Research Journal of Recent Sciences ______ ______________________________ ______ ___ __ _ ISSN 2277 - 2502 Vol. 1( ISC - 2011 ), 1 05 - 109 (201 2 ) Res.J. Recent .Sci. International Science Congress Association 105 Microwave assisted synthesis of 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1, 3, 5 - triazine - 2, 4 (1H, 3H) - dione derivatives Under solvent free condition with high yields Yaddanapudi Prabhakar, Kottapalli R S Prasad and Jagarlapudi V S Kumar Department of Chemistry, K . L . University, Vaddeswaram , Andhra Pradesh, INDIA Available online at: www.isca.in (Received 27 th November 2011, revised 31 th December , accepted 24 th January 2012 ) Abstract A simple and highly efficient procedure has been described for the synthetic derivatives of 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1,3,5 - triazine - 2,4(1H, 3H) - dione under solvent free condition at microwave power 400 W using domestic microwave. The structures of synthesised compounds are confirmed by using spectral studies. Keywords: S ynthesis, microwave irradiation, heterocyclic compounds and spe ctral studies. Introduction Microwave assisted organic synthesis has become a field of increasing interest in the use of environmentally safe conditions. Microwave irradiation provides a way for flash heating as an alternative to standard th ermal heating in chemical reactions. This technology has been employed to drastically reduce reaction times and even modify selectivity. In addition to this feature, the use of microwave irradiation may outperform conventional reaction conditions in other aspects, such as easier workup, reduction of the usual thermal degradation products, reduction of toxic and expensive quantities of solvents (green chemistry), and reduction of secondary products. Also, microwave irradiation has proven to be of benefit par ticularly for reactions under dry media (i.e. in the absence of solvents or solid support) and reactions without catalysts . Recent advances in the technology have now made microwave energy a more efficient means of heating reaction. The use of microwave irradiation has introduced several new concepts in chemistry, since the absorption and transmission of the energy is completely different from the conventional mode of heating. Particularly, reactions involving a heterogeneous mixture of the two neat react ants can eventually lead to a clean, eff icient and be more economical . Microwave irradiation has become a very useful tool in organic synthesis and has been used to enhance a great number of classical reactions in the last 20 years due to the advantages t hey provide over conventional heating methods. So we designed solvent free microwave assisted synthesis of 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1 , 3, 5 - triazine - 2,4(1H, 3H) - dione derivatives 1 - 4 . Material and Methods Bv8 is a small protein secreted by frog ’s skin. Mammalian homologues of Bv8 (Bombina variegata molecular mass ~8 kDa) the prokinetici a n receptor PK1 and PK2, and their G - protein coupled receptors PKR1 and PKR2 have been identified and linked to several biological effects 6, 8, 9, 11 . T riazine compounds as antagonists at Bv8prokinetician receptors , we proposed a convenient and solvent free microwave assisted synthetic approach for 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1,3,5 - triazine - 2,4(1H, 3H) - dione derivatives 1, 2, 3, 4, 5, 7, 12 . First three steps are synthesised in reported procedures and we got consistent yields to the reported method. But in the step - 4 we faced a solubility issue of triazine compound. Because of this reason we end up with poor yields. So we look forward for the better synthetic procedure. We found 4 - bromobenzene sulfonyl chloride as one of the better leaving groups in substitution reactions. Fist we coupled with 4 - bromo benzenesulfonyl chloride with 4 - ethyl benzyl alcohol then we did a subst itution reaction with triazine compound. We got yield of 76% with high purity with microwave irradiation at 70 0 C (400W) with in 0.5 h. This result made us to think of microwave assisted synthesis of 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1 ,3,5 - triazine - 2,4(1H, 3H) - dione derivatives. Microwave irradiation reduces the reaction time at the maximum and avoids other unwanted side reactions. Solvent free conditions reduce lot of synthetic process and also environmental ly safe. Purification of th ese types of reactions makes much easier than the conventional reactions. High recovery of unreacted raw materials is the major advantage in solvent free conditions which gives economical synthetic approach. Here majorly we synthesised triazine derivatives by substituting “ - SMe” with primary amine group. Research Journal of Recent Sciences ______ _ _ _______________________________ ______________ _ ______ ISSN 2 277 - 2502 Vol. 1( ISC - 2011 ), 1 05 - 109 (201 2 ) Res.J.Recent.Sci International Science Congress Association 106 Conventional route is taking 8 h time for the complete conversion of starting compound to product but in microwave irradiation w e synthesised same compound with in 5 min. This result has given good support f or our basic idea. We synthesised few derivatives, but all the derivative s gave above 90% yield and a complete recovery of unreacted starting material. Figure - 1 THF, DEAD, PPh 3 , room temp. Y =70%; (b) TFA, room temp. Y = 97%; (c) Dichloromethane, chlorocarbonyl isocyanate, N,N - diisopropylethylamine, 18 h, Y = 30%.Synthesis of 1 - (4 - Methoxybenzyl) - 6 - (methylthio) - 1 , 3,5 - triazine - 2,4(1H, 3H) - dione Figure - 2 (d) N,N - diisopropylethylamine, N,N - dimethylaminopyridine, di chloromethane, room temperature, 18 h. (e) Cs 2 CO 3 , DMF, 70 0 C, Microwave, 0.5 h .Y=72% Synthesis of 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1,3,5 - triazine - 2,4(1H,3H) - dione Figure - 3 Microwave assisted synthesis of 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1, 3, 5 - triazine - 2,4(1H, 3H) - dione derivatives. Research Journal of Recent Sciences ______ _ _ _______________________________ ______________ _ ______ ISSN 2 277 - 2502 Vol. 1( ISC - 2011 ), 1 05 - 109 (201 2 ) Res.J.Recent.Sci International Science Congress Association 107 Table - 1 List of substituted aromatic primary amines (R) used for the derivatisation process and the obtained products S. No. (R) Product Yield (%) 1 97 2 95 3 93 4 98 5 96 Results and Discussion We followed the s ynthetic procedure for 1 - (4 - Methoxybenzyl) - 6 - (methylthio) - 1,3,5 - triazine - 2,4(1H, 3H) - dione 4 . Even for compound (5) also we tried to follow but because of solubility issue with compound (3) we got very poor yield. So we tried to make – OH as good leaving group by coupling with 4 - b romobenzenesulfonylchloride and substitution with compound (3) then we got good yield (72%). But in a conventional route it took 18 h to complete starting material. Same conditions , we tried in microwave to reduce reaction time , strangely starting material was consumed in 0.5 h and with same yield as conventional. “ – SMe” is one of the better leaving groups in organic chemistry . B ased on this logic we prepared derivatives of compound (5). Substituted benzyl amines are taken for this process because these are liquid in nature, so it helps in solvent free synthesis. When we took compounds (a - e) and compound (5) in a microwave vial , homogeneous solution appeared. After 5 min microwave irradiation at 120 0 C compound (5) was consumed. Crude as it is was purified by silica gel column chromatography without any workup. Unreacted compounds (a - e) were recovered. Experimental procedure: 1,3 - Bis - (tert - butoxycarbonyl) - 1 - (4 - methoxybenzyl) - 2 - methyl - 3 - thiopseudourea (1): To a solution of 1,3 - bis(tert - butoxycarbonyl) - 2 – me thyl – 2 - thiopseudourea (2.0 g, 6.90 mmol), 4 - methoxybenzyl alcohol (0.94 mL, 7.59 mmol) and triphenylphosph i ne (1.99 g, 7.59 mmol), at 0 0 C in anhydrous THF, was added solution of diethyl azodicarboxylate (1.4 mL, 7.59 mmol) dissolved in anhydrous THF. Af ter 10 min, the reaction was warmed to room temperature and stirred for 18 h. The solvent was removed under vacuum, and the crude intermediate was purified by flash chromatography (EtOAc/Pe tether , 1:9, v/v): yield 2.04 g (72%); m/z 411 (M + H)+. 1 H NMR (CDCl 3 ): δ 7.2 9 - 7.2 8 (d, 2H, J = 8.4 Hz), 6.87 - 6.86 (d, 2H, J = 8.4 Hz), 4.73 (s, 2H), 3.81 (s, 3H), 2.28 (s, 3H), 1.5 4 (s, 9H), 1.4 4 (s, 9H). 1 - (4 - Methoxy - benzyl) - 2 - methyl - 3 - thiopseudourea (2): Intermediate (1) (1.51 g, 3.68 mmol ) was treated with TFA (10 mL) for 3 h. at room temperature. TFA was removed Research Journal of Recent Sciences ______ _ _ _______________________________ ______________ _ ______ ISSN 2 277 - 2502 Vol. 1( ISC - 2011 ), 1 05 - 109 (201 2 ) Res.J.Recent.Sci International Science Congress Association 108 under vacuum, crude was cooled to 0 0 C and the deprotected intermediate was precipitated from Et 2 O: yield 1.15 g (97%); m/z 211 (M +H)+. 1 H NMR (DMSO - d6): δ 9.17 (s,2H), 7.26 - 7.23( d, 2H, J=8.6), 6.95 - 6.92 (d, 2H, J=8.6), 4.47 - 4.45 (d, 2H, J=5.5), 3.73(s, 3H), 2.60 (s, 3H). 1 - (4 - Methoxybenzyl) - 6 - (methylthio) - 1 , 3,5 - triazine,4(1H, 3H) - dione (3): To a solution of (2) (1.1 g, 3.57 mmol) in dichloromethane (20 mL) at 0 0 C N,N - diisopropylethylamine (1.83 mL, 10.7 mmol) was added. At the same tem perature, N - Chlorocarbonyl isocy anate (0.26 mL, 3.57 mmol), dissolved in dichloromethane (5 mL), was added drop wise. The reaction mixture was allowed to stir while slowly warming to room temperature (1 h) and was then stirred for an additional 24 h. The solvent was evaporated, and the residue was partitioned between EtOAc and H 2 O. The EtOAc layer was washed with brine and dried over Na 2 SO 4 . The solution was filtered, the solvent evaporated , and the residual oil was precipitated from methanol: yield 0.276 g (30%); m/z 280 (M + H)+. 1 H NMR (DMSO - d6): δ 11.58 (bs, 1H), 7.2 3 - 7.2 0 (d, 2H, J= 8.7 Hz), 6.9 0 - 6.8 7 (d, 2H, J= 8 . 7 Hz), 4.97 (s, 2H), 3.73 (s, 3H), 2.45 (s, 3H). 4 - Ethylbenzyl 4 - bromobe nzenesulfonate (4) (Scheme - 2) : To a solution of (4 - ethylphenyl)methanol (0.5 g, 3.67 mmol) in dichloromethane (10 mL) at 0 0 C N,N - diisopropylethylamine (1.25 mL, 7.34 mmol) and N,N - dimethyl amino pyridine (0.089 g, 0.73 mmol ) was added. After 10 min, 4 - bromobenzenesulfonylchloride (1.03 g, 4.03 mmol) was added portion wise and stirred at room temperature for 18 h. The solvent was evaporated, and the residue was partitioned between EtOAc and water, EtOAc layer was separated, w ashed with saturated sodium bicarbonate solution, dried over Na 2 SO 4 , filtered and evaporated the solvent. Crude (1.2 g) was taken for the next step without any further purification. 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1,3 ,5 - triazine - 2,4( 1H, 3H) - dione (5) (Scheme - 2): A solution of (4) (0.6 g crude), (3) (0.250 g, 0.89 mmol) and Cs 2 CO 3 (0.583 g, 1.79 mmol) in dry DMF (3 mL) was subjected for microwave irradiation (400W) at 70 0 C for 0.5 h. The reaction mass was diluted with ethyl acetate, f iltered and evaporated the filtrate. Crude intermediate was purified by flash chromatogr aphy (EtOAc/Petether, 2:8, v/v) ; Yield=0.256 g (72%). m/z=(M+ H )+=420 . 1 H NMR (DMSO - d6): δ 7.24 - 7.20 (m, 4H), 7.15 - 7.12 (d, 2H, J=8Hz), 6.90 - 6.87 (d, 2H, J=8.6 Hz), 3.71 (s, 3H), 2.58 - 2.53 (q, 2H, J=7.5Hz), 2.46 (s, 3H), 1.15 - 1.10 (t, 3H, J=7.5 Hz). 13 C NMR (CDCl 3 ): 169.84, 159.52, 152.19, 150.43, 143.91, 133.30, 129.39 (2 carbon atoms), 129.20 (2 carbon atoms), 127.88 (2 carbon atoms), 126.23, 114.05 (2 carbon atoms), 55 .20, 47.93, 45.36, 28.49, 15.44, 15.23. 6 - ( B enzylamino) - 3 - (4 - ethylbenzyl) - 1 - (4 - methoxybenzyl) - 1,3,5 - triazine - 2,4(1H, 3H) - dione (5a) (Scheme - 3): The mixture of (5) (0.05 g, 0.12 mmol) and (a) (0.134 g, 1.25 mmol) in a vial stirred for 1 min and subjected to microwave irradiation (400W) at 120 0 C for 5 min. Reaction mass was directly purified by flash chromatography (EtOAc/Petether, 4:6, v/v); yield=0.055 g (97%). m/z (M+H)+= 457. 1 H NMR (CDCl 3 ): δ 8.26 (bs, 1H), 7.26 - 7.19 (m, 7H), 7.13 - 7.08 (m, 4H), 6.91 - 6.89 (dd, 2H, J= 2.04Hz, 2.0Hz), 5.08 (s, 2H), 4.86 (s, 2H), 4.51 - 4.50 (d, 2H, J=4.6), 3.73 (s, 3H), 2.58 - 2.52 (q, 2H, J=7.6Hz), 1.16 - 1.12 (t, 3H, 7.5Hz). 13 C NMR (CDCl 3 ): 159.83,154.43, 153.87, 151.37, 143 .59, 136.33, 134.08, 129.07 (2 c a r bon atoms ), 128.69 (2 c a r bon atoms), 127.91 (3 c a r bon atoms), 127.81 (2 c a r bon atoms), 127.44 (2 c a rbon atoms), 125.64, 114.90 (2 c a r bon atoms), 55.29, 45.88, 45.37, 45.33, 28.49, 15.45. 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (4 - ethylbenzyla mino - 1,3,5 - triazine - 2, 4(1H,3H) - dione (5b) (Scheme - 3): The mixture of (5) (0.05 g, 0.12 mmol) and (b) (0.152 g, 1.25 mmol) in a vial stirred for 1 min and was subjected to microwave irradiation (400W) at 120 0 C for 5 min. Reaction mass directly purified by flash chromatography ( EtOAc/Petether, 4:6, v/v); yield=0.056 g (95%). m/z(M+H)+= 471. 1 H NMR (CDCl 3 ): δ 8.22 (bs, 1H), 7.18 - 7.10 (m, 7H), 7.04 - 6.958 (m, 4H), 6.90 - 6.87 (d, 2H, 8.6Hz), 5.06 (s, 2H), 4.84 (s, 2H), 4.45 - 4.43 (d, 2H, 5.4Hz), 3.72 (s, 3H), 2.57 - 2.52 (q, 2H, 7.5Hz), 2.25 (s, 3H) 1.15 - 1.10 (t, 3H, 7.6Hz). 13 C NMR (CDCl 3 ): 159.79, 154.53, 153.84, 151.57, 143.56 , 137.56, 134.12, 133.30, 129.33 (2 carbon atoms), 129.18 (2 carbon atoms), 127.94 (2 carbon atoms), 127.80 (2 carbon atoms), 127.46 (2 carbon atoms), 125.72, 114.85 (2 carbon atoms), 55.27, 45.69, 45.34, 45.28, 28.49, 21.0, 15.45. 3 - (4 - Ethylbenzyl) - 6 - (4 - fluorobenzylamino) - 1 - (4 - methoxy benzyl) - 1,3,5 - triazine - 2,4(1H,3H) - dione (5c) (Scheme - 3): The mixture of (5) (0.05 g, 0.12 mmol) and (c) (0.157 g, 1.25 mmol) in a vial stirred for 1 min and was subjected to microwave irradiation (400W) at 120 0 C for 5 min. Reaction mass was directly purified by flash chromatography (EtOAc/Petether, 4:6, v/v); yield=0.055 g (93%). m/z(M+H)+= 475. 1 H NMR (CDCl 3 ): δ 8.28 (bs, 1H), 7 .20 - 7.17 (m, 8H), 7.15 - 7.05 (m, 2H), 6.92 - 6.90 (d, 2H, J=8.6Hz), 5.07 (s, 2H), 4.86 (s, 2H), 4.49 - 4.48 (d, 2H, J=5.2Hz), 3.74 (s, 3H), 2.58 - 2.55 (q, 2H, J=7.5Hz), 1.16 - 1.13 (t, 3H, J=7.6Hz). 13 C NMR (CDCl 3 ): 159.75, 154.67, 153.90, 151.49, 143.64, 134.02, 132.41,132.36, 129.25, 129.15, 128.96 (2 carbon atoms), 127.99 (2 carbon atoms), 127.82 (2 carbon atoms), 125.78, 115.57, 115.28, 114.74 (2 carbon atoms), 55.26, 45.36, 45.14, 44.87, 28.47, 15.44. 6 - (4 - Chlorobenz ylamino) - 3 - (4 - ethylbenzyl) - 1 (4 methoxy ben zyl) - 1,3,5 - triazine - 2,4(1H,3H) - dione (5d) (Scheme - 3): The mixture of (5) (0.05 g, 0.12 mmol) and (d) (0.178 g, 1.25 mmol) in a vial stirred for 1min and was subjected to microwave irradiation (400W) at 120 0 C for 5 min. Reaction mass was directly purified b y flash chromatography (EtOAc/Petether, 4:6, v/v); yield=0.060 g (98%). Research Journal of Recent Sciences ______ _ _ _______________________________ ______________ _ ______ ISSN 2 277 - 2502 Vol. 1( ISC - 2011 ), 1 05 - 109 (201 2 ) Res.J.Recent.Sci International Science Congress Association 109 m/z(M+H)+ =491. 1 H NMR (CDCl 3 ): δ 7.42 - 7.40 (d, 2H), 7.16 - 7.09 (m, 6H), 6.86 - 6.82 (m, 4H), 5.72 (bs, 1H), 5.06 - 5.04 (d, 4H, J=6.4Hz), 4.44 - 4.42 (d, 2H, 4.9Hz), 3.79 (s, 3H), 2.66 - 2.6 0 (q, 2H, 7.4Hz),1.26 - 1.22 (t, 3H, 7.5Hz). 13 CNMR(CDCl 3 ): 159.78, 154.60, 153.94, 151.47, 143.66, 135.09, 133.50, 128.99 (2 carbon atoms), 128.76 (2 carbon atoms), 128.70, 128.53, 128.40, 127.96 (2 carbon atoms), 127.83 (2 carbon atoms), 125.71, 114.78 (2 carbon atoms), 55.29, 45.38, 45.17, 44.86, 28.48, 15.46. 6 - (2 - Bromobenzylamino) - 3 - (4 - ethylbenzyl) - 1 - (4 - methoxy benzyl) - 1,3,5 - triazine - 2,4(1H,3H) - dione (5e) (Scheme - 3): The mixture of (5) (0.05 g, 0.12 mmol) and (e) (0.234 g, 1.25 mmol) in a vial stirred for 1 min and was subjected to microwave irradiation (400W) at 120 0 C for 5 min. Reaction mass directly purified by F lash chromatography (EtOAc/Petether, 4:6, v/v); yield=0.064 g (96%). m/z(M+H)+ 535. 1 H NMR (CDCl 3 ): δ 7.46 - 7.41 (m, 3H), 7.18 - 7.14 (t, 7H, J=6.4Hz), 6.85 - 6.83 (d, 2H, J=8.6Hz)), 5.95 - 5.92 (t, 1H, J=5.0Hz), 5.04 - 5.02 (d, 4H, J=7.4Hz), 4.58 - 4.56 (d, 2H, J=5.4Hz), 3.79 (s, 3H), 2.65 - 2.59 (q, 2H, J=7.5Hz), 1.23 - 1.20 (t, 3H, J=7.6Hz). 13 C NMR (CDCl 3 ): 159.77, 154.59, 154.05, 151.56, 143.59, 135 .79, 134.05, 132.60, 130.62, 129.47, 129.07 (2 carbon atoms), 128.09, 127.8, 127.71 (2 carbon atoms), 127.64, 125.68, 123.58, 114.79 (2 carbon atoms), 55.29, 45.76, 45.39, 45.36, 28.48, 15.47. Conclusion In conclusion, we have synthesised a series of 3 - (4 - Ethylbenzyl) - 1 - (4 - methoxybenzyl) - 6 - (methylthio) - 1, 3, 5 - triazine - 2,4(1H, 3H) - dione derivatives in very short time with high yield. Our main interest is to show that solvent free synthesis is environmentally safe and economical. 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