BF3.SiO2: An efficient heterogeneous alternative for regio-chemo and stereoselective claisen-schmidt condensation

J. Iran. Chem. Soc., Vol. 5, No. 4, December 2008, pp. 694-698. JOURNAL OF THE Iranian Chemical Society BF3.SiO2: An Efficient Heterogeneous Alternative for Regio-Chemo and Stereoselective Claisen-Schmidt Condensation B. Sadeghia, B.F. Mirjalilib,* and M.M. Hashemic Faculty of Chemistry, Islamic Azad University, Science and Research Campus, Tehran, Iran b Department of Chemistry, College of Sciences, Yazd University, Yazd, Iran, P.O.Box 89195-741 c Department of Chemistyr, Sharif University of Technology, P.O. Box 11365-9516, Tehran, Iran a (Received 7 October 2007, Accepted 16 February 2008) Under solvent free conditions between 40-50 ºC, BF3.SiO2, a mild solid acid catalyst, is applied to regio-chemo and stereoselective Claisen-Schmidt condensation. The procedure is very simple and the products are isolated with an easy workup in good to excellent yields. Keywords: Claisen-Schmidt and crossed aldol condensations, Silica supported boron trifluoride, Solid acid, Solvent free conditions, Aldehydes, Ketones INTRODUCTION BF3, as a strong Lewis acid, has been used in small and large-scale reactions as an acid catalyst. In many synthetic reports, BF3.Et2O has been used. The silica supported form of BF3 is a bench-top reagent which is easy to handle providing better accessibility of the reactants to the active sites [1]. When BF3.OEt2, or BF3.2H2O, is added to a reaction mixture, particularly in a protic medium, it can also function as a Brönsted acid. Exposure of high surface area oxides such as Si-O-Si or Al-O-Al to BF3 at room temperature results in irreversible adsorption. The resulting surfaces possess surface species such as Al-OBF2, Si-OBF2, or the ion pairs, Al-OBF3H+ or Si-OBF3-H+. It has been claimed that supported BF3 is a solid superacid. When the complex BF3.OEt2 in EtOH is used to prepare a silica-supported BF3 catalyst, Brönsted surface sites are obtained [2]. BF3 has been used for the rearrangement of 4-substituted*Corresponding author. E-mail: fmirjalili@yazduni.ac.ir 5,5-diphenyl-azepan-4-ols [3], the Beckmann rearrangement [4], the reduction of aromatic azides with EtSH [5], the alkylation of acetals with manganate [6], the synthesis of 2substituted benzimidazoles and 3,1,5-benzoxadiazepines [7], the conversion of alcohols to azides with NaN3 [8], the reduction of 4,6-o-benzylidenes using triethylsilane [9], the polymerization of styrene [10] and the synthesis of 2′-ocyanoethyluridine [11]. In the Claisen-Schmidt condensation, a type of crossed aldol condensation, an aromatic aldehyde combines with alkyl ketones or aldehyde to form a β-hydroxyl ketone, which is easily dehydrated to form an α,β-unsaturated ketone. Note that dehydration is especially favorable because the resulting enone is also conjugated with the aromatic ring. The resulting α,β-unsaturated ketones are useful intermediates for a large variety of compounds. Mixed or crossed aldol condensation is an effective pathway for the preparation of α,ά-bis (substituted benzylidene) cycloalkanones as precursors for the synthesis of bioactive pyrimidine derivaties or nikkomycine. Aldol condensation can be catalyzed by acids, bases, Sadeghi et al. organometallic compounds or metal ions such as Mg(HSO4)2 [12], TiCl3(SO3CF3) [13], silica sulfuric acid [14], CsOH.SiO2 [15], V2O5-P2O5 [16], RuCl3 [17], LiClO4 [18], TiCl4 [19], ZrO2/SO42- [20], Cu(OTf)2 [21], Mg/Al mixed oxides [22], [Cp*Rh(η6-C6H6)](BF4)2 [23], NaOAc/HOAc [24], FeCl3. 6H2O [25], ZrCl4 [26], LiOH.H2O [27], I2 [28], acid-base functionalized catalyst [29] and polymer supported sulphonic acid [30]. EXPERIMENTAL Preparation of BF3.SiO2 A mixture of BF3.OEt2 (0.57 g, 4 mmol) and preheated silica gel (0.5 g) in MeOH (5 ml) was prepared and was stirred for 1 h at room temperature. The slurry was dried slowly on a rotary evaporator at 40 °C. The obtained solid was dried in an ambient temperature for 2 h and then was stored under dry atmosphere in a container for months. General Procedure for Claisen-Schmidt Condensation of Aldehydes with Ketones Ketone (2 or 4 mmol), aldehyde (4 mmol) and BF3.SiO2 (0.32 g) were placed in a round bottom flask. The resulting mixture was mixed thoroughly and heated at 40-50 ºC for 1575 min (Table 3). The progress of the reaction was followed by TLC. After the completion of the reaction, the mixture was cooled to room temperature. Chloroform was added to the mixture which was filtered to remove the catalyst. Upon evaporation of the solvent, an oily residue or an impure solid was obtained. By adding ethanol and water to the resulting residue, a yellow to orange solid was obtained. The solid was then crystallized from ethanol. All products are known and were identified by comparing their physical or spectral data with those of authentic samples. RESULTS AND DISCUSSION Following the previous report about the application of solid acids in organic synthesis [31], in this work, we performed the Claisen-Schmidt condensation reaction in the presence of various available Lewis acids under thermal and solvent-free conditions or reflux (Table 1). The results showed Table 1. Claisen-Schmidt Condensation of Acetophenone and 4-Chloro Benzaldehyde in Different Acidic Media O O O CH3 C Ph + H C Cl Catalyst Ph H C C C H Cl Catalyst Condition/solvent Yield (%)a FeCl3 (28 mol%) 1 2 AlCl3 (28 mol%) 3 ZnCl2 (28 mol%) 4 SnCl4 (28 mol%) 5 SbCl5 (28 mol%) 6 BF3.Et2O (28 mol%) 7 BF3.TiO2 (28 mol%) 8 BF3.ZrO2 (28 mol%) 9 BF3.SiO2 (28 mol%) 10 BF3.Al2O3 (28 mol%) 11 BF3.SiO2 (28 mol%) 12 BF3.SiO2 (28 mol%) 13 BF3.SiO2 (28 mol%) 14 BF3.SiO2 (14 mol%) 15 BF3.SiO2 (21 mol%) 16 BF3.SiO2 (35 mol%) a Isolated yield. 40-50 °C/40-50 °C/40-50 °C/40-50 °C/40-50 °C/40-50 °C/40-50 °C/40-50 °C/40-50 °C/40-50 °C/Reflux/n-Hexane Reflux/HOAc Reflux/EtOH 40-50 °C/40-50 °C/40-50 °C/- 45 40 30 45 40 60 25 14 90 75 85 86 81 72 85 90 Entry 695 BF3.SiO2: An Efficient Heterogeneous Alternative that, in this reaction, BF3.SiO2 is one of the best catalysts in comparison with the previously applied catalysts (Table 2). The best condition for this reaction was solvent free between 40-50 ºC and the best ratio of aldehyde (mmol): BF3.SiO2 (g) was 1:0.08. Therefore, some aldehydes and ketones were subjected to Claisen-Schmidt condensation (Scheme 1 and Table 3). The results showed that the reactions are completed within 45-60 min and α,β-unsaturated carbonyl compounds can be obtained with good to excellent yields (72-93%) without any self-condensation products. The stereoselectivity of this method was confirmed by the formation of a trans double bond in the Claisen-Schmidt condensation of methyl ketones (Table 3, entries 13-18). The regioselectivity of this method was examined by the crossed aldol condensation of 2-butanone and 4-methyl-2-pentanone with 4-chloro benzaldehyde (Scheme 2). Because of the preference for acid catalyzed enolization to give more substituted enol under BF3.SiO2 catalyzed condensation, the branched chain ketol was formed rapidly (Scheme 2). Also, the chemoselectivity of the reaction was evaluated via a competitive BF3.SiO2 catalyzed Claisen-Schmidt reaction of 4-chloro benzaldehyde (2 mmol) with a mixture of cyclohexanone (1 mmol) and acetone (1 mmol). It was found that cyclohexanone reacts with benzaldehyde in a high yield. No chemoselectivity was observed for cyclohexanone vs. Table 2. Comparision of BF3.SiO2 with Previously Applied Catalysts in Condensation Reaction of Cyclohexanone and Benzaldehyde Entry Catalyst Condition 1 2 3 4 5 6 7 Silica sulfuric acid (95 mol%) Mg(HSO4)2 (100 mol%) RuCl3 (1 mol%) TiCl3 (SO3CF3) (5 mol%) FeCl3.6H2O (50 mol%) I2 (14 mol%) Polymer supported sulphonic acid ( 35.5 mol%) NaOAc/HOAc (10 mol%) BF3.SiO2 (28 mol%) 8 9 Time (h)/Yield (%) Ref. 80 °C/solvent-free 60 °C/solvent-free 120 °C/solvent-free R.T./solvent-free 80 °C/solvent-free R.T./CH2Cl2 Reflux/CHCl3 2.5/91 2.5/88 6/95 0.7/99 6/90 4.5/92 4/86 [14] [12] [17] [13] [25] [28] [30] 80 °C/solvent-free/N2 40-50 °C/solvent-free 7/86 0.5/85 [24] - O O O BF3.SiO2 + H Ar R2 R1 solvent-free o 40-50 C H H Ar Ar R1 (II) (I) R2 (III) R1=R2=H R1,R2=(CH2)n, n=2,3 O O O H C Ar + CH3 C Ar' (IV) (V) BF3.SiO2 solvent-free o 40-50 C Ar Scheme 1 696 C H C C H (VI) Ar ' Sadeghi et al. Table 3. Claisen-Schmidt Condensation Promoted by BF3.SiO2 Under Solvent-Free Conditions Between 40-50 ºCa Time (min)/Yield (%)b Ref.c M.P. (ºC) III: R1,R2 = (CH2)3, Ar = 3-NO2-C6H4 20/84 [25] 89-90 2 III: R1,R2 = (CH2)3, Ar = 4-CH3-C6H4 83/60 [25] 165-166 3 III: R1,R2 = (CH2)3, Ar = -C6H5 85/30 [18] 116-117 4 III: R1,R2 = (CH2)3, Ar = 3-OCH3, 4-OH-C6H3 72/50 [28] 168-170 5 III: R1,R2 = (CH2)3, Ar = 2-Cl-C6H4 87/30 [27] 88-89 6 III: R1,R2 = (CH2)3, Ar = 4-OCH3-C6H4 60/73 [18] 202-204 7 III: R1,R2 = (CH2)2, Ar = 4-OCH3-C6H4 60/75 [28] 215-216 8 III: R1,R2 = (CH2)2, Ar = 4-CH3-C6H4 45/73 [18] 245-246 9 III: R1,R2 = (CH2)2, Ar = 4-NO2-C6H4 88/35 [12] 230-231 10 III: R1,R2 = (CH2)2, Ar = -C6H4 85/45 [25] 189-190 11 III: R1,R2 = (CH2)2, Ar = 2-Cl-C6H4 79/25 [25] 152-153 12 III: R1,R2 = (CH2)2, Ar = 4-Cl-C6H4 73/25 [14] 225-226 13 VI: Ar' = Ph, Ar = 4-NO2-C6H4 70/77 [26] 159-160 14 VI: Ar' = Ph, Ar = 3-NO2-C6H4 20/75 [26] 144-145 15 16 VI: Ar' = Ph, Ar = 4-Cl-C6H4 VI: Ar' = Ph, Ar = 4-OMe-C6H4 45/90 45/80 [14] [14] 108-109 75-76 17 VI: Ar' = Ph, Ar = 4-CH3-C6H4 40/77 [14] 97-98 Entry Product 1 VI: Ar' = 4-Cl- C6H4-C=C-, Ar = 4-Cl-C6H4 45/86 [29] 192-194 18 b c ratio of aldehyde (mmol):catalyst (g) is 1:0.08. Isolated yield. All products are known and were identified by their melting points, IR and 1H-NMR spectra. a Cl O + Cl H O Cl H H BF3.SiO2 + solvent-free o 40-50 C H O 88% 12% O Cl Cl O O H H H BF3.SiO2 + Cl + solvent-free o 40-50 C H O 90% O 10% Scheme 2 697 BF3.SiO2: An Efficient Heterogeneous Alternative acetophenone or 4-nitro benzaldehyde vs. 4-methyl benzaldehyde. It can be inferred that silica supported boron trifluoride (BF3.SiO2), an inexpensive solid acid, has a high efficiency and catalyzes the Claisen-Schmidt condensation reaction in solvent-free conditions. This simple procedure offers several advantages, such as; a simple work up, easy to scale up, improved yields, regio-, stereo- and chemo-selectivity and a clean reaction. ACKNOWLEDGEMENTS The researchers gratefully acknowledge the financial support granted for the study by the research affairs of Science and Research Campus of Azad University, Yazd University and Sharif University of Technology. 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