Microwave-assisted, one-pot multicomponent synthesis of highly substituted pyridines using KF/alumina

Transcription

1 General Papers ARKIVOC 2009 (xiii) 11 Microwaveassisted, onepot multicomponent synthesis of highly substituted pyridines using Krishna Nand Singh* and Satish Kumar Singh Department of Chemistry, Faculty of Science, Banaras indu University, Varanasi22, India Abstract in conjunction with monomode microwave irradiation brings about an efficient onepot synthesis of substituted pyridines in high yields using a multicomponent reaction of aromatic aldehydes, malononitrile, and thiophenol in ethanol. The effect of different bases on the product yield has also been investigated under conventional heating as well as under microwave conditions by varying power (Watt), temperature and time. Keywords: Microwave, multicomponent synthesis, pyridines, heterogeneous catalyst, privileged medicinal scaffold Introduction Microwave (MW) provides a powerful way to do synthetic chemistry in the light of the current paradigm shift to Green Chemistry. It provides many chemical reactions with attributes, such as enhanced reaction rates, higher yields of pure products, better selectivity, improved ease of manipulation, rapid optimization of reactions and several ecofriendly advantages. 1 Multicomponent reactions (MCRs) have recently taken a new dimention in organic synthesis, as they comply well with the requirements for ideal organic syntheses. 2 According to the current synthetic requirements, environmentally benign multicomponent procedures employing microwave methodology are particularly welcome. The usefulness of MCRs is even greater when they provide access to "privileged medicinal scaffolds". One such significant scaffold is the pyridine nucleus which is key constituent of a wide range of both natural and synthetic bioactive compounds. 4 Owing to its vast medicinal utility, various methods have been adopted for the preparation of substituted pyridines, viz., heterodielsalder reaction of siloxy1aza1,butadiens and 21,4oxazinones with acetylenes, rutheniumcatalyzed cycloisomerization of azadienynes, 6 Mannich reaction of aldehydes and iminium salts, Vilsmeieraack reaction of αhydroxyketenedithioacetals, 8 6π ISSN Page 1

2 General Papers ARKIVOC 2009 (xiii) 11 azaelectrocyclization of azatrienes, catalytic oxidation of 1,4dihydropyridines by RuCl /O 9 2, [4+2] cycloadditions of oximinosulfonates, 10 conversion of conjugated oximes under Vilsmeier conditions, 11 Nmethylenetertbutylamine with enamines, 12 conversion of ketene dithioacetals to substituted pyridines 1 and multicomponent reactions using triethyl amine/dabco 14 [bmim]o 1, DBU 16 and ZnCl 1 2. Many of these methods, however, require high temperature and suffer from the serious limitations like formation of considerable amounts of side products and lower product yields. Subsequently, there stands a demand and scope for an efficient, facile and ecosafe approach. Organic reactions promoted by a solid heterogeneous catalyst have attracted widespread interest and are advantageous because of operational simplicity, high selectivity, and clean separation of the product. Potassium fluoride impregnated over alumina () has been recognized as a remarkably useful green heterogeneous catalyst to promote a wide range of organic reactions. 18 We herein report a rapid and green approach to achieve highly substituted pyridines in excellent yields in the presence of catalytic amount of under controlled MW irradiation. Results and Discussion In view of the potential medicinal importance of the products and considering the limitations of the existing methods, we have investigated a (10 mol%) catalyzed, onepot, simple and efficient procedure for the rapid construction of substituted pyridines via a threecomponent reaction of aldehydes, malononitrile and thiophenols (molar ratio 1:2:1) in ethanol under reflux (682 %) and also under controlled microwave conditions (629 %) (Scheme 1)., Microwave R CO R 2 CN R 1 CN 1a1n 2 S R 4 ac R 1 =R =, OC, R 2 =, OC, C, F, Cl, Br, O, NO 2 R 4 =, OC, C o C, 10 min. (629%) R 1 NC 2 N EtO, reflux, 00min. (682%) R 2 N 4a4n R CN S R 4 Scheme 1 ISSN Page 14

3 General Papers ARKIVOC 2009 (xiii) 11 The observed synthesis of substituted pyridines works well for unsubstituted as well as for electronrich/electrondeficient aromatic aldehydes. In case of aliphatic and heterocyclic aldehydes, however, some intractable products of unidentified nature were obtained. In order to optimize the reaction conditions, a typical reaction of benzaldehyde (1a, 1 mmol), malononitrile (2 mmol) and thiophenol (1 mmol) was carried out in the presence of different bases under conventional heating as well as under microwave irradiation at different power (Watt), temperature and time in ethanol. The outcome is presented in Table 1. It is evident from the table that a catalytic amount of accomplishes the reaction successfully and the use of the microwave irradiation further enhances the yield of the product considerably with dramatic reduction in the reaction time, the best result being obtained using 120W at ºC in minutes in the presence of (10 mol%) (cf. entry 6). Table 1. Optimization of reaction conditions using compound 1a as reference Entry Base (10 mol%) Basic alumina Basic alumina KF KF K 2 CO NaO MW (Watt) Microwave Temp. (ºC) Time (min.) Yield (%) Temp. (ºC) RT 8 RT 8 RT Conventional Time (h) Yield (%) Under the optimized set of reaction conditions (entry 6), a number of aromatic aldehydes 1 were allowed to undergo multicomponent reaction with malononitrile 2 and thiophenol in a molar ratio of 1:2:1 with (10 mol%) in ethanol under reflux (8 ºC) as well as under microwave (120W, ºC) heating. After completion of the reaction, the resulting precipitate was filtered and recrystallized from acetonitrile/methanol to yield pure substituted pyridine 4a4n. All the products were crystalline and fully characterized based on their melting points, elemental analyses and spectral data (IR, 1 NMR, 1 CNMR). The reaction data are indicated in Table 2 and reveal that the aldehydes containing electron withdrawing groups undergo reaction sluggishly with diminution of the product yield. ISSN Page 1

4 General Papers ARKIVOC 2009 (xiii) 11 Table 2. catalyzed threecomponent reaction of substituted aldehydes with malononitrile and thiols Entry R 1 R 2 R R 4 Reaction Conditions Microwave b Conventional Time Yield Time Yield (min.) (%) a (min.) (%) a Cl Br OC OC OC OC NO 2 Cl F Br C O OC OC C OC OC a Isolated yield based on aldehydes. b Microwave heating performed on 120 Watt power and ºC temperature. Conclusions The present work describes an efficient onepot multicomponent synthesis of 2amino, dicarbonitrile6sulfanylpyridines through a condensation of aldehydes, malononitrile and thiols in ethanol under controlled microwave as well as conventional heating conditions using as a heterogeneous green catalyst. Experimental Section General. All the chemicals were procured from Aldrich, USA, and E. Merck, Germany and were purified prior to their use. IR spectra were recorded on a JASCO FT/IR00 spectrophotometer. NMR spectra were run on a JEOL AL00 FTNMR spectrometer; chemical shifts are given in δ ppm, relative to TMS as internal standard. Elemental microanalysis was performed on Exeter Analytical Inc Model CE440 CN Analyzer. Melting points were measured in open capillaries ISSN Page 16

5 General Papers ARKIVOC 2009 (xiii) 11 and are uncorrected. The microwave irradiation was effected using the CEM s Discover Bench Mate singlemode microwave synthesis system using safe pressure regulation 10mL pressurized vials with snapon cap. KF/Alumina was prepared according to a method described in literature. 18 General conventional procedure for synthesis of polysubstituted pyridines 4 To a mixture of aldehyde (1. mmol) and malononitrile ( mmol) in anhydrous ethanol ( ml) was added (10 mol%) and the resulting mixture was stirred at room temperature. A precipitation took place within 2 minutes, after which thiophenol (1. mmol) was added while continuing the stirring. The reaction mixture was subsequently reflux for 00 minutes to complete the reaction (TLC) and then allowed to cool at room temperature. The resulting precipitate was filtered and recrystallized from acetonitrile/methanol to yield pure product 4a4n. General microwave procedure for synthesis of polysubstituted pyridines 4 Aldehyde (1 mmol), malononitrile (2 mmol), (10 mol%), thiophenol (1 mmol) and anhydrous ethanol (1. ml) were mixed and placed in a sealed pressure regulation 10mL pressurized vials with snapon cap and was irradiated in the singlemode microwave synthesis system at 120W power and ºC temperature for 10 minutes. After the completion of reaction (TLC), the mixture was cooled and precipitate formed was filtered and recrystallized from acetonitrile/methanol to yield the pure product 4a4n. 2Amino4phenyl6phenylsulfanylpyridine,dicarbonitrile 4a. Colourless solid, mp: 2121 ºC (Lit. 1 mp: ºC). IR (KBr): 4,, 292, 2212, 1619, 144, 1461, 124, 114, 108, 0 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.8 (bs, 2, N 2 ),.1.9 (m, 10, Ar). 1 C NMR ( Mz, DMSOd 6 ): δ = 16.6, 161.0, 18., 16.1, 14.2, 10.9, 10.1, 129., 129.2, 128.6, 12.8, 116.1, 94., 8.4. Anal. Calcd for C N 4 S (28.9): C, 69.49;,.69; N, Found: C, 69.24;,.8; N, Amino6(4methylphenylsulfanyl)4phenylpyridine,dicarbonitrile 4b. LightYellow solid, mp: ºC. IR (KBr): 42, 2, 209, 06, 2922, 221, 161, 14, 142, 110, 1181, 1020, 4, 04 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.8 (bs, 2, N 2 ),.46.6 (m, 6, Ar),.29.2 (m,, Ar), 2. (s,, C ). 1 C NMR ( Mz, DMSOd 6 ): δ = 166.6, 19.6, 18.6, 19.6, 1.0, 1.9, 10., 10.1, 128., 128.4, 12.4, 11., 11.0, 9.1, 86.9, Anal. Calcd for C N 4 S (42.42): C, 0.1;, 4.12; N, Found: C, 0.28;, 4.19; N, Amino6(4methoxyphenylsulfanyl)4phenylpyridine,dicarbonitrile (4c). Colourless solid, mp: ºC. IR (KBr): 42, 2, 222, 0, 266, 2210, 1629, 140, 141, 126, 11, 1028, 99, 4, 08 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =. (bs, 2, N 2 ),.49.6 (m, 6, Ar),.04.0 (m,, Ar),.82 (s,, OC ). 1 C NMR ( Mz, DMSOd 6 ): δ = 166.4, 161.2, 1.0, 18., 1., 10., 10.1, 129.9, 12.6, 126., 11.9, 114., 9., ISSN Page 1

6 General Papers ARKIVOC 2009 (xiii) 11 8.,.4. Anal. Calcd for C N 4 OS (8.42): C, 6.02;,.94; N, 1.6. Found: C, 6.1;,.88; N, Amino4(4methoxyphenyl)6phenylsulfanylpyridine,dicarbonitrile 4d. Colourless solid, mp: C (Lit. 1 mp: ºC). IR (KBr): 49, 0, 226, 282, 2218, 1641, 14, 11, 12, 118, 1021, cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.2 (bs, 2, N 2 ),.48.9 (m, 6, Ar), (m,, Ar),.8 (s,, OC ). 1 C NMR ( Mz, DMSOd 6 ): δ = 166.1, 1.8, 19., 18.2, 14., 10.2, 129.6, 129.4, 12.2, 12., 11., 11.2, 114.0, 9., 86.9,.. Anal. Calcd for C N 4 OS (8.42): C, 6.02;,.94; N, 1.6. Found: C, 66.8;,.91; N, 1.. 2Amino4(4methoxyphenyl)6(4methoxyphenylsulfanyl)pyridine,dicarbonitrile 4e. White solid, mp: C. IR (KBr): 99, 21, 222, 29, 2840, 221, 1642, 14, 10, 14, 121, 114, 102, 82, 6 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.69 (bs, 2, N 2 ),.48.2 (m, 4, Ar),.04.1 (m, 4, Ar),.8 (s,, OC ),.82 (s,, OC ). 1 C NMR ( Mz, DMSOd 6 ): δ = 16., 1.9, 1.6, 19.8, 18.2, 16.1, 12.8, 11.2, 11.6, 11.4, 11.1, 114.1, 92.9, 86.,.4,.. Anal. Calcd for C N 4 O 2 S (88.44): C, 64.9;, 4.1; N, Found: C, 64.;, 4.21; N, Amino4(4nitrophenyl)6phenylsulfanylpyridine,dicarbonitrile 4f. Yellow solid, mp: ºC (Lit. 1 mp: ºC). IR (KBr): 420, 2, 24, 08, 222, 2210, 16, 14, 10, 146, 1422, 12, 126, 116, 890, 846, 6, cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ = 8.8 (d, 2, Ar), 8.10 (bs, 2, N 2 ),.86 (d, 2, Ar),.8. (m, 2, Ar),.4.46 (m,, Ar). 1 C NMR ( Mz, DMSOd 6 ): δ = 166.2, 19., 16., 148.8, 140.2, 14.9, 10., 10.1, 129., 124.0, 11.2, 114.6, 9.0, Anal. Calcd for C N O 2 S (.9): C, 61.12;, 2.9; N, Found: C,.8;,.0; N, Amino4(4chlorophenyl)6phenylsulfanylpyridine,dicarbonitrile 4g. Colourless solid, mp: 2222 C (Lit. 1 mp: ºC). IR (KBr): 42, 46, 221, 29, 2216, 1, 12, 1486, 12, 1112, 8 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.6 (bs, 2, N 2 ), (m, 6, Ar), (m,, Ar). 1 C NMR ( Mz, DMSOd 6 ): δ = 166., 19.8, 1., 1.4, 1.1, 12.9, 10., 129., 129., 129.0, 126.9, 11., 11.0, 9.4, 8.. Anal. Calcd for C ClN 4 S (62.84): C, 62.89;,.06; N, Found: C, 6.0;, 2.9; N, 1.. 2Amino4(chlorophenyl)6phenylsulfanylpyridine,dicarbonitrile 4h. Colourless solid, mp: C. IR (KBr): 42, 44, 222, 068, 2218, 1628, 11, 128, 146, 12, 1021, 8, 08 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.1 (bs, 2, N 2 ),.6.69 (m, 2, Ar),.6 (s, 1, Ar),.4.4 (m, 6, Ar). Anal. Calcd for C ClN 4 S (62.84): C, 62.89;,.06; N, Found: C, 6.0;,.10; N, 1.. 2Amino4(4fluorophenyl)6phenylsulfanylpyridine,dicarbonitrile 4i. Colourless solid, mp: C (Lit. 1 mp: ºC). IR (KBr): 489, 40, 224, 292, 221, 161, 11, 109, 142, 129, 116, 1022, 82, 8 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.84 (bs, 2, N 2 ),.1. (m, 6, Ar),.49.1 (m,, Ar). Anal. Calcd for C FN 4 S (46.8): C, 6.88;,.20; N, Found: C, 6.;,.28; N, ISSN Page 18

7 General Papers ARKIVOC 2009 (xiii) 11 2Amino4(4bromophenyl)6phenylsulfanylpyridine,dicarbonitrile 4j. Lightyellow solid, mp: 2224ºC (Lit. 16 mp: 2 2 ºC). IR (KBr): 4, 48, 218, 068, 221, 161, 141, 1484, 1419, 11, 129, 106, 99 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.6 (bs, 2, N 2 ),.46.4 (m, 6, Ar),.2.9 (m,, Ar). Anal. Calcd for C BrN 4 S (40.29): C, 6.0;, 2.2; N, 1.6. Found: C, 6.19;, 2.6; N, Amino4(bromophenyl)6phenylsulfanylpyridine,dicarbonitrile 4k. Colourless solid, mp: 22 C (Lit. 1 mp: 2628 ºC). IR (KBr): 441,, 220, 2218, 162, 12, 128, 14, 12, 1021, 82, 6 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =.6 (bs, 2, N 2 ), (m, 2, Ar),.9 (s, 1, Ar),.4.48 (m, 6, Ar). Anal. Calcd for C BrN 4 S (40.29): C, 6.0;, 2.2; N, 1.6. Found: C, 6.1;, 2.81; N, Amino4(4methylphenyl)6phenylsulfanylpyridine,dicarbonitrile 4l. Colourless solid, mp: C (Lit. 1 mp: ºC). IR (KBr): 42, 48, 212, 291, 221, 1616, 18, 112, 101, 12, 1118, 1020, 86, 8 cm 1. 1 NMR (00 Mz, CDCl ): δ =.4. (m,, Ar),..4 (m, 6, Ar),.44 (bs, 2, N 2 ), 2.4 (s,, C ). 1 C NMR ( Mz, CDCl ): δ = 168.9, 19., 18., 141.4, 1., 10.2, 129.8, 129., 129., 128.4, 12.2, 11.4, 114.9, 9.8, 8., 21.. Anal. Calcd for C N 4 S (42.42): C, 0.1;, 4.12; N, Found: C, 0.0;, 4.19; N, Amino4(4hydroxymethoxyphenyl)6phenylsulfanylpyridine,dicarbonitrile 4m. Colourless solid, mp: C (Lit. 1 mp: ºC). IR (KBr): 46, 4, 222, 2928, 2218, 219, 1646, 12, 141, 1262, 114, 100, 0 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ = 9.68 (s, 1, O),.1 (bs, 2, N 2 ),.9 (d, 2, Ar),.16 (s 1, Ar), (m,, Ar),.81 (s,, OC ). Anal. Calcd for C N 4 O 2 S (4.42): C, 64.16;,.; N, Found: C, 64.26;,.1; N, Amino6(phenylsulfanyl)4(,4,trimethoxyphenyl)pyridine,dicarbonitrile 4n. White solid, mp: 2829 C (Lit. 14a mp: 2829 ºC). IR (KBr): 420, 6, 21, 299, 2210, 1622, 144, 10, 146, 141, 11, 122, 1126, 989, 841, 6, 44, 01 cm 1. 1 NMR (00 Mz, DMSOd 6 ): δ =. (bs, 2, N 2 ),.1.9 (m,, Ar), 6.9 (s, 2, Ar),.82 (s, 6, OC ),.6 (s,, OC ). Anal. Calcd for C N 4 O S (418.4): C, 6.14;, 4.4; N, 1.9. Found: C, 6.19;, 4.28; N, 1.1. Acknowledgements The authors are thankful to the Department of Biotechnology, New Delhi for financial assistance. References 1. (a) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 6, 2. (b) Kappe, C. O. Angew. Chem., Int. Ed. Engl. 2004, 4, 620. (c) Dallinger, D.; Kappe, C. O. Chem. Rev. 200, 10, 26. (d) Chow, W. S.; Chan, T.. Tetrahedron Lett. 2009, 0, ISSN Page 19

8 General Papers ARKIVOC 2009 (xiii) (a) Dcmling, A.; Ugi, I. Angew. Chem. 2000, 112, 00. (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 9, 168. (c) JimenezAbnso, S.; Chavez,.; EstevezBraan, A.; Ravelo, A.; Feresin, G.; Tapia, A. Tetrahedron 2008, 64, 898. (d) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 200, 44, 12. (e) Shi, D.; Ni, S.; Yang, F.; Ji, S. J etrocycl. chem. 2008, 4, 12.. (a) Gerencser, J.; Dorman, G.; Darvas, F. QSAR Comb. Sci. 2006, 49. (b) Orru, R. V. A.; de Greef, M. Synthesis 200, 141. (c) ulme, C.; Gore, V. Curr. Med. Chem. 200, 10, 1. (d) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.A.; Springer, J. P.; irshfield, J. J. Med. Chem. 1988, 1, (a) Boger, D. L.; Nakahara, S. J. Org. Chem. 1991, 6, 8. (b) Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989, 111, 11. (c) Reddy, T. R. K.; Mutter, R.; eal, W.; Guo, K., Gillet, V. J.; Pratt, S.; Chen, B. J. Med.Chem. 2006, 49,. (d) Zhang, T. Y.; Stout, J. R.; Keay, J. G.; Scriven, E. F. V.; Toomey, J. E.; Goe, G. L. Tetrahedron 199, 1, 11.. (a) Fletcher, M. D.; urst, T. E.; Miles, T. J.; Moody, C. J. Tetrahedron 2006, 62, 44. (b) Van Aken, K. J.; Lux, G. M.; Deroover, G. G.; Meerpoel, L.; oornaert, G. J. Tetrahedron 1994, 0, (a) Movassaghi, M.; ill, M. D. J. Am. Chem. Soc. 2006, 128, 492. (b) Winter, A.; Risch, N. Synthesis 200, Thomas, A. D.; Asokan, C. V. Tetrahedron Lett. 2002, 4, Tanaka, K.; Mori,.; Yamamoto, M.; Katsumara, S. J. Org. Chem. 2001, 66, Mashraqui, S..; Karnik, M. A. Tetrahedron Lett. 1998, 9, Renslo, A. R.; Danheiser, R. L. J. Org. Chem. 1998, 6, (a) Vijn, R. J.; Arts,. J.; Green, R.; Castelijns, A. M. Synthesis 1994,. (b) Ahmed, S.; Baruah, R. C. Tetrahedron Lett. 1996,, Komatsu, M.; Ohgishi,.; Takamatsu, S.; Ohshiro, Y.; Agawa, T. Angew. Chem., Int. Ed. Engl. 1982, 21, Anabha, E. R.; Nirmala, K. N.; Thomas, A.; Asokan, C. V. Synthesis 200, (a) Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8, 899. (b) Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.; Antipin, M. Y.; Magedov, I. V.; Kornienko, A. J. Org. Chem. 200, 2, Ranu, B. C.; Jana, R.; Sowmiah, S. J. Org. Chem. 200, 2, Mamgain, R.; Singh, R.; Rawat, D. S. J. eterocycl. Chem. 2009, 46, Sridhar, M.; Ramanaiah, B. C.; Narsaiah, C.; Mahesh, B.; Kumarswamy, M.; Mallu, K. K. R.; Ankathi, V. M.; Rao, P. S. Tetrahedron Lett. 2009, 0, (a) Yamawaki, J.; Ando, T. Chem. Lett. 199,. (b) Clark, J.. Chem. Rev. 19,, 429. (c) Wang, X. S.; Zhang, M. M.; Li, Q.; Yao, C. S.; Tu, S. J. Synth. Commun. 2008, 8, (d) Blass B. E. Tetrahedron 2002, 8, 902. (e) Schmittling, E. A.; Sawyer, J. S. Tetrahedron Lett. 1991, 2, 20. (f) Basu, B.; Das, P.; Das, S. Curr. Org. Chem. 2008, 12, 141. ISSN Page 1