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Catalyst-free and Solvent-free Cyanosilylation and Knoevenagel Condensation of Aldehydes Weifan Wang, Man Luo, Weiwei Yao, Mengtao Ma, Sumod A Pullarkat, Li Xu, and Pak-Hing Leung ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b05486 • Publication Date (Web): 03 Dec 2018 Downloaded from http://pubs.acs.org on December 4, 2018
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ACS Sustainable Chemistry & Engineering
Catalyst-free and Solvent-free Cyanosilylation and Knoevenagel Condensation of Aldehydes Weifan Wang,† Man Luo,† Weiwei Yao,‡ Mengtao Ma,*,† Sumod A. Pullarkat,§ Li Xu,*,† and Pak-Hing Leung*,§ †
Department of Chemistry and Materials Science, College of Science, Nanjing Forestry University, Nanjing 210037, China College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China § Division of Chemistry & Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore Supporting Information ‡
ABSTRACT: A simple catalyst-free and solvent-free method for the cyanosilylation of a variety of aldehydes with trimethylsilyl cyanide as well as the Knoevenagel condensation reaction of various aldehydes with malononitrile was developed. The developed protocol demonstrated high efficiency in the two C−C bond formation scenarios. KEYWORDS: Catalyst-free, Solvent-free, Aldehyde, Cyanosilylation, Knoevenagel condensation and Knoevenagel condensation reaction of a wide range of INTRODUCTION aromatic and aliphatic aldehydes for C−C bond formation. The cyanosilylation reaction is a powerful synthetic tool for the C–C bond formation and provides access to versatile cyaEXPERIMENTAL SECTION nohydrins that can be easily transformed to a plenty of useful All reactions were performed under an atmosphere of nitrogen compounds in chemical industry, such as α-hydroxy acids, αusing standard Schlenk-line technique. 1H, 13C{1H}, 29Si{1H}, amino acids, β-amino alcohols and other valuable intermediand 19F{1H} NMR spectra were recorded at 25°C on Bruker 1 ates. So far trimethylsilyl cyanide (TMSCN) is the most pop400 MHz BBFO1, BBFO2 or Ascend 500 MHz spectrometer ular cyanating reagent for nucleophilic addition to carbonyl in deuterated solvents and were referenced to the resonances compounds to produce cyanohydrin trimethylsilyl ethers of the solvent used. Brand new and never used NMR tubes and which circumvents the high toxicity and difficulties associated magnetic stir bars were used in order to eliminate potential with the handling of hydrogen cyanide (HCN).2 As a result, traces of metal. Aldehydes, ketones, TMSCN and malononumerous catalysts based on Lewis acids, Lewis bases, transinitrile were purchased from Sigma-Aldrich, Alfa, Aesar, and tion metals, and main group elements3-27 have been reported Acros and used without further purification. for the cyanosilylation of carbonyls. However, all of them General Procedure for Cyanosilylation of Aldehydes. utilize mostly metal complexes or organic compounds which Under a nitrogen atmosphere, aldehyde (0.5 mmol) and make the reaction complicated and are usually detrimental to TMSCN (0.75 mmol) were added to a new NMR tube with a the environment. new magnetic stir bar at rt, 60°C or 100°C. The progress of the Knoevenagel condensation reaction is another crucial memreaction was monitored by 1H NMR, 13C NMR, 29Si NMR, and 19 ber of the C−C bond formation reaction family, which is inF NMR. Two examples were selected to purify to get pure herently environment-friendly due to the fact that only water is products: upon completion of the reaction, the combined orproduced as the by-product. It also plays an important role in ganic layers were dried, evaporated and purified by column the syntheses of pharmaceutical products, fragrances and vital chromatography over silica-gel (100-200 mesh) using ethyl chemical intermediates.28-30 Commonly, the Knoevenagel acetate/hexane (1:5) mixture as eluents to obtain the pure transformation occurs between aldehydes/ketones and active products (2a, 2h). methylene hydrogen compounds such as malononitriles, maGeneral Procedure for Knoevenagel condensation of Allonates, diketones, 1,3-ketoesters, ketothioesters, keto amides, dehydes. Under a nitrogen atmosphere, Aldehyde (0.5 mmol) and cyclic esters promoted by homogeneous catalysts like and malononitrile (0.5 mmol) were added to a new NMR tube ammonia, ammonium salts, pyridine, piperidine, urea, primary with a new magnetic stir bar at 140°C. The progress of the and secondary amines in organic solvents.31-34 Unfortunately, reaction was monitored by 1H NMR, 13C NMR, and 19F NMR. these conventional catalysts are difficult to separate and recyTwo examples were selected to purify to get pure products: cle which leads to resource consumption and environmental upon completion of the reaction, the combined organic layers pollution. Well-defined heterogeneous catalysts can also prowere dried, evaporated and purified by column chromatogmote this reaction.35-38 However, these catalytic systems still raphy over silica-gel (100-200 mesh) using ethyl acehave some disadvantages.39 Thus, it is quite evident that there tate/hexane (1:5) mixture as eluents to obtain the pure prodis a need to develop a new methodology in order to mitigate ucts (4a, 4h). the aforementioned drawbacks. Modern chemical research must make progress on the baRESULTS AND DISCUSSION sis of sustainable and environmentally benign practices.40-42 As We embarked on our investigation with the cyanosilylation of Sheldon said that the “best catalyst is no catalyst” and “the benzaldehyde using different concentration of TMSCN at dif43 best solvent is no solvent”. Herein, we report the first examferent temperatures in a catalyst-free and solvent-free manner ple of a simple, catalyst-free and solvent-free cyanosilylation
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(Table 1). At first the reaction of benzaldehyde with TMSCN (2 equiv.) without any catalyst was carried out at room temperature, the yield is slightly lower (44%) after 24 h (Table 1, entry 1). However, only increasing the reaction temperature, the quantitative conversion was obtained (Table 1, entries 2–4). This indicated that the reaction temperature was very influential in the reaction outcome. To investigate the impact of the concentration of TMSCN, we tested different equivalents of TMSCN and the results revealed that 1.5 equiv. of TMSCN gave the same conversion that was achieved whilst employing 2 equiv. However, lowering down the equivalents, led to a slightly lower conversion (Table 1, entries 5–7). It should be noted that when d-toluene was used as a solvent, only 32% yield was observed (Table 1, entry 8). Next, the applicability of various aldehydes was explored in the absence of catalyst and solvent was analyzed (Table 2). It should be noted that the conversions of several substrates were indeed better than that of some previously reported catalysts which also involved the use of solvents.3-27 Interestingly, irrespective of whether the substrate employed is aromatic and aliphatic aldehydes bearing different functionalities, the conversions were all better than that of benzaldehyde. This phenomenon was quite different from what has been reported previously, where benzaldehyde has no obvious difference when compared with other substrates in catalytic cyanosilylation.3-27 It was revealed that the position of methyl moiety on the phenyl ring has an important effect on the reactivity. It can be seen that for the para/meta-methyl-substituted benzaldehyde, the reaction went smoothly to completion at room temperature within a few hours whilst an increase in temperature to 60°C could shorten the reaction time to 10 min. However, for ortho-methyl-substituted benzaldehyde, the corresponding reaction required 5 h at 100°C (Table 2, 2a–2c). Benzaldehyde substrates with other electron-donating groups such as –OMe, or –Ph also required longer time at higher temperature (Table 2, 2d, 2e). For electron-withdrawing groups such as halogens, the type of halogen has a vital effect on the reactivity, as demonstrated by the cyanosilylation of 4-fluoro/chloro/bromo benzaldehyde (Table 2, 2f–2h). We can see that although 4chlorobenzaldehyde required 6h at rt or 10 min at 60°C and 4bromobenzaldehyde required 2.5 h at 60°C or 50 min at 100°C, 4-fluorobenzaldehyde on the other hand required more stringent conditions (6 h at 100°C) to achieve full conversion. The substitution position of halogen affected the reactivity as well. Compared with para-chlorobenzaldehyde, meta/orthochlorobenzaldehyde required 2 h at 100°C (Table 2, 2i, 2j). This halogen effect is different from that reported in previous protocols, wherein the type (F, Cl, Br) and position (o, m, p) of halogen on the benzene ring has no significant impact on the reactivity.3-27 The benzaldehyde substrate with an electronwithdrawing group such as –CN also can afford the corresponding cyanohydrin trimethylsilyl ethers in 99% yield both at rt or 60°C (Table 2, 2k). Sterically bulky 1-naphthaldehyde and 9-anthraldehyde, heterocyclic 2-furaldehyde, and aliphatic aldehyde also underwent cyanosilylation in very high yields under the catalyst-free and solvent-free protocol (Table 2, 2l– 2o). Subsequently the cyanosilylation of ketones was also investigated. We started the test reaction using acetophenone with 1.5 equiv. of TMSCN at different temperatures under catalystfree and solvent-free conditions (Table S1). However, only trace amounts of desired product was observed, even after raising the temperature to 140°C (Table S1, entries 1–3).
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Table 1. Optimization of aldehydes cyanosilylation O
Ph
H
+
n TMSCN
OTMS
catalyst-free solvent-free
Ph
H
CN
1a
Yield (%)a Entry n Temp (°C) Time (h) 1 2.0 rt 24 44 2 2.0 60 12 99 3 2.0 80 10 99 4 2.0 100 7 99 5 1.5 100 7 99 6 1.2 100 7 95 7 1.0 100 7 92 8 1.5 100 24 32b a Yield was determined by 1H NMR spectroscopy. bD8-toluene.
Table 2. Cyanosilylation of aldehydesa O R
H
+
1.5 TMSCN
catalyst-free solvent-free rt-100oC
OTMS R
H
CN
2a: rt, 3h, 99% 60°C,
