SiO2/H2SO4: An Efficient Catalytic System for Solvent-free 1, 5-benzodiazepines Synthesis.

BACKGROUND
1, 5-Benzodiazepines have been investigated extensively by organic chemists due to their medicinal and pharmacological properties. These compounds are synthesized by condensation of o-phenylenediamines with carbonyl compounds in the presence of acid catalysts.


OBJECTIVES
During our studies on the application of silica resin with acid functional moieties, we found that SiO2/H2SO4 mixture is a simple and efficient catalyst for this method under microwave irradiation.


MATERIALS AND METHODS
The reaction was carried out simply by grinding SiO2/H2SO4 mixture with o-phenylenediamine, and ketone in the mortar; then the mixture was poured out into a sealed flask. Subsequently, it was irradiated in a microwave oven.


RESULTS
In this method a series of cyclic and acyclic ketones underwent above conversion to form corresponding 1, 5-benzodiazepines.


CONCLUSIONS
In conclusion, this method is a simple, rapid, and high yielding reaction (78-95%).


Background
1,5-Benzodiazepines and their derivatives have been investigated extensively by organic chemists due to their medicinal properties such as analgesic and anti-inflammatory activities (1). These compounds are widely used as anticonvulsant, antianxiety, analgesic, sedative, antidepressive, hypnotic agents as well as anti-inflammatory agents (2). Moreover, 1,5-benzodiazepine derivatives are valuable synthons that can be used in the preparation of other fused ring compounds such as triazolo-, pyrolo-, oxadiazolo-, oxazino-, or furano-benzodiazepines (3). As a result, research in this area is still very active and is directed toward the synthesis of compounds with enhanced pharmacological activity (4).
In addition, benzodiazepines were synthesized using green solvents, such as water, ionic liquids and glycerol (14). However, many of these methodologies are associated with several shortcomings like long reaction times, harsh reaction conditions, low product yields, occurrence of several side products, and difficulty in recovery and reusability of the catalysts. Moreover, some of the reagents employed are very expensive. Recently considerable attention has been devoted to heterogeneous organic transformations utilizing inorganic solid acids (15). Some of these compounds such as silica sulfuric acid (SSA) have been employed widely as efficient catalysts for several organic reactions (16). Generally, heterogeneous catalysts offer several advantages including mild reaction conditions, high selectivity, high throughput, and ease of work-up procedures.
Application of microwave energy for conducting organic reactions at highly accelerated rates is an emerging technique. In recent years, microwaves have become popular among synthetic organic chemists for improving classical organic reactions, shortening reaction times, and increasing yields, as well as promoting new reac-tions (17). Moreover, often when carrying out a reaction in a microwave oven, the use of a solvent can be avoided, which is important in order to make the synthesis more environmentally friendly as it is observed in green chemistry. These observations led us to investigate possibility of improving methods used for solvent-free synthesis of 1,5-benzodiazepine scaffold.

Objectives
During our studies on the application of silica resin with acid functional moieties (18), we found that SiO 2 / H 2 SO 4 mixture is a simple and efficient catalyst for solvent-free synthesis of 1,5-benzodiazepines under microwave irradiation, as it was followed in (Figure 1).

Reagents and Materials
All starting materials were purchased from Merck and Aldrich companies. The IR spectra were recorded on a Perkin-Elmer RXI infrared spectrometer. 1 H NMR spectra were recorded by a 400 MHz Broucker FT-NMR spectrometer. TLC accomplished purity of substrates and is contained silica gel polygram SIGL/UV254 plates. The reaction mixture was irradiated in a butane 1000 w microwave oven.

Preparation of SiO 2 /H 2 SO 4 Mixture
SiO 2 /H 2 SO 4 mixture was prepared simply in a mortar by grinding 3 g silica gel and 0.5 mL concentrated sulfuric acid for about 5 minutes until a fine and homogeneous mixture was obtained.

General Procedure
The reaction was carried out simply by grinding 0.5 g SiO 2 /H 2 SO 4 mixture with substrates, to achieve 10 % mole ratio, 10 mmol o-phenylenediamine, and 21 mmol ketone in the mortar; , then the mixture was poured out into a sealed flask. Subsequently, it was irradiated in a microwave oven, and reaction was kept to continue for about 5-25 minutes until completion of reaction that was confirmed by TLC monitoring. Then the products were extracted twice by 20 ml diethyl ether. The combined so-lutions were dried over anhydrous magnesium sulfate. Evaporation of the solvent made the products affordable as seen in Table 1. Structures of products were characterized by their melting points, 1 H NMR, and IR spectral data. Table 1 shows a series of cyclic and acyclic ketones un-  Table 1, e.g. acetone and acetophenone, as aliphatic and aromatic ketones worked well while cyclic ketones, entries 5-8 in Table 1, afforded desired products in lower yields than others. Reaction occurred in a mild condition and experimental procedure was simple. Yield of products was acquired from78% to 95%. Structures of products were determined by their 1 H NMR, IR and MS spectral data. Figure 1 shows a plausible mechanism for 1,5-benzodiazepines formation that involves intermediate Schiff's base formation, 1, and undergoes 1,3-hydrogen shift to form enamine, 2; intramolecular hydrogen shift provids desired product.

Characterization of Products
Selected spectral data for products shown in Table 1

Discussions
In conclusion, we have shown that SiO 2 /H 2 SO 4 mixture is an efficient and simple catalyst for solvent-free synthesis of 1,5-benzodiazepine derivatives the base skeletal backbone for natural products of BDs; it benefits reaction of a wide range of ketones with o-phenylene-diamine under microwave irradiation. Additional eco-friendly attributes of this synthetic protocol are solid state of SiO 2 /H 2 SO 4 , relatively low toxicity, and cost saving.