Microwave Assisted Synthesis of 3, 5-Disubstituted 1, 2, 4-Triazole Based Piperazine Amide and Urea Derivatives

We reported here the microwave-assisted synthesis of 3,5-disubstituted 1,2,4-triazole based piperazine amide and urea derivatives with very good yield under mild reaction conditions.


Introduction
Substituted 1,2,4-triazole and its derivatives have gained a considerable interest of the medicinal chemist in search for the new drugs. Because 1,2,4-triazoles are key skeletons of many biologically active molecules and exhibits versatile applications like pesticides, medicines, organocatalysts and functional materials [1,2]. Based on the high importance of this scaffold, the development of methods for its synthesis has been a focus in organic chemistry [3]. Previously, 1,2,4-triazole derivatives were prepared from the Nacyl amidrazones obtained from hydrazines and carboxylic acid derivatives by intramolecular cyclization [4]. However, the major drawback of this method is tedious synthetic procedures and low yields. Therefore, the development of a simple and efficient procedure to prepare 1,2,4-triazole derivatives is still essential. Recently, the transition-metalcatalyzed synthesis of 1,2,4-triazoles from readily available starting materials were reported with low yield and harsh conditions [5]. Subsequently, Yeung synthesized 1,2,4triazoles using a convenient and efficient one-pot synthesis of by condensation of nitriles and hydrazides in presence of base [6]. In 2009, Nagasawa's group reported copper-catalyzed synthesis of 1,2,4-triazole derivatives via coupling of amidines with nitriles [7], which was the first example of the synthesis of 1,2,4-triazole derivatives using transitionmetal. In 2014, Huang group report the synthesis of trisubstituted 1,2,4-triazole by a new 1,3-dipolar cycloaddition between oxime and hydrazonoyl chloride under basic condition [8]. In the same year, Beifuss's group reported the synthesis of symmetrically substituted 3,5-diaryl-1,2,4-triazoles using a novel and efficient copper-catalyzed reaction between imidates and ammonium carbonate [9]. A more recent report has shown that nitriles and Dhanamoorthy Vaithiyalingam et al.
Here, we report the direct reaction between piperazine substituted nitrile and hydrazide under microwave condition for the efficient synthesis of the intermediate (3,5-substituted 1,2,4-triazoles) with good yield and very less reaction time (Scheme 1). Further, we synthesized a series of various urea derivatives with the use of this intermediate.
The melting points were measured in open capillary tubes and are uncorrected. The 1 H and 13 C NMR spectra were recorded on a Bruker (Avance) 300 MHz NMR instrument using TMS as an internal standard, CDCl3 and DMSO-d6 as a solvent. Standard Bruker software was used throughout. Chemical shifts are given in parts per million (δ-scale) and the coupling constants are given in Hertz. Silica gel-G plates (Merck) were used for TLC analysis with a mixture of n-hexane and ethyl acetate as an eluent.

Preparation of tert butyl 1-cyano piperazine carboxylate (2)
To a stirred solution of N-bocpiperazine (9 g, 0.048 mol) and NaHCO3 (4.05 g, 0.048 mol) in ethanol (60 mL), was added cyanogen bromide (6.10 g, 0.0576 mol) portion wise at 0°C. The reaction mixture was stirred at room temperature for about 4 h. After completion of reaction, ethanol was concentrated under reduced pressure, water was added into the residue (40 mL), extracted with ethyl acetate (2 x 40 mL), washed with brine (20 mL) dried over anhydrous Na2SO4 and concentrated under reduced pressure. Yield: 9.

Preparation of 2-fluorobenzohydrazide (4)
To a stirred solution of methyl 2-fluorobenzoate 3 (6 g, 0.038 mol) in ethanol, was added hydrazine hydrate (2.87 g, 0.057 mol) drop wise and gradually heated to 90 º C and maintained for 5 h. After completion of reaction, the solvent was removed under reduced pressure. The solid was formed, filtered and washed with minimum amount of water. Yield

Preparation of intermediate (5)
The mixture of 2-fluoro benzohydrazide 4 (2.5 g, 0.016 mol) and compound 2 (3.77 g, 0.017 mol) were dissolved in DMF and kept in a microwave at 120 º C for about 15 mins. After completion of reaction, reaction mixture was concentrated under reduced pressure to remove DMF and added water, extracted with ethyl acetate (40 mL), washed with brine solution and dried over anhydrous Na2SO4 and concentrated under reduced pressure. Then the compound was purified by silica gel (60 -120 mesh) using pet ether and ethyl acetate as eluent. Yield

General procedure
To the well stirred mixture of corresponding carboxylic acid (1.1 eq), EDCI.HCl (1.2 eq) and HOBT (1.2 eq) in DCM, were added triethylamine followed by addition of intermediate 6 at 0°C and the reaction mixture was stirred for room temperature for 3 h. After completion of reaction, water was added to reaction mixture. The solid formed was filtered, washed with water, and dried under reduced pressure. The crude was purified by column chromatography using silica gel 230-400 mesh to get compounds 7a-g. 1-(4-(5-(2-Fluorophenyl)-1H-1,2,4-triazol-3-yl)

Results and discussion
Based on above initial information's, we planned to optimize the reaction condition of intermediate 5. The reaction between nitrile (4) and hydrazide (3) was used to identify the reaction parameters that would provide optimal results. As presented in Table 1, to improve yields and demonstrate the methodology. To this effort, we decided to evaluate the various solvents and bases with microwave heating conditions. DMSO 150 40 150 75 Based on the above results, we comparing the conventional heating with microwave condition, MW mediated reactions are the best method for the synthesis of intermediate 5 without using any base or metal. In this method, it takes only few minutes to complete the reaction and it offers good yield with easy work up, when compared to conventional heating method. Further, the intermediate 6 reactions with various isocyanates to give urea derivatives with electron donating and electron withdrawing substituents in the aromatic [12][13][14][15][16][17]. As shown in Table 4, both electron donating and electron withdrawing substituents on phenyl rings does not affect the reaction, and the corresponding reactions proceeded smoothly to afford the desired products with excellent yield in shorter reaction time.

Conclusion
We synthesized piperazine linked 3,5-disubstituted 1,2,4-triazole intermediate that proceeds by the direct reaction of a nitrile and a hydrazide in microwave irradiation without using any base and solvents. The obtained triazole derivatives as an intermediate for preparing some urea and amide derivatives using their corresponding isocyanates and carboxylic acids through coupling reaction to give very good yield (up to 99 %) in very short time.