An Efficient One Pot Protocol to the Annulation of Face ‘‘d’’ of Benzazepinone Ring with Pyrazole, Isoxazole, and Pyrimidine Nucleus through the Corresponding Oxoketene Dithioacetal Derivative

A highly facile single step approach to the annulation of face “d” of benzazepinone nucleus with pyrazole, isoxazole, and pyrimidine ring has been described. The annulation proceeded smoothly on the reaction of oxoketene dithioacetal derivative 3 with (i) NH 2 – NH 2 ⋅H 2 O, (ii) NH 2 OH⋅HCl, (iii) acetamidine hydrochloride, (iv) guanidine nitrate, (v) urea, and (vi) thiourea which yielded the pyrazolo, isoxazolo, and pyrimido annulated analogues of benzazepinone 4–9, respectively, in acceptable yields. The 4-ketene dithioacetal analogue of 7-fluorobenzo[b]azepine-2,5-dione (3)was in turn obtained from the reaction of 7-fluoro-3,4-dihydro-1Hbenzo[b]azepine-2,5-dione (2) (with CS 2 + CH 3 I in presence of t-BuOK). 7-Fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (2) resulted from the acylation of p-fluoroanilinewith succinyl chloride followed by cyclocondensation of the later with polyphosphoric acid (PPA).


Introduction
Koch et al. [1] have carried out a quantitative analysis of physiologically active natural products and showed that compound molecules with two or three rings were most often found in active natural products.The interest in the various facets of the chemistry and biology of small bicyclic and tricyclic (carbocyclic and heterocyclic) systems has expanded exponentially thereafter.Since then the development of small molecule libraries with potential biological activities has been a major focus of research in the area of chemical biology and medicinal chemistry.In view of this, the development of efficient methodologies to access small molecules of medicinal utility has been currently of special interest, with particular emphasis on the preparation of compound libraries from the privileged medicinal structures or from those structures akin to these.
Benzodiazepine framework in general has been recognized to belong to the family of "privileged medicinal structures, " by virtue of their ability to provide ligands to a number of functionally and structurally discrete biological receptors.A derivative of benzazepine "the mirtazapine, " being in close analogy to its activity, with 1,4-benzodiazepines, has emerged as an active antidepressant for the treatment of moderate to severe depression [2,3] (Figure 1).This discovery provided optimism towards the development of other novel agents from benzazepine class of compounds to find if there were others too, to show a higher level of medicinal efficacy.This search resulted in the discovery of 7-phenyl sulfonyl-tetrahydro-3-benzazepine derivative for its use as antipsychotic agent [4] and 6-chloro-2,3,4,5-tetrahydro-3methyl-1H-3-benzazepine to give relief in benign prostatic hypertrophy [5,6].
Literature is replete with ample examples to show that the presence of an additional heterocyclic ring onto the seven membered ring of benzodiazepines exerts a profound influence on the biological activity in the resulting materials.Due to this, we considered it of interest to functionalize the benzazepine-2,5-dione system 2 with ketene dithioacetal function in consideration of their amenability to the corresponding pyrazolo, isoxazolo, and pyrimido annulated analogues 4-9, respectively, (Scheme 1) on the premise that their presence in tandem in the same molecular framework could inherit its positive impact onto the overall biological efficacy in the resulting molecules.Herein, in this communication, we report the preliminary results of our endeavour, focused in this direction.

Materials and Method
p-Fluoroaniline (1) and succinyl chloride were obtained from commercial sources and were used as obtained, from the sigma suppliers without further purification.Melting points were determined in open glass capillaries and are uncorrected.The purity of the compounds was checked by TLC on silica gel (G) plates.IR spectra were recorded on CE (Schimatzu) FTIR-9050 S. 1 H-NMR spectra and 13 C NMR spectra were recorded on Sea 400 (Bruker) using CDCl 3 as solvent and TMS as an internal reference.Chemical shifts are expressed in  ppm.Mass spectra were recorded on Bosch Tech.X.

Synthesis of 4-(Bis(methylthio)methylene)-7-fluoro-3,4dihydro-1H-benzo[b]azepine-2,5-dione (3).
A mixture of 7fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (2) (2.82 g, 0.01 mol) and CS 2 (1.6 mL, 0.01 mol) was added to a wellstirred and cold suspension of t-BuOK (2.23 g, 0.02 mol) in dry benzene (7.0 mL) and DMF (3.0 mL) and the reaction mixture was allowed to stand for 4 h.Methyl iodide (3.3 mL, 0.02 mol) was gradually added with stirring and reaction mixture was maintained at low temperature by placing it in ice cold water bath.The reaction mixture was allowed to stand for 4 h at room temperature with occasional shaking followed by reflux on a water bath for 3 h.The mixture was poured on crushed ice and the benzene layer was separated.
The aqueous portion was extracted with benzene and the combined extracts were washed with water and dried over anhydrous sodium sulfate and the solvent was removed by distillation.The product thus obtained was purified by crystallization with ethanol to give pyrazolo [3,4-d]

Results and Discussion
The synthetic importance of oxoketene dithioacetals specially the dimethyl thioacetal in the construction of a variety of novel fused heterocyclic systems encouraged us to explore its potential in the annulation of face "d" of 7-fluorobenzazepine-2,5-dione (2) with such pharmacophoric scaffolds as pyrazole, isoxazole, and pyrimidine which have been accredited in the literature with a proven record of their bioactive profiles.In consideration of the easy accessibility of the corresponding ketene dimethyl acetals from the base catalyzed reaction of CS 2 and CH 3 I with compounds containing an active methylene group, we applied this strategy on 2 to append this functionality onto its 4-position to form 3. The versatility of 3 in allowing a facile annulation of its face "d" with the above bioactive pharmacophores was exploited in its reaction with (i) hydrazine hydrate [7], (ii) hydroxylamine hydrochloride [8][9][10], (iii) acetamidine hydrochloride [11], (iv) guanidine nitrate [11], (v) urea [12], and (vi) thiourea [12] to generate 4-9, respectively, in acceptable yields.The structures of the compounds 2-9 were established on the basis of their microanalysis, IR, 1 H NMR, 13 C NMR, and MS data which corroborated strongly to the structures assigned to these molecules.The formation of compound 2 from 1 was ascertained by the appearance of two carbonyls in the IR spectrum of 2 (at 1680 and 1710 cm −1 ).The presence of a multiplet (due to two overlapping triplets of two CH 2 's) at  3.49 in its NMR spectrum corroborated strongly its formation from 1.The appearance of a carbonyl group peak at 1640 cm −1 for the ,-unsaturated ketone in the IR spectrum of 3 and a singlet of 2H for the CH 2 group at  3.53 in its NMR spectrum indicated clearly its formation from 2. The most diagnostic evidence which substantiated their formation was the disappearance of one of the carbonyl group peaks of 3 in the IR spectrum of 4-9 which confirmed its involvement in cyclocondensation reactions.The 1 H NMR spectrum (400 MHz, in CDCl 3 ) of 3, 5, 6, and 7 showed the presence of an NH peak at , 8.0, 8.11, 8.15, and 8.13, respectively, (for the azepinone NH) whereas compound 4 exhibited two NH peaks at , 12.82 (pyrazole NH) and , 8.03 (for azepinone NH).Apart from this, compounds 8 and 9 also exhibited two NH peaks at , 8.04 (for azepinone NH) and , 2.0 (pyrimidine NH), all of which exchanged with D 2 O.