A Simple and Efficient Grindstone Chemistry Solid-state Reaction Procedure for the Synthesis of Heterocyclic Oximes in Dry Media

무수조건하에서 헤테로 옥심의 합성을 위한 간단하고 효율적인 맷돌화학 고체상태의 반응과정

INTRODUCTION

Solvent-free synthesis of organic compounds involving easily separable solid catalysts has attracted notable interest and offers a clean, economical and environmentally-safe protocol. Nowadays, bioactive heterocyclic ring systems having 2,6-diarylpiperidin-4-one moiety and their analogous thiopyran and pyran nuclei have aroused great interest due to their wide variety of biological properties such as antiviral, antitumour,1,2 central nervous system,3 local anesthetic,4 anticancer,5 and antimicrobial activity,6 and also act as neurokinin receptor antagonists,7 analgesic and anti-hypertensive agents.8 Oximes of various substituted piperidones were also reported to exhibit antimicrobial, analgesic, local anesthetic and antifungal activities.9

Oximation has attracted intensive attention for several decades as an efficient method for characterization and purification of carbonyl compounds. Due to the nucleophilic character of oximes, they have been widely used for the preparation of a variety of nitrogen containing compounds such as amides,10 hydroximinoyl chlorides,11 nitrones12 and nitriles.13 Oximes are usually prepared by the reaction of carbonyl compounds and hydroxylamine hydrochloride with adjustment of pH using a basic aqueous medium. Recently, some new techniques such as microwave irradiation14 and solvent-free heating15 were applied to this reaction. Oxidation of amines was another usual method of the synthesis of oximes.16

It has been about 70 years to research and use fly ash. With its application, the action mechanism of fly ash had been recognized. During the initial stage, only its pozzolanic activity is paid attention.17,18 Many researchers were devoted to the research of the potential activity of fly ash and the hydration process of fly ash cement.19 Recently, microwaveassisted activated fly ash has been reported to catalyze Knoevenagel condensation, synthesis of amides, Schiff Bases formation, and Biginelli and Hantzsch reactions.20

In continuation of our interest in synthesizing pharmacologically important compounds in ‘dry media’,21-24 we wish to report activated fly ash as an efficient catalyst for the synthesis of 3-alkyl-2,6-diarylpiperidin-4-one oximes, 2,6-diaryltetrahy-drothiopyran-4-one oximes, and 2,6-diaryltetrahy-dropyran-4-one oximes using a mortar and pestle in dry media.

 

RESULTS AND DISCUSSION

Chemistry

The oximes of aldehyde and ketone are served as protecting,25 selective activating groups26 and intermediates for many reactions such as Beckmann rearrangement for the preparation of amides. Further, oximes are used for the purification of carbonyl compounds. The oximes can be prepared by the addition of hydroxylamine to aldehydes and ketones. The formation of oximes is usually catalyzed by acids.27 The preparations of oximes from aldehydes or ketones using hydroxylamine as reactant and sulphuric acid as catalyst27 have many disadvantages. This procedure is not applicable for acid-sensitive compounds, the yields of the oximes are pH dependent28 and it requires costly solvent like pure ethanol. Cyclohexanone oximes are synthesized by liquid-phase ammoximation of cyclohexanone using ammonia, hydrogen peroxide as the oxidizing agent and titanium silicate as a catalyst. The ammoximation reaction is suitable for the synthesis of several oximes29 but use of H2O2 and titanium silicate increased the cost of production. To avoid liquid phase oximation reactions, we use activated fly ash as a solid catalyst for the oximation reaction.

The fly ash collected from Neyveli Lignite Corporation, Neyveli, Tamil Nadu, India was utilized for catalyzing the reactions. Specific gravity and specific surface area of the fly ash were 1.9 and 127 m2/g, respectively. The chemical compositions (%) of insoluble residues of the fly ash after ignition were SiO2, Fe2O3, Al2O3, CaO, MgO, in the ratio of 64.03, 6.50, 15.50, 4.62, 3.00, 4.35, and 2.00, respectively.

Target molecules, 2,6-diarylpiperidin/tetrahydrothiopyran/ tetrahydropyran-4-one oximes 14-28 are synthesized as a result of single-step solid-state synthetic strategy. In a typical experiment, corresponding 3-alkyl-2, 6-diaryl-piperidin/tetrahydrothiopyran/ tetrahydropyran-4-ones 1-14 were mixed with hydroxylamine hydrochloride and activated fly ash in a mortar and pestle. The mixture was grinded briskly for 5 to 10 min to yield the title compounds in high yields. The reaction in dry media provides advantages over the classical method,21 which requires a longer reaction time using ethanol as solvent medium and the use of column chromatographic technique to purify the products. The most acceptable ratio in terms of efficiency were 50 mg of activated fly ash to 0.001 moles of substrates. Introduction of bulky dimethyl moiety at position 3 of the piperidone ring did not affect the oximation reaction. Also, there is no need of any purification technique to purify the formed oximes since the reaction mixture was shaken well with dichloromethane and the catalyst was removed by simple filtration. Concentration of dichloromethane layer by distilled off under reduced pressure yield the respective oximes.

Fig. 1.Flow charr for the preparation of activated fly ash.

Scheme 1.Synthesis of biolabile oximes under dry media reaction conditions.

Table 1.Physical and analytical data of compounds 15-28

The schematic representation and the analytical data of compounds 15-28 are given in Scheme 1 and Table 1, respectively. The structures of the newly synthesized compounds 15-28 were confirmed by their melting points, elemental analyses, MS, FT-IR, and 1H NMR spectroscopic data. This new synthetic method is applicable to synthesize simple ketoximes and aldoxime from cyclohexanone, cyclopentanone, acetone, butan-2-one, and benzaldehyde, in good to excellent yields.

Fig. 2.Reuse of Activated fly ash catalyst for oximation.

The reusability of activated fly ash catalyst was studied using compounds 15, 23 and 26 with hydroxylamine hydrochloride. After filtering, washing with dichloromethane, drying at 120℃ for 1h, the fly ash was reused for the next round of the reactions to provide excellent reproducibility, as shown in Fig. 2. It is evident that the system retains high catalytic efficacies after repeating the reuse procedure up to 4 times since recycling led to loss of efficiency of the catalyst owing to absorption of organics. Organics on the solid surface result in the reduction of the number of active centres. Organic species could be removed at higher temperature, reactivating the catalyst.

 

CONCLUSION

The present work describes the synthesis of heterocyclic oximes namely 3-alkyl-2,6-diarylpiperidin-4-one oximes 15-22, 2,6-diphenylthiopyran-4-one oximes 13-15, and 2,6-diphenylpyran-4-one oximes 16-18 in dry media under solvent-free conditions catalyzed by activated fly ash using grindstone chemistry. Using this protocol, various structurally diverse oximes were synthesized with excellent yields.

 

EXPERIMENTAL

General

The reactions and the purity of the products were monitored and estimated by TLC. The melting points were measured in open capillaries and are reported uncorrected. IR spectra were recorded in KBr (pellet forms) on a Nicolet-Avatar–330 FT-IR spectrophotometer and noteworthy absorption values are listed in cm-1. 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively, on Bruker AMX 400 NMR spectrometer using CDCl3 as solvent. The positive ESI MS spectra were recorded on a Bruker Daltonics LC-MS spectrometer. Microanalysis was obtained on Carlo Erba 1106 CHN analyzer.

By adopting the literature precedent, 2,6-diarylpiperidin-4-ones30 1-8, 2,6-diaryltetrahydrothiopyran-4-ones31 9-11 and 2,6-diaryltetrahydropyran-4-ones32 12-14 are prepared.

General synthetic procedure for the synthesis of 2,6-diarylpiperidin-4-one oximes in dry media 15-17

Appropriate 2,6-diarylpiperidin-4-ones 1-3 (0.001 mol) and hydroxylamine hydrochloride (0.001 mol) were mixed thoroughly with activated fly ash (50 mg) in a mortar and pestle. The mixture was grinded briskly for 5-10 min. (monitored by TLC) and the reaction mixture was shaken well with dichloromethane (15 mL). The catalyst was removed by simple filtration. The dichloromethane layer was dried over anhydrous sodium sulphate and distilled off under reduced pressure to yield the respective 2,6-diarylpiperidin-4-one oximes 15-17.

2,6-diphenylpiperidin-4-one oxime 15 Reaction time: 9 min. IR (KBr) (cm-1): 3250, 3031, 2917, 2801, 1674, 1600, 754, 700; 1H NMR (δ, ppm): 2.00 (s, 1H, H1), 3.94 (dd, 1H, H2a, J2a,3a=11.4 Hz), 3.88 (dd, 1H, H6a, J6a,5a=11.6 Hz), 3.54 (t, 1H, H5e, J6a,5e=2.98Hz), 2.56 (t, 1H, H3e, J2a,3e=2.92Hz), 2.38 (m, 1H, H3a), 2.01 (m, 1H, H5a), 7.48-7.18 (m, 10H, Harom), 8.00 (s, 1H, N-OH).

2,6-bis(4-methylphenyl)piperidine-4-one oxime 16 Reaction time: 5 min. IR (KBr) (cm-1): 3248, 3028, 2914, 2841, 2804, 1671, 1604, 748, 696; 1H NMR (δ, ppm): 1.98 (s, 1H, H1), 3.92 (dd, 1H, H2a, J2a,3a=11.30 Hz), 3.86 (dd, 1H, H6a, J6a,5a=11.41 Hz), 3.51 (t, 1H, H5e, J6a,5e=2.95 Hz), 2.54 (t, 1H, H3e, J2a,3e=2.90 Hz), 2.32 (s, 3H, CH3 at phenyl ring); 2.36 (m, 1H, H3a), 2.04 (m, 1H, H5a), 7.52-7.09 (m, 8H, Harom), 8.03 (s, 1H, N-OH).

2,6-bis(4-chlorophenyl)piperidine-4-one oxime 17 Reaction time: 10 min. IR (KBr) (cm-1): 3253, 3035, 2921, 1677, 1598, 762, 705; 1H NMR (δ, ppm): 2.02 (s, 1H, H1), 3.96 (dd, 1H, H2a, J2a,3a=11.7 Hz), 3.89 (dd, 1H, H6a, J6a,5a=11.8 Hz), 3.56 (t, 1H, H5e, J6a,5e=2.94 Hz), 2.58 (t, 1H, H3e, J2a,3e=2.92 Hz), 2.40 (m, 1H, H3a), 2.08 (m, 1H, H5a), 7.52-7.24 (m, 8H, Harom), 8.06 (s, 1H, N-OH).

General synthetic procedure for the synthesis of 3,3-dimethyl-2,6-diarylpiperidin-4-one oximes in dry media 18-22

Appropriate 3,3-dimethyl-2,6-diarylpiperidin-4-ones 4-8 (0.001 mol) and hydroxylamine hydrochloride (0.001 mol) were mixed thoroughly with activated fly ash (50mg) in a mortar and pestle. The mixture was grinded briskly for 5-10 min. (monitored by TLC) and the reaction mixture was shaken well with dichloromethane (15 mL). The catalyst was removed by simple filtration. The dichloromethane layer was dried over anhydrous sodium sulphate and distilled off under reduced pressure to yield the respective 3,3-dimethyl-2,6-diarylpiperidin-4-one oximes 18-22.

3,3-dimethyl-2,6-diphenylpiperidin-4-one oxime 18 Reaction time: 5 min. IR (KBr) (cm-1): 3260, 3030, 2980, 2924, 2851, 2819, 1493, 742, 702; 1H NMR (δ, ppm): 0.98 (s, 3H, CH3 at C-3), 1.24 (s, 3H, CH3 at C-3), 2.42 (t, 1H, H5a); 3.62 (dd, 1H, H5e, J5e,5a=14.95; J5e,6a=3.86 Hz), 3.70 (d, 1H, H2a), 3.79 (dd, 1H, H6a, J5a,6a =12.85 Hz), 2.10 (s, 1H, H1), 7.25-7.71 (m, 10H, Harom), 8.93 (s, 1H, C=N-OH)

3,3-dimethyl-2,6-bis(p-methylphenyl)piperidin-4-one oxime 19: Reaction time: 7 min. IR (KBr) (cm-1): 3254, 3028, 2977, 2922, 2855, 1513, 816; 1H NMR (δ, ppm): 0.97 (s, 3H, CH3 at C-3), 1.22 (s, 3H, CH3 at C-3), 2.12 (s, 1H, H1), 2.34 (t, 1H, H5a); 2.35 (s, 6H, CH3 at phenyl rings), 3.58 (dd, 1H, H5e J5e,5a=14.92; J5e,6a=3.93 Hz), 3.63 (d, 1H, H2a), 3.73 (dd, 1H, H6a J5a,6a =12.82 Hz), 7.15-7.41 (m, 8H, Harom), 8.21 (s, 1H, C=N-OH)

3,3-dimethyl-2,6-bis(p-methoxyphenyl)piperidin-4-one oxime 20: Reaction time: 8 min. IR (KBr) (cm-1): 3287, 3026, 2931, 2836, 1513, 831; 1H NMR (δ, ppm): 0.95 (s, 3H, CH3 at C-3), 1.25 (s, 3H, CH3 at C-3), 2.10 (s, 1H, H1), 2.49 (t, 1H, H5a); 3.61 (dd, 1H, H5e, J5e,5a=14.85; J5e,6a=3.85 Hz), 3.80 (s, 6H, OCH3 at phenyl rings), 3.74 (d, 1H, H2a), 3.81 (dd, 1H, H6a, J5a,6a=12.81 Hz), 6.92-7.71 (m, 8H, Harom), 8.34 (s, 1H, C=N-OH).

3,3-dimethyl-2,6-bis(p-chlorophenyl)piperidin-4-one oxime 21: Reaction time: 8 min. IR (KBr) (cm-1): 3492, 3027, 2981, 2836, 1513, 831; 1H NMR (δ, ppm): 0.98 (s, 3H, CH3 at C-3), 1.20 (s, 3H, CH3 at C-3), 2.16 (s, 1H, H1), 2.33 (t, 1H, H5a); 3.58 (dd, 1H, H5e, J5e,5a=14.94; J5e,6a=3.88 Hz), 3.67 (d, 1H, H2a), 3.74 (dd, 1H, H6a, J5a,6a=12.96 Hz), 7.26-7.58 (m, 8H, Harom), 8.23 (s, 1H, C=N-OH).

3,3-dimethyl-2,6-bis(p-fluorophenyl)piperidin-4-one oxime 22: Reaction time: 7 min. IR (KBr) (cm-1): 3491, 3027, 2980, 2924, 2851, 1496, 1089, 836; 1H NMR (δ, ppm): 0.97 (s, 3H, CH3 at C-3), 1.18 (s, 3H, CH3 at C-3), 2.18 (s, 1H, H1), 2.31 (t, 1H, H5a); 3.55 (dd, 1H, H5e, J5e,5a=14.91; J5e,6a=3.85 Hz), 3.65 (d, 1H, H2a), 3.72 (dd, 1H, H6a, J5a,6a =12.94 Hz), 7.24-7.55 (m, 8H, Harom), 8.20 (s, 1H, C=N-OH).

General synthetic procedure for the synthesis of 2,6-diaryltetrahydrothiopyran-4-one oximes in dry media 23-25

Appropriate 2,6-diaryltetrahydrothiopyran-4-ones 9-11 (0.001 mol) and hydroxylamine hydrochloride (0.001 mol) were mixed thoroughly with activated fly ash (50mg) in a mortar and pestle. The mixture was grinded briskly for 7-10 min. (monitored by TLC) and the reaction mixture was shaken well with dichloromethane (15 mL). The catalyst was removed by simple filtration. The dichloromethane layer was dried over anhydrous sodium sulphate and distilled off under reduced pressure to yield the respective 2,6-diaryltetrahydrothiopyran-4-one oximes 23-25.

2,6-diphenyltetrahydrothiopyran-4-one oxime 23 Reaction time: 10 min. IR (KBr) (cm-1): 3172, 3060, 2900, 1649, 748, 696; 1H NMR (δ, ppm): 4.20 (dd, 1H, H2a, J2a,3a=12.16 Hz), 4.14 (dd, 1H, H6a, J6a,5a=12.4 Hz), 3.96 (dd, 1H, H5e, J6a,5e=2.44 Hz), 2.93 (dd, 1H, H3e, J2a,3e=2.72 Hz), 2.77 (dd, 1H, H3a, J3a,3e=13.52 Hz), 2.37 (dd, 1H, H5a, J5a,5e=13.62 Hz ), 7.40-7.29 (m, 10H, Harom), 7.55 (s, 1H, N-OH).

2,6-bis(4-methylphenyl)tetrahydrothiopyran-4-one oxime 24 Reaction time: 8 min. IR (KBr) (cm-1): 3170, 3057, 2896, 1647, 744, 693; 1H NMR (δ, ppm): 4.17 (dd, 1H, H2a, J2a,3a=12.16 Hz), 4.12 (dd, 1H, H6a, J6a,5a=12.30 Hz), 3.94 (dd, 1H, H5e, J6a,5e=2.43 Hz), 2.91 (dd, 1H, H3e, J2a,3e=2.70 Hz), 2.75 (dd, 1H, H3a, J3a,3e=13.54 Hz), 2.30 (s, 3H, CH3 at phenyl ring); 2.35 (dd, 1H, H5a, J5a,5e=13.60 Hz ), 7.37-7.26 (m, 8H, Harom), 7.51 (s, 1H, N-OH).

2,6-bis(4-chlorophenyl)tetrahydrothiopyran-4-one oxime 25 Reaction time: 7 min. IR (KBr) (cm-1): 3175, 3066, 2905, 1652, 756, 690; 1H NMR (δ, ppm): 4.22 (dd, 1H, H2a, J2a,3a=12.18 Hz), 4.16 (dd, 1H, H6a, J6a,5a=12.41 Hz), 3.97 (dd, 1H, H5e, J6a,5e=2.40 Hz), 2.95 (dd, 1H, H3e, J2a,3e=2.71 Hz), 2.78 (dd, 1H, H3a, J3a,3e=13.55 Hz), 2.39 (dd, 1H, H5a, J5a,5e=13.64 Hz ), 7.45-7.31 (m, 8H, Harom), 7.58 (s, 1H, N-OH).

General synthetic procedure for the synthesis of 2,6-diaryltetrahydropyran-4-one oximes in dry media 26-28

Appropriate 2,6-diaryltetrahydropyran-4-ones 12-14 (0.001 mol) and hydroxylamine hydrochloride (0.001 mol) were mixed thoroughly with activated fly ash (50 mg) in a mortar and pestle. The mixture was grinded briskly for 7-10 min. (monitored by TLC) and the reaction mixture was shaken well with dichloromethane (15 mL). The catalyst was removed by simple filtration. The dichloromethane layer was dried over anhydrous sodium sulphate and distilled off under reduced pressure to yield the respective 2,6-diaryltetrahydropyran-4-one oximes 26-28.

2,6-diphenyltetrahydropyran-4-one oxime 26 Reaction time: 7 min. IR (KBr) (cm-1): 3226, 3030, 2896, 1661, 736, 690; 1H NMR (δ, ppm): 4.78 (dd, 1H, H2a, J2a,3a=10.30 Hz), 5.13 (dd, 1H, H6a, J6a,5a=12.53 Hz), 3.34 (m, 1H, H5e), 2.70 (m, 2H, H3), 2.84 (m, 1H, H5a), 7.62-7.14 (m, 10H, Harom), 7.90 (s, 1H, N-OH).

2,6-bis(4-methylphenyl)tetrahydropyran-4-one oxime 27 Reaction time: 6 min. IR (KBr) (cm-1): 3223, 3027, 2891, 1658, 733, 688; 1H NMR (δ, ppm): 4.77 (dd, 1H, H2a, J2a,3a=10.29 Hz), 5.10 (dd, 1H, H6a, J6a,5a=12.54 Hz), 3.32 (m, 1H, H5e), 2.28 (s, 3H, CH3 at phenyl ring); 2.67 (m, 2H, H3), 2.81 (m, 1H, H5a), 7.58-7.11 (m, 8H, Harom), 7.87 (s, 1H, N-OH).

2,6-bis(4-chlorophenyl)tetrahydropyran-4-one oxime 28 Reaction time: 8 min. IR (KBr) (cm-1): 3229, 3035, 2899, 1665, 739, 696; 1H NMR (δ, ppm): 4.79 (dd, 1H, H2a, J2a,3a=10.29 Hz), 5.15 (dd, 1H, H6a, J6a,5a=12.55 Hz), 3.37 (m, 1H, H5e), 2.73 (m, 2H, H3), 2.88 (m, 1H, H5a), 7.68-7.19 (m, 8H, Harom), 7.92 (s, 1H, N-OH).