Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 4(9), 16-21, September (2014) Res. J. Chem. Sci. International Science Congress Association 16 Simple Grinding, Catalyst-free, One-Pot, Three-Component Synthesis of Polysubstituted Amino Pyrazole Pravin S. Bhale,* Sakharam B. Dongare, Umakant B. Chanshetti Department of Chemistry, Arts, Science and Commerce College, Naldurg, Tq-Tuljapur, Dist.- Osmanabad- 413602, MS, INDIAAvailable online at: www.isca.in, www.isca.me Received 13th August 2014, revised 2nd September 2014, accepted 11th September 2014Abstract An efficient, one-pot, three-component catalyst free synthesis of various biologically important heterocyclic compounds is described by simple grinding of aromatic aldehydes, malononitrile, and phenyl hydrazine. Keywords: Multi-component reactions (MCRs), grinding, catalyst-free, Pyrazole, 5-amino pyrazole, green chemistry. IntroductionHeterocyclic compounds containing nitrogen linkage have received considerable attention in recent times due to their wide applications. The cyclization reaction of suitable linear compounds is one of the most common and popular methods for preparing these heterocyclic compounds1,2. Between these aza containing heterocyclic compounds, pyrazoles have a long history of application in various agrochemical and pharmaceutical industries. These compounds are known to display anti-tumor, anti-bacterial, anti-microbial, anti-fungal, anti-inflammatory, analgesic, anti-depressant10, antimalarial11, anti-tumor12, and anti-viral activities13. It is well-known that the study of pyrazole derivatives is significant in pesticide chemistry, because of their herbicidal14, and insecticidal activities15. A previous investigation revealed that 5- amino-4cyanopyrazole derivatives have anti-bacterial activity16. The pyrazole moiety makes the core structure of blockbuster drugs such as Celebrex(R) [17] and Viagra(R)18 that act as PDE-5 inhibitors (figure-1). CF H3C NO Celecoxib NN O O S N N O O ViagaraFigure-1 Biological active compounds based on pyrazole derivatives Many synthetic methods are available for the synthesis of pyrazole derivatives19-21. The most popular methods for the preparation of 1,3,4,5-tetrasubstituted pyrazoles are the reactions between 1,3-dipolar cycloadditions of diazo compounds onto triple bonds22. A survey of the literature shows that the majority of the strategies involve either multistep sequences or expensive catalysts, inert atmosphere, anhydrous conditions, lengthy reaction times, and laborious workup. It is well-known that nitriles are widely used as intermediates for a large number of heterocyclic compounds23. In continuation of our research interest in the synthesis of biologically important heterocyclic compounds, we have synthesized a series of new pyrazole derivatives by simple grinding of aromatic aldehydes, malanonitrile, and phenyl hydrazine (scheme-1). O H CN CN NH-NH NN NH CN R 1a-o4a-oGrinding5-7Min.Scheme-1 Synthesis of poly-substituted amino pyrazoles by simple grinding Material and MethodsAll chemicals were purchased from Merck or Fluka Chemical Companies and they were used as received. The 1 H NMR (500 MHz, 400 MHz) and 13 C NMR (125 MHz, 100 MHz) spectra were recorded on a Bruker Avance DPX-250, FT-NMR spectrometer (in ppm). Tetramethylsailane (TMS) was used as internal standard. The abbreviations used for NMR signals are: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Melting points were recorded on a Bόchi B-545 apparatus in open capillary tubes and are uncorrected. General procedure for the preparation of 5-Amino-1, 3-diaryl-1 -pyrazole-4-carbonitriles derivatives: Phenyl hydrazine, (1 mmol) aromatic aldehyde (1 mmol), and malononitrile (1 mmol) were taken in mortar and the resulting mixture was grinded at room temperature for 5-7 min. After Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(9), 16-21, September (2014) Res. J. Chem. Sci. International Science Congress Association 17 completion of the reaction (as monitored by TLC), the product were isolated by adding ethanol to obtain pure products. Representative spectral data of the products: 5-Amino-1,3-diphenyl-1H-pyrazole-4-carbonitrile (table 1, entry 1). White powder (85 %), M.P. = 160 161 C, IR (KBr) 3485, 3341, 3083, 2359, 1599, 1412, 1253, 1126, 1100, 1075 cm 1. 1H NMR (CDCl3, 500 MHz): (ppm) 6.91 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.29– 7.35 (m, 3H), 7.41 (t, J = 7.7 Hz, 2H), 7.64 (s, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.72 (s, 1H). 13 C NMR (CDCl3, 125 MHz): (ppm) 112.80, 113.26, 120.58, 126.65, 128.9, 129.05, 129.75, 135.74, 137.81, 145.09, 150.41, 156.50. MS (): 260 (M+). Anal.Calcd for C16H12N4: C, 73.83; H, 4.65; N, 21.52%. Found: C, 73.48; H, 4.86; N, 21.72%. 5-Amino-1-phenyl-3-p-tolyl-1H-pyrazole-4-carbonitrile (table 1, entry 2): Pink powder (76%), M.P. = 117–118 C, IR (KBr) 3482, 3319, 3095, 2925, 2359, 1598, 1415, 1257, 1127, 1113, 1096 cm 1. 1H NMR (CDCl3, 500 MHz): (ppm) 2.41 (s, 3H), 6.91 (dd, J = 3.5 Hz and J = 7.3 Hz, 1H), 7.15 (d, J = 7.76 Hz, 2H), 7.22 (d, = 7.9 Hz, 2H), 7.29–7.33 (m, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.70 (s, 2H). 13 C NMR (CDCl3 125 MHz): (ppm) 21.90, 104.65, 113.22, 120.44, 126.62, 129.71, 129.77, 132.95, 138.14, 138.97, 145.20, 148.82, 153.20. Anal.Calcd for C17H14N4: C, 74.43; H, 5.14; N, 20.42%. Found: C, 74.88; H, 5.18; N, 20.12%. 5-Amino-3-(2-hydroxyphenyl)-1-phenyl-1H-pyrazole-4- carbonitrile (table 1, entry 3): Yellow powder (85 %), M.P. = 161–162 C, IR (KBr) 3583, 3487, 3341, 3102, 2358, 2197, 1602, 1413, 1222, 1192, 1108, 1050 cm 1 .1H NMR (DMSO–d6, 500 MHz): (ppm) 6.76 (t, J = 7.3 Hz, 1H), 6.85–6.90 (m, 2H), 6.96 (d, J = 7.6 Hz, 2H), 7.14–7.18 (m, 1H), 7.24 (dd, J = 7.5 Hz and J = 8.3 Hz, 2H), 7.53 (dd, J = 1.5 Hz and J = 7.7 Hz, 1H), 8.14 (s, 1H), 10.38 (s, 1H), 10.52 (s, 1H).13 C NMR (DMSO–d6, 125 MHz): (ppm) 112.60, 116.80, 119.83, 120.25, 121.35, 125.45, 128.17, 130.05, 130.15, 138.13, 145.62, 150.55, 152.30, 156.51. Anal.Calcd for C16H12N4 O: C, 69.55; H, 4.38; N, 20.28%. Found: C, 69.48; H, 4.46; N, 20.35%. 5-Amino-3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carbonitrile (table 1, entry 4): White powder (83 %), M.P. = 129–130 C, IR (KBr) 3448, 3315, 3074, 2358, 1595, 1414, 1293, 1254, 1133, 1083cm 1. 1HNMR(CDCl3, 500 MHz): (ppm) 6.93 (t, J = 7.3Hz, 1H), 7.15 (d, J = 7.7 Hz, 2H), 7.29–7.34 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.67 (s, 2H).13 CNMR(CDCl3, 125 MHz): (ppm) 110.24, 113.29, 120.85, 127.71, 129.26, 129.77, 134.26, 134.44, 136.35, 144.78, 150.21, 155.45. Anal.Calcd for C16H11ClN4: C, 65.20; H, 3.76; N, 19.01%. Found: C, 65.37; H, 3.81; N, 18.95%. 5-Amino-3-(4-nitrophenyl)-1-phenyl-1H-pyrazole-4- carbonitrile (table 1, entry 5): Red powder (86 %),M.P. = 164–165 C, IR (KBr) 3467, 3350, 3102, 2359, 1600, 1415, 1457, 1344, 1256, 1123, 1107, 1095 cm 1. 1HNMR(CDCl3, 500 MHz): (ppm) 6.98 (s, 1H) 7.18 (d, J = 7.5 Hz, 2H), 7.29–7.34 (m, 2H), 7.73– 7.79 (m, 3H), 8.05 (s, 1H), 8.24 (d, J = 7.6 Hz, 2H). MS (m/z): 305 (M+). Anal.Calcd for C16H11N5O2: C, 62.95; H, 3.63; N, 22.94%. Found: C, 63.05; H, 3.58; N, 23.03%. 5-Amino-3-(3-nitrophenyl)-1-phenyl-1H-pyrazole-4- carbonitrile (table 1, entry 6): Orange powder ( 84 %), M.P. = 129–130 C, IR (KBr) 3452, 3324, 3103, 2357, 1594, 1478, 1447, 1344, 1338, 1263, 1147, 1100, 1096 cm 1. 1HNMR(CDCl3, 500 MHz): (ppm) 6.97 (t, J =7.2 Hz, 1H), 7.18 (d, J =8.4 Hz, 2H), 7.35 (t, J =7.5 Hz, 2H), 7.56 (t, J =7.9 Hz, 1H), 7.74 (s, 1H), 7.89 (s, 1H), 8.01 (d, J =7.5 Hz, 1H), 8.14 (d, J =8.0 Hz, 1H), 8.48 (s, 1H). 13C NMR (CDCl3, 125 MHz): (ppm) 112.44, 113.42, 121.10, 121.38, 122.98, 129.85, 129.94, 131.80, 134.30, 137.72, 144.27,149.16, 156.41. Anal.Calcd for C16H11N5O2: C, 62.95; H, 3.63; N, 22.94%. Found: C, 62.78; H, 3.77; N, 22.90%. 5-Amino-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4- carbonitrile (table 1, entry 10): Yellow powder ( 75 %), M.P. = 140–141 C, IR (KBr) 3412, 3325, 3092, 2357, 1600, 1478, 1298, 1264, 1138, 1069 cm 1. 1H NMR (CDCl3, 500 MHz): (ppm) 6.92 (t, J = 7.3 Hz, 1H), 7.05 (dd, J = 3.6 Hz and J = 4.9 Hz, 1H), 7.12 (d, J = 7.4 Hz, 3H), 7.31 (dd, J = 5.0 Hz and J = 14.1Hz, 3H), 7.56 (s, 1H), 7.84 (s, 1H). 13CNMR(CDCl3, 125 MHz): (ppm) 113.24, 114.21, 120.64, 122.44, 126.33, 126.89, 127.66, 129.76, 132.70, 140.91, 144.86, 155.22. Anal.Calcd for C14H10N4S: C, 63.14; H, 3.78; N, 21.04%. Found: C, 63.33; H, 3.82; N, 20.88%. 5-Amino-3-(5-methylthiophen-2-yl)-1-phenyl-1H-pyrazole- 4-carbonitrile (table 1, entry 11): Yellow powder ( 76 %), M.P. = 131–132 C, IR (KBr) 3427, 3303, 3102, 2919, 2357, 1600, 1469, 1257, 1230, 1126, 1100, 1070 cm 1. 1H NMR (CDCl3 , 500 MHz): (ppm) 2.53 (s, 3H), 6.68–6.71 (m, 1H), 6.88–6.92 (m, 2H), 7.10 (d, J = 7.7 Hz, 2H), 7.28–7.32 (m, 2H), 7.46 (s, 1H), 7.76 (s, 1H). 13 C NMR (CDCl3, 125 MHz): (ppm) 16.08, 113.15, 114.13, 120.42, 125.86, 126.10, 127.16, 129.71, 133.18, 138.66, 141.38, 145.05, 156.73. Anal.Calcd for C15H12N4 S: C, 64.26; H, 4.31; N, 19.98%. Found: C, 64.37; H, 4.25; N, 20.05%. Results and Discussion To find the optimized reaction conditions, we initiated a catalyst screening exercise employing benzaldehyde (1 mmol), malononitrile (1 mmol), and phenyl hydrazine (1 mmol) in the presence of various base catalysts such as EtN, DABCO, DBU, NaOH, and KCO3 at room temperature. Screening of the reaction conditions established that the nature of the catalyst had no significant effect on the yield of pyrazole. Interestingly, in the absence of any base catalyst, this three-component coupling cyclization reaction proceeded smoothly to afford the desired 5-amino-4-cyano 1, 3 diphenyl pyrazole in excellent yield after 5-7 min by simple grinding method. Therefore, the phenyl hydrazine itself is acting as both a Brψnsted base catalyst in this reaction and as a nucleophile. This is why the bases had no effect on the reaction yield. Hence, we monitored the effect of the amount of phenyl hydrazine on the yield of reaction. With a higher amount of phenyl hydrazine no increase in the yield of 5- Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(9), 16-21, September (2014) Res. J. Chem. Sci. International Science Congress Association 18 amino-4-cyano 1, 3 diphenyl pyrazole is observed. However, diminishing the amount of phenyl hydrazine resulted in incomplete conversion. With these optimized conditions in hand, this three component reaction can be readily diversified through a combination of a range of aryl aldehydes, malononitrile, and phenyl hydrazine. Table-1 Substituted Synthesis Product with Yield Entry Aldehyde Product Yield a (%) 1 CHO 1a NN H2N CN 4a 85 2 CHO CH 3 1b NN H2N CN CH 4b 76 3 CHO OH 1c NN H2N CN HO 4c 85 4 CHO C l 1d NN H2N CN Cl 4d 83 5 CHO NO 2 1e NN H2N CN NO 4e 86 6 CHO NO 2 1f NN H2N CN NO 4f 84 7 CHO NO 1g NN H2N CN O2N 4g 82 Entry Aldehyde Product Yield a (%) Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(9), 16-21, September (2014) Res. J. Chem. Sci. International Science Congress Association 19 8 CHO C N 1h NN H2N CN CN 4h 79 9 CHO 1i NN H2N CN 4i 77 10 S CHO 1j NN H2N CN S 4j 75 11 S CHO 1k NN H2N CN S 4k 76 12 CHO C H O 1l NN H2N CN NN NC NH 4l 80 13 CHO 1m NN H2N CN 4m 78 14 CHO C 2 H 5 O 1n H2N CN OC 4n 75 15 CHO CO OCH 3 1o NN H2N CN OCH OCH 4o 68 16 CHO -- -- 17 CHO -- -- Isolated yields Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 4(9), 16-21, September (2014) Res. J. Chem. Sci. International Science Congress Association 20 Similarly, dialdehydes were also successfully employed to give bis poly-substituted pyrazoles in excellent yields (table-1, entries 12). To explore the generality of the reaction, aldehydes with electron-withdrawing substituents on aromatic ring were also employed (table 1, entries 5, 6, 7, 8). It is worth mentioning that sterically bulky aldehydes were readily converted into the desired products (table 1, entries 3, 7). To further expand the scope of the reaction, the use of heteroaryl aldehydes was investigated (table 1, entries 10, 11). Some aliphatic aldehydes were also screened to carry out the three-component coupling by this method and the results are listed in table 1. However, no products were obtained when aliphatic aldehydes were involved in this one-pot catalyst-free reaction (table 1, entries 16, 17). The trend observed due chiefly to the lower reactivity of alyphatic aldehydes toward nucleophilic addition in comparison with aromatic aldehydes. Thus, from a practical point of view, the newly developed protocol is a significant proof of the fact that nitrile is one of the most versatile functional groups as it can be readily transformed into various other functional groups. Significantly, the reaction occurred in a catalyst-free fashion with high selectivity and atom economy. To our knowledge, the use of catalyst-free reactions, namely Knoevenagel reaction, Michael-type reaction, ring closure, and subsequent aromatization, in one pot has not been previously reported. Conclusion In conclusion, we have disclosed a novel and convenient one-pot synthesis of polysubstituted amino pyrazole analogues via multi-component reactions. This catalyst-free reaction proceeded smoothly in good to excellent yields and offered several other advantages including short reaction time, simple experimental workup procedures, and no toxic by-products. The approach to pyrazole systems presented herein avoids the use of catalyst, toxic organic solvent. This protocol represents a promising green route for the synthesis of this class of compounds. Acknowledgment The authors are thankful to Principal, ASC College, Naldurg, Dist- Osmanabad, Maharashtra, India for providing laboratory facilities. 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