A new facile route to synthesize thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives

ICC Original Research Article Iranian Chemical Communication Payame Noor University http://icc.journals.pnu.ac.ir A new facile route to synthesize thieno[3,2-e][1,2,4]triazolo[4,3c]pyrimidine derivatives Mehdi Soleimany*, Jalil Lari, Hooshang Vahedi, Morteza Imanpour Department of Chemistry, Payame Noor University, P.O. BOX 19395-4697, Tehran, Iran Received: 2 July 2014, Accepted: 22 September 2014, Published: 1 January 2015 Abstract A new facile route for synthesis of 3-(aryl)-8,9-di(alkyl)thieno[3,2-e][1,2,4]triazolo pyrimidines derivative from the same starting material, 2-amino-4,5-di(alkyl)thiophene-3carboxamide, has been developed through heterocyclization of the corresponding arylidenehydrazino-5,6-di(alkyl)thieno[2,3-d]pyrimidine under refluxing condition with acetic anhydride followed by air oxidation. The products were obtained in high yield with an easy work-up in simple reaction along with the purification of products by non-chromatographic method. This general synthetic procedure can be extended to the preparation of a wide variety of isomeric triazoles using 2-aminothiophene-3-carboxamide bifunctional derivatives. Keywords: Thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines; heterocyclization; acetic anhydride; air oxidation. Introduction Fused pyrimidines are found in a variety of natural products (e.g., purines, pyrrolopyrimidines, pyridopyrimidines, pteridines), agrochemicals and veterinary products [1–3]. Pyrimidine derivatives and heterocyclic annelated pyrimidines continue to attract great interest due to the wide variety of interesting biological activities observed for these compounds, such as anticancer [4], antiviral [5], antitumor [6], anti-inflammatory [7], antimicrobial [8], antifungal [9], antihistaminic [10] and analgesic [11] activities. Further, when a fused pyrimidine such as thieno[2,3-d]pyrimidine links the pyrimidine ring to triazol ring, it plays significant roles such as antimicrobial, antitumor [12] and adenosine receptor [13]. 2-Aminothiophene-3-carboxamide derivatives are useful substrates for the *Corresponding author: Mehdi Soleimany Tel: +98 (915) 5070940, Fax: +98 (511) 7273358 E-mail: preparation of various condensed pyrimidine heterocyclic systems [14]. As indicated by its organic chemistry, acetic anhydride is a versatile reagent for acetylations, the introduction of acetyl groups to organic substrates. In these conversions, acetic anhydride is viewed as a source of CH3CO+ [15]. Acetic anhydride is mainly used for acetylations, leading to commercially significant materials. Its largest application is for the conversion of cellulose to cellulose acetate, which is a component of photographic film and other coated materials. Similarly, it is used in the production of aspirin, which is prepared by the acetylation of salicylic acid [16]. To the best of our knowledge, heterocyclization of arylidene-hydrazino5,6-di(alkyl)thieno[2,3-d]pyrimidine derivatives with acetic anhydride followed by air oxidation and isolation of the variety of thienotriazolopyrimidines has not been reported in the literature. Due to our Iran. Chem. Commun. 3 (2015) 114-120 Page | 114 M. Soleimany et al. / Iranian Chemical Communication 3 (2015) 114-120 interest in the synthesis of new heterocyclic compounds with potential biological activities [17], the synthesis of novel arylidene-hydrazino-5,6di(alkyl)thieno[2,3-d]pyrimidine derivatives was carried out. Experimental General Melting points were recorded with Electrothermal 9100 apparatus. Evaporation of solvents was performed under reduced pressure on a Buchi rotary evaporator. Thin layer chromatography was performed on Kieselgel GF254 and visualization was accomplished by iodine Flask or UV Lamp. The IR spectra were recorded on a Shimadzu 8400 instrument (the samples as KBr disks for the range 400-4000 cm-1).1H and 13C NMR spectra were measured (CDCl3 and DMSO-d6 as solvents) with a BRUKER DRX-400 AVANCE spectrometer. Chemical shifts were reported in δ unit (ppm) with reference to TMS as an internal standard. Elemental analysis was performed on a Thermo Finnigan (San Jose, CA, USA) Flash EA microanalyzer, and the results were found to match satisfactorily with the calculated and observed values. General procedure for the synthesis of arylidene-hydrazino-5,6di(alkyl)thieno[2,3-d]pyrimidine (6a-6d) Compounds (4a-4d) were prepared according to the literature [20]. To synthesize (6a-6d), a mixture of hydrazino compound (2b) (2 mmol) and aromatic aldehydes (3a-3e) (3 mmol) in ethanol (10 cm3) were refluxed at 80 °C for 3 hours with continuous stirring. The progress of the reaction was monitored by TLC (ethyl acetate: n-hexane, 1:1, v/v) and showed complete conversion of the reactant to the product. The reaction mixture was then left to cool overnight to room temperature for complete precipitation. The solid was filtered off, dried and recrystallized from ethanol to give arylidene-hydrazino-5,6- di(alkyl)thieno[2,3-d]pyrimidines in good yield. (6a-6d) 4-(4-Methylbenzylidenehydrazino)5,6,7,8-tetrahydro[1]benzothieno[2,3d]pyrimidine (6a) Brown crystals, Yield: 86 %, (0.55 g), mp: 219-220 °C. IR (ν, cm-1): 3255 (NH), 3055 (CH-aromatic), 2924 (CH-aliphatic), 1620 (C=N) cm-1. 1H NMR (CDCl3); δ (ppm): 1.80-1.92 (m, 4H, 2CH2), 2.40 (s, 3H, CH3), 2.75-2.84 (m, 2H, CH2), 2.84-2.93 (m, 2H, CH2), 7.20-7.69 (dd, 4H-aromatic ring), 8.00 (br s, 1H, NH), 8.46 (s, 1H, N=CH), 8.63 (s, 1H, CH-pyrimidine). 13C NMR (CDCl3); δ (ppm): 21.56, 22.24, 23.04, 25.59, 119.26, 127.03, 128.16, 131.31, 132.42, 139.76, 144.40, 148.64, 153.48, 157.12. Anal. calcd. for C18H18N4S (322.43): C (67.05), H (5.63), N (17.38), S (9.94). Found: C (66.95), H (5.72), N (17.25), S (10.08) (%). 4-(4-Nitrobenzylidenehydrazino)-5,6,7,8tetrahydro[1]benzothieno[2,3d]pyrimidine (6b) Red crystals, Yield: 90 %, (0.63 g), mp: 270-271 °C. IR (υ, cm-1): 3325 (NH), 3055 (CH-aromatic), 2931 (CH-aliphatic), 1620 (C=N) cm-1. 1H NMR (DMSO-d6); (δ ppm): 1.70-2.00 (m, 4H, 2CH2), 2.70-2.80 (m, 2H, CH2), 2.95-3.05 (m, 2H, CH2), 7.88 (s, 1H, N=CH), 8.16-8.31 (dd, 4H-aromatic ring), 8.49 (s, 1H, CH-pyrimidine), 12.12 (br s, 1H, NH). 13C NMR (DMSO-d6); (δ ppm): 22.47, 22.88, 25.11, 27.07, 119.32, 123.07, 126.69, 127.02, 132.42, 141.03, 144.41, 148.66, 149.46, 153.42, 157.18. Anal. calcd. for C17H15N5O2S (353.40): C (57.78), H (4.28), N (19.82), S (9.07). Found: C (57.49), H (4.43), N (19.65), S (8.92) (%). 4-(4-Chlorobenzylidenehydrazino)5,6,7,8-tetrahydro[1]benzothieno[2,3d]pyrimidine (6c) Brown crystals, Yield: 89 %, (0.61 g), mp: 192-193 °C. IR (υ, cm-1): 3309 (NH), 3063 (CH-aromatic), 2932 (CH-aliphatic), 1620 (C=N) cm-1. 1H NMR (CDCl3); (δ ppm): Page | 115 A new facile route to synthesize thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 1.80-1.93 (m, 4H, 2CH2), 2.75-2.84 (m, 2H, CH2), 2.84-2.92 (m, 2H, CH2), 7.34-7.77 (dd, 4H-aromatic ring), 7.99 (br s, 1H, NH), 8.44 (s, 1H, N=CH), 8.64 (s, 1H, CHpyrimidine). 13C NMR (CDCl3); (δ ppm): 18.46, 22.52, 2 (...truncated)