 0.1% formic acid), and infused using a syringe pump with a flow rate of 2 µL/min.External calibration was conducted using arginine cluster in a mass range m/z 175-871.2-(2-Bromoethoxy)benzaldehydes 6-12 and benzoxazepines 13, 18, 19 were prepared according to the literature. 22,23Benzoxazepines 14-17 were prepared as 13, 18 and 19. 22Their physical properties and spectroscopic analyses were as follows:

General Procedure for the Preparation of [1,4]Benzoxazepines (20-26) and (27-33).
In a 20 mL one-necked round-bottom flask equipped with a magnetic stirrer bar, saturated benzoxazepine 13-19 (1 mmol) was dissolved in DMF (5 mL).To this well-stirred solution at rt, KMnO 4 (2 mmol) was added gradually.The reaction mixture was left stirring at rt for 24h.The reaction mixture was diluted with CHCl 3 (20 ml) and filtered.The filtrate was washed with 10 mL of saturated aq NaCl and then with 10 mL of H 2 O.After drying and evaporating the solvent, the crude product was purified as indicated for individual reaction.

Crystal structure determination
The crystal structures of compounds 16, 29 and 36 were determined at rt using an 'Xcalibur, Eos' diffractometer (Mo Kα radiation, λ = 0.7107 Å).Data were acquired and processed to give hkl files using CrysAlisPro software. 26A preliminary solution of the structures was obtained using the Olex2 program, then, the structure solutions were refined and finalized using the SHELXTL program package. 27Atoms other than hydrogen were refined anisotropically.Hydrogen atoms were placed in the calculated positions using a riding model.Summary of data collection parameters and refinement results are given in Supplementary Material.The CIF files of compounds 16, 29 and 36 were deposited in Cambridge Crystallographic Data Center.Their CCDC are 1897620, 1897621 and 1897622, repectively.

Figure 1 .
Figure 1.Structures of some benzoxazepines and similar structures that have potent activity against P13Kα and NIK.
. The Br…N distances are 3.374 Å and 3.392 Å for 29 and 36, which are around the sum of van der Waals radii (3.4Å).Also, the C-H…N angles are 158.0and 158.2 which are in suitable arrangement for halogen bonding interactions.25