Ring Rearrangements and Reactivity of 3-((4-oxo-4H-chromen-3- yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one Towards Some Nucleophiles

Condensation of 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) with 3formylchromone (2) afforded a mixture of 3-(chromenylmethylene)[1,5]benzodiazepinone 3 and 14-chromenylbenzodiazepino[2,3:6,5]pyrano[2,3b]benzodiazepine 4. Ring rearrangements of compound 3 with different nucleophilic reagents, such as; potassium hydroxide and/or ammonium acetate led to rearrangement into pyranobenzodiazepine 5 and pyridobenzodiazepine 6, respectively. Treatment of compound 3 with hydrazine hydrate, hydroxylamine hydrochloride, malononitrile, cyanothioacetamide, 2-cyano-3,3-disufanylacrylonitrile, and/or 2-cyano-3-phenylamino-3sufanylacrylonitrile, have been carried out at different conditions, leading to versatile heterocyclic substituted benzodiazepines at position 3, viz; pyrazole 8, isoxazole 9, pyridines 10 and 11, 1,3-dithiine 12, and 1,3-thiazine 13 derivatives.


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Similarly, when compound 3 was subjected to react with cyanothioacetamide, in presence of sodium ethoxide, chromone ring-opening and a consequent pyridine ringclosure took place. This ring transformation led to 3-(2-thioxopyridin-5-yl)methylene) benzodiazepin-2-one 11, in 78 % yield (Scheme 5). The reaction mechanism may proceed via first nucleophilic addition of carbanion of cyanothioacetamide, at the α-carbon of chromone, leading to ring-opening. Thence, nucleophilic addition of NH2 and elimination of water molecule took place, resulting in pyridinethione ring-closure. The product gave a violet color against ferric chloride color test, indicating the presence of phenolic OH function. Elemental analysis revealed presence of sulfur in the product. IR spectrum showed bands corresponding to O-H, N-H and C≡N groups at ν 3436, 3344-3280 and 2156 cm -1 , respectively. 1 H NMR spectrum showed two singlet signals corresponding to methylenic and γ-proton of pyridone at δ 6.90 and 8.14, respectively. Furthermore, inspection of the 1 H NMR spectrum using deuterium oxide showed that there are three deuterium exchangeable protons appeared as broad singlets at δ 8.55, 10.60, and 13.18.
The first two are back to the ring N-H of both pyridinethione and diazepinone while the last one is attributed to the phenolic O-H.
Ketene S,S-and N,S-acetals had attracted an exceptional concern due to their synthetic role in preparation of a versatile heterocyclic compounds [28][29][30]. Hence, multicomponent reaction (MCR) including compound 3 and a mixture of carbon disulfide and malononitrile or phenyl isothiocyanate and malononitrile was investigated. The reaction was carried out under phase transfer catalysis conditions (PTC), using potassium carbonate as base catalyst and tetrabutylammonium bromide (TBAB) as PTC-agent.
Surprisingly, the reaction in both cases afforded a mixture of pyrano[b]benzodiazepine 5 and 2-(4-benzodiazepinyl-1,3-dithiinylidene)malononitrile 12 or 2-(4-benzodiazepinyl-1,3-thiazinylidene)malononitrile 13, in 30-38 % yields (Scheme 5). Formation of compound 5 as the main product, in 45-55 % yields, can be attributed to effect of base catalyst (K2CO3) which is mandatory used during this reaction. It is well known that chromone ring can be easily opened under this conditions which is also enough for annulation of pyrano[b]benzodiazepine ring. Elemental analyses of both products 12 and 13 revealed the presence of sulfur element. Also both of them gave violet coloration against ferric chloride color test. IR spectra of these two compounds exhibited vibrational bands at ν 2205 cm -1 , characteristic for C≡N function in addition to strong stretching vibration at ν 1660-1669 and 1645-1635 cm -1 due to C=O functions of benzoyl and diazepinone moieties, respectively. 1 H NMR spectrum of dithiine derivative 12 demonstrated two chemical shifts due to dithiine ring hydrogens appeared as singlet peaks at δ 3.80 and 6.80 in addition to three deuterium exchangeable protons appeared as broad singlets at δ 8.92, 10.60, and 13.14 due to two N-H of diazepinone and O-H of salicyloyl moiety. Similar evidences were observed in spectra and analysis of compound 13. Furthermore 13 C NMR of compound 13 revealed the presence of two chemical shifts at δ 190 and 188 due to two sp carbons of C≡N functions and two signals at δ 183 and 180 due two sp 2 carbons of C=O functions. Elemental microanalyses for C, H, and N-elements (within ± 0.4 %) of both compounds 12 and 13, are satisfactorily in good accordance with the calculated formula.

Experimental Section
General 9 All melting points were determined on a Koffler melting points apparatus and are uncorrected. IR spectra were obtained on a Nicolet 710 FT-IR spectrometer. 1 H NMR spectra, at 400 MHz, and 13 C NMR spectra, at 100 MHz, were recorded on a Bruker Avance III-400 MHz instrument, using DMSO-d6 as solvent. The mass spectra were scanned on a Varian Mat CH-7 instrument at 70 eV. Elemental microanalyses were performed on a Perkin-Elmer CHN-2400 elemental analyzer. All compounds were checked for their purity on TLC plates. Starting materials; 4-phenyl-1H- [1,5]benzodiazepin-2(3H)-one (1) [22] and 3-formylchromone (2) [23] were prepared as described in the literature.

Formylchromone (2)
A mixture of benzodiazepinone 1 (2.36 g, 10 mmol), 3-formylchromone 2 (1.74 g, 10 mmol), and freshly fused sodium acetate (3 g, 36 mmol), in glacial acetic acid (50 mL) was heated under reflux 4 h. The reaction mixture was left to cool to room temperature, and then poured onto crushed-ice. The solid so formed was filtered, washed with cold water, and dried. This crude solid material was boiled in absolute ethanol (50 mL) for 15 min. and filtered off insoluble residue. The filtered solid was washed thoroughly several times with hot ethanol (ca. 50 mL) and crystallized from glacial acetic acid to give compound 3. The collected ethanol filtrate was concentrated to about one-fourth of its volume (ca. 25 mL) and left to stand at room temperature over-night to give crystalline needle-like deposits which were collected by filtration to afford compound 4.

General Procedure for Preparation of 3-(Diazolylmethyl-ene)benzodiazepinones 8 and 9
A mixture of compound 3 (0.78 g, 2 mmol) and hydrazine hydrate (0.1 mL, 2 mmol) or hydroxylamine hydrochloride (0.14 g, 2 mmol) was heated under reflux, in glacial acetic acid (20 mL), for 3 hrs. Then the reaction mixture was left to cool and the precipitate so formed was filtered, dried, washed with water and crystallized from ethanol.