untitled European Journal of Chemistry 3 (2) (2012) 179‐185 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2012 EURJCHEM DOI:10.5155/eurjchem.3.2.179‐185.562 European Journal of Chemistry Journal homepage: www.eurjchem.com Tetra‐n‐butylammonium fluoride‐mediated dimerization of (α‐methylbenzylidene)malononitriles to form polyfunctional 5,6‐dihydropyridines derivatives under solvent‐free conditions Abdul Hameed*, Ayaz Anwar, Sammer Yousaf, Khalid Mohammed Khan and Fatima Zahra Basha Husein Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan *Corresponding author at: Husein Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan. Tel.: +92.219.9261701‐2/Ext. 240; fax: +92.213.4819018. E‐mail address: abdul.hameed@iccs.edu (A. Hameed). ARTICLE INFORMATION ABSTRACT Received: 25 November 2011 Received in revised form: 09 January 2012 Accepted: 09 January 2012 Online: 30 June 2012 KEYWORDS A series of polyfunctional dihydropyridine 28‐46 were prepared via dimerization of readily available substituted (‐methylbenzylidene)‐malononitriles 10‐27 by treating with neat TBAF.3H2O under solvent‐free conditions at 85‐90 oC. All the dimers 28‐46 were obtained in high yield from their corresponding substituted alkylidenemalononitriles except in the case of 2‐chloro (15), 2‐hydroxy (21), and 2‐nitro (26) substituted alkylidenemalononitriles where the reaction was unsuccessful due to the steric interaction between methylene group and the substituents present at ortho position. The X‐ray crystallographic studies of compounds 28 and 30 were carried out to confirm the structure of dimerized product. The method is eco‐ friendly and wider is scope to prepare a range of substituted dihydropyridine derivatives 28‐ 46. Dimerization X‐ray crystallography Solvent‐free conditions Alkylidenemalononitrile Acetophenone derivatives Knoevenagel condensation 1. Introduction Alkylidenemalononitriles are important class of compounds in organic chemistry. They are derived from acetophenone derivatives via Knoevenagel condensation [1‐3] and frequently used in the preparation of many medicinally important heterocyclic compounds. Pyridine ring containing compounds are also important class of the heterocyclic compounds, which are frequently used in the many fields including medicinal chemistry, agro chemicals etc. [4]. Pyridine ring is the basic unit in many known natural products and medicinally important compounds [5]. For example, nifedipine 1 and its different derivatives4 contains pyridine core ring in their structure (Figure 1). These compounds show significant biological potential against cardiovascular diseases (calcium antagonist) [5,6]. Many research groups are involved in the synthesis of useful pyridine derivatives possessing significant biological potential. Our group is also interested in the synthesis of potentially useful pyridine derivatives via efficient, cost‐effective and scalable methods. It is envisaged that preparation of polyfunctional 5,6‐pyridine derivatives i.e. compound 2 would carry significant biological interests (Figure 1). Towards our interest, readily available alkylidenemalononitriles 10‐27 were selected as suitable candidates due to the reactive nature of the dicyanoolefin and the acidic nature of the methyl group. Both of these functionalities are very advantageous in promoting the dimerization reaction to prepare desired 5,6‐dihydropyridine derivatives 28‐46 (Scheme 1). Previously, Dunkel and Heb (1997) [7] reported the synthesis of different dicyano substituted dimers in the presence of DIMCARB (dimethylamine carbondioxide complex), whilst Abdelrazak et al. (2011) [8] carried out the dimerization of phenyl alkylidenemalononitrile in ethanol by using excessive amount of NaOEt to complete the reaction. However, we have developed a novel solvent‐free method, where reaction is mediated by TBAF.3H2O (Tetrabutylammonium fluoride trihydrate) to produce highly functionalized compound 8. These conditions are eco‐friendly, wider in scope and free of anhydrous environment. We have explored this method on a range of different substituted alkylidenemalononitriles 10‐27 and synthesized different dihydropyridine derivatives 28‐46. Figure 1. Nifedipine and related polyfunctional pyridine derivatives. TBAF (Tetrabutylammonium fluoride) is commonly used as desylating agent in organic reactions [9]. However, in last few years chemists have explored many utilities of this reagent which involves nucleophilic substitution to synthesize organo‐ fluoro compounds [10], cyclization reactions to produce different heterocyclic rings systems via 5‐exo‐dig cyclization or 6‐endo‐dig cyclization [11‐13], oxidation of aromatic aldehydes to benzoic acid [14] [3+2]‐cycloaddition (click chemistry) [15] and [4+2]‐cycloaddition [16]. 180 Hameed et al. / European Journal of Chemistry 3 (2) (2012) 179‐185 Scheme 1 Homoallyl coupling of aryl halides [17], activation of epoxide ring opening with aryl sulfonamide to form morpholine derivatives [18] and N‐arylation of benzazoles [19] are some other applications of TBAF in organic chemistry. Thus, we explored TBAF.3H2O as a base for the dimerization of alkylidenemalononitriles 10‐27 under solvent‐free conditions. 2. Experimental All the acetophenone derivatives and other starting materials were used without purification unless otherwise stated. Infrared spectra were recorded on Shimadzu FTIR 8900 spectrometer and 1H NMR spectra were obtained on Bruker 300 MHz and 400 MHz spectrometers. Coupling constant were calculated in Hertz (Hz). Mass spectra were obtained at JEOL MS Route 600 H spectrometer by using electron impact (EI+) techniques. HRMS was carried out at Thermo Finnigan MAT 95XP instrument. Single crystal X‐ray diffraction data was collected on Bruker Smart APEX II, CCD 4‐K area detector diffractometer. Data reductions were performed by using SAINT program and refined by full‐matrix least squares on F2 by using the SHELXTL‐PC package [20]. The figures were plotted with the aid of ORTEP program [21]. The Merck silica gel 60 was used for column chromatography. 2.1. General procedure for the synthesis of polyfunctional 5,6‐dihydropyridine derivatives (28‐46) In a typical reaction, an oven dried screw‐capped vial having magnetic stirrer bar was charged with alkylidene‐ malononitrile (10‐27) (1.0 equiv) and neat TBAF.3H2O (1.0 equiv). The reaction mixture was then heated at 85‐90 °C with constant stirring for 15 h. The completion of the reaction was monitored by Thin layer chromatography (TLC) analysis. The reaction mixture was cooled to room temperature and diluted with dioxane (2‐3 mL) and then 1.0 M HCl (100 mL) aqueous solution to remove excess TBAF. The resulting mixture was stirred for additional 5 min and then formed precipitate was filtered and washed with more 1.0 M HCl to give the pure compounds 28‐46 in good to excellent yield (52 to 95%). The structure of these compounds 28‐46 was confirmed by using different spectroscopic techniques including 1H NMR, 13C NMR, EI‐HRMS and IR spectroscopy. 2‐(3‐Cyano‐6‐methyl‐4,6‐diphenyl‐5,6‐dihydropyridin‐2(1H)‐ ylidene)malono‐nitrile (28): Brown solid. Yield: 98%. M.p.: 193‐ 195 oC [Lit. [7]: 201‐203 °C). IR (KBr, νmax, cm‐1): 3448 (NH), 2925, 2215, 1598, 1546, 1445, 1257. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.50‐7.40 (6H, m, ArH), 7.35 (2H app d, J = 8.0 Hz, ArH), 7.24 (2H app d, J = 8.0 Hz, ArH), 6.58 (1H, brs, NH), 3.49 (1H, d, J = 18.0 Hz, CH2), 3.15 (1H, d, J = 18.0 Hz, CH2), 1.79 (3H. s, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.5, 157.2, 141.3, 135.5, 132.3, 129.5, 129.2, 128.6, 127.9, 124.4, 114.6, 112.7, 112.6, 102.0, 56.8, 54.2, 45.7, 29.3. HRMS calcd. for C22H16N4 (M): 336.1375, Found: 336.1355. The data are identical to those previously reported [8]. X‐ray crystallographic data : C22H16N4, (Mr = 336.39 g/mol), Monoclinic, space group P21/c, a = 6.4827(6) Å, b = 16.2837(16) Å, c = 17.8649(17) Å, α = 90◦, β = 100.047(2)◦, V = 1856.9(3)Å 3, Z = 4, calc = 1.203 mg/m3, F(000) = 704, μ(MoKα = 0.71073 Å, max/min transmission: 0.9891/0.9656, crystal dimensions: 0.48 x 0.19 x 0.15, 1.70o < < 25.5o , 10830 reflections were collected, of which 3442 reflections were observed (Rint = 0.0248). The R values were: R1 = 0.0433, wR2 = 0.1043 for I  2(I), and R1 = 0.0634, wR2 = 0.1182 for all data; max/min residual electron density: 0.123/‐0.136 e Å−3. 2‐(3‐Cyano‐6‐methyl‐4,6‐dip‐tolyl‐5,6‐dihydropyridin‐2(1H)‐ ylidene)malono‐nitrile (29): Light brown solid. Yield: 95%. M.p.: 125‐128 oC. IR (KBr, νmax, cm‐1): 3391 (NH), 3279, 2923, 2214, 1591, 1427, 1259. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.32 (2H, d, J = 8.4 Hz, ArH), 7.25‐7.18 (4H, m, ArH), 6.11 (2H, d, J = 8.0 Hz, ArH), 6.50 (1H, br s, NH), 3.46 (1H, d, J = 18, CH2), 3.09 (1H, d, J = 18, CH2), 2.37 (3H, s, CH3), 2.33 (3H, s, CH3), 1.76 (3H. s, CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 166.8, 157.8, 143.4, 138.4, 132.6, 130.0, 129.8, 128.2, 124.4, 114.9, 113.3, 113.1, 100.9, 56.7, 53.2, 45.4, 29.3, 21.6, 20.9. HRMS calcd. for C24H20N4 (M): 364.1688, Found: 364.1645. 2‐(3‐Cyano‐4,6‐bis(4‐fluorophenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (30): Dark brown solid. Yield: 75%. M.p.: 120‐122 oC. IR (KBr, νmax, cm‐1): 3446 (NH), 2216, 1602, 1507, 1432, 1237. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.39 (2H, app dd, J = 8.8 Hz, 5.0 Hz, ArH), 7.23 (2H, app dd, J = 9.0 Hz, 5.0 Hz, ArH), 7.12 (4H, app dd, J = 16 Hz, 8.5 Hz, ArH), 6.41 (1H, br s, NH), 3.40 (1H, d, J = 18 Hz, CH2), 3.15 (1H, d, J = 18 Hz, CH2), 1.79 (3H, s, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.2, 164.9, 163.7, 163.7, 161.3, 157.1, 133.2, 137.1, 130.5, 130.4, 126.4, 126.3, 116.8, 116.6, 116.6, 116.4, 114.5, 112.6, 112.5, 101.9, 56.5, 52.3, 45.7, 29.3. HRMS calcd. for C24H14F2N4 (M): 372.1187, Found: 372.1166. X‐ray crystallographic data: Yellow crystals, C22H14F2N4 (Mr = 372.37 g/mol), triclinic, space group P‐1, a = 6.7445(8) Å, b = 9.5052(12) Å, c = 14.6186(18) Å, α = 88.777◦, β = 78.218(2)◦, γ = 80.893(2)◦, V = 905.80(19) Å3, Z = 2, calc = 1.365 mg/m3, F(000) = 384, μ(MoKα = 0.71073 Å, max/min transmission: 0.9836/0.9518, crystal dimensions: 0.51 x 0.31 x 0.17, 1.42o< Hameed et al. / European Journal of Chemistry 3 (2) (2012) 179‐185 181 < 25.5 o, 10262 reflections were collected, of which 3372 reflections were observed (Rint = 0.0162). The R values were: R1 = 0.0380, wR2 = 0.0979 for I  2(I), and R1 = 0.0434, wR2 = 0.1031 for all data; max/min residual electron density: 0.221/‐0.223 e Å−3. 2‐(3‐Cyano‐4,6‐bis(3‐fluorophenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (31): Yellow solid. Yield: 75%. M.p.: 130‐135 oC. IR (KBr, νmax, cm‐1): 3249 (NH), 2222, 2204, 1614, 1584, 1487, 1437, 1270. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.45‐7.39 (2H, m, ArH), 7.22‐7.15 (2H, m, ArH), 7.07 (1H, app td, J = 8.0 Hz, 2.0 Hz, ArH), 7.03‐6.99 (2H, m, ArH), 6.94 (1H, app dt, 7.6, 2.0, ArH), 6.15 (1H, br s, NH), 3.40 (1H, d, J = 18 Hz, CH2), 3.16 (1H, d, J = 18 Hz, CH2), 1.79 (3H, s, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 164.5, 164.1, 163.9, 162.0, 161.4, 156.4, 144.0, 143.9, 137.4, 137.3, 131.4, 131.4, 131.3, 131.2, 123.7, 123.6, 120.1, 120.0, 119.4, 119.2, 116.1, 115.9, 114.9, 114.7, 114.2, 112.1, 112.0, 111.9, 111.8, 103.0, 56.6, 56.5, 55.6, 45.5. HRMS calcd. for C24H14F2N4 (M): 372.1187, Found: 372.1176. 2‐(3‐Cyano‐4,6‐bis(4‐chlorophenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (32): Brown solid. Yield: 90%. M.p.: 132‐135 oC. IR (KBr, νmax, cm‐1): 3449 (NH), 2218, 1593, 1542, 1489, 1260. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.42 (4H, app t, J = 8.8 Hz, ArH), 7.22 (2H, d, J= 8.7 Hz, ArH), 7.16 (2H, d, J = 8.7 Hz, ArH), 6.43 (1H, br s, NH), 3.39 (1H, d, J = 18 Hz, CH2), 3.15 (1H, d, J = 18 Hz, CH2), 1.78 (3H. s, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 164.9, 156.9, 139.9, 138.8, 134.7, 133.7, 129.6, 129.6, 129.3, 125.9, 114.5, 112.6, 112.6, 102.2, 56.6, 54.4, 45.3, 29.3. HRMS calcd. for C22H14Cl2N4 (M): 404.0596, Found: 404.0571. 2‐(3‐Cyano‐4,6‐bis(4‐bromophenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (34): Dark brown solid. Yield: 90%. M.p.: 138‐140 oC. IR (KBr, νmax, cm‐1): 3438 (NH), 1591, 1544, 1429, 1259. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.56 (4H, app dd, J = 16 Hz, 8.4 Hz, ArH), 7.21 (2H, d, J = 8.4 Hz, ArH), 7.09 (2H, d, J = 8.4 Hz, ArH), 6.83 (1H, br s, NH), 3.38 (1H, d, J = 18 Hz, CH2), 3.15 (1H, d, J = 18 Hz, CH2), 1.77 (3H, s, CH3): 13C NMR (100 MHz, CDCl3, δ, ppm): 167.3, 157.2, 142.3, 134.4, 132.0, 132.5, 130.2, 127.3, 125.9, 120.8, 115.3, 114.6, 113.4, 101.4, 56.7, 50.0, 43.5, 28.0. HRMS calcd. for C22H15Br2N4 (M+H): 492.9663, Found: 492.9691. 2‐(3‐Cyano‐4,6‐bis(3‐bromophenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (35): Yellow solid. Yield: 84%. M.p.: 148‐150 oC. IR (KBr, νmax, cm‐1): 3447 (NH), 3285, 2220, 2190, 1585, 1560, 1433, 1408. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.63 (1H, app dt, J = 6.4 Hz, 1.6 Hz, ArH), 7.51 (1H, d, J = 7.6 Hz, ArH), 7.40 (2H, app d, J = 6.4 Hz, ArH), 7.34‐7.30 (H, m, ArH), 7.16 (1H, d, J = 7.6 Hz, ArH), 6.15 (1H, br s, NH), 3.39 (1H, d, J = 18 Hz, CH2), 3.14 (1H, d, J = 18 Hz, CH2), 1.79 (3H, s, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 163.9, 156.2, 143.6, 173.3, 135.2, 132.2, 131.1, 130.8, 130.4, 127.8, 126.4, 123.8, 123.4, 123.1, 114.1, 111.9, 111.8, 103.2, 56.5, 55.8, 45.4, 29.2. HRMS calcd. for C22H15Br2N4 (M+H): 492.9663, Found: 492.9691. 2‐(3‐Cyano‐4,6‐bis(4‐iodophenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (36): Yellow solid. Yield: 89%. Mixture (4/1 ratio) of 36/47. IR (KBr, νmax, cm‐1): 3441 (NH), 1589, 1548, 1429, 1261. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.77 (4H, app dd, J = 17 Hz, 8.8 Hz, ArH), 7.07 (2H, d, J = 8.4 Hz, ArH), 6.96 (2H, d, J = 8.8 Hz, ArH), 6.41 (1H, br s, NH), 3.37 (1H, d, J = 18 Hz, CH2), 3.14 (1H, d, J = 18 Hz, CH2), 1.77 (3H. s, CH3). Data for minor isomer 47 where different from major isomer 36, 7.75 (4H, app dd, J = 14 Hz, 8.8 Hz, ArH), 7.02 (2H, d, J = 8.4 Hz, ArH), 6.88 (2H, d, J = 9.0, ArH), 6.2 (1H, brs, C=CH). 13C NMR (75 MHz, CDCl3, δ, ppm): 164.8, 156.7, 140.9, 138.6, 138.6, 134.6, 129.1, 126.3, 114.3, 112.4, 112.2, 102.2, 99.8, 94.5, 56.6, 55.0 m, 45.1, 29.3. HRMS calcd. for C22H14I2N4 (M): 587.9308, Found: 587.9291. 2‐(3‐Cyano‐4,6‐bis(4‐hydroxyphenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (37): Orange solid. Yield: 75%. M.p.: 253‐255 oC. IR (KBr, νmax, cm‐1): 3382 (NH), 1575, 1510, 1435, 1261. 1H NMR (300 MHz, DMSO): 10.55 (1H, br s, NH), 9.55 (1H, br s, ArOH), 9.45 (1H, br s, ArOH), 7.50 (2H, d, J = 8.7 Hz, ArH), 7.17 (2H, d, J = 8.4 Hz, ArH), 6.87 (2H, d, J = 8.7 Hz, ArH), 6.73 (2H, d, J = 8.4 Hz, ArH), 3.75 (1H, d, J= 18 Hz, CH2), 3.14 (1H, d, J= 18 Hz, CH2), 1.65 (3H, s, CH3). 13C NMR (75 MHz, DMSO, δ, ppm): 168.5, 161.9, 158.9, 156.5, 132.9, 131.4, 125.9, 125.5, 115.9, 115.8, 115.3, 115.2, 114.9, 97.3, 56.5, 48.1, 43.5, 28.8. HRMS calcd. for C22H16N4O2 (M): 368.1230, Found: 368.1273. 2‐(3‐Cyano‐4,6‐bis(3‐hydroxyphenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (38): Yellow solid. Yield: 93%. M.p.: 270‐272 oC. IR (KBr, νmax, cm‐1): 3449 (NH), 3250, 2213, 1594, 1451, 1429. 1H NMR (300 MHz, DMSO, δ, ppm): 9.92 (1H, br s, NH), 9.65 (1H, br s, ArOH), 9.55 (1H, br s, ArOH), 7.29 (1H, app t, J = 7.8 Hz, ArH), 7.18 (1H, app t, J = 7.8 Hz, ArH), 6.92 (1H, d, J = 8.0 Hz, ArH), 6.85‐6.78 (3H, m, ArH)), 6.70‐6.65 (2H, m, ArH), 3.61 (1H, d, J= 18 Hz, CH2), 3.27 (1H, d, J= 18 Hz, CH2), 1.67 (3H, s, CH3). 13C NMR (75 MHz, DMSO, δ, ppm): 169.1, 157.9, 157.4, 157.3, 144.4, 136.8, 130.1, 1 29.7, 119.0, 118.8, 115.6, 115.5, 115.0, 114.8, 114.2, 113.7, 112.0, 100.7, 56.8, 49.1, 44.2, 28.4. HRMS calcd. for C22H16N4O2 (M): 368.1272, Found: 368.1273. 2‐(3‐Cyano‐4,6‐bis(4‐methoxyphenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (41): Brown solid. Yield: 77%. M.p.: 119‐121 oC. IR (KBr, νmax, cm‐1): 3449 (NH), 2926, 2212, 1510, 1459, 1259. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.45 (2H, d, J = 9.0 Hz, ArH), 7.15 (2H, d, J = 8.7 Hz, ArH), 6.91 (4H, app t, J = 9.4 Hz, ArH), 6.73 (1H, br s, NH), 3.82 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.46 (1H, d, J = 18 Hz, CH2), 3.05 (1H, d, J = 18 Hz, CH2), 1.75 (3H, s, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.8, 163.2, 159.5, 157.9, 133.2, 130.5, 127.4, 125.7, 114.9, 114.7, 114.6, 113.6, 113.0, 99.4, 56.4, 55.6, 55.4, 55.0, 45.4, 29.2. HRMS Calcd. for C24H20N4O2 (M): 396.1586, Found: 396.1515. 2‐(3‐Cyano‐4,6‐bis(3‐methoxyphenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (42): Yellow solid. Yield: 80%. M.p.: 133‐135 oC. IR (KBr, νmax, cm‐1): 3449 (NH), 3284, 2212, 1598, 1427. 1H NMR (300 MHz, CDCl3, δ, ppm): 7.34 (2H, app t, J = 8.0 Hz, ArH), 7.01 (1H, app dd, J = 8.0 Hz, 2.0 Hz, ArH), 6.93 (1H, d, J = 8.0 Hz, ArH), 6.87‐6.79 (3H, m, ArH), 6.73 (1H, app t, J = 2.1 Hz, ArH), 6.38 (1H, br s, NH), 3.80 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.45 (1H, d, J = 18 Hz, CH2), 3.11 (1H, d, J = 18 Hz, CH2), 1.77 (3H, s, CH3). 13C NMR (75 MHz, CDCl3, δ, ppm): 166.3, 160.3, 157.1, 143.0, 136.7, 130.3, 120.2, 118.2, 116.6, 114.6, 113.2, 112.8, 112.7, 112.5, 111.5, 101.9, 67.1, 56.7, 55.5, 55.4, 45.5, 29.3. HRMS calcd. for C24H21N4O2 (M+H): 397.1665, Found: 397.1638 2‐(3‐Cyano‐4,6‐bis(4‐nitrophenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (43): Brown solid. Mixture (2/1 ratio) of 43/48. IR (KBr, νmax, cm‐1): 3447 (NH), 3419, 2963, 2928, 2188, 2160, 1596, 1520, 1453. 1H NMR (300 MHz, DMSO, δ, ppm): 9.68 (1H, br s, NH), 8.30 (2H, dd, J = 9.0 Hz, ArH), 8.26 (2H, d, J = 9.0 Hz, ArH), 7.73 (2H d J = 9.0 Hz, ArH), 7.62 (2H, d, J = 9.0 Hz, ArH), 3.70 (1H, d, J = 18 Hz, CH2), 3.53 (1H, d, J = 18 Hz, CH2), 1.77 (3H, s, CH3). Data for minor isomer 48 where different from major isomer 43, 8.19 (4H, dd, J = 8.7 Hz, 5.4 Hz, ArH), 7.68 (2H, d, J = 9.0 Hz, ArH), 7.60 (2H, d, J = 9.0 Hz ArH), 6.95 (1H, br s, CH=C), 1.61 (3H, s, CH3) 13C NMR (75 MHz, DMSO, δ, ppm): 166.1, 157.2, 156.5, 150.3, 148.8, 146.9, 146.7, 146.2, 145.4, 141.5, 135.5, 129.6, 128.9, 126.7, 125.8, 124.0, 123.8, 123.2, 123.1, 121.8, 120.6, 117.3, 115.1, 114.4, 112.7, 103.4, 57.1, 56.9, 51.1, 43.5, 30.1, 27.7. MS (ESI) calcd. for C22H15N6O4 (M+H): 427.1155, Found: 427.1130. 2‐(3‐Cyano‐4,6‐bis(3‐nitrophenyl)‐6‐methyl‐5,6‐dihydro pyridin‐2(1H)‐ylidene)malononitrile (44): Brown solid. Yield: 80%. Mixture (2/1 ratio) of 44/49. IR (KBr, νmax, cm‐1): 3447 (NH), 3382, 3266, 2219, 2202, 1612, 1523, 1437. 1H NMR (300 MHz, DMSO, δ, ppm): 9.84 (1H, br s, NH), 8.37 (1H, app dt, J = 8.0 Hz, 2.0 Hz, ArH), 8.33 (1H, br s, ArH), 8.26 (2H, app d, J = 9.6 Hz, ArH), 8.20‐8.13 (3H, m, ArH), 8.07 (1H, d, J = 8.0, Hz, ArH), 7.94‐7.89 (2H, m, ArH), 7.84 (1H, app d, J = 3.6 Hz, ArH), 7.80 182 Hameed et al. / European Journal of Chemistry 3 (2) (2012) 179‐185 Figure 2. X‐ray crystallographic structures of acetophenone dimer 28 and 4 fluoro dimer 30. (1H, d, J = 8.0 Hz, ArH), 7.74 (1H, d, J = 8.0 Hz, ArH), 7.70‐7.62 (3H, m, ArH), , 3.90 (1H, d, J = 18 Hz, CH2), 3.46 (1H, d, J = 18 Hz, CH2), 1.78 (3H, s, CH3). Data for minor isomer 44 where different from major isomer 49, 6.97 (1H, br s, CH=C), 1.62 (3H, s, CH3). 13C NMR (75 MHz, DMSO, δ, ppm): 165.6, 156.5, 148.1, 147.7, 147.6, 145.3, 140.3, 136.9, 134.4, 134.3, 131.8, 131.4, 130.8, 130.4, 129.6, 129.5, 126.1, 122.8, 122.7, 122.5, 121.9, 121.7, 121.6, 120.2, 119.4, 116.4, 115.2, 114.4, 112.9, 103.2, 56.8, 42.3, 30.3, 27.6. HRMS calcd. for C22H14N6O4 (M): 426.1077, Found: 426.1068. 2‐(3‐Cyano‐4,6‐bis(6‐methoxynaphthalen‐2‐yl)‐6‐methyl‐5,6‐ dihydropyridin‐2(1H)‐ylidene)malononitriles (46): Brown solid. Yield: 65%. M.p.: 148‐150 oC. IR (KBr, νmax, cm‐1): 3448 (NH), 2926, 2212, 1627, 1579, 1540, 1482, 1269. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.90 (1H, app d, J = 1.4 Hz, ArH), 7.81 (1H, app d, J = 8.8 Hz, ArH), 7.81 (3H, app d, J = 8.8 Hz, ArH), 7.60 (1H, app d, J = 1.4 Hz, ArH), 7.43 (1H, dd, J = 8.8 Hz, 2.0 Hz, ArH), 7.38 (1H, dd, J = 8.8 Hz, 2.0 Hz, ArH), 7.19 (2H, app td, J = 8.8 Hz, 2.8 Hz, ArH), 7.12 (1H, d, J = 2.0 Hz, ArH), 7.08 (6H, d, J = 2.4, Hz, ArH), 6.49 (1H, br s, NH), 3.91 (6H, s, 2 x OCH3), 3.70 (1H, d, J = 18 Hz, CH2), 3.27 (1H, d, J = 18 Hz, CH2), 1.89 (3H, s, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.2, 160.1, 158.6, 157.6, 136.6, 136.1, 134.2, 130.8, 130.3, 129.7, 129.4, 128.5, 128.0, 127.9, 127.8, 124.7, 123.6, 122.5, 120.4, 120.1, 114.9, 113.3, 112.8, 105.8, 105.6, 100.8, 56.8, 55.5, 55.4, 53.9, 45.4, 29.2. HRMS calcd. for C32H24N4O2 (M): 496.1939, Found: 496.1912. 3. Results and discussion Towards our proposed synthetic target, we required to prepare the alkylidenemalononitriles 10‐27 via an appropriate method to test the TBAF mediated cyclization conditions to form dicyano substituted dihydropyridine derivatives 28‐46 (Scheme 1). The desired precursors 10‐27 for this purpose were prepared from commercially available substituted acetophenone derivatives via Knoevenagel condensation with malononitrile by following the procedure developed by Barnes et al. [2] in good to excellent yield (50 to 95%). The successful preparation of alkylidenemalononitriles 10‐ 27 were enabled us to explore their dimerization under solvent‐free conditions for the preparation of dicyano substituted dihydropyridine derivatives 28‐46. Initially, the phenyl alkylidenemalononitrile 10 was treated with neat TBAF.3H2O under solvent‐free conditions to get the desire dimerized product 28 in low yield (20%) having molecular ion peak at m/z = 336. The next step involved, was the structure elucidation of this new compound. There are different possibilities in which the alkylidenemalononitrile could be dimerized to give different structures as shown in Scheme 1. The 1H NMR spectra of compound 28 showed four distinguished signals for four groups, a) singlet for methyl group at δH = 1.79, b) two doublets for two non‐equivalent protons of methylene group at δH = 3.49, 3.15, c) multiplet for aromatic protons between 7.24‐7.50, and d) broad singlet for NH group at δH = 6.58 ppm. Interestingly, it has been observed that the value of NH group resonated between 6.00 to 9.50 ppm depends upon the solvent used to run the 1H NMR spectrum. It shifted towards downfield region when 1H NMR run in DMSO solvent and this was later confirmed by obtaining the 1H NMR of 4‐fluoro dimer 30 in both CDCl3 (δH = 6.41 ppm) and DMSO (δH = 9.72 ppm). The above mentioned data is pretty much comparable with the reported data of structure 5 [22,23] and structure 8 [8]. Therefore, in order to solve the structural ambiguity, the compound was treated with NaOMe by using literature procedure to produce compound 6 by assuming the structure 5 of the new compound [24]. But the experiment proved to unsuccessful and we would not be able to obtain the desired compound 6. The reaction mixture became very sluggish and even no starting material was recovered. Thus, with all these results, the X‐ray crystallographic technique became obligatory to establish the structure of this new dimer. For this purpose, the compound was crystallized with little effort in the mixture of Ethanol/H2O mixture and then X‐ray crystallographic structure of compound 28 was then obtained which clearly showed the attachment of malononitrile group to the C‐2 via double bond, cyano group at C‐3 position, phenyl ring at C‐4 position and quaternary center at C‐6 position [8] (Figure 2). The X‐ray crystallographic structure of the 4‐flouro 30 derivative was also obtained for further verification (Figure 2). All the spectroscopic data includes 1H NMR, 13C NMR, IR and mass spectra showed complete agreement with the structure 28. After the confirmation of dimer structure 30, the reaction condition was optimized to increase the yield of the reaction product. Initially, the temperature reaction mixture was raised from 35 to 85 oC and proceeded the reaction for 14 h until TLC analysis showed no starting material. The reaction mixture was cooled and quenched with 2.0 N HCl to get the compound 28 in excellent yield (95%) as a single product. The isolated product 28 was found to be analytically pure > 95% by 1H NMR spectroscopy without tedious silica gel column chromatography. The scope of the reaction was further explored to prepare a range of dihydropyridine derivatives 28‐ 46 in good to excellent yield (52 to 98%) as shown in the Table 1. Hameed et al. / European Journal of Chemistry 3 (2) (2012) 179‐185 183 Table 1. Synthesis of functionalized dicyano substituted dihydropyridine 28‐46 via TBAF‐mediated dimerization. Entry Alkylidene‐malononitriles Dihydropyridine derivatives Dihydropyridine derivatives Isolated Yield (%) 1 ‐ 98 2 ‐ 95 3 N H CN CN CN Me F F 30 ‐ 75 4 ‐ 75 5 ‐ 90 6 ‐ No reaction 7 ‐ 90 8 N H CN CN CN Me Br Br 35 ‐ 90 9 89 (4:1 ratio) 184 Hameed et al. / European Journal of Chemistry 3 (2) (2012) 179‐185 Table 1. (continued). Entry Alkylidene‐malononitriles Dihydropyridine derivatives Dihydropyridine derivatives Isolated Yield (%) 10 N H CN CN CN Me OH HO 37 ‐ 75 11 ‐ 93 12 ‐ No reaction 13 N H CN CN CN Me OMe MeO 41 ‐ 95 14 ‐ 80 16 N H CN CN CN Me NO2 O2N 43 52 (2:1 ratio) 17 N H CN CN CN Me O2N O2N 44 80 (4:1 ratio) 18 ‐ No reaction 19 ‐ 65 Hameed et al. / European Journal of Chemistry 3 (2) (2012) 179‐185 185 Ar H3C CN CN Ar H2C C CN Ar H2C C CN Ar CH3 CN NC N H CN CN CN Ar Ar Me H2C C CN Ar N TBAF (base) -H+ NN Ar CH3 CN NC Me Ar H2C C CN Ar N NC CN 4 50 51 4 8 53 52 Scheme 2 The results presented in the Table 1 showed that in almost all cases we have only obtained dicyano substituted dihydropyridine derivatives 28‐46 as single product in high yields. However, In the case of 4‐iodo 18, 4‐nitro 24 and 3‐nitro 25 derivatives, an inseparable mixture of corresponding dihydropyridines and their other derivatives were obtained in 4/1 to 2/1 ratio, as judged by 1H NMR spectroscopy (Table 1). The dimerization of 2‐chloro 15 ylidene, 2‐hydroxy ylidene 21 and 2‐nitro ylidene 26 was unsuccessful which could be possibly due to the steric interaction of methylene group, generated in situ deprotonation by TBAF, with the hydroxy and nitro substituents present at 2‐position of the phenyl ring. A plausible mechanism of this dimerization has been outlined in Scheme 2. The carbanion 50, generated by the abstraction of proton from methyl group by TBAF which acts as base, rearrange itself to keteneimine 51 which then attacks to dicycano alkene 4 of another molecule to afford intermediate 52. The intermediate 52 then undergo rearrangement to afford compound 53, which on cyclization give final product 8 (Scheme 2) [7, 8]. 4. Conclusion In summary, we have successfully developed a new broad spectrum, eco‐friendly method of alkylidenemalononitriles 10‐ 27 dimerization to form the dihydropyridine derivative 28‐46 under solvent‐free conditions. TBAF is found to be an efficient base for promoting the reaction to desire products. Further work on other kind of ylidenes e.g. PhCH(CN)2, further chemical transformations on above mentioned dimers 28‐46 and their biological properties are under progress. Acknowledgements We are thankful to Higher Education Commission (HEC), Pakistan and Husein Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi‐75270, Pakistan for providing financial support. Supplementary materials CCDC‐845736 (28) and 845735 (30) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by e‐mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223‐336033. References [1]. Knoevenagel, K. Ber. Dtsch. Chem. Ges. 1988, 31, 2596‐2619. [2]. Barnes, D. M.; Haight, A. R.; Hameury, T.; Mclaughlin, M. A.; Mei, J.; Tedrow, J. S.; Toma, J. , D. R. Tetrahedron 2006, 62, 11311‐11319. [3]. Sharif, A.; Ahmad, E.; Munawar, M. A.; Jabeen, S.; Khan, M. U. A.; Begum, R.; Farrukh, A.; Ashraf, M.; Arshad, S.; Afza, N. J. Chem. Soc. Pak. 2011, 33, 578‐786. [4]. Bogdanowicz‐Szwed, K.; Krasodomska, M. Monatsh. Chem. 2006, 137, 347‐355. [5]. Johnson, D. S.; Li, J. J. The Art of Drug Synthesis, John Wiley and Sons, Inc.: New Jersey, 2007. [6]. Lichitsky, B. V.; Dudinov, A. A.; Krayushkin, M. M. Arkivoc 2001, 9, 73‐ 79. [7]. Dunkel, S.; Heb, U. J. Prakt. Chem. 1997, 339, 414‐419. [8]. Abdelrazek, F. M.; Metwally, M. H.; Kassab, N. A.; Sobhy, N. A.; Metz, P.; Jaeger, A. J. Heterocyclic Chem. 2010, 47, 348‐388. [9]. Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 6190‐6192 [10]. Cox, D. P.; Terpinski, J.; Lawrynowicz, W. J. Org. Chem. 1984, 49, 3216‐ 3219. [11]. Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. J. Org. Chem. 1996, 61, 5013‐ 5023. [12]. Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata, A.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. I 1999, 529‐534. [13]. Hiroya, K.; Jouka, R.; Kameda, M.; Yasuhara, A.; Sakamoto, T. Tetrahedron 2001, 57, 9697‐9710. [14]. Chung, K. ‐H.; Moon, B. ‐C.; Lim, C. H.; Kim, J. P.; Lee, J. H.; Chi, D. Y. Bull. Korean Chem. Soc. 2006, 27, 1203‐1205. [15]. Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2004, 69, 2896‐2898. [16]. Alden‐Danforth, E.; Scerba, M. T.; Lectka, T. Org. Lett. 2008, 10, 4951‐ 4953. [17]. Albanese, D.; Landini, D.; Penso, M.; Petricci, S. Synlett. 1999, 199‐200. [18]. Albanese, D.; Donghi, A.; Landini, D.; Lupi, V.; Penso, M. Green Chem. 2003, 5, 367‐369. [19]. Lee, H. ‐G.; Won, J. ‐E.; Kim, M. ‐J.; Park, S. ‐E.; Jung, K. ‐J.; Kim, B. R.; Lee, S. ‐G.; Yoon, Y. ‐J. J. Org. Chem. 2009, 74, 5675‐5678. [20]. Sheldrick, G. M. SHELXTL/PC version 5. 1; Siemens Analytical X‐ray Instruments Inc.: Madison, WI, 1997. [21]. Johnson, C. K. ORTEPII. Report ORNL‐5138; Oak Ridge National Laboratory: Oak Ridge, TN, 1976. [22]. Nanjo, K.; Suzuki, K.; Sekiya, M. Chem. Pharm. Bull. 1977, 25, 2396‐ 4000. [23]. Ohnishi, Y.; Kagami, M.; Numakunai, T.; Ohno, A. Chem. Lett. 1976, 915‐916. [24]. Quincoses, J.; Peseke, K. Quim. Tecnol. Quim. 1978, 6, 95‐102.