Efficient Knoevenagel Condensation Reactions Catalyzed by Activated Gel Zirconium(IV) Oxide

Poor Heravi, Mohammad Reza; Piri, S.

doi:https://doi.org/10.1155/2013/652805

Journal of Chemistry

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Abstract Introduction Experimental Results and Discussion Conclusion References Copyright Related Articles

Research Article | Open Access

Volume 2013 | Article ID 652805 | https://doi.org/10.1155/2013/652805

Efficient Knoevenagel Condensation Reactions Catalyzed by Activated Gel Zirconium(IV) Oxide

Mohammad Reza Poor Heravi¹and S. Piri¹

Academic Editor: Albert Demonceau

Received01 Feb 2012

Revised15 Jun 2012

Accepted23 Jun 2012

Published28 Jul 2012

Abstract

The condensation reaction has been carried out very conveniently to obtain the corresponding substituted 2,-(arylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) in excellent yields. The reaction conditions are very mild and applicable to various aldehydes as well as active methylene compounds.

1. Introduction

In past decades, several carbon-carbon bond-forming reactions have been discovered, and their applications in organic chemistry have also been well documented in the literature [1–6]. Base-catalyzed transformations are frequently used both on small scale as well as large scale in organic synthesis, for example, in Aldol [7], Knoevenagel [8], Henry [9], and Michael [10] reactions. To catalyze these processes, organic amines, alkali alkoxides, and alkali hydroxides are commonly used as a homogeneous phase with the reagents. Although effective, these reagents are difficult to separate and, in many cases, are not recycled. To alleviate this problem, solid basic catalysts have been developed utilizing either inorganic solid materials, such as base metal oxides and carbonates, or by supporting organic bases, for example, amines, on inorganic or polymeric supports. This approach has attracted intense interest and has been reviewed extensively [11, 12]. Effective heterogeneous base catalysis have been found for Aldol [13–15], Knoevenagel [16–18], Henry [19, 20], and Michael [21] reactions, and, in many, cases the solid base is recyclable [22]. Chalcones are the main precursors for the biosynthesis of flavonoids, which are frequent components of the human diet [23]. Recently, studies on biological evaluation of chalcones revealed some to be anticancer [24, 25], anti-inflammatory [26, 27], antimitotic [28], antitubercular [29], cardiovascular [30], cell differentiation inducing [31], nitric oxide regulation modulatory [32], and antihyperglycemic agents [33]. Of the many methods available for the synthesis of chalcones, the most widely used is the base-catalyzed Claisen-Schmidt reaction in which the condensation of a ketone with an aldehyde is carried out in the presence of aq. NaOH [34], KOH [35], Ba(OH)₂ [36, 37], hydrotalcites [38], LiHDMS [39], and calcined NaNO₃/natural phosphates [40]. The acid-catalyzed methodologies include the use of AlCl₃ [40], dry HCl [41], Zn(bpy)(OAC)₂ [42], TiCl₄ [43], CpZrH₂/NiCl₂ [44], Zeolites [45], RuCl₃ [46], and Selectfluor [47].

2. Experimental

Aldehydes were distilled before use. Melting points were determined using a Linkman HF591 heating stage, used in conjunction with a TC92 controller, and reuncorrected. NMR spectra were recorded using a Bruker DRX500 machine at room temperature. ¹H and ¹³C NMR spectra were measured using deuterochloroform as solvent, and chemical shifts were measured relatives to residual solvent as an internal standard and are expressed in parts per million (). Mass spectra were obtained using a Micro Mass LCT machine in ES or EI mode. Infrared spectra were measured on a Perkin Elmer Paragon 100 FT-IR spectrometer.

2.1. Typical Procedure for 2,2′-(Phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3a)

A mixture of benzaldehyde (1) (1 mmol) dimedone (2) (1 mmol), ZrOCl₂-THF (0.048 g, 0.15 mmol), and sodium amide (0.005 g, 0.15 mmol) was added at room temperature. The solution was stirred for 20 min at room temperature. After dilution with moist ether (10 mL), the solution was washed with water (3 × 20 mL) to discharge the colour and the ZrOCl₂ and sodium amide. The ethereal solution obtained after extraction was dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude mixture was passed through a silica gel column chromatography to afford desired product (3a).

2.2. -(Phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3a)

FT-IR (KBr) 3435, 3093, 2982, 1721 (C=O), 1558, 1441, 1366, 1237, 919, 855 and 821 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): 1.10 (s, 6H), 1.24 (s, 6H), 2.38 (m, 8H), 5.54 (s, 1H), 7.29 (ddd, J = 8.5, 2.5 and 1.5 Hz, 1H), 7.32 (m, J = 8.5 Hz, 2H) and 7.36 (dd, J = 8.5 and 1.5 Hz, 2H), 11.89 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): 27.4, 29.64, 31.40, 32.72, 46.43, 47.40, 115.57, 125.83, 126.75, 128.20, 138.2, 196.42 (C=O), 190.13 (C=O); (EI) Found: M⁺, 368.2005, C₂₃H₂₈O₄ requires M⁺, 368.3202; LRMS m/z (EI): 368 (M⁺, 93%), 293 (M–C₆H₅, 45%). Elemental analysis: found (%): C, 75.12; H, 7.86. Calcd. for C₂₃H₂₈O₄: C, 74.97; H, 7.66.

2.3. -((4-Chlorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3b)

FT-IR (KBr) 3456, 3100, 2978, 1719 (C=O), 1550, 1453, 1355, 1264, 918, 850 and 825 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 0.85 (s, 6H), 1.22 (s, 6H), 2.40 (m, 8H), 5.55 (s, 1H), 7.02 (d, J = 8.03 Hz, 1H), 7.24 (m, J = 8.03 Hz, 2H) and 11.87 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): δ 27.39, 29.59, 31.40, 32.38, 46.39, 47.01, 115.31, 128.18, 131.55, 136.68, 189.42 (C=O), 190.63 (C=O); (EI) Found: M⁺, 402.3805, C₂₃H₂₇ClO₄ requires M⁺, 402.1678; LRMS m/z (EI): 402 (M⁺, 86%), 325 (M–C₆H₅, 45%). Elemental analysis: found (%): C, 68.88; H, 6.86; Cl, 8.91. Calcd. for C₂₃H₂₇ClO₄: C, 68.56; H, 6.75; Cl, 8.80.

2.4. -((3-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3c)

FT-IR (KBr) 3356, 3103, 2965, 1704 (C=O), 1555, 1450, 1345, 1254, 967, 835 and 811 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): 1.10 (s, 6H), 1.41 (s, 6H), 2.38 (m, 8H), 4.66 (s, 1H), 7.41–7.56 (m, 4H) and 12.01 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): δ 27.32, 29.67, 31.41, 32.90, 47.01, 128.99, 132.93, 144.04, 151.32, 184.47 (C=O), 190.88 (C=O); (EI) Found: M⁺, 413.1805, C₂₃H₂₇NO₆ requires M⁺, 413.1618; LRMS m/z (EI): 413 (M⁺, 56%), 336 (M–C₆H₅, 45%). Elemental analysis: found (%): C, 66.91; H, 6.86; N, 3.41. Calcd. for C₂₃H₂₇NO₆: C, 66.81; H, 6.58; N, 3.39.

2.5. -((4-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3d)

FT-IR (KBr) 3397, 3096, 2923, 1705 (C=O), 1551, 1455, 1355, 1250, 927, 825 and 819 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 1.01 (s, 6H), 1.23 (s, 6H), 1.98 (m, 8H), 4.56 (s, 1H), 7.52–7.98 (m, 4H), and 12.11 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): δ 25.23, 26.45, 30.31, 31.98, 47.01, 114.79, 120.90, 122.22, 128.99, 132.93, 134.94, 145.23, 148.37, 189.73 (C=O), 198.8 (C=O); (EI) found: M⁺, 413.1805, C₂₃H₂₇NO₆ requires M⁺, 413.1618; LRMS m/z (EI): 413 (M⁺, 66%), 336 (M–C₆H₅, 55%). Elemental analysis: found (%): C, 66.91; H, 6.86; N, 3.41. Calcd. for C₂₃H₂₇NO₆: C, 66.81; H, 6.58; N, 3.39.

2.6. -((2,4-Dinitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3e)

FT-IR (KBr) 3453, 3114, 2925, 1701 (C=O), 1565, 1456, 1332, 1245, 915, 826, and 808 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 1.05 (s, 6H), 1.31 (s, 6H), 2.24 (m, 8H), 4.56 (s, 1H), 7.65–8.20 (m, 4H), and 12.43 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): δ 26.30, 28.66, 30.40, 32.91, 45.01, 108.65, 114.65, 124.02, 128.56, 131.53, 132.74, 142.33, 144.37, 187.98 (C=O), 192.76 (C=O); (EI) found: M⁺, 458.1805, C₂₃H₂₆N₂O₈ requires M⁺, 458.1709; LRMS m/z (EI): 458 (M⁺, 75%), 386 (M-C₆H₅, 65%). Elemental analysis: found (%): C, 60.34; H, 5.83; N, 6.21. Calcd. for C₂₃H₂₆N₂O₈: C, 60.26; H, 5.72; N, 6.11.

2.7. -((4-Fluorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3f)

FT-IR (KBr) 3523, 3115, 2865, 1706 (C=O), 1535, 1433, 1298, 1222, 950, 838 and 816 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 1.02 (s, 6H), 1.23 (s, 6H), 2.42 (m, 8H), 4.86 (s, 1H), 7.02 (d, J = 8.01 Hz, 2H), 7.24 (d, J = 8.01 Hz, 2H), and 11.98 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): 27.32, 29.67, 31.41, 32.92, 47.01, 56.87, 112.65, 138.93, 141.94, 146.33, 156254 (d, J = 285.5 Hz, CF), 188.27 (C=O), 191.88 (C=O); (EI) Found: M⁺, 386.1911, C₂₃H₂₇FO₄ requires M⁺, 386.1904; LRMS m/z (EI): 386 (M⁺, 76%), 309 (M–C₆H₅, 45%). Elemental analysis: found (%): C, 71.56; H, 7.12. Calcd. for C₂₃H₂₇FO₄: C, 71.48; H, 7.04.

2.8. -((4-(Trifluoromethyl)phenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3g)

FT-IR (KBr) 3556, 3121, 2865, 1698 (C=O), 1550, 1420, 1376, 1244, 927, 865, and 831 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 1.12 (s, 6H), 1.29 (s, 6H), 2.28 (m, 8H), 4.76 (s, 1H), 7.41–7.56 (m, 4H), and 12.37 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): δ 27.39, 29.59, 31.40, 32.38, 46.31, 47.01, 115.31, 123.54, 126.11 (q, J = 283.4 Hz, CF₃), 131.55, 136.68, 148.98, 184.57(C=O), 190.88 (C=O); (EI) found: M⁺, 436.1905, C₂₄H₂₇F₃O₄ requires M⁺, 436.1910; LRMS m/z (EI): 436 (M⁺, 86%), 359 (M–C₆H₅, 35%). Elemental analysis: found (%): C, 66.01; H, 6.26. Calcd. for C₂₄H₂₇F₃O₄: C, 66.04; H, 6.24.

2.9. -((4-Methoxyphenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3h)

FT-IR (KBr) 3421, 3098, 2876, 1717 (C=O), 1552, 1450, 1362, 1291, 951, 835, and 823 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 1.15 (s, 6H), 1.51 (s, 6H), 2.54 (m, 8H), 4.78 (s, 1H), 7.41–7.56 (m, 4H), and 11.76 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): δ 28.43, 30.67, 32.61, 33.93, 49.02, 116.65, 122.91, 122.22, 128.99, 132.93, 134.94, 145.23, 148.37, 181.37 (C=O), 189.78 (C=O); (EI) found: M⁺, 398.2111, C₂₄H₃₀O₅ requires M⁺, 398.2103; LRMS m/z (EI): 398 (M⁺, 46%), 321 (M–C₆H₅, 55%). Elemental analysis: found (%): C, 72.43; H, 7.64. Calcd. for C₂₄H₃₀O₅: C, 72.34; H, 7.59.

2.10. -(p-Tolylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3i)

FT-IR (KBr) 3427, 3111, 2901, 1707 (C=O), 1495, 1450, 1345, 1264, 943, 835 and 819 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): 1.04 (s, 6H), 1.21 (s, 6H), 2.21 (m, 8H), 4.51 (s, 1H), 7.32–7.546 (m, 4H), and 11.12 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): δ 26.31, 26.67, 30.31, 31.9, 46.11, 112.79, 119.90, 121.62, 124.99, 131.73, 134.94, 141.23, 148.37, 182.07 (C=O), 189.08 (C=O); (EI) found: M⁺, 382.4970, C₂₄H₃₀O₄ requires M⁺, 382.4906; LRMS m/z (EI): 382 (M⁺, 43%), 305 (M–C₆H₅, 45%). Elemental analysis: found (%): C, 75.64; H, 8.04. Calcd. for C₂₄H₃₀O₄: C, 75.36; H, 7.91.

2.11. -((4-Bromophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3j)

FT-IR (KBr) 3453, 3121, 2908, 1710 (C=O), 1567, 1444, 1376, 1254, 917, 835, and 821 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): 1.13 (s, 6H), 1.53 (s, 6H), 2.62 (m, 8H), 476 (s, 1H), 7.65–7.87 (m, 4H), and 11.75 (s, ex. with D₂O, 2H); ¹³C NMR (126 MHz, CDCl₃): δ 24.33, 28.76, 31.31, 32.9, 47.04, 115.81, 121.91, 122.02, 128.99, 132.93, 134.94, 145.23, 148.37, 187.79 (C=O), 190.69 (C=O); (EI) found: M⁺, 446.1201, C₂₃H₂₇BrO₄ requires M⁺, 446.1128; LRMS m/z (EI): 446 (M⁺, 56%), 336 (M–C₆H₅, 45%). Elemental analysis: found (%): C, 61.82; H, 5.96; Br, 17.474. Calcd. for C₂₃H₂₇BrO₄: C, 61.75; H, 6.08; Br, 17.86.

3. Results and Discussion

In our continued interest, in the Knoevenagel condensations and its application in the synthesis of bioactive molecules, we report here a very simple and highly efficient method for the condensation of various aromatic (1) with active methylene compound (2), for example, dimedone, in the presence of ZrOCl₂/NaNH₂ as catalysis in THF at room temperature with stirring (Scheme 1).

It was exciting to observe that all the reactions occurred rapidly and were complete in just a few minutes giving excellent yields of the Knoevenagel products (3) (Table 1).

To determine the appropriate concentration of the catalyst zirconium oxychloride/sodium amide, we investigated the model reaction at different concentration of zirconium oxychloride/sodium amide such as 5, 10, 15, and 20 mol%. The product was found in 35%, 65%, 88%, and 88% yield, respectively. This indicates that 15 mol% of zirconium oxychloride/sodium amide is sufficient to carry out the reaction smoothly (Table 2).

The temperature of 25°C was chosen as optimum temperature. Any further increase in the temperature failed to enhance the reaction rate substantially, while lowering the temperature below 25°C did show down the reaction rate (Table 3).

In order to evaluate the effect of solvent, various solvents such as dichloromethane, chloroform, ethyl acetate, methanol, water, and tetrahydrofurane were used for the model reaction in the presence of zirconium oxychloride/sodium amide. Surprisingly, use of dichloromethane stopped the reaction at the Knoevenagel condensation step and no further reaction took place (TLC). Reaction in chloroform, ethyl acetate, methanol, and water resulted in moderate yields trace, whereas water brought the reaction to completion efficiently to furnish the product in excellent 88% yield (Table 4, entry 6).

4. Conclusion

In summary, we have developed an expedient and clean protocol for the synthesis of substituted 2,2′-(arylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) derivatives. This method has the advantages of a wide scope of substrates, operational simplicity, easy work-up procedures, shorter reaction times, and high yields.

Acknowledgment

Generous support of this work by the Payame Noor University, Tehran, is gratefully acknowledged.

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Copyright © 2013 Mohammad Reza Poor Heravi and S. Piri. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Journal of Chemistry

Efficient Knoevenagel Condensation Reactions Catalyzed by Activated Gel Zirconium(IV) Oxide

Abstract

1. Introduction

2. Experimental

2.1. Typical Procedure for 2,2′-(Phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3a)

2.2. 2 , 2  -(Phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3a)

2.3. 2 , 2  -((4-Chlorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3b)

2.4. 2 , 2  -((3-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3c)

2.5. 2 , 2  -((4-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3d)

2.6. 2 , 2  -((2,4-Dinitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3e)

2.7. 2 , 2  -((4-Fluorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3f)

2.8. 2 , 2  -((4-(Trifluoromethyl)phenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3g)

2.9. 2 , 2  -((4-Methoxyphenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3h)

2.10. 2 , 2  -(p-Tolylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3i)

2.11. 2 , 2  -((4-Bromophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3j)

3. Results and Discussion

4. Conclusion

Acknowledgment

References

Copyright

2.2. -(Phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3a)

2.3. -((4-Chlorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3b)

2.4. -((3-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3c)

2.5. -((4-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3d)

2.6. -((2,4-Dinitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3e)

2.7. -((4-Fluorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3f)

2.8. -((4-(Trifluoromethyl)phenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3g)

2.9. -((4-Methoxyphenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3h)

2.10. -(p-Tolylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3i)

2.11. -((4-Bromophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3j)