A highly efficient procedure for the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres via a one-pot multicomponent reaction of 3,4-dimethoxyacetophenone, malonitrile or ethyl cyanoacetate, an aldehyde and ammonium acetate in the presence of K2CO3 is achieved in good yields. KEY WORDS: 3-Cyano-2(1H)-pyridinones, 2-Imino, Cardiotonic, Dimethoxyacetophenone  Bull. Chem. Soc. Ethiop. 2010, 24(3), 433-438

Baghernejad, Bita

Khorshidi, Maliheh

M. Heravi, Majid

Sh. Beheshtia, Yahia

English

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Bull. Chem. Soc. Ethiop. 2010, 24(3), 433-438.                                                                              ISSN 1011-3924 Printed in Ethiopia                                                                                           2010 Chemical Society of Ethiopia  __________ *Corresponding author. E-mail: bitabaghernejad@yahoo.com  A CATALYTIC METHOD FOR THE SYNTHESIS OF 4-ALKYL(ARYL)-6-ARYL-3-CYANO-2(1H)-PYRIDINONES AND THEIR 2-IMINO ISOSTERES AS NONSTEROIDAL CARDIOTONIC AGENTS  Yahia Sh. Beheshtia, Maliheh Khorshidi, Majid M. Heravi* and Bita Baghernejad  Department of Chemistry, School of Science, Azzahra University, Vanak, Tehran, Iran  (Received October 19, 2009; revised June 8, 2010)  ABSTRACT. A highly efficient procedure for the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres via a one-pot multicomponent reaction of 3,4-dimethoxyacetophenone, malonitrile or ethyl cyanoacetate, an aldehyde and ammonium acetate in the presence of K2CO3 is achieved in good yields.  KEY WORDS: 3-Cyano-2(1H)-pyridinones, 2-Imino, Cardiotonic, Dimethoxyacetophenone  INTRODUCTION Among the various classes of nitrogen containing heterocyclic compounds, pyridine derivatives display a broad spectrum of biological activities. Substituted 3-cyano pyridines are important intermediates in pharmaceuticals and dyes and therefore development of efficient procedures towards functionalized pyridines is an attractive target for organic synthesis.                                                             Cardiac glycosides (digoxin and digitoxin), discovered in the 18th century, still represent the corner stone of therapy for congestive heart failure (CHF), despite their low therapeutic index and their propensity to cause life-threatening arrhythmia [1-3]. The newer sympathomimetic agents (dobutamine, dopamine) are orally inactive and may lead to tachyphylaxis due to β-receptor down regulation [4, 5]. Because of the need for safer and orally effective drugs, the synthesis of milrinone analogues as a series of nonglycosidic, non-sympathomimetic, cardiotonic agents has been developed [6]. 4-Alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres are milrinone analogues which can also be used as as nonsteroidal cardiotonic agents [7] and their syntheses are categorized by the following three types: (i) Knoevenagel and Hantzsh condensation chemistry from β-keto esters [8-10], (ii) pyridine synthesis from α,β-unsaturated ketones [11, 12] and (iii) Krohnke type cyclization with 1,5-diketone and ammonium acetate [13], but many of reported methods have drawbacks such long reaction times, harsh reaction conditions, the use of stoichiometric reagents or of toxic and inflammable solvents, difficult work-ups or low yields of products. Consequently, there is a need to develop new methods for the synthesis of these compounds. In this communication we wish to report the application of K2CO3 in the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres. (Scheme 1)  COCH3OMeOMeNHRZMeOOMeXCN+ CH3COONH4reflux+ +X = CN, COOEt1 2 3 4 56Z = NHZ = OCNRCHOK2CO3 Scheme 1 Yahia Sh. Beheshtia et al. Bull. Chem. Soc. Ethiop. 2010, 24(3) 434RESULTS AND DISCUSSION  As part of our program aimed at developing new selective and environmental friendly methodologies for the preparation of fine chemicals [14], we performed the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres through one-pot multi–component reaction of 3,4-dimethoxyacetophenone, malonitrile or ethyl cyanoacetate, an aldehyde and ammonium acetate in the presence of K2CO3.  This reaction proceeded smoothly and rapidly to give the corresponding pyridinones and 2-imino analogues in good yields (Table 1). Initially, we examined the effect of varying the solvent on the synthesis of 5b. This reaction was carried out in various solvents such as water, DMF, chloroform, ethanol, CH2Cl2 and toluene. As shown in Table 2, the best results in terms of yield and time were obtained in ethanol. By carrying out reactions with different amounts of ammonium acetate, it has been found that 8 mmol of the ammonium acetate furnished the maximum yield for 1 mmol of the reactants. When ethyl cyanoacetate was used instead of malononitrile, the corresponding 2-pyridone was obtained in good yield (Table 1, entries 6-10).  Table 1. Synthesis of 3-cyanopyridines derivatives with K2CO3.  Yield (%)a Entry R X Z  Product Time (h) 25 ˚C     45 ˚C    78 ˚C 1 -CH3 CN NH 5a 3 45 65 81 2  CN NH 5b 3 45 70 82 3 CL CN NH 5c 3 40 68 85 4 OH CN NH 5d 3 45 72 82 5 OCH3 CN NH 5e 3 50 71 83 6 -CH3  COOEt O 6a 3 45 65 82 7  COOEt O 6b 3 45 72 82 8 CL COOEt O 6c 3 40 70 84 9 OH COOEt O 6d 3 45 72 82 10 OCH3 COOEt O 6e 3 50 75 82 11 ClCl  COOEt O 6f 3 45 70 86 aYield of isolated products.                       A catalytic method for the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones   Bull. Chem. Soc. Ethiop. 2010, 24(3) 435Table 2. Synthesis of 5b with K2CO3 in the presence of different solvent.                           Entry Solvent Temperature Time (h) Yield (%)a 1 Ethanol Reflux 3 82 2 Acetonitrile Reflux 3 80 3 Ethyl acetate Reflux 4 78 4 THF Reflux 4 75 5 Dichloromethane Reflux 6 65 aYield of isolated products.     After optimizing the reaction condition, various aromatic aldehydes reacted very well with malononitrile and ethyl cyanoacetate as the active methylene compounds to give the corresponding 2(1H)-pyridinones and their 2-imino isosteres in good yields (Table 1). The effect of temperature in ethanol as a solvent was studied by carrying out the reactions at different temperatures [room temperature (25 ˚C), 45 ˚C and under refluxing temperature (78 ˚C)]. As it is shown in Table 1, the yields of reactions increased as the reaction temperature was raised. From these results, it was decided that refluxing temperature would be the best temperature for all reactions. The reaction proceeds very cleanly under reflux and is free from side products.  We have used Et3N instead of K2CO3 in these reactions, but K2CO3 affords better yields. (Table 1, 3). In addition, the time required for completion of the reaction was found to be less with K2CO3.   Table 3. Synthesis of 3-cyanopyridines derivatives with ET3N.  Yield (%)a Entry R X Z  Product Time (h) 25 ˚C   45 ˚C   78 ˚C 1 -CH3 CN NH 5a 4 25 45 55 2  CN NH 5b 4 25 40 57 3 CL CN NH 5c 4 20 48 55 4 OH CN NH 5d 4 25 42 57 5 OCH3 CN NH 5e 4 20 41 58 6 -CH3  COOEt O 6a 4 25 45 56 7  COOEt O 6b 4 25 42 58 8 CL COOEt O 6c 4 20 40 59 9 OH COOEt O 6d 4 25 42 57 10 OCH3 COOEt O 6e 4 20 45 57 aYield of isolated products. Yahia Sh. Beheshtia et al. Bull. Chem. Soc. Ethiop. 2010, 24(3) 436 A reasonable mechanism for this reaction is shown in the Scheme 2. The enamine formed from dimethoxyacetophenone and ammonia adds to the aldol condensation product of the aldehyde and malononitrile. Subsequent addition to a cyano group followed by dehydrogenation affords the desired product 5.  COCH3OMeOMe+1 4 CH3COONH4OMeOMe8HN CH3OMeOMe9H2N CH2XCN+2 3RCHO..7-H2ORCNCNOMeOMeNH2OMeOMeNH2CRCNNRCNCNOMeOMeNHRCNNH9OMeOMeNHRCNNH510 11air  Scheme 2   In summary, we have developed a simple and efficient protocol for the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres with K2CO3. The short reaction times, simple work-up, isolation of the products in high yields with high purity, mild reaction conditions are features of this new procedure.  EXPERIMENTAL  All the products are known compounds and were characterized by mp, IR, 1H NMR and GC/MS. Melting points were measured by using the capillary tube method with an Electrothermal 9200 apparatus (Germany). 1H NMR spectra were recorded on a Bruker AQS AVANCE-500 MHz spectrometer (Germany) using TMS as an internal standard (CDCl3 solution). IR spectra were recorded from KBr disk on the FT-IR Bruker Tensor 27 (Germany). GC/MS spectra were recorded on an Agilent Technologies 6890 network GC system and an Agilent 5973 network mass selective detector (USA). Thin layer chromatography (TLC) on commercial aluminum-backed plates of silica gel, 60 F254 was used to monitor the progress of reactions. All the products were characterized by spectra and physical data.                             A catalytic method for the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones   Bull. Chem. Soc. Ethiop. 2010, 24(3) 437Typical procedure for preparation of 4-aryl(alkyl)-3-cyano-6-(3,4-dimethoxyphenyl)-2(1H)-iminopyridines (5a-e)                                                                                       A mixture of 3,4-dimethoxyacetophenone (1 mmol), malononitrile (1 mmol), the appropriate aldehyde (1 mmol), ammonium acetate (8 mmol) and K2CO3 (0.5 mmol) in ethanol (5 mL) was refluxed for 3 h. The mixture was cooled to room temperature and the precipitated products were separated by filtration then washed successively with water, dried and crystallized.                                                                                                            Typical procedure for preparation of 4-aryl(alkyl)-6-(3,4-dimethoxyphenyl)-3-cyano-2(1H)-pyridinones (6a-e)                                                                                         The foregoing method was carried out except that malononitrile was replaced by ethyl cyanoacetate (Table 1, entries 6-10).                                                                                     Selected physical data  5c. Mp: 207 ºC (lit. 203-207 ºC [15]). IR (KBr) (νmax, cm−1): 2225, 3340. 1H NMR (DMSO-D6, 500 MHz) δH (ppm): 3.75 (s, 3H, 3-OCH3), 3.89 (s, 3H, 4-OCH3), 7.12-7.58 (m, 8H, aromatic), 10.51 (brs, 1H, NH), 10.62 (brs, 1H, NH). GC/MS: 365 (M+).                            5d. Mp: 202 ºC (lit. 205-207 ºC [15]). IR (KBr) (νmax, cm−1): 2246, 3345. 1H NMR (DMSO-D6, 500 MHz) δH (ppm): 3.85 (s, 3H, 3-OCH3), 3.91 (s, 3H, 4-OCH3), 7.12-7.58 (m, 8H, aromatic), 9.86 (brs, 1H, NH), 9.98 (brs, 1H, NH), 10.65 (1H, OH), 10. GC/MS: 347 (M+).                                                                                                                                        6a. Mp: 255 ºC (lit. 255-257 ºC [15]). IR (KBr) (νmax, cm−1): 1670, 2220, 3320.1H NMR (DMSO-D6, 500 MHz) δH (ppm): 2.43 (s, 3H, CH3), 3.75 (s, 3H, 3-OCH3), 3.89 (s, 3H, 4-OCH3), 7.01-7.49 (m, 4H, aromatic), 12.05 (brs, 1H, NH). GC/MS: 270 (M+).                    6b. Mp: 285 ºC (lit.287-289 ºC [15]). IR (KBr) (νmax, cm−1): 1641, 2228, 3330.1H NMR (DMSO-D6, 500 MHz) δH (ppm): 3.89 (s, 3H, 3-OCH3), 4.01 (s, 3H, 4-OCH3), 7.09-7.52 (m, 9H, aromatic), 12.51 (brs, 1H, NH). GC/MS: 332 (M+).  REFERENCES  1. Braunwald, E. Am. Heart. J. 1981, 102, 486. 2. Muller, J.E.; Turi, Z.G.; Stone, P.H.; Rude, R.E.; Raabe, D.S.; Jaffe, A.S.; Gold, H.K.;  Gustafson, N.; Poole,  W.K.; Passamani, E.; Smith, T.W.; Braunwald, E. New Engl. J.  Med.  1986, 314, 265. 3. Yusuf, S.; Wittes, J.; Bailey, K.; Furberg, C. Circulation. 1986, 73, 14. 4. Lathers, C.M.; Roberts, J. Life Sci. 1980, 27, 1713. 5. Su, Y.S.; Harden, T.K.; Perkins, J.P. J. Biol. Chem. 1980, 255, 7410. 6. Dorigo, P.; Fraccarollo, D.; Santostasi, G.; Gaion, R.M.; Maragno, I.; Floreani, M.;  Carpenedo, F. II Farmaco. 1994, 49,19. 7. Abadi, A.; Al-Deeb, O.; Al-Afify, A.; El-Kashef, H. II Farmaco. 1999, 54, 195. 8. Gordeev, M.F.; Patel, D.V.; Wu, J.; Gordon, E.M. Tetrahedron Lett. 1996, 37, 4643. 9. Bhandari, A.; Li, B.; Gallop, M.A. Synthesis 1999, 11, 1951. 10. Breitenbucher, J.G.; Figliozzi, G. Tetrahedron Lett. 2000, 41, 4311. 11. Marzinzik, A.L.; Felder, E.R. J. Org. Chem. 1998, 63, 723. Yahia Sh. Beheshtia et al. Bull. Chem. Soc. Ethiop. 2010, 24(3) 43812. Katritzky, A.R.; Serdyuk, L.; Chassaing, C.; Toader, D.; Wang, X.; Forood, B.; Flatt, B.;  Sun, C.; Vo, K. J. Comb. Chem. 2000, 2, 182. 13. Chiu, C.; Tang, Z.; Ellingboe, J. J. Comb. Chem. 1999, 1, 73. 14. (a) Bamoharram, F.F.; Heravi, M.M.; Roshani, M.; Gharib, A.; Jahangir, M.  Appl. Cata. 2006, 302, 42; (b)  Heravi, M.M.; Hekmatshoar, R.; Pedram, L. J. Mol. Cata. A: Chem. 2005, 89, 231; (c) Tajbakhsh, M.; Mohajerani, B.; Heravi, M.M.; Ahmadi, A.N. J. Mol. Cata. A: Chem. 2005, 236, 216; (d) Heravi, M.M.; Motamedi, R.; Siefi, N.; Bamoharram, F.F.; J. Mol. Catal. 2006, 249, 1; (e) Bamoharram, F.F.; Heravi, M.M.;  Roshani, M. J. Chin. Chem.  Soc. 2007, 54, 1017; (f) Heravi, M.M.; Bakhtiari, K.; Oskooie, H.A. J. Chin. Chem. Soc. 2007, 54, 579; (g) Heravi, M.M.; Oskooie, H.A.; Baghernejad, B. J. Chin. Chem. Soc. 2007, 54, 767. 15. Abadi, A.; Al-Deeb, O.; Al-Afify, A.; El-Kashef, H. Farmaco II 1999, 54, 195.   

A catalytic method for the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres as nonsteroidal cardiotonic agents

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A catalytic method for the synthesis of 4-alkyl(aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres as nonsteroidal cardiotonic agents

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