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MICROWAVE-ASSISTED SOLVENT-FREE SYNTHESIS OF 3,4-DIHYDROPYRIMIDIN-2(1H)-ONES CATALYZED BY NH [Collection of Czechoslovak Chemical Communication](Collection of Czechoslovak Chemical Communications Via Acquire Media NewsEdge) Catalytic potential of ammonium hypobromite in the one-pot synthesis of 3,4-dihydropyrimidin- 2(1H)-ones from Biginelli-type condensation reaction between an aldehyde, ß-keto ester and urea has been explored. The reaction proceeds under solvent-free conventional heating as well as microwave-irradiation conditions to afford the respective products in excellent yields. Keywords: 3,4-Dihydropyrimidin-2(1H)-one; Biginelli-type condensation; Ammonium hypobromite; Aldehydes; ß-Keto ester; Urea; Solvent-free; Aromaticity; Asymmetric synthesis; C-C coupling; Heterocycles; Heterogeneous catalysis. Dihydropyrimidinones and their derivatives are of remarkable biological and pharmacological importance as antitumor, antiflammatory, antibiotics, antiviral, antibacterial, antifungal agents, and tyrosinase inhibitors1. In the last few decades, these compounds have also found applications as calcium channel blockers, antihypertensive, a1a-antagonists, and neuropeptide Y (NDY) antagonists used for the treatment of prostatic hyperplasia2. Moreover, several dihydropyrimidine derivatives including dihydropyrimidin- 5-carboxylate core have been discovered as marine-extracted alkaloids which show interesting biological activities, e.g. as potent HIV gp-120CD4 inhibitors3. The synthesis of 3,4-dihydropyrimidin-2(1H)-ones was first reported by Biginelli in 1893 by a simple one-pot condensation of a ß-keto ester, an aldehyde and urea under strongly acidic conditions4. However, this protocol often suffers from low yields of the more demanding products in the cases of aliphatic and certain substituted aromatic aldehydes. Owing to the extensive biological and pharmacological applications of 3,4-dihydro- pyrimidin-2(1H)-ones1c,5, many improved and more robust routes have been continuously reported for the synthesis of these compounds either by the classical one-pot Biginelli approach4,6, or through the development of novel multistep procedures7. In recent years, a variety of catalytic methods for promoting the Biginelli reaction have been developed employing various metal salts as Lewis acid catalysts including LiBr 8, NiCl2.6H2O and FeCl3.6H2O 9, CuCl2.2H2O 10, CeCl3.7H2O 11, Mn(OAc)3.2H2O 12, ZrCl4 13, InCl3 3a, InBr3 14, ZnCl2 15, ZnI2 16, CdCl2 17, BiCl3 18, LiClO4 19, Zn(OTf)2 20, Al(HSO4)3 21, BiO(NO3)22, LnCl3 5, and Ln(OTf)3 (Ln = Yb, Sc, La)23, trichloroisocyanuric acid24, Yb(PFO)3 25, thiamine hydrochloride26, silicasupported tin chloride and titanium tetrachloride27, H3PO3 28, hexaaquaaluminium(III) tetrafluoroborate29. In addition, several other methods have been reported to promote the Biginelli reaction including solid phase reactions30, microwave irradiation31, Biginelli reaction starting directly from alcohols32, and other catalytic reactions such as the use of various ionic liquids, e.g. 1-butyl-3-methylimidazolium tetrafluroborate (BMImBF4) to accelerate the Biginelli reaction33. RESULTS AND DISCUSSION In continuation of our studies to explore new and more benign approaches towards one-pot synthesis of heterocyclic compounds34, including dihydropyrimidinones35, we are prompted to report herein a simple and practical method for the direct synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4) by the Biginelli-type reaction using ammonium hypobromite as an effective and non-polluting catalyst. In the presence of a catalytic amount of NH4OBr (10 mole %), the reaction of ß-keto ester 1, aldehyde 2 and urea 3 was carried out in a one-pot condensation under solvent-free conventional heating as well as microwave-irradiation conditions (Scheme 1). To optimize the reaction conditions, we initially examined the condensation of urea with benzaldehyde and ethyl acetoacetate (excess) as test compounds (entry 1). The effect of solvent was studied by using different solvents such as AcOH, DMF, MeCN, H2O, EtOH as well as solvent-free condition under various amounts of catalyst. The experimental results indicated that the highest yields of the reaction product obtained when the reaction was conducted under solvent- free condition using excess amount of ethyl acetoacetate under microwave irradiation at a power level of 60% or reflux conditions were 92 and 83%, respectively in the presence of NH4OBr (10 mole %). This achievement encouraged us to extend this reaction to a variety of aromatic aldehydes 4 and ß-keto esters 1 under the optimized conditions (ethyl acetoacetate (twofold excess)/NH4OBr (10 mole %)/refluxing or microwave irradiation), furnishing the corresponding 3,4-dihydropyrimidin- 2(1H)-ones (4) and the experimental results are summarized in Table I. As shown in this Table, the reactions performed under microwave-irradiation condition (60% power level) were brought to completion in much shorter reaction times (2-6 min) and higher yields (80-98%) compared with those obtained under conventional heating condition. The structures of the products 4 were fully established by analysis of their spectral (1H and 13C NMR, IR) and physical data and compared with those reported (Table I). In reliance on the mechanism previously proposed for the Biginelli reaction by Kappe41, and others5, we propose a mechanism for the ammonium hypobromite-promoted Biginelli reaction as shown in Scheme 2. In this mechanism, a Br+ ion-coordinated and -stabilized acyl imine intermediate 5 is formed by Br+ ion-catalyzed condensation of the aldehyde 2 with urea 3. This intermediate subsequently undergoes reaction with Br+ ion-activated ß-keto ester (A) to yield the intermediate 6 followed by dehydrative cyclization to the product 4. CONCLUSION In summary, the present work offers a simple and efficient procedure for the direct solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones both under microwave irradiation and conventional heating conditions catalyzed by NH4OBr as non-toxic and inexpensive compound in good yields. The reactions occur in shorter times and higher yields when carried out under microwave-irradiation condition. EXPERIMENTAL Material and Instruments All chemicals were purchased from Merck Company. Melting points were measured using the capillary tube method with an electrothermal 9200 apparatus. 1H and 13C NMR spectra were recorded on a JEOL FX 90 MHz spectrometer in DMSO-d6 solution. IR spectra were run from KBr disk on a Perkin-Elmer GX FT-IR spectrometer. Microwave-assisted reactions were conducted in a Milstone CombiChem Microwave Synthesizer. In all irradiation experiments, rotation of rotor, irradiation time, temperature, and power were monitored with the 'easy WAVE' software package. Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones 4. General Procedure A) Thermal heating condition. A mixture of threefold excess amount of ß-keto ester 1 (30 mmol), the appropriate aldehyde 2 (10 mmol), urea 3 (1.2 g, 20 mmol) and NH4OBr (0.114 g, 1.0 mmol) were let to stir under reflux for an appropriate time (Table I). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, poured onto crushed ice and stirring was continued for further few minutes. The resulting mixture was filtered, washed with cold water (2 × 50 ml) and crystallized from EtOH to yield the pure product. All products are known compounds which were characterized by their IR, 1H and 13C NMR spectral data and their melting points, and compared with those reported (Table I). B) Microwave-irradiation condition. 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Commun. 2006, 373. 39. Besoluk S., Kucukislamoglu M., Nebioglu M., Zengin M., Arslan M: J. Iran. Chem. Soc. 2008, 5, 62. 40. Shaabani A., Bazgir A., Teimouri F.: Tetrahedron Lett. 2003, 44, 857. 41. Kappe C. O.: J. Org. Chem. 1997, 62, 7201. Davood AZARIFAR1,*, Kaveh KHOSRAVI2, Khadijeh SOLEIMANI3 and Zohreh NAJMINEJAD4 Department of Chemistry, University of Bu-Ali Sina, 65178 Hamedan, Iran; e-mail: 1 [email protected], 2 [email protected], 3 [email protected], 4 [email protected] Received February 19, 2011 Accepted April 20, 2011 Published online July 13, 2011 (c) 2011 Institute of Organic Chemistry and Biochemistry |