Ultrasound-assisted green synthesis of pyrroles and pyridazines in water via three-component condensation reactions of arylglyoxals

Article history: Received October 25, 2012 Received in Revised form December 6, 2012 Accepted 22 February 2013 Available online 23 February 2013 A green and efficient method for the preparation of 5-aryl-4-hydroxy-2-methyl-1H-pyrrole-3carboxylic acid esters and 6-aryl-3-methylpyridazine-4-carboxylic acid esters via threecomponent reaction of arylglyoxal hydrates with β-dicarbonyl compounds in the presence of ammonium acetate and hydrazine hydrate using water as solvent under ultrasonic irradiation was reported. The reactions proceeded rapidly and afforded the corresponding pyrroles and pyridazines in good to high yields in very short reaction time. © 2013 Growing Science Ltd. All rights reserved.


Introduction
Condensation reactions of arylglyoxals, aromatic α-keto aldehydes, containing both aldehyde and ketone functional groups with different reactivity, play an important role in organic synthesis especially in synthesis of heterocyclic compounds 1 .Pyrroles are one of the most important heterocycles that broadly found in natural products 2 , pharmaceuticals 3 and bioactive molecules 4 and also used in material science 5 .Many methods have been developed for pyrrole synthesis 6 , which include Knorr, Paal-Knorr, and Hantzsch syntheses and 1,3-dipolar cycloaddition reactions.Additionally, pyridazine ring is broadly present in biologically 7 and pharmacologically active compounds 8 such as anti-depressants.Pyridazines are also of considerable interest because of their synthetic utility 9 and applications in physical organic chemistry 10 .A number of pyridazines syntheses have been previously reported in the literature 11 .
There are many published comprehensive books 12 and papers 13 indicate chemical application of ultrasound irradiation in organic chemistry, which offers an efficient and facile route for a large variety of syntheses.So, a large number of organic reactions 14 and synthesis of pyrroles and pyridazines 15 were reported under ultrasound (US) irradiation.Despite the large number of reports on the construction of pyrrole and pyridazine heterocycles are available in the literature, due to the importance of these heterocycles in medicinal and material chemistry, development of new routes, which lead to these heterocycles in higher yields, shorter reaction time or milder conditions could receive considerable attention in organic synthesis.In continuation of our works 16 , herein, we wish to report an efficient and facile procedure for the synthesis of pyrrole 3 and pyridazine 4 heterocycles by the reaction of various substituted phenylglyoxal hydrates 1 and β-dicarbonyl compounds 2 in the presence of ammonium acetate and hydrazine hydrate under US irradiation, respectively (Scheme 1).

Results and Discussion
Arylglyoxals hydrates 1 were prepared by oxidation of acetophenones using SeO 2 in refluxing dioxane in the presence of water as Riley and co-worker's report 17 .Arylglyoxals 1 were transformed into the corresponding pyrroles 3 by sonification of a mixture of 1 with β-dicarbonyl compound 2 in water in the presence of an excess amount of NH 4 OAc.The reactions were monitored by TLC.After completion of the reaction, the solid product was isolated by simple filtration.The products were obtained in high yields in a short reaction time.The color changes of the reaction mixture during the reaction of acetylacetone, phenylglyoxal hydrate and NH 4 OAc in water are indicated in Fig. 1.

Fig. 1. Gestures of color changes of the reaction mixture during the reaction
The gray colored suspension, resulting from non-dissolving of starting materials in water, was changed to yellow after 1 min and the reaction was finished along with appearance of the white solid in about 3 min.In the previous report, 6g in addition to desired pyrrole 3, corresponding 3-aroyl-4(5)arylimidazols were produced as by-products via cyclo-condensation of two molecules of arylglyoxals with NH 4 OAc, while in the presence of ultrasound irradiation, pyrroles 3 were obtained as sole products.The yields and the structure of obtained pyrroles 3 are illustrated in Table 1.All known compounds 3a-g were characterized by their 1 H NMR spectra and compared with those reported in the literature.The unknown 4-nitrophenyl substituted pyrroles 3h-k, were characterized by FT-IR, 1 H NMR and 13 C NMR techniques.As shown in Scheme 2, the proposed mechanism involves the attack of enamino ester 5, produced in situ as the reaction intermediate, onto the phenylglyoxal, and then regeneration of enamino ester 6.By nucleophilic addition of amine to the second carbonyl group of phenylglyoxal, 7 was produced, which underwent dehydration to afford the corresponding hydroxyl pyrroles 3. To prove this statement, we carried out the reaction between enamino ester 5 with phenylglyoxal in water under US irradiation, which afforded the corresponding pyrrole 3b in 90% yield.Also the condensation reaction of different arylglyoxals 1 with 2 were carried out in water in the presence of hydrazine hydrate under US irradiation to furnish corresponding pyridazines 4 in good to high yields in short reaction times.

Scheme 2. The plausible reaction mechanism
The results are summarized in Table 2. Obtained products were characterized by m.p. and 1 H NMR and compared with reported in the literature data.

Conclusions
In conclusion, we have developed a simple and facile procedure for the synthesis of 5-aryl-4hydroxy-2-methyl-1H-pyrrol-3-carboxylates and 6-(4-aryl)-3-methylpyridazine-4-carboxylates involving the ultrasonic irradiation of reaction mixture in water.The advantages of this methodology are operational simplicity, high yields, short reaction times, mild reaction conditions, without using any catalysts which make it a useful and attractive process in the view of environmental and economical points.

Experimental
All chemicals were purchased from Merck and Fluka companies.The 1 H NMR and 13 C NMR spectra were recorded on Bruker AVANCE (400 MHz) spectrometer using CDCl 3 and DMSO-d 6 as solvents.Sonication was performed in Bandeline sonoplus, GM 2200.

General procedure for synthesis of 3-hydroxy pyrroles 3
To a mixture of β-dicarbonyl compound 2 (0.5 mmol) in water (2.5 mL), were added arylglyoxal 1 (0.5 mmol) and ammonium acetate (5 mmol).The resultant mixture was irradiated and solidified within 3-5 min, the obtained solid was then filtered.The filtrate washed with water (3-10 mL), and the crude material was purified by crystallization from ethanol.The products (3a-g) were known compounds, their authenticity was established by 1 H NMR and their melting point compared with that reported in literatures.The assignment of chemical structures for compounds 3h-k was confirmed by FT-IR, 1 H NMR, 13 C NMR spectral analysis and elemental analysis data.

General procedure for synthesis of pyridazines 4
To a mixture of β-dicarbonyl compound 2 (0.5 mmol) in water (2.5 mL), were added arylglyoxal 1 (0.5 mmol) and hydrazine hydrate (3 mmol).The resultant mixture was irradiated and solidified within 3-5 min, the obtained solid was then filtered, the filtrate washed with water (3-10 mL), and the crude material was purified by crystallization from ethanol.The products (4b-h) were known compounds and their authenticity was established by 1 H NMR and their melting point compared with that reported in literatures.Compounds 4a and 4i were unknown and established by 1 H NMR, 13 C NMR and elemental analysis data.

Physical and Spectral Data
The spectroscopic data for new compounds are as follows:

reported Mp] (°C) Yield (%) a
a Yields refer to isolated products.