SHORT COMMUNICATION Environmentally benign

Chemical Papers 65 (5) 743–746 (2011) DOI: 10.2478/s11696-011-0046-x

SHORT COMMUNICATION

Environmentally benign one-pot synthesis and antimicrobial activity of 1-methyl-2,6-diarylpiperidin-4-ones a

Pattusamy Nithya,

a Organic

a,c

Fazlur-Rahman Nawaz Khan*, a Selvaraj Mohana Roopan, b Uma Shankar, c Jong Sung Jin

Chemistry Division, School of Advanced Sciences, b School of Bio Sciences & Technology, VIT University, Vellore, Tamil Nadu 632 014, India

c Division

of High Technology Materials Research, Busan Center, Korea Basic Science Institute (KBSI), Busan 618-230, Republic of Korea Received 6 December 2010; Revised 29 March 2011; Accepted 5 April 2011

An efficient and environmentally benign one-pot method for the synthesis of 1-methyl-2,6diarylpiperidin-4-ones using montmorillonite K-10 as a catalyst has been developed. Antimicrobial activity of the compounds has been tested against selected representatives of Gram-positive and Gram-negative bacteria and fungi. c 2011 Institute of Chemistry, Slovak Academy of Sciences Keywords: montmorillonite K-10, catalyst reusability, mild conditions, antimicrobial activity

One-pot reaction strategy (Zeng et al., 2009; Ma et al., 2000; Juang et al., 2005; Menche et al., 2007; Gu et al., 2004) improves the efficacy of a chemical reaction, significantly reduces the time needed for some reaction steps to proceed, avoids lengthy separation and purification of the reaction products, with resultant important commercial implications. The piperidone moiety (Noller & Baliah, 1948; Balasubramanian & Padma, 1963a, 1963b), an interesting component of natural alkaloids (Katritzky & Fan, 1990; Edwards et al., 1988) possesses antibacterial (Rameshkumar et al., 2003; Srinivasan, et al. 2006), antipyretic (Aridoss et al., 2009), anti-inflammatory (Ganellin & Spickett, 1965; Venkatesa Perumal et al., 2001), and anti-cancer (Pati et al., 2009; Dimmock et al., 1994; Mobio et al., 1989) activities. Although there are a number of reports on the synthesis of 1,3-dimethyl-2,6-diarylpiperidin-4ones (Noller & Baliah, 1948; Balasubramanian & Padma, 1963a, 1963b, 1968; Balasubramanian & D’Souza, 1963; Jeyaraman et al., 1995; Eliel et al., 1982; Vijayalakshmi et al., 2006; Baliah et al., 1983; Weintraub et al., 2003; Srinivasan et al., 2005; Nithya

O 1

R

O

+ ArCHO + CH3NH2

R2

R

I

II

III

i

R2 Ar

N

R1 R Ar

CH3 IV

Fig. 1. One-pot synthesis of 1-methyl-2,6-diarylpiperidin-4ones. Reaction conditions: i) montmorillonite K-10, 45– 50 ◦C.

et al., 2009; Roopan & Khan, 2010), there remains a need for the introduction of safer and more efficient methods of synthesis. It has been reported (Nikalje et al., 2000; Varma, 2002; Polshettiwar & Varma, 2008; Dasgupta & T¨ or¨ ok, 2008) that montmorillonite K-10 is a reusable heterogeneous solid clay used as an acidic catalyst to enhance the yield of the Mannich reaction. In this paper, we report on a one-pot synthesis of 1-methyl-2,6-diarylpiperidin-4-one derivatives using montmorillonite K-10 as a catalyst (Fig. 1). It was found that the established method is effective for

*Corresponding author, e-mail: nawaz [email protected]

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P. Nithya et al./Chemical Papers 65 (5) 743–746 (2011)

Table 1. Characterisation data of prepared piperidin-4-one derivatives Compound

R

R1

R2

Ar

M.p./ ◦C

Yielda /%

IVa IVb IVc IVd IVe IVf IVg IVh IVi

CH3 CH3 CH3 CH3 CH3 CH3 H H H

H H H H CH3 H CH(CH3 )2 CH3 CH3

H H H H H CH3 H H CH3

C6 H 5 3-MeO-C6 H4 4-HO-C6 H4 4-Cl-C6 H4 C6 H 5 C6 H 5 C6 H 5 4-MeO-C6 H4 3,4-(MeO)2 -C6 H3

130–131b 132–133 139–140 143–144 131–132c 90–92d 108–110e 132–133g 147–148f

78 72 75 66 70 67 68 71 69

a) Isolated yields after column chromatography; b) 130–131 ◦C reported by Balasubramanian and Padma (1963b); c) 131–132 ◦C; d) 91–92 ◦C; e) 109–110 ◦C; f ) 148–149 ◦C reported by Noller and Baliah (1948); g) 104–105 ◦C reported by Baliah and Gopalakrishnan (1954). Table 2. Spectral data of newly synthesised compounds Compound

Spectral data

IVb

IR, ν˜/cm−1 : 1703, 702 NMR (CDCl3 ), δ: 0.9 (s, 3H), 2.25 (s, 3H, CH3 ), 2.55–2.79 (m, 3H, H-3, H-5), 3.67 (dt, 1H, J = 6.8 Hz, J = 7.1 Hz, H-2), 3.79 (s, 3H, OCH3 ), 3.80 (s, 3H, OCH3 ), 4.15 (dd, 1H, J = 7.2 Hz, J = 7.6 Hz, H-6), 6.69 (d, J = 6.3 Hz, Haryl ), 7.45 (d, J = 6.8 Hz, Haryl ) 13 C NMR (CDCl ), δ: 10.1, 35.8, 51.2, 51.5, 54.9, 55.3, 61.5, 68.1, 113.2, 113.5, 127.5, 129.6, 143.4, 144.3, 159.8, 3 159.9, 209.5 LCMS, m/z: 339 (M+ ) IR, ν˜/cm−1 : 3426, 1702, 700 1 H NMR (CDCl ), δ: 0.95 (s, 3H, CH ), 2.28 (s, 3H, CH ), 2.74–2.86 (dt, 2H, J = 7.2 Hz, J = 7.6 Hz, H-5), 3.65 3 3 3 (dt, 1H, J = 6.8 Hz, H-2), 3.74 (dt, 1H, J = 7.0 Hz, J = 7.3 Hz, H-3), 4.19 (dd, 1H, J = 7.3 Hz, J = 7.7 Hz, H-6), 6.86 (d, J = 6.7 Hz, Haryl ), 7.88 (d, J = 6.9 Hz, Haryl ), 8.91 (bs, 1H, OH) 13 C NMR (CDCl ), δ: 10.5, 38.5, 51.5, 51.7, 61.9, 68.2, 126.2, 127.6, 127.9, 128.3, 128.5, 128.7, 141.7, 142.6, 209.7 3 LCMS, m/z: 309 (M+ )

IVc

IVd

1H

IR, ν˜/cm−1 : 1705, 689 NMR (CDCl3 ), δ: 0.98 (s, 3H, CH3 ), 2.23 (s, 3H, CH3 ), 2.64–2.71 (dt, 2H, J = 7.2 Hz, J = 7.6 Hz, H-5), 3.65 (dt, 1H, J = 6.8 Hz, J = 7.1 Hz, H-2), 3.77 (dt, 1H, J = 6.85 Hz, J = 7.2 Hz, H-3), 4.17 (dd, 1H, J = 7.2 Hz, J = 7.5 Hz, H-6), 6.89 (d, J = 6.8 Hz, Haryl ), 8.05 (d, J = 7.1 Hz, Haryl ) 13 C NMR (CDCl ), δ: 10.8, 37.8, 51.6, 51.7, 61.8, 68.7, 127.5, 127.8, 128.6, 128.7, 129.5, 141.3, 142.8, 209.8 3 LCMS, m/z: 347 (M+ ) 1H

the preparation of tetrasubstituted piperidin-4-ones (IVa–IVi) from various aromatic aldehydes (II ) in good yields without the formation of any by-products. To optimise the efficiency of the catalyst, 10 mg to 100 mg of montmorillonite K-10 was used. The best catalytic effect was found to be with 100 mg. After completion of the reaction, the catalyst can be readily recovered by diluting the reaction mixture with dichloromethane, followed by filtration and washing with diethyl ether (93–96 % average recovery yields). The recovered catalyst was reused in five subsequent runs without significant decrease in activity. All chemicals were purchased from Sigma–Aldrich (India) and Merck (India). Melting points were measured on an Elchem microprocessor-based DT apparatus (India) in open capillary tubes and are uncorrected. Column chromatography was performed using silica gel (230–400 mesh). FTIR spectra (in KBr pellets) were recorded on a Nucon infrared spectrophotometer (India). Mass spectra (LCMS, 70 eV)

were recorded using an Agilent 1100 Series LC-MSD Ion Trap system (India) in EI mode. 1 H (500 MHz) and 13 C (125 MHz) NMR spectra (in CDCl3 ) were recorded on a Bruker AVIII-500 spectrometer (India). 1-Methyl-2,6-diarylpiperidin-4-ones (IVa–IVi) were synthesised in accordance with the general method as follows: a mixture of methylamine (40 % solution in water, 2.5 mmol), montmorillonite K-10 (100 mg), ketone I (1 mmol), and freshly distilled aromatic aldehyde II (2 mmol) was heated in a water bath at 45– 50 ◦C until the solution turned yellow and was then set aside at room temperature overnight. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ether (10 mL) and treated with aqueous hydrochloric acid (20 mL). The hydrochloride salt of the piperidin-4-one was filtered off, washed with ether and dissolved in ethanol (10 mL) followed by the addition of a slight excess of aqueous ammonia and finally diluted with water (200 mL) at 0 ◦C. The precipitated piperidin-4-one deriva-


745 – 0.5 0.5 – 0.25 – – 0.5 0.25 – 0.031 – 13 13 – 16 – – 15 16 – 21 – – 0.25 0.5 0.25 0.25 0.25 0.5 0.5 – 0.031 – – 16 10 14 15 18 12 13 – 19 0.25 0.25 0.5 – 0.25 – 0.25 0.25 0.25 – 0.031 12 12 18 – 15 – 12 12 12 – 22 – – 0.25 – 0.5 – 0.5 – 0.25 – 0.031 – – 12 – 17 – 15 – 12 – 18 1.0 – 2.0 – 0.25 – – 1.0 0.25 0.125 – 10 – 9 – 14 – – 12 15 22 – 2.0 0.5 – 0.5 – – 0.5 – – 0.125 – 7 12 – 13 – – 12 – – 25 – a) Inhibition zone (IZ) and minimum inhibitory concentration (MIC).

1.0 – 0.25 – 0.5 1.0 0.5 – – 0.125 – 9 – 15 – 12 9 11 – – 26 – 0.25 0.25 – – 0.5 0.25 – 0.25 0.25 0.125 – 12 11 – – 15 8 – 9 10 23 – 0.5 0.5 0.5 0.5 0.5 – 0.5 – – 0.125 – 8 10 12 11 10 – 12 – – 22 – – 0.5 – 0.5 0.5 0.5 0.25 – 0.25 0.125 – – 8 – 10 9 8 13 – 15 19 – IVa IVb IVc IVd IVe IVf IVg IVh IVi Ampicillin Ciproflaxin

mm mg mL−1 mm mg mL−1 mm mg mL−1 mm mg mL−1 mm mg mL−1 mm mg mL−1 mm mg mL−1 mm mg mL−1 mm mg mL−1 mm mg mL−1

MIC IZ MIC IZ

MIC

IZ

MIC

IZ

MIC

IZ

MIC

IZ

MIC

IZ

MIC

IZ

MIC

IZ

MIC

IZ

A. niger A. fumigatus A. flavus P. aeruginosa K. pneumonia E. coli B.subtilis


Compound

Aridoss, G., Parthiban, P., Ramachandran, R., Prakash, M., Kabilan, S., & Jeong, Y. T. (2009). Synthesis and spectral characterization of a new class of N-(N-methylpiperazinoacetyl)-2,6-diarylpiperidin-4-ones: Antimicrobial, analgesic and antipyretic studies. European Journal of Medicinal Chemistry, 44, 577–592. DOI: 10.1016/j.ejmech.2008.03.031. Balasubramanian, M., & D’Souza, A. (1963). Preparation and configuration of some cyclohexanols. Tetrahedron Letters, 4, 1891–1895. DOI: 10.1016/S0040-4039(01)90936-0. Balasubramanian, M., & Padma, N. (1968). Catalytic reduction of some 4-piperidones. Tetrahedron, 24, 5395–5398. DOI: 10.1016/S0040-4020(01)96333-1. Balasubramanian, M., & Padma, N. (1963a). Boat-chair equilib-

S. epidermidis

References

S. aureus

Acknowledgements. The authors wish to express their thanks to the Technology Business Incubator, VIT University and the SAIF, Indian Institute of Technology, Madras, for providing analytical facilities.

Table 3. Antibacterial activitya of compounds IVa–IVi

tive was re-crystallised from ethanol or ethanol/ethyl acetate mixture. The structure of all new compounds was confirmed by spectral data. The spectral and physical and chemical data of known compounds were in agreement with the published data (Tables 1 and 2). Synthesised piperidin-4-ones VIa–IVi were screened for antibacterial activity against Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (ATCC 3583), Bacillus subtilis (ATCC 2063) (Grampositive bacteria) and Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 13883), and Pseudomonas aeruginosa (ATCC 27853) (Gram-negative bacteria) by a well-diffusion method (Barry, 1976; Dhar et al., 1968). Ampicillin was used as a standard drug. The antifungal activity was screened against Aspergillus niger, Aspergillus flavus, Aspergillus fumigatus, and Candida albicans. Ciproflaxin (25 µg mL−1 ) was used as a standard drug. For the bioassay, the compounds were dissolved in DMSO. The two-fold dilution of the compounds was prepared (2.0 mg mL−1 , 1.0 mg mL−1 , 0.5 mg mL−1 , 0.25 mg mL−1 , 0.125 mg mL−1 , 0.062 mg mL−1 , 0.031 mg mL−1 , 0.015 mg mL−1 , 0.0078 mg mL−1 , 0.0039 mg mL−1 ). No antimicrobial activity was observed in the solvent employed. The results of antimicrobial testing are presented in Table 3. It was found that compounds with unsubstituted phenyls (IVa, IVe–IVg) exhibited moderate activity against most of the tested microorganisms. Similarly, a compound with methyl groups at C-3 and C-5 (IVi) showed better activity against all strains in comparison with compounds having H and isopropyl groups at C-3 position. As to antifungal activity, the compounds with the methyl group at C-3 position exhibited a good zone of inhibition against all the strains tested. Replacement of the methyl group with isopropyl (compound IVg) resulted in a positive response towards A. niger (100 mg mL−1 ). It is worth mentioning that the compounds with unsubstituted phenyls at C-2 and C6 (IVe–IVg) showed better activity against A. niger.

C. albicans


746


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