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new densely functionalized piperidine derivatives using amines, aldehydes and β-keto esters. The meritorious aspects of this novel protocol are atom economic ...
Indian Journal of Chemistry Vol. 54B, April 2015, pp 545-550

Multicomponent synthesis of highly functionalized piperidines using sulfamic acid as a heterogeneous and cost effective catalyst Dayanand Patila, Dattatray Chandama, Abhijeet Mulika, Prasad Patilb, Suryabala Jagdalea & Madhukar Deshmukh*a a

Heterocyclic Laboratory, Department of Chemistry, Shivaji University, Kolhapur 416 004, India

b

Department of Agrochemicals and Pest Management, Shivaji University, Kolhapur 416 004, India E-mail: [email protected] Received 1 October 2013; accepted (revised) 14 February 2015

Sulfamic acid has been found as an efficient and cost effective catalyst for one pot multicomponent synthesis of some new densely functionalized piperidine derivatives using amines, aldehydes and β-keto esters. The meritorious aspects of this novel protocol are atom economic process, heterogeneous and easily accessible catalyst, good to excellent yield, convenient work up and eco-friendly route. Keywords: Enamine, Mannich reaction, sulfamic acid, functionalized piperidine, multicomponent reaction

Multi-component reactions (MCRs) allow molecular complexity and diversity to be created by facile formation of new co-valent bonds in organic transformations which could be extended into combinatorial synthesis for developing new lead structures of active agents and catalysts1,2. MCRs usually entail eco-friendly, atom economic, time saving processes avoiding the protection-deprotection steps3. MCRs have emerged as efficient tools in organic and medicinal chemistry4. Synthesis of functionalized heterocyclic scaffolds by MCRs has been proposed as an alternative approach in organic synthesis5. Among the heterocyclic systems, the piperidine nucleus is of significant importance owing to its composition as a core unit in several biologically active compounds, natural products and synthetic pharmaceuticals6. Many naturally occurring and synthetically prepared piperidine derivatives show important biological and medicinal properties including anticancer7, antitumor8, antihistamine9, antibacterial10 and antifungal11, etc. A thorough survey of the reported literature reveals application of diverse catalytic scaffolds such as InCl3 (Ref 12), ZrOCl2.8H2O (Ref 13), BF3.SiO2 (Ref 14), bromodimethylsulfonium bromide (BDMS)4, CAN6, molecular I2 (Ref 15), BiNO3.5H2O (Ref 16), tetrabutylammonium tribromide (TBATB)17, picric acid18, 7 19 L-proline , p-toluenesulfonic acid monohydrate , PEG-embedded KBr3 (Ref 20), LaCl3.7H2O (Ref 21) and more recently by acetic acid22. However, most of

the reported methods suffer from demerits like longer reaction time, toxic and costly catalyst, low yields, etc. Therefore, there emerges an urgent need for exploration of enhanced and generalized methods for the synthesis of these vital scaffolds using commercially available and reasonable catalysts. Recently, the use of solid acid catalyst has been found to be an innovative aspect in contemporary organic chemistry7,12,13. Sulfamic acid is one of the heterogeneous catalysts which serves as a promising alternative for conventional Brønsted and Lewis acid catalysts23,24. Along with its ability to efficiently catalyze ketal formation, deprotection and many other organic transformations, it drives the reaction processes in convenient, economic and environmentally benign manner25,26. Sulfamic acid is bestowed with unique features like moderate acidity (pKa 1.0), insolubility in common organic solvents, thermal stability, Zwitterionic character, non-volatile, non-corrosive, non-hygroscopic nature and high miscibility in water along with recyclability and reusability27-29. As part of the ongoing efforts to achieve new routes for the synthesis of heterocyclic compounds30, herein is reported a one-pot multicomponent synthesis of highly functionalized piperidine derivatives by condensing acetoacetic esters, aryl aldehydes and aryl amines in the presence of catalytic amounts of sulfamic acid (SA) as a proficient and viable catalyst (Scheme I).

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Results and Discussion Initially, a mixture of p-chlorobenzaldehyde, pmethyl aniline and ethyl acetoacetate was refluxed in ethanol in the presence of catalytic amount of sulfamic acid to obtain the corresponding piperidine derivative. The product was obtained in good to excellent yield with elevated reaction rate which was assumed to be a result of the significant role played by the catalyst in the above transformation. Optimization studies of the above reaction were carried out by altering the organic solvents, amount of incorporated catalyst and the reaction temperature. The results have been summarized in Table I. The reaction did not proceed in the absence of catalyst even after prolonged boiling (25 hr, Table I, Entry 3). Increment in catalyst quantity from 10 to 15 mol% increases both yield and rate of the reaction (Table I, Entries 9, 10). A

further increment of catalyst amount (above 15 mol%) does not affect the yield and rate of the reaction (Table I, Entry 11). Finally, among all the experimental variations the 15 mol% sulfamic acid in ethanol at reflux temperature gave the best results with 89% yield (Table I, Entry 10). To check the generality and scope of the optimized protocol, the methodology was evaluated by employing different aromatic aldehydes, aryl amines and βketoesters. The resultant corresponding functionalized piperidines (4a-p) were obtained in good to excellent yields (Table II). It was observed that the aldehydes with electron donating groups proved dominance affording higher yields (Table II, Entries 3, 8, 16) as compared to electron withdrawing groups which were obtained in comparatively lower yields (Table II, Entries 2, 4, 6, 9, 11-15).

Scheme I — Synthesis of piperidine derivatives 4 Table I — Optimization of the catalyst and solvent for one-pot synthesis of functionalized piperidinesa Entry

Catalyst (mol%)

Solvent

Condition

Time (hr)

1 Water RT 15 2 Water:Ethanol(1:1) Reflux 10 3 EtOH RT 25 4 EtOH Reflux 20 5 Amberlyst IR 120 (50 mg) MeOH Reflux 10 6 TMSiCl (20%) EtOH Reflux 10 7 SnCl2 (10%) EtOH RT 13 8 SA (15%) EtOH RT 15 9 SA (10%) EtOH Reflux 5 10 SA (15%) EtOH Reflux 2 11 SA (20%) EtOH Reflux 2 12 SA (10%) MeOH Reflux 6 RT 22 13 SA (10%) CH3CN a Experimental conditions: 4-Cl benzaldehyde (2 mmol), 4-CH3 aniline (2 mmol), Ethyl acetoacetate (1 mmol) b Isolated yield c No reaction occurred SA = Sulfamic acid

Yield (%)b -c -c -c -c -c -c 25 55 60 89 80 30 37

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Table II — Synthesis of functionalized piperidines (4a-p) with different aryl aldehydes, aryl amines and β-keto estersa Entry

Aldehyde

Amine

β-Keto ester

Product

Time (hr)

1 C6H5 C6H5 MAA 7 4a C6H5 MAA 5.5 2 4-Cl C6H4 4b 3 4-OCH3 C6H4 C6H5 MAA 6.5 4c 4 3-NO2 C6H4 C6H5 MAA 6 4d C6H5 EAA 5 5 C6H5 4e 4-Cl C6H4 EAA 6.5 6 3-Cl C6H4 4f 7 C6H5 4-Cl C6H4 EAA 8 4g 8 4-OCH3 C6H4 4-Cl C6H4 MAA 3.5 4h 4-Cl C6H4 MAA 4.5 9 4-F C6H4 4i 4-Cl C6H4 EAA 7 10 4-Cl C6H4 4j 11 4-NO2 C6H4 4-CH3 C6H4 EAA 5 4k 4-CH3 C6H4 EAA 5.5 12 3-CF3 C6H4 4l 13 3-Cl C6H4 4-CH3 C6H4 MAA 6 4m 14 4-Cl C6H4 4-CH3 C6H4 EAA 2 4n 15 C6H5 4-CH3 C6H4 MAA 5 4o 16 4-OCH3 C6H4 4-CH3 C6H4 MAA 7 4p 17 n-Butanal C6H5 EAA 15 18 3-Cl C6H4 C6H5 CH2 EAA 13 a Reaction conditions: aromatic aldehyde (2 mmol), aromatic amine (2 mmol), MAA ethanol at reflux condition b Isolated yield c No reaction MAA-Methyl acetoacetate, EAA-Ethyl acetoacetate

Similarly, the use of aliphatic aldehyde and amine for the present protocol proved to be ineffective and failed to give the desired piperidine derivative even after prolonged stirring (Table II, Entries 17, 18). A probable mechanism for the product formation is proposed in Scheme II, which is in accordance with the reported literature13,15-17. Sulfamic acid acts as a Lewis acid for the reaction of aromatic amine 2 and β-keto ester 1 to give enamine 5 and the reaction of aromatic aldehyde 3 and aromatic amine 2 to give the corresponding imine 6 (Schiff base). Then nucleophilic attack of enamine 5 will take place preferentially on the activated imine 6 followed by inter-and intramole-cular Mannich type reaction to give intermediate 10 which tautomerises to give the final piperidine scaffold 4. Thereafter, the performance of sulfamic acid was evaluated using other relevant catalysts for the synthesis of piperidine derivatives as shown in Table III. Considering the criteria of reaction time and yields of the products, sulfamic acid performed efficiently outperforming the others catalysts engaged for the same reaction. Experimental Section All the chemicals were purchased from SD Fine Chem Limited and Thomas Baker and used as

Yield (%)

m.p.°C Obs.

m.p.°C Lit.

73 193-94 194-95 (Ref 6) 81 221-23 225-26 (Ref 6) 87 178-79 182-83 (Ref 6) 76 182-83 181-82 (Ref 6) 78 176-77 175-76 (Ref 6) 74 189-91 189-90 (Ref 6) 72 199-201 201-02 (Ref 6) 84 193-94 194-95 (Ref 6) 78 184-86 178 (Ref 13) 77 207-209 83 211-13 76 170-71 73 189-90 89 232-35 77 221-23 220-22 (Ref 13) 90 180-81 181 (Ref 13) -c -c or EAA (1 mmol) and catalyst (15 mol%) in

received without further purification. All the melting points were determined on Labstar melting point apparatus and are uncorrected. The IR spectra were run on a Perkin-Elmer FTIR-1600 spectrophotometer and the data expressed in cm-1 (KBr). 1H and 13C NMR spectra were recorded on Bruker Avance (300 MHz) spectrometer in CDCl3 using TMS as the internal standard. Mass spectra were recorded on a Performa spectrometer. General procedure for the preparation of piperidine derivatives (4a-p) A mixture of β-ketoester (1 mmol), aryl amine (2 mmol) and sulfamic acid (15 mol%) in 5 mL ethanol was stirred at RT for 15 min, aryl aldehyde (2 mmol) was then added and stirring was continued at 78°C till the completion of TLC. A solid precipitate of the desired product was formed as the reaction mass was gradually cooled to RT. The crude solid was filtered and washed with cold ethanol. In those cases, where a solid was not formed after cooling, the solvent was evaporated by rotary evaporation and the crude product obtained was purified by column chromatography over silica gel (EtOAc/pet ether) to give pure functionalized piperidine product (Table II, Entries 3,6,7). The products were analyzed by IR, 1H and 13 C NMR and mass spectrometry.

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Scheme II — A plausible mechanism for the formation of functionalized piperidine

Spectroscopic data of new compounds Ethyl-1-(4-chloro phenyl)-4-(4-chloro phenyl amino)2, 6-bis(4-chloro phenyl)-1, 2, 5,6-tetrahydropyridine3-carboxylate, 4j (Table II, Entry 10): White solid, m.p. 207-209°C, IR (KBr): 3234, 2975, 2922, 1652, 1600, 1494, 1408, 1369, 1328, 1256, 1176, 1091 cm-1; 1 H NMR (300 MHz, CDCl3): δ 1.44-1.49 (t, J = 7.2 Hz, 3H), 2.67-2.86 (m, 2H), 4.30-4.52 (m, 2H), 5.07 (s,

1H), 6.30-6.31 (d, J = 4.8Hz, 2H), 6.34-6.35 (d, J = 3.9Hz, 2H), 6.39 (s, 1H), 7.01-7.28 (m, 12H), 10.26 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 14.7, 33.5, 54.9, 57.4, 60.0, 98.2, 114.0, 121.8, 126.8, 127.6, 127.8, 128.5, 128.8, 128.9, 129.1, 131.6, 132.4, 133.2, 136.1, 140.3, 141.6, 145.0, 155.1, 167.8; TOF-MS: Calcd for C32H26Cl4N2O2 Na [M+Na]+: m/z 636.369, Found: 636.9.

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Table III — Evaluation of the results of sulfamic acid with literature reported catalysts Entry 1 2 3 4 5 6 7 8 9 10 11

Catalyst

Solvent

Condition

Time (hr)

Yield (%)

InCl3 ZrOCl2.8H2O BF3.SiO2 CAN I2 TBATB L-Proline/ TFA PTSA PEG-embedded KBr3 Bi(NO3)3.5H2O H2NSO3H

CH3CN EtOH MeOH CH3CN MeOH EtOH CH3CN EtOH EtOH EtOH EtOH

RT Reflux 65°C RT RT RT RT RT RT RT Reflux

24 3-7 7-9 15-45 8-48 8-47 16-24 7-24 8-16 12-55 2-8

16-74 (Ref 12) 65-91 (Ref 13) 31-92 (Ref 14) 51-86 (Ref 6) 36-85 (Ref 15) 28-75 (Ref 17) 55-75 (Ref 7) 44-89 (Ref 19) 30-90 (Ref 20) 41-81 (Ref 16) 72-90 [This Work]

Ethyl-1-(4-methyl phenyl)-4-(4-methyl phenyl amino)-2,6-bis (4-nitro phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate, 4k (Table II, Entry 11): Yellow solid, m.p. 211-13°C, IR (KBr): 3430, 3235, 2975, 2922, 2853, 1652, 1598, 1518, 1347, 1255, 1177, 1109, 1073 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.45-1.50 (t, J = 6.9 Hz, 3H), 2.18 (s, 3H), 2.29 (s, 3H), 2.84-2.85 (d, J = 3.6Hz, 2H), 4.31-4.53 (m, 2H), 5.24 (s, 1H), 6.30-6.33 (d, J = 8.1Hz, 4H), 6.44 (s, 1H), 6.90-6.98 (dd, J = 7.8Hz, J = 8.1Hz, 4H), 7.29-7.32 (d, J = 8.4Hz, 2H), 7.51-7.53 (d, J = 8.4Hz, 2H), 8.13-8.18 (m, 4H), 10.25 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 14.7, 20.0, 20.8, 33.5, 55.4, 57.3, 60.1, 96.3, 113.0, 123.6, 123.8,125.5, 126.8, 129.7, 129.8, 134.5, 136.3, 143.6, 146.7, 147.2, 150.1, 152.0, 155.6, 167.6; TOFMS: Calcd for C34H32N4O6Na [M+Na]+: m/z 616.637, Found: 616.2. Ethyl-1-(4-methyl phenyl)-4-(4-methyl phenyl amino)-2,6-bis (3-trifluoro methyl Phenyl)-1,2,5,6tetrahydropyridine-3-carboxylate, 4l (Table II, Entry 12): White solid, m.p. 170-71°C, IR (KBr): 3240, 2983, 2925, 2861, 1652, 1618, 1594, 1517, 1447, 1372, 1330, 1256, 1161, 1119, 1075 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.45-1.50 (t, J = 6.9Hz, 3H), 2.28 (s, 3H), 2.27-2.78 (d, J = 3.9Hz, 2H), 4.28-4.55 (m, 2H), 5.20 (s, 1H), 6.19-6.21 (d, J = 8.1Hz, 2H), 6.35-6.38 (d, J = 8.7Hz, 2H), 6.42 (s, 1H), 6.89-6.95 (t, J = 8.1Hz, 4H), 7.26-7.56 (m, 7H), 7.73 (s, 1H), 10.22 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 14.7, 20.1, 20.8, 33.5, 55.3, 57.5, 59.7, 96.7, 113.0, 123.6, 124.1, 126.0, 128.5, 129.1, 129.6, 129.9, 130.7, 136.2, 143.7, 144.1, 145.4, 156.0, 167.8; TOF-MS: Calcd for C36H32F6N2O2Na [M+Na]+: m/z 662.637, Found: 662.3. Methyl-1-(4-methyl phenyl)-4-(4-methyl phenyl amino)-2,6-bis (3-chloro phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate, 4m (Table II, Entry 13):

White solid, m.p. 189-90°C; IR (KBr): 3224, 3147, 2947, 2918, 2880, 1648, 1618, 1591, 1571, 1516, 1471, 1366, 1258, 1187, 1068 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.19 (s, 3H), 2.31 (s, 3H), 2.69-2.75 (dd, J = 15.3Hz and J = 2.7Hz, 1H), 2.78-2.85 (dd, J = 15.0Hz and J = 5.4Hz, 1H), 3.94 (s, 3H), 5.09 (s, 1H), 6.24-6.27 (d, J = 8.1Hz, 2H), 6.35-6.38 (d, J = 7.5Hz, 2H), 6.40 (s, 1H), 6.89-6.92 (d, J = 8.4Hz, 2H), 6.97-6.99 (d, J = 8.1Hz, 2H), 7.02-7.04 (d, J = 7.2Hz, 1H), 7.18-7.24 (m, 5H), 7.32 (s, 1H), 10.18 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 20.17, 20.97, 33.45, 51.01, 55.0, 57.5, 96.6, 112.9, 124.7, 125.8,126.5, 126.6, 126.7, 127.3, 129.4, 129.6, 129.9, 134.2, 134.4, 134.8, 136.1, 144.2, 145.0, 156.3, 168.3; TOF-MS: Calcd for C33H30Cl2N2O2 [M+H]+: m/z 557.509, Found: 557.2. Ethyl-1-(4-methyl phenyl)-4-(4-methyl phenyl amino)-2,6-bis (4-chloro phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate, 4n (Table II, Entry 14): White solid, m.p. 232-35°C; IR (KBr): 3428, 3248, 2977, 2920, 1654, 1618, 1595, 1556, 1456, 1367, 1253 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.43-1.47 (t, J = 6.9Hz, 3H), 2.18 (s, 3H), 2.30 (s, 3H), 2.70-2.83 (m, 2H), 4.30-4.47 (m, 2H), 5.07 (s, 1H), 6.28-6.31 (d, J = 7.8Hz, 2H), 6.33 (s, 1H), 6.36-6.39 (d, J = 8.4 Hz, 2H), 6.89-6.92 (d, J = 8.1Hz, 2H), 6.95-6.98 (d, J = 7.8Hz, 2H), 7.06-7.09 (d, J = 8.1Hz, 2H), 7.24-7.26 (s, 6H), 10.23 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 14.8, 20.1, 20.8, 33.6, 54.8, 57.3, 59.7, 97.2, 114.0, 125.7, 125.8, 127.8, 128.0, 128.3, 128.7, 129.5, 132.0, 135.0, 135.8, 141.2, 142.8, 144.3, 156.1, 168.0; TOF-MS: Calcd for C34H32Cl2N2O2 [M+H]+: m/z 571.536, Found: 571.2. Conclusion In summary, an efficient and mild protocol for the synthesis of widely functionalized piperidine derivatives

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using sulfamic acid as an inexpensive heterogeneous catalyst has been demonstrated. This MCR protocol offers several significant advantages including operational simplicity, superior atom-economy, short reaction time and good to excellent yields. Acknowledgement The authors are thankful to the Department of Chemistry, Shivaji University, Kolhapur for spectral measurements. One of the authors, D. R. Patil is grateful to the UGC New Delhi for the award of a Junior Research Fellowship [F.No.41-211/2012 (SR)]. References 1

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