Two step One-Pot Synthesis of Novel 5-(4-Fluorophenyl)-1 H -Beno[ e ][1,4]Diazepin-2(3 H )-One and it’s Base Catalyzed Transformation to N -Alkyl and C-3 Arylidene Derivatives

We have demonstrated two step one-pot synthesis of novel 5-(4-Fluorophenyl)-1 H - Beno[ e ][1,4]Diazepin-2(3 H )-one using 2-Amino-4’-fluorobenzophenone as initial stating material. The small library of N-alkylation and C-3 benzylidene derivatives have been synthesized by base catalyzedreaction of 5-(4-fluorophenyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (3) nucleus with various alkyl halides and aromatic aldehydes respectively.


INTRODUCTION
In heterocyclic chemistry one of the most prominent class of privileged structure is 1,4benzodiazepine. This important class of central nervous system (CNS) active agents and its peptidomimetic nature makes them the important target to study in medicinal aspects. Diazepine ring system and its derivatives have shown considerable uses in medicinal drug discovery towards wide range of biological activities [1][2][3][4] such as anticonvulsant, antianxiety, analgesic, sedative, anti-depressive and hypnotic agents as well as anti-inflammatory agents [5] .
In the last few years, the area of biological importance of 1,4-benzodiazepines have been extended to many diseases such as cancer, viral infection and cardiovascular disorders [6,7] . In addition, 1,4-benzodiazepine derivatives are key intermediates in the synthesis of various fused heterocyclic system [8] .
Owing to their versatile applications, various methods for the synthesis of benzodiazepines have been reported in the literature. These include condensation reactions of o-phenylenediamines with α,β-unsaturated carbonyl compounds [9] in the presence of various kind of catalysts [10][11][12][13][14][15][16][17][18] . The most extensively used methods for preparing 1,4-benzodiazepines begins with an 2-aminobenzophenone. The first method involves the treatment of appropriate2-aminobenzophenone with haloacetyl halide to afford the amide, followed by the addition of ammonia to first displace the chlorine giving the glycinamide. Then cyclization by imine formation will give the 1,4-benzodiazepine with higher yield [18] .The other method involves treating the 2-aminobenzophenone with an amino acid ester hydrochloride in pyridine to give 1,4-benzodiazepine in one step, with a variety of substituent.

RESULT AND DISCUSSION
We have demonstrated two step one-pot synthesis of 5-(4-fluorophenyl)-1Hbenzo[e] [1,4]diazepin-2(3H)-one (3) starting from commercially available2-Amino-4'fluorobenzophenone and chloroacetyl chloride followed by cyclization using hexamethylenetetramine and ammonium acetate. The synthesized compound 5-(4fluorophenyl)-1H-benzo[e] [1,4]diazepin-2(3H)-one (3) possess amidic proton indiazepine International Letters of Chemistry, Physics and Astronomy Vol. 30 107 nucleus which favors any aliphatic alkyl halide to react as a electrophile in presence of base. On the other side the diazepine ring (3) with active methylene group adjacent to carbonyl behave as a synthon for cross-aldol reaction with different aldehydes in the presence of base. Initially, to optimize the reaction condition and yield, compound 5-(4-fluorophenyl)-1Hbenzo[e] [1,4]diazepin-2(3H)-one (3) was reacted with Methyl iodide in the presence of various base and solvent to generated targeted compound (4a). Similarly, compound (3) was reacted with benzaldehyde in the presence of various base and solvent to generated targeted compound (5a). As a result, we found that maximum yield and smooth conversion to related product 4a and 5a obtained from (3) by using KOH. NaOH also gives good result. But in weak inorganic base and organic base, the reaction takes much more time and yields are less (Table 1). Having established the optimal condition, we next examined the scope of the reaction for the construction of small library of N-alkylation and C-3 benzylidine derivatives was synthesized by using various alkyl halides and substituted benzaldehydes respectively. The results were summarized in Table 2.

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ILCPA Volume 30 The characterization of synthesized compounds was carried out by Mass, 1 H NMR and IR spectroscopy. In 1 H NMR spectrum of compound 3 shows singlet of amidic -NH-at 8.83 δ ppm which is disappered in compound 4a and the promising peak of methyl substitution is observed at 3.42δ ppm. Further it is confirmed by IR that the absorption band 3282 cm -1 of secondary amide in compound 3 is diappeared in compound 4a. Mass spectra is also supports the molecular weight of 4a.In 1 H NMR spectrumof compound 3 shows methylene proton (-CH 2 -) at 4.31δ ppm, which is absent in 5a. The promising peak of arylidine proton (-CH=) is observed at 6.39 δ ppm. Further mass and IR spectra supports the structure of 5a.

1. Experimental
For all these conversions, progress of reaction was carried out on TLC plate silica gel GF 254 and the melting points were recorded by open capillary method. IR spectra were recorded on a Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded on Shimadzu GCMS-QP-2010 model using Direct Injection Probe technique. 1 H NMR was determined in CDCl 3 /DMSO solution on a Bruker AVANCE II 400 MHz and 300 MHzspectrometer. Elemental analysis of the all the synthesized compounds were carried out on Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements with the structures assigned.

International Letters of Chemistry, Physics and Astronomy Vol. 30
compound 2-chloro-N-(2-(4-fluorobenzoyl)phenyl)acetamide (2) was taken in ethanol (40 mL), hexamethylenetetramine (13.8 mmol) and ammonium acetate (13.8 mmol) were added. The reaction mixture was refluxed for 3 h. Then the reaction mixture was evaporated to dryness. Distilled water (30 mL) was added, and the resulting suspension was stirred at 60 °C for 0.5 h. The suspension was cooled to 20 °C and filtered. The crude product was crystallized from toluene to obtained 3 in 85 % yield.