Synthesis of (E)-nitroalkenes Catalysed by Ethanolamine Supported on Silica.

Synthesis of (E)-nitroalkenes Catalysed by Ethanolamine Supported on Silica Manuel Mora • Ce´sar Jime´nez-Sanchidria´n • Francisco Jose´ Urbano • Jose´ Rafael Ruiz Received: 23 July 2009 / Accepted: 9 November 2009 / Published online: 24 November 2009 � Springer Science+Business Media, LLC 2009 Abstract A simple method for preparing (E)-nitroalkenes based on a Henry reaction in the presence of a heteroge- nized homogeneous catalyst consisting of silica-supported ethanolamine is proposed. With 4-substituted benzalde- hydes, the reaction gives the corresponding (E)-nitrosty- renes in high yields and a short time. Heterocyclic carboxaldehydes also give good results, but the presence of an N or S atom in the ring has a slightly adverse effect on the reaction. The synthetic process is quite novel and interesting. The catalyst remains active and exhibits no substantial loss of activity or selectivity over up to three reaction cycles. Keywords Henry reaction � Nitroaldol condensation � Ethanolamine � Silica 1 Introduction Nitroalkenes are highly useful organic chemicals. Thus, nitrostyrenes possess medical properties [1, 2] and, even more interesting, are the precursors of phenylalkylamines, which constitute an extremely important family of bioac- tive compounds in humans. Phenylalkylamines can be obtained in various ways [3] one of the most commonly used of which involves the formation of a C–C bond by nitroaldol condensation between a benzaldehyde and a nitroalkane (i.e., a Henry reaction). The process takes place via a nitroalcohol intermediate that undergoes anti-peri- planar elimination of water to form the corresponding nitrostyrene. The Henry reaction was named after the French scientist L. Henry, who developed it in the late XIX century [4, 5]. As stated above, it is a condensation reaction between a primary or secondary nitroalkane and a carbonyl compound (usually an aldehyde) that gives a mixture of 2-nitroalkanol diastereomers. Because the process is essentially an aldol condensation (Scheme 1), it requires the presence of a base—usually in catalytic amounts. The Henry reaction is catalysed by a variety of sub- stances including organic bases (alkoxides mainly) and inorganic bases (aqueous or alcoholic solutions of an alkaline hydroxide) [6]. These are all strong bases and can therefore affect other functional groups present in the reactant molecules. Also, they can only act in a homoge- neous medium, so they require isolation and purification of the end products, and may even be rendered useless for recycling. These shortcomings of homogeneous catalysts in the Henry reaction have lately been circumvented by using heterogeneous systems with results as good as or even better than those obtained with homogeneous cata- lysts [4, 7]. The greatest advantages of using a heteroge- neous catalyst in this context are the ease with which it can be removed from the reaction medium and the ability to re- use it over several reaction cycles. Heterogeneous catalysts consisting of alumina [8–10], anionic clays [11–14] and metal oxides [7–15], among other substances, have so far provided excellent activity and conversion results in many applications. Heterogenized homogeneous catalysts are also being widely used in various synthetic processes obviously including the Henry reaction [16–18]. These catalysts provide a number of advantages such as energy savings, M. Mora � C. Jime´nez-Sanchidria´n � F. J. Urbano � J. R. Ruiz (&) Departamento de Quı´mica Orga´nica, Universidad de Co´rdoba, Campus de Rabanales, Edificio Marie Curie, Carretera Nacional IV-A, km. 396, 14014 Cordoba, Spain e-mail: qo1ruarj@uco.es 123 Catal Lett (2010) 134:131–137 DOI 10.1007/s10562-009-0223-5 Administrator 高亮 Administrator 高亮 Administrator 高亮 Administrator 高亮 Administrator 下划线 Administrator 下划线 minimal waste production and increased purity in the end products [19]. In this work, we successfully used a catalyst consisting of silica-supported ethanolamine in the Henry reaction of substituted benzaldehydes and heterocyclic carboxaldehy- des with nitromethane. Supported alkylamines have pre- viously been used in a number of synthetic procedures [20–22] where alkylamine groups tether on silica via covalent bonds. In our catalyst, ethanolamine groups are physisorbed on the silica; this reduces its stability and shelf-life, and may lead to leaching of the reagent from the matrix. In any case, the catalyst remained stable and reusable over 3 reaction cycles. 2 Experimental 2.1 Reagents and Products Nitromethane, ethanolamine and all aldehydes studied were purchased from Aldrich or Fluka and used as received. Silica was supplied by Merck (ref. 7734). The products of the Henry reaction were all identified by mass spectrometry. 2.2 General Procedure for Preparation of Catalyst The silica support was obtained by calcining commercially available silica at 650 �C in the air for 3 h. The catalyst was prepared by mixing 5 g of calcined silica and 10 mL of ethanolamine at 80 �C for 12 h, after which the solid was filtered off, washed with methanol three times and refluxed with 100 mL of methanol for 12 h in order to remove all unsupported ethanolamine prior to filtering and drying in a stove at 100 �C for 24 h. 2.2.1 Characterization of the Catalyst The textural properties of the solids (specific surface area, pore volume and average pore radius) were determined from nitrogen adsorption–desorption isotherms obtained at liquid nitrogen temperature on a Micromeritics ASAP- 2010 instrument. Surface areas were calculated with the Brunnauer–Emmett–Teller (BET) method [23], and pore distributions with the Barrett–Joynet–Halenda (BJH) method [24]. All samples were degassed to a pressure below 3 mm Hg at 423 K prior to analysis. 13C-CP/MAS NMR spectra were recorded at 100.62 MHz on a Bruker ACP-400 spectrometer. Samples were spun at the magic angle at 3.5 kHz on a zirconia rotor. All measurements were made at room temperature. The contact time for magnetization transfer between protons and 13C was 5 ms (15,000 scans). Tetramethylsilane was used as internal standard. Thermogravimetric curves were obtained with a Seta- ram Setsys instrument. Samples were heated from 25 to 800 �C at 10 �C/min in an argon atmosphere. 2.2.2 General Procedure for the Henry Reaction The Henry reaction was performed in two-neck flasks containing 6 mL of nitromethane, 5 mmol of aldehyde and 0.1 g of catalyst at 85 �C. One of the flask necks was fitted with a reflux condenser and the other used to withdraw samples for analysis at regular intervals. The system was stirred throughout the process. Products were identified from their retention times as measured by GC–MS on an HP 5980 GC instrument furnished with a Supelcowax 30 m 9 0.32 mm column and interfaced to an HP 5971 MSD instrument. 3 Results and Discussion 3.1 Characterization of the Catalyst The silica-supported ethanolamine catalyst used was des- ignated ETAM/SiO2 and readily obtained as described in the Sect. 2 Nitrogen adsorption at –196 �C was used to determine the textural properties of the pure silica support (SiO2) and silica-supported ethanolamine catalyst (ETAM/SiO2). R CH2 NO2 R CH NO2 − R CH N O − R´ C O H δ δ R CH NO2 CH O R´ − R NO2 CH OH R´ O :BH :B H+ CH R NO2 CH R´ C + H2O − + Scheme 1 General Henry reaction 132 M. Mora et al. 123 Administrator 高亮 Administrator 高亮 Administrator 高亮 Administrator 高亮 Figure 1 shows the adsorption–desorption isotherms for each solid. As can be seen, there were no substantial dif- ferences between them; thus, the curves were of type IV in the BDDT classification and exhibited hysteresis cycles of type H1 (open-ended cylindrical pores) in the de Boer classification [25]. Table 1 shows the specific surface areas of the support and catalyst as established from the previous isotherms. Based on them, ethanolamine slightly reduced the surface area of the support. The silica-supported ethanolamine phase was examined by using various instrumental techniques. 13C-CP/MAS NMR revealed the presence of ethanolamine on the catalyst surface. Figure 2a shows the spectrum for the catalyst, which exhibits the two typical signals for the two methy- lene groups in ethanolamine. A comparison of the chemical shifts with those of a spectrum for pure liquid ethanolamine recorded under identical conditions (Fig. 2a) reveals that the signals for the catalyst are shifted slightly upfield. The amount of ethanolamine sorbed by the silica was determined by comparing the thermogravimetric curves for the support and pure catalyst (Table 1). Also, desorbed products present on the catalyst surface were unambigu- ously identified by thermal programmed desorption–mass spectrometry (TPD–MS). Based on the electron-impact mass spectrum for ethanolamine, the monitored peaks were those at m/z 30 (base peak), 43 (7% abundance) and 61 (molecular peak, 6% abundance) obtained in the TPD–MS tests. Fig. 3 shows their TPD-MS profiles. As can be seen, the signals appeared within a narrow temperature range (320–340 �C). Such high temperatures suggest that etha- nolamine somehow binds to the support surface, from which it can only be desorbed at temperatures well above its boiling point. This result, together with the chemical shifts of the 13C signals in the CP/MAS NMR spectrum, suggests that ethanolamine does not simply deposit onto the silica surface, but rather interacts with it—possibly via the hydroxyl groups in both. 3.2 Henry Reaction The primary aim of this initial work on the Henry reaction was to check whether the proposed catalyst would be active if nitromethane were used in overstoichiometric amounts. SET V a ds (cm 3 /g ) 0 100 200 300 400 500 600 Adsortion Desortion Relative Pressure (P/P0) 0,0 0,2 0,4 0,6 0,8 1,0 V a ds (cm 3 /g ) 0 100 200 300 400 500 600 Adsortion Silica gel Desortion ETAM/SiO2 SiO2 Adsorption Desorption Adsorption Desorption Fig. 1 Nitrogen adsorption– desorption isotherms for the support (SiO2) and catalyst (ETAM/SiO2) Table 1 Specific surface area of the support (SiO2) and catalyst (ETAM/SiO2), and amount of ETAM on the catalyst Entry Solid SBET a Amount of ETAMb 1 SiO2 410 – 2 ETAM/SiO2 270 12 a Specific surface area, in m2/g catalyst b lg ETAM/100 mg catalyst Synthesis of (E)-nitroalkenes 133 123 The reaction of benzaldehyde with nitromethane over the proposed catalyst was used as a model to optimize some operating conditions. Table 2 illustrates the influence of the temperature and amount of catalyst used on (E)-nitrosty- rene conversion. Temperatures below 60 �C resulted in very low conversion and TOF values at fairly short reaction times. At 85 �C, an amount of 100 mg of catalyst provided near-quantitative conversion after 7 h. By contrast, obtaining similar results at 65 �C required a few more hours of reaction. Also, the reaction hardly developed below 65 �C. An amount of catalyst of 100 mg (12.1 lg of ETAM) was therefore chosen for further testing since smaller amounts lengthened the reaction time considerably (Table 2, entries 5 and 6). Also, no reaction occurred in the absence of catalyst (entry 7 in Table 2) or the sole presence of SiO2 (i.e. the absence of ethanolamine, entry 8 in Table 2). A temperature of 85 �C and an amount of cata- lyst (ETAM/SiO2) of 100 mg were thus adopted. Finally, ethanolamine was found to provide much poorer results in the absence of support than when supported on silica. Table 3 shows the conversion to p-substituted (E)-ni- trostyrenes and TOF values obtained by using p-substituted benzaldehydes as substrates. As can be seen, the results were moderate to good in all cases except with substrates bearing strongly electron-withdrawing substituents. This testifies to the efficiency of ETAM/SiO2 as a catalyst for the Henry reaction, where it provides near-quantitative conversion in most cases. We also studied the Henry reaction with heterocyclic aldehydes as substrates (Table 4). As can be seen, the conversion and TOF values for furaldehydes (entries 7 and 8 in Table 4) were similar to those previously obtained with benzaldehyde. However, the presence of a sulphur or nitrogen atom in the ring had an adverse effect on con- version. Thus, the presence of a carboxaldehyde group in position 3 of the thiophene ring resulted in a substantially increased TOF value. This suggests that the sulphur atom takes part in the reaction, possibly through electronic interactions. This effect was also observed in 2-furaldehyde and 3-furaldehyde—the latter exhibited high conversion and TOF values. With pyridines, conversion increased with increasing distance of the carboxaldehyde group to the pyridine nitrogen. Similar trends were observed in fural- dehydes and thiophene carboxaldehydes. 3.3 Catalyst Re-use and Leaching Catalyst re-usability was assessed in the reaction of benz- aldehyde with nitromethane. To this end, the reaction was stopped after 7 h (i.e. at 98% conversion) and the catalyst removed by filtration and washed with methanol several times. Figure 4 shows the results obtained after four re-use cycles. As can be seen, the catalytic retained virtually its whole activity, and also its selectivity. These results by themselves suggest that the catalyst undergoes no leaching during the reaction. However, in order to check that no catalyst passed into the solution and acted in the homo- geneous phase, a hot filtering test was conducted. Such a ppm 020406080100120140160180 - 41 .9 - 58 .6 (b) (a) Fig. 2 13C-CP/MAS NMR spectra for the catalyst (a) and liquid ethanolamine (b) T (°) 150 300 450 600 P (to rr) 1 10 m/z = 30 m/z = 61 m/z = 43 Fig. 3 TPD–MS profiles for the catalyst 134 M. Mora et al. 123 test, which was previously applied by our group to other heterogenized homogeneous catalysts [26, 27], involves stopping the reaction at a low conversion level to remove the catalyst by hot filtering and then using the filtrate to continue the process for a further 24 h. This test was per- formed under the experimental conditions described in Table 2 Influence of the reaction temperature and amount of catalyst on conversion in the reaction of benzaldehyde with nitromethane in the presence of ETAM/SiO2 as catalyst O H 3NO2 ETAM/SiO2 H NO2 H 21 + CH Entry T (�C)a Catalyst (mg)b Time (h)c Conversion (%)d TOFe 1 R.T. 100 24 0 0 2 40 100 24 6 0.062 3 65 100 24 72 0.7541 4 85 100 7 98 3.514 5 85 60 12 76 0.982 6 85 25 24 14 0.037 7f 85 – 24 0 0 8 g 85 100 24 0 0 9 h 85 – 7 55 1.971 Reaction conditions: 5 mmol benzaldehyde; 6 mL nitromethane a Reaction temperature b Amount of catalyst c Reaction time d Conversion to (E)-nitrostyrene e Turnover frequency (mmol nitrostyrene/lmol ETAM h) f Without catalyst g With SiO2 as catalyst h Amount of catalyst: 1.2 lL of ethanolamine Table 3 Synthesis of 4-substituted (E)-nitrostyrenes in the presence of ETAM/SiO2 as catalyst O H R + CH3NO2 ETAM/SiO2 H NO2 H R 43 Entry R Product Time (h)a Conversion (%)b TOFc 1 3a: H- 4a 7 98 3.514 2 3b: CH3CH2O- 4b 7 96 3.449 3 3c: CH3O- 4c 7 97 3.484 4 3d: CH3COO- 4d 7 96 3.449 5 3e: CH3CH2- 4e 8 92 2.892 6 3f: CH3- 4f 8 93 2.923 7 3 g: Cl- 4 g 14 98 1.760 8 3 h: Br- 4 h 16 94 1.477 9 3i: O2N- 4i 24 56 0.587 10 3j: NC- 4j 24 68 0.713 Reaction conditions: 5 mmol benzaldehyde; 6 mL nitromethane. Amount of catalyst: 100 mg a Reaction time b Conversion to (E)-nitrostyrene c Turnover frequency [mmol 4-substituted (E)-nitrostyrene/lmol ETAM h] Synthesis of (E)-nitroalkenes 135 123 Administrator 下划线 entry 4 of Table 2. Thus, the reaction was stopped after 1 h (viz. at 16.5% conversion to nitrostyrene) and the catalyst removed. The process was then allowed to continue at 85 �C in the filtrate for a further 24 h but no increase in conversion was observed. This allows one to exclude the possibility that some ethanolamine may leach from the Table 4 Synthesis of heterocyclic (E)-nitroalkenes in the presence of ETAM/SiO2 as catalyst S N H O O N N N S S CH3 N CH3 N H CH3 CH3 N CH3 NCH3 Entr R Producty Time (h)a Conversion (%)b TOFc 1 2 3 4 5 6 7 8 9 10 11 12 5a: 6a 13 24 28 0.29 5b: 6b 3 12 96 2.01 5c: 6c 2 24 25 0.26 5d: 6d 2 24 66 0.69 5e: 6e 2 24 51 0.53 5f: 6f 4 25 57 0.59 5g: 6g 7 8 93 2.92 5h: 6h 3 8 100 3.14 5i: 6i 3 24 57 0.59 5j: 6j 7 24 64 0.67 5k: 6k 1 24 72 0.75 5l: 6l 4 24 59 0.61 5m: 6m 8 24 56 0.608 + CH3NO2 ETAM/SiO R O H R H H NO2 65 Reaction conditions: 5 mmol aldehyde: 6 mL nitromethane. Amount of catalyst: 100 mg a Reaction time b Conversion to (E)-nitroalkene c Turnover frequency (mmol aldehyde/lmol ETAM h) 136 M. Mora et al. 123 Administrator 下划线 catalyst to the solution and cause the reaction to take place under homogeneous catalysis to some extent. 4 Conclusions A basic catalyst consisting of silica-supported ethanolamine proved highly efficient in the synthesis of (E)-nitrostyrenes. In fact, only if the starting benzaldehyde bore an electron- withdrawing substituent, was conversion to the corre- sponding nitrostyrene incomplete. The proposed catalyst is also active with heterocyclic aldehydes, which were con- verted in a quantitative manner as well. Finally, the catalyst can be re-used at least three times with no appreciable loss of reactivity or selectivity following easy removal from the liquid reaction mixture. Also, based on the results of a hot filtering test, no leaching of the catalyst from the support occurs at any time during the process. References 1. Wang WY, Hsieh PW, Wu YC, Wu CC (2007) Biochem Pharm 74:601 2. 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