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

Authors: Mohammad Reza Poor Heravi; S. Piri
Journal: Journal of Chemistry
 (2013)

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## Abstract

The condensation reaction has been carried out very conveniently to obtain the corresponding substituted 2,2′-(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.


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## Body

## 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 (δ). 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).


### 2.2.2,2′-(Phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3a)

FT-IR (KBr)νmax 3435, 3093, 2982, 1721 (C=O), 1558, 1441, 1366, 1237, 919, 855 and 821 cm−1; 1H NMR (500 MHz, CDCl3): δ 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): δ 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.


### 2.3.2,2′-((4-Chlorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3b)

FT-IR (KBr)νmax 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.


### 2.4.2,2′-((3-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3c)

FT-IR (KBr)νmax 3356, 3103, 2965, 1704 (C=O), 1555, 1450, 1345, 1254, 967, 835 and 811 cm−1; 1H NMR (500 MHz, CDCl3): δ 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.


### 2.5.2,2′-((4-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3d)

FT-IR (KBr)νmax 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.


### 2.6.2,2′-((2,4-Dinitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3e)

FT-IR (KBr)νmax 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.


### 2.7.2,2′-((4-Fluorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3f)

FT-IR (KBr)νmax 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): δ 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.


### 2.8.2,2′-((4-(Trifluoromethyl)phenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3g)

FT-IR (KBr)νmax 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.


### 2.9.2,2′-((4-Methoxyphenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3h)

FT-IR (KBr)νmax 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.


### 2.10.2,2′-(p-Tolylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3i)

FT-IR (KBr)νmax 3427, 3111, 2901, 1707 (C=O), 1495, 1450, 1345, 1264, 943, 835 and 819 cm−1; 1H NMR (500 MHz, CDCl3): δ 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.


### 2.11.2,2′-((4-Bromophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3j)

FT-IR (KBr)νmax 3453, 3121, 2908, 1710 (C=O), 1567, 1444, 1376, 1254, 917, 835, and 821 cm−1; 1H NMR (500 MHz, CDCl3): δ 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.


## 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).


## 2.2.2,2′-(Phenylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3a)

FT-IR (KBr)νmax 3435, 3093, 2982, 1721 (C=O), 1558, 1441, 1366, 1237, 919, 855 and 821 cm−1; 1H NMR (500 MHz, CDCl3): δ 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): δ 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.


## 2.3.2,2′-((4-Chlorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3b)

FT-IR (KBr)νmax 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.


## 2.4.2,2′-((3-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3c)

FT-IR (KBr)νmax 3356, 3103, 2965, 1704 (C=O), 1555, 1450, 1345, 1254, 967, 835 and 811 cm−1; 1H NMR (500 MHz, CDCl3): δ 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.


## 2.5.2,2′-((4-Nitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3d)

FT-IR (KBr)νmax 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.


## 2.6.2,2′-((2,4-Dinitrophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3e)

FT-IR (KBr)νmax 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.


## 2.7.2,2′-((4-Fluorophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3f)

FT-IR (KBr)νmax 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): δ 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.


## 2.8.2,2′-((4-(Trifluoromethyl)phenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3g)

FT-IR (KBr)νmax 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.


## 2.9.2,2′-((4-Methoxyphenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3h)

FT-IR (KBr)νmax 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.


## 2.10.2,2′-(p-Tolylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3i)

FT-IR (KBr)νmax 3427, 3111, 2901, 1707 (C=O), 1495, 1450, 1345, 1264, 943, 835 and 819 cm−1; 1H NMR (500 MHz, CDCl3): δ 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.


## 2.11.2,2′-((4-Bromophenyl)methylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (3j)

FT-IR (KBr)νmax 3453, 3121, 2908, 1710 (C=O), 1567, 1444, 1376, 1254, 917, 835, and 821 cm−1; 1H NMR (500 MHz, CDCl3): δ 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).Scheme 1
The Knoevenagel condensation between substituted benzaldehydes(1a–j) and dimedone (2) in presence of ZrOCl2·8H2O/NaNH2 as catalysis to yield the product (3a–j).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).Table 1
Reaction time, yields, and melting points of the products(3a–j).
Entry
X
Time (min)
Yield(%)a
Mp (°C)
1
H
20
88
188-189
2
4-Cl
25
83
144-145
3
3-NO2
20
90
151-152
4
4-NO2
10
96
162-163
5
2, 4-(NO2)2
5
97
172-173
6
4-F
15
90
183-184
7
4-CF3
10
98
133-134
8
4-OCH3
25
90
166-167
9
4-CH3
30
91
178-179
10
4-Br
30
91
184-185
Reaction conditions: 1 (1 mmol), 2 (1 mmol), ZrOCl2·8H2O/NaNH2 (15 mol %), in THF (5 mL) at 25°C.
a
Isolated yield.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 (Table2).Table 2
Effect of concentrations of catalyst.
Entry
ZrOCl2·8H2O (mol %)
Yield(%)a
1
5
35
2
10
65
3
15
88
4
20
88
Reaction conditions:1a(1 mmol), 2 (1 mmol), ZrOCl2·8H2O/NaNH2 (15 mol %), in THF (5 mL) at 25°C.
a
Isolated yields.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 (Table3).Table 3
Effect of temperature.
Entry
Temperature (°C)
Yield(%)a
1
0
35
2
5
45
3
10
48
4
15
55
5
20
60
6
25
88
7
35
75
8
40
68
Reaction condition:1a (1 mmol), 2 (1 mmol), ZrOCl2·8H2O/NaNH2 (15 mol %), in THF (5 mL).
a
Isolated yield.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 (Table4, entry 6).Table 4
Screening of solvents.
Entry
Solvent
Temperature (°C)
Time (h)
Yield(%)a
1
Dichloromethane
25
—
2
Chloroform
25
Trace
3
Ethyl acetate
25
Trace
4
Methanol
25
Trace
5
Water
25
Trace
6
Tetrahydrofurane (dry)
25
88
Reaction condition:1a (1 mmol), 2 (1 mmol), ZrOCl2·8H2O/NaNH2 (15 mol %), in solvent (5 mL) at 25°C.
a
Isolated yields.


## 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.



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*Source: 652805-2012-07-28.xml*