Octaniumdiacetate Multicomponent Synthesis of Benzodiazepines : A Novel , Highly Efficient and Green Protocol

A simple and efficient method is presented for the synthesis of benzodiazepines through the multicomponent reaction of o-phenylenediamine, various aldehydes and 5,5-dimethylcyclohexane-1,3-dione (dimedone) in the presence of the acidic bis ionic liquid 1,4-diazabicyclo[2.2.2]octanium diacetate under ultrasound irradiation. The ionic liquid used is recoverable and reusable. This procedure is simple and environmentally friendly, and offers easy work-up, mild conditions and excellent yield in a short reaction time. All of the synthesized compounds were characterized by IR, 1H NMR, mass spectrometry and elemental analysis.


Introduction
2][3][4][5][6][7] Some benzodiazepines are used in industry as dyes. 8][11][12] Benzodiazepines are generally synthesized by the reaction of β-haloketones with o-phenylenediamine, 13 condensation of α,β-unsaturated compounds with o-phenylenediamines 14 and condensation of ketones with o-phenylenediamine in the presence of ytterbium trichloride. 150][21][22][23] On the other hand, ionic liquids are suitable compounds because they are non-flammable, non-volatile, soluble, exhibit polarity and are highly thermal and chemically stable. 24CRs combined with ionic liquid can assist in the synthesis of the benzodiazepines to reduce the cost of starting materials and decrease the generation of undesirable by-products.In continuation of our studies on the green synthesis of organic materials, [25][26][27][28][29] some derivatives of benzodiazepine were synthesized using the ionic liquid 1,4-diazabicyclo[2.2.2]octaniumdiacetate (DABCO-diacetate) under ultrasound irradiation in an MCR.

Results and Discussion
The MCR of benzaldehyde, 5,5-dimethylcyclohexane-1,3-dione (dimedone) and o-phenylendiamine is essentially a condensation reaction.The reaction rate can be increased either by activating the carbonyl group of aldehydes using acidic reagents or using a strong nucleophilic dimedone derivative in basic media.In the current study, we used the acidic bis ionic liquid DABCO-diacetate as green media for the synthesis of benzodiazepines in a condensation reaction of o-phenylenediamine, aldehydes and/ or dimedone (Scheme 1).
Initially, a sample reaction was carried out using 4-nitrobenzaldehyde (1mmol) 3d, o-phenylenediamine 1 (1 mmol) and dimedone 2 (1 mmol) in DABCO-diacetate as an efficient catalyst for the synthesis of benzodiazepines 4a.This protocol proceeded smoothly at room temperature to afford product 4a in a fairly high yield.The reactions were also carried out using the neutral ionic liquids [BMIM]Br and [BMIM]BF 4 or in the absence of ionic liquids for purpose of comparison with our target reaction.It was interesting to note that the sample reaction did not proceed in the presence or absence of imidazolium ionic liquids, confirming the important role of DABCO-diacetate in the synthesis of benzodiazepines.
To optimize the amount of ionic liquid media required for this reaction, a sample reaction was carried out using different quantities of ionic liquid.The best results were obtained with 0.5 mmol of DABCO-diacetate per 1 mmol of substrate.For further investigation, the reaction between 4-nitrobenzaldehyde, o-phenylendiamine and dimedone was done in the presence of a catalytic amount of DABCO-diacetate at different temperatures.When the reaction was performed at room temperature, product 4a formed smoothly at a low yield.To achieve better results, the temperature was increased to 90 °C and benzodiazepine 4a was obtained at a yield of 82%.The results are summarized in Table 1.
Recently, ultrasound irradiation has been introduced as a useful, clean and mild protocol for organic synthesis.The well-known features of ultrasound-assisted reactions are formation of purer products at high yields, increased Scheme 1. Multicomponent synthesis of benzodiazepines in the presence of DABCO-diacetate.selectivity, enhanced reaction rates, easier experimental procedures and cleaner reactions.For these reasons, we were interested in the synthesis of benzodiazepines under ultrasound irradiation at various temperatures.The results are summarized in Table 1.Ultrasonic irradiation at room temperature was the best choice to shorten the reaction times and enhance productivity.The reaction scope was checked using various aromatic aldehydes for reaction with 1 and 2 under optimized conditions.The results are summarized in Table 2.
As shown in Table 2, the reaction under ultrasound irradiation at room temperature afforded products in shorter reaction times at higher yields.The structures of products 4a-j were characterized by IR, 1 H NMR, mass spectroscopy, elemental analysis and by comparison of their melting points with those of available authentic samples.
A reasonable mechanism for the formation of benzodiazepines is shown in Scheme 2. Initially, DABCO-diacetate can increase the electrophilic character of the carbonyl species through its inherent Brønsted acidity under ultrasound irradiation.Because the ionic liquid can polarize the carbonyl group of aldehyde, the nucleophilic addition of dimedone 2 and subsequent dehydration led to intermediate 6.The Michael addition reaction between 1 and 6 afforded intermediate 7, followed by simple condensation of the amino group with carbonyl and dehydration, leading to product 4.

Experimental
Melting points were measured on an Electrothermal 9100 apparatus.The IR spectra were determined using a Shimadzu IR-470 spectrometer.The 1 H NMR spectra were recorded on a 400 MHz Bruker DRX-400 using CDCl 3 as the solvent and TMS as the internal standard.The chemicals were purchased from Merck and Fluka.Elemental analysis was done on a Carlo-Erba EA1110CNNO-S analyzer and the results agreed with the calculated values.All solvents used were dried and distilled according to standard procedures.For the ultrasound reactions, an Astra 3D ultrasound apparatus (9.5 dm 3 , 45 kHz frequency, input power with heating at 305 W, 2 transducers) from Techno-Gaz was used.

2. General Procedure for Synthesis of Benzodiazepines
A mixture of appropriate o-phenylendiamine (1 mmol), the corresponding aldehydes (1 mmol), dimedone and DABCO-diacetate (0.5 mmol) was placed into a Pyrex open vessel and irradiated in a water bath under silent conditions by ultrasound (45 kHz) at room temperature for the required reaction times as indicated in Table 2. Af-Scheme 2. Plausible mechanistic method for synthesis of benzodiazepines.

Sarhandi et al.:
ter completion of the reaction, as indicated by TLC, the reaction mixture was dissolved in 20 mL of H 2 O.The product was separated by filtration, recrystallized from EtOH and dried to afford the crystalline compounds 4a-j.The ionic liquid was recovered for subsequent use.All synthesized compounds were characterized by their physical constant, IR, 1 H NMR, mass spectroscopy and elemental analysis.

Conclusion
In conclusion, DABCO-diacetate was used under ultrasound irradiation as a mild and efficient protocol for synthesis of diazepines.This method can be very useful for synthesis because it offers a high yield and decreased reaction time.DABCO-diacetate is inexpensive, non-toxic and easy to handle, and can act as green media.Its simple work-up procedure, short reaction time and high yield of the product are additional advantages of this protocol.

Acknowledgement
Financial support from the Research Council of Payame Noor University of Rasht and Zanjan is gratefully acknowledged.

Table 1 .
Optimization of reaction conditions.

Table 2 .
Synthesis scope of benzodiazepines 4a