A one-​pot five-​component coupling of aryl aldehydes, aryl amines and β-​keto ester affords functionalized piperidines I [R1 = C6H5, 4-​FC6H4, 3,​4,​5-​(OCH3)​3C6H2; R2 = C6H5, 4-​CH3C6H4; R3 = CH3, CH2CH3] under sonication (35 kHz) is developed.  Cerium trichloride acts as a good catalyst and ultrasound acts as an excellent rate accelerator for this reaction resulting in good yield of the products

Pasha, M.A.

Sudha, S.

ePrints@Bangalore University

Chemical Science Review and Letters                                                                                 ISSN 2278-6783   Chem Sci Rev Lett 2014, 3(9), 5-9                                                                              Article CS01204307                      5 Research Article  Ultrasound accelerated one-pot five component reaction: A Facile Access to Functionalized Piperidines    S. Sudha and M. A. Pasha* Department of Studies in Chemistry, Central College Campus, Bangalore University, India.         Abstract A one-pot five-component coupling reaction between aromatic aldehydes, aromatic amines and a β-keto ester yielding functionalized piperidines is studied under sonic condition at 35 kHz. Cerium trichloride acts as a good catalyst and ultrasound acts as an excellent rate accelerator for this reaction resulting in good yield of the products.   *Correspondence M. A. Pasha Department of Studies in Chemistry,  Central College Campus, Bangalore University, Email: m_af_pasha@ymail.com   Keywords: aromatic aldehydes, aromatic amines, β-keto ester, coupling reaction, cerium trichloride, ultrasound.  Introduction   Piperidine and poly-substituted piperidine rings are present in many natural products; they act as anti-hypertensive, anti-bacterial, anti-convulsant, anti-inflammatory, anti-HIV and anticancer drugs [1]. Apart from this, the 1,4-piperidine derivatives/analogous are found to posses enzyme inhibitory activity against farnesyl transferase, and are found to be useful in the treatment of Parkinson’s disease and schizophrenia [2].  There are some reports on the preparation of poly-substituted piperidines via imino-Diels-Alder reactions [3], aza-Prins-cyclizations [4], intra-molecular Michael reactions [5], intra-molecular Mannich reaction onto iminium ions [6], tandem cyclopropane ring-opening/Conia-ene cyclization, [7] and methods involving multi-component strategies are available in the literature [8]. The limitations of the existing methods are; longer reaction durations and use of expensive and excess amounts of catalysts with lesser yields. Hence, a method which uses optimal catalyst load with lesser reaction time for this synthesis is always in demand.               Scheme 1 Synthesis of highly functionalized pipridines  Sonochemistry is a branch of chemistry dealing with the chemical effects and applications of ultrasonic waves on chemical reactions. Sonochemical reactions contribute to sustainable chemistry as it is known to avoid/minimize the use of hazardous chemicals and solvents. Ultrasound accelerates the reactions, reduces the energy consumption and gives increased yields [9]. Based on our experience in the study of organic reactions under sonic condition [10], we have studied the present reaction in a sonic bath at 35 kHz (Scheme 1). OR3O ONNHR1R1R2OOR3R2CeCl3 / CH3CN2 R1CHO 2 R2NH212+ +34)))), 25 °CChemical Science Review and Letters                                                                                 ISSN 2278-6783   Chem Sci Rev Lett 2014, 3(9), 5-9                                                                              Article CS01204307                      6  Experimental  Materials and Instrument  All starting materials were procured from commercial sources and were used without further purification, except aldehydes and amines which were distilled before use. All the reactions were carried out using SIDILU, Indian make sonic bath working at 35 kHz (constant frequency, 120 W) maintained at 25 °C by continuously circulating water. All the reactions were carried out in open vessels without mechanical stirring. Yields refer to yield of the isolated products. Melting points were measured on a Raaga, Indian make melting point apparatus. All the products are known and were compared on TLC with the authentic samples prepared by known methods [8].  General Procedure  A mixture of aldehyde (2 mmol), aniline (2 mmol) and β-keto ester (1 mmol) was taken in acetonitrile (3 mL), mixed well, and to this, cerium chloride (20 mol %) was added. The contents were subjected to sonication for about 180 min (35 kHz, 25 °C). The reaction was monitored on TLC, after the completion of the reaction, the solid obtained was diluted with ethyl acetate (5 mL), washed with 10% HCl (5 mL), followed by saturated NaHCO3 (2 × 5 mL) and water (2 × 5 mL).  The organic layer was dried over sodium sulphate and evaporated to get the crude product, which was subjected to silica gel column chromatography for purification. In some cases the pure product was obtained directly after the evaporation of the solvent.  Spectral data   4a [8]: White solid, mp 194–196 °C.  IR (KBr) cm –1: ν 3859, 3427, 3020, 2360, 1653, 1592, 1498, 1257. 1H NMR (300 MHz, CDCl3 + CCl4) δ: 2.73 (dd, J = 15.0 and 2.2 Hz, 1H, H-5a), 2.85 (dd, J = 15.0 and 5.4 Hz, 1H), 3.91 (s, 3H), 5.1 (brs, 1H, H-6), 6.25–6.28 (m, 2H), 6.42–6.50 (m, 2H), 6.54–6.59 (t, J = 7.2 Hz, 1H), 6.99– 7.09 (m, 5H), 7.13–7.29 (m, 10H), 10.29 (brs, 1H). 13C NMR (50 Hz, CDCl3 + CCl4) δ: 34.0, 51.4, 55.5, 58.7, 98.5, 113.4, 116.7, 126.1, 126.2, 126.8, 127.0, 127.6, 128.7, 129.0, 129.2, 129.3, 129.7, 138.3, 143.2, 144.3, 147.3, 156.5, 168.9. C31H28N2O2: calcd C, 80.84; H, 6.13; N, 6.08; found: C, 80.82; H, 6.15; N, 6.06. ESMS (m/z): [M+H] + 460.  4b [8]: Light yellow solid, mp 153–156 °C.   IR (KBr) cm –1: ν 3241, 2996, 2938, 2835, 1656, 1592, 1502, 1461, 1416, 1323, 1256, 1126, 1006.  1H NMR (400 MHz, CDCl3) δ: 2.74 (dd, J = 2.4 Hz, J = 14.8 Hz, 1H), 2.93 (dd, J = 5.6 Hz, J = 14.8 Hz, 1H), 3.67 (s, 6H), 3.71 (s, 6H), 3.81 (s, 3H), 3.82 (s, 3H), 3.88 (s, 3H), 5.01-5.02 (m, 1H), 6.33 (s, 3H), 6.37 (d, J = 6.8 Hz, 2H), 6.51 (s, 2H), 6.55 (d, J = 8.4 Hz, 2H), 6.62 (t, J = 7.2 Hz, 1H), 7.06 –7.16 (m, 5H), 10.24 (brs, 1H).  13C NMR (100 MHz, CDCl3) δ: 33.8, 51.0, 55.6, 56.0, 58.3, 60.9, 97.3, 103.2, 103.9, 113.1, 116.6, 126.1, 126.3, 128.9, 137.8, 138.5, 139.7, 146.9, 153.1, 153.4, 157.0, 168.5.  C37H40N2O8 : calcd C, 69.36; H, 6.29; N, 4.37.; found C, 69.21; H, 6.34; N, 4.51. HRMS: calcd 641.2863; found: 641.2800.   4c [8]: White solid, mp 193–195 °C. IR (KBr) cm –1: ν 3442, 1659, 1591, 1498, 1447, 1384, 1251, 1186, 1070, 1013, 976, 826, 754, 698. 1H NMR (400 MHz, CDCl3) δ: 2.74 (d, J = 15.5 Hz, 1H), 2.82 (dd, J = 15 Hz, 3.0 Hz, 1H), 3.91 (s, 3H), 5.09 (s, 1H), 6.35 (s, 1H), 6.40 (d, J = 7.5 Hz, 2H), 6.45 (d, J = 7.5 Hz, 2H), 6.64 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.07 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.0 Hz, 2H), 7.24–7.36 (m, 5H), 10.25 (brs, 1H)  13C NMR (100 MHz, CDCl3) δ:  33.7, 51.2, 54.8, 57.4, 97.6, 112.9, 116.8, 125.8, 126.1, 127.8, 128.1, 128.4, 128.8, 129.0, 129.1, 132.2, 132.9, 137.6, 140.9, 142.4, 146.5, 156.0, 168.3.  Chemical Science Review and Letters                                                                                 ISSN 2278-6783   Chem Sci Rev Lett 2014, 3(9), 5-9                                                                              Article CS01204307                      7 C31H26N2O2F2: calcd C, 74.98; H, 5.28; N, 5.64.; found C, 74.91; H, 5.11; N, 5.84.    HRMS (ESI): calcd 497.2241; found 497.2245  4d [8]: White crystal; mp 220–222 °C.  IR (KBr) cm –1: ν 3259, 3206, 2947, 2862, 2361, 1653, 1592, 1517, 1452, 1318, 1257, 1077. 1H NMR (400 MHz, CDCl3) δ: 2.18 (s, 3H) 2.28 (s, 3H), 2.73–2.89 (m, 2H), 3.94 (s, 3H), 5.14 (s, 1H), 6.18 (d, J = 7.5 Hz, 2H), 6.45 (d, J = 8.3 Hz, 3H), 6.90–6.91 (m, 4H), 7.20–7.33 (m, 10H), 10.20 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 20.1, 20.9, 31.0, 51.8, 58.2, 59.6, 97.5, 112.9, 125.1, 126.0, 126.2, 126.5, 126.7, 127.1, 127.9, 128.2, 128.6, 129.5, 135.2, 135.7, 143.0, 144.3, 144.8, 156.7, 168.6.  C33H32N2O2: calcd C, 81.15; H, 6.64; N, 5.70 found C, 81.12; H, 6.60; N, 5.73. ESI-HRMS: calcd 488.2463; found 511.2365[M+Na] +.  4e [8]: White solid mp 174–175 °C.  IR (KBr) cm –1: ν 3242, 3059, 2979, 1651, 1594, 1500, 1251, 1068. 1H NMR (400 MHz, CDCl3) δ: 1.47 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 2.32 (s, 3H), 2.77 (dd, J = 2.4 Hz, J = 15.2 Hz, 1H), 2.87 (dd, J = 5.6 Hz, J = 15.2 Hz, 1H), 4.29–4.37 (m, 1H), 4.42–4.50 (m, 1H), 5.14–5.15 (m, 1H), 6.27–6.29 (m, 2H), 6.46 (s, 1H), 6.52 (d, J = 8.0 Hz, 2H), 6.61 (t, J = 7.2 Hz, 1H), 7.05–7.11 (m, 5H), 7.16-7.19 (m, 2H), 7.22 (d, J = 7.2 Hz, 1H), 7.25–7.30 (m, 5H), 7.34 (d, J = 7.6 Hz, 2H ), 10.29 (brs, 1H).  13C NMR (100 MHz, CDCl3) δ: 15.0, 21.2, 21.3, 33.8, 55.3, 58.4, 59.9, 98.4, 113.1, 116.3, 125.9, 126.0, 126.5, 126.6, 126.8, 127.3, 128.4, 128.8, 129.0, 129.1, 138.1, 143.0, 144.2, 147.2, 156.3, 168.4.  C34H34N2O2: calcd C, 81.24; H, 6.82; N, 5.57; found C, 81.23; H, 6.87; N, 5.54 HRMS: calcd 502.2620; found 502.2619.  Results and Discussion   In order to optimize the reaction condition, the reaction of 4-fluorobenzaldehyde (2 mmol), aniline (2 mmol) and methyl acetoacetate (1 mmol) was treated with various Lewis acids under sonication without any solvent for about 5 h, since all the reactants are liquids we expected the reaction to proceed to completion and give better yields, however this did not happen, we obtained the product in 40% yield with cerium chloride (Table 1, entry 5). We then worked on a suitable solvent for this reaction and it was observed that, the reaction works well in acetonitrile as a solvent (Table 2, entry 4). To have a meaning full comparison we also carried out the reaction under silent condition with different catalysts and found that there was no product formation either under solvent-free condition or in a solvent.   Table 1 Optimization of the catalyst for the one-pot five-component reaction.  S.No Catalyst (20mol %) Time (h) Silent conditiona Yield (%) Sonic conditionb Yield (%) 1 Aluminium chloride 5 No product  No product 2 Ferric chloride 5 10 10 3 Zinc bromide 5 No product 10 4 Cuprous chloride 5 No product No product 5 Cerium chloride 5 10 40¥  a Silent condition: stirring all the starting material without solvent and with the respective catalyst at 25 °C. b Sonic Condition: mixing the starting materials without solvent and subjecting for sonication at 25 °C. ¥Isolated yield of the product  To study the scope and limitations of this one-pot five-component sonic reaction, a variety of aromatic aldehydes, aromatic amines and β-keto esters were studied and the results are given in Table-3. It is clear from this table that, both electron-donating and electron-withdrawing aldehydes the substrates did not have much effect of the yield of the products. Both aromatic aldehydes and aryl amines gave the respective products in very good yield. Chemical Science Review and Letters                                                                                 ISSN 2278-6783   Chem Sci Rev Lett 2014, 3(9), 5-9                                                                              Article CS01204307                      8 In the present reaction, aniline is expected to react with a molecule of aromatic aldehyde and a molecule of β-keto ester to form the corresponding intermediates 5 (a β-enaminone) and 6 (an imine) respectively. The intermediates 5 and 6 are expected to get activated by cerium chloride on sonication and give the intermediate 7 by an inter-molecular addition reaction. The reaction between the intermediate 7 with a molecule of the aromatic aldehyde is expected to give 8. The intermediate 8 may then tautomerize to 9 and undergo an intra-molecular addition to give 10 which may get tautomerized to 4 as shown in the Scheme 2.  Table 2 Optimization of the solvent for the cerium chloride catalysed reaction.  S.No Solvent Time (h) Silent conditiona Yield (%) Sonic conditionb Yield (%) 1 DCM 5 No product No product 2 Water 5 No product No product 3 Water: acetonitrile (1:1) 4 20 40 4 Acetonitrile 2–3 50%c   75¥ % [product only]  a Silent condition: stirring all the starting materials + 20 mol% CeCl3 with solvent at 25 °C. b Sonic Condition: mixing the starting materials with 20 mol% CeCl3 and subjecting for sonication at 25 °C. c intermediate 5 was obtained and increase in time did not make much difference. ¥Isolated yield of the desired product                        Scheme 2 A plausible mechanism  Conclusions   To summarize, cerium chloride catalysed, atom-economic, one-pot five-component synthesis of highly functionalized piperidines under sonic condition is developed. Shorter reaction durations and reduced by-product formation, use of an energy efficient technique are the added advantages of this protocol. NOORNAr2Ar2Ar1Ar1NOORNHAr2Ar2Ar1Ar1ONH ORAr2OO OCeCl3, ))))NHAr2Ar1NAr2OORAr1CHO NAr1NOORAr2Ar1Ar2NAr1NHOORAr2Ar1Ar2N Ar2Ar1Ar1CHOAr2NH25 65  +  6Inter-molecularaddition reactionIntra-molecularaddition reaction7 89104)))), -H2OR)))) ))))))))))))))))Chemical Science Review and Letters                                                                                 ISSN 2278-6783   Chem Sci Rev Lett 2014, 3(9), 5-9                                                                              Article CS01204307                      9 Table 3 Ultrasound assisted synthesis of highly substituted piperidines.  Aldehyde (Ar1) Amine (Ar2) R Product Yield (%) a,b C6H5  C6H5 Me 4a 82 3,4,5-(OMe)3C6H2     C6H5 Me 4b 73 4-FC6H4   C6H5 Me 4c 81 C6H5     4-Me C6H4 Me 4d 85 C6H5   4-MeC6H4 Et 4e 75  a Isolated yields. b Products were confirmed on TLC by comparing with authentic samples prepared by the known method [8]                        Acknowledgement:  We express our sincere thanks to the University Grants Commission (UGC), New Delhi, INDIA for the financial assistance and a fellowship through the Major Research Project [UGC-MRP. F. No. 37-71/ (SR) 2009].  References:  [1] N. N. Mateeva, L. L Winfield, K. K Redda, Curr. Med. Chem., 2005, 12, 551–556.  [2] P. S. Watson, B. Jiang, B. Scott, Org. Lett., 2000, 2, 3679–3681. [3] H. Bin, A. M. Crider, J.P. Stables, Eur. J. Med. Chem., 2001, 36, 265–286. [4] B. Beeler, V. S. Gadepalli, S. Rama, S. Steyn, N. Castagnoli Jr, J. M. Rimoldi, Bioorg. Med. Chem., 2003, 11, 5229–5234.  [5] J. Barluenga, C. Mateos, F. Aznar, F. Valdes, Org Lett., 2002, 4, 3667–3670 . [6] R. M. Carballo, M. A. Ramírez, M. L. Rodríguez, V. S. Martín, J. I Padrón,  Org. Lett., 2006, 8, 3837–3840. [7] S. Fustero, D. Jiménez, J. Moscardó, S. Catalán, P. Carlos, Org. Lett., 2007, 9, 5283–5286.  [8] F. A. Davis, B. Chao, R. Ashwin, Org. Lett., 2001, 3, 3169–3172. [9] T. P. Lebold, A. B. Leduc, M.A. Kerr, Org. Lett., 2009, 11, 3770–3772. [10] T. K. Abu, P. Tasneem, H. Lokman, Choudhury, J. Org. Chem., 2008, 73, 8398–8402.  [11] P. A . Clarke, P. A. Zaytzev, A. C. Whitwood, Tetrahedron Lett., 2007, 48, 5209–5212.  [12] M. Misra, S.K. Pandey, V. P. Pandey, J. Pandey, R. Tripathi, R. P. Tripathi, Bioorg. Med. Chem., 2009, 17, 625–633. [13] S. Mishra, R. Ghosh, Tetrahedron Lett., 2011, 52, 2861–2897. [14] J. W. Hong, P.M. Li, H.Z. Zhan, ACS Comb. Sci., 2011, 13, 181–185. [15] T. K. Abu, M.K. Musawwer, K.R.B. Kranthi, Tetrahedron 2010, 66, 7762–7772. [16] T. J Mason, Chem. Soc. Rev., 1997, 26, 443–451.  [17] J. L. Luche, Synthetic Organic Sonochemistry, Plenum Press, New York, 1998.  [18] P. Cintas, G. Cravotto, Chem. Soc. Rev., 2006, 35, 180–196. [19] B. Datta, M. A. Pasha, Ultrason. Sonochem., 2013, 20, 303–307. [20] S. Nagashree, M. A. Pasha, Ultrason. Sonochem., 2013, 20, 810–814.  [21] S. Sudha, M. A. Pasha, Ultrason. Sonochem., 2012, 19, 994–998.  [22] B. Datta, M. A. Pasha, Ultrason. Sonochem., 2012, 19, 725–728.  Publication History Received    01st July 2013 Revised 26th Mar 2014 Accepted 28th Mar 2014 Online 29th Apr 2014  © 2014, by the Authors. The articles published from this journal are distributed to the public under “Creative Commons Attribution License” (http://creativecommons.org/licenses/by/3.0/). Therefore, upon proper citation of the original work, all the articles can be used without any restriction or can be distributed in any medium in any form.  

Ultrasound accelerated one-​pot five component reaction: a facile access to functionalized piperidines

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Ultrasound accelerated one-pot five component reaction: a facile access to functionalized piperidines

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Ultrasound accelerated one-​pot five component reaction: a facile access to functionalized piperidines

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Ultrasound accelerated one-pot five component reaction: a facile access to functionalized piperidines