Interestingly, indole derivatives are regioselectively acylated in the 3-position under mild conditions with high yields without NH protection. Three new ketone products are synthesized. The Friedel—Crafts acylation using ionic liquids as green solvents aims to increase the yield and to recycle the catalytic system without significant loss of the catalytic activity. Recently, Abbott and co-workers have promoted and developed a new class of ionic liquids called deep eutectic solvents DES which are often composed of choline chloride and one or two other components.
In this paper, we report a green and efficient method with high regio- and chemoselective Friedel—Crafts acylation using acid anhydrides and [CholineCl][ZnCl 2 ] 3 as catalyst under microwave irradiation. A deep eutectic solvent was used as catalyst for many organic transformations. This is the first application, to our knowledge, of [CholineCl][ZnCl 2 ] 3 as a catalyst for Friedel—Crafts acylation reactions. First, our investigation focused on finding the optimal mixture of choline chloride and zinc chloride.
The best conversions were obtained under microwave irradiation with high regio-selectivity when [CholineCl][ZnCl 2 ] 3 was used as the catalyst Table 1 , entries 4 and 8. It could be explained by the stronger Lewis acidity with more zinc chloride used. The results are summarized in Table 2. Interestingly, all acid anhydrides, such as acetic anhydride, propionic anhydride, butyric anhydride, iso-butyric anhydride and benzoic anhydride, gave ketone products with major p -isomer and no demethylation products were observed.
Surprisingly, pivalic anhydride was not reactive under the same reaction conditions Table 2 , entries 9— Among the tested acid anhydrides, propionic and benzoic anhydride provide the highest yields. The above mentioned conditions were applied to the Friedel—Crafts acylation of a variety of aromatic compounds as seen in Table 3. The aromatic compounds with electron-donating methoxy substituents are reactive under optimized conditions, affording the benzoylated products in good to excellent yields entries 1, 2, 4, 5.
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The Friedel—Crafts propionylation of veratrole gave a lower yield than benzoylation under similar conditions. Thioanisole was reactive under optimized conditions in excellent yield. Indoles are important compounds used in many pharmaceuticals. Among these triflates, yttrium triflate showed the best catalytic activity for Friedel-Crafts 3-propionylation of indole. Yttrium triflate showed the highest yield and exhibited stronger catalytic activity than the other metal triflates.
This metal triflate has been studied extensively in organic synthesis in general [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Table 1. Effect of metal triflates on Friedel-Crafts propionylation of indoles under microwave irradiation. Next, we tested the effect of solvents on Friedel-Crafts propionylation of indole. The aim of this test was to find the solvent leading to the highest yield with maximum formation of only 3-propionylindole. Eighteen solvents, including traditional organic solvents and commercially available ionic liquids, were investigated.
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The results are listed in Table 2. The ionic liquid [BMI]BF 4 was found to be the most effective for Friedel-Crafts propionylation of indole in excellent yield with high regioselectivity, and in this case N -propionylation was completely absent.
The result indicates that the presence of [BMI]BF 4 enhances the catalytic activity of yttrium triflate. Friedel-Crafts acylation using metal triflates in ionic liquids has recently attracted attention [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 49 ]. However, this is the first time that tis catalytic system was applied in the Friedel-Crafts acylation of indoles.
Table 2. With optimized conditions in hand, we next investigated the substrate and reagent scope for the Friedel-Crafts 3-acylation of indoles with acid anhydrides using yttrium triflate in [BMI]BF 4 , and the results are presented in Table 3. Indole afforded 3-acylindole in excellent yields with high regioselectivity for the 3-position when using aliphatic acid anhydrides as acylating reagents Table 3 , entries 1—5.
The slightly lower yields of 3-acylated products are due to increased substitution at the 1- and 2-position Table 3 , entries 7— However, acylation of 4- or 5-haloindoles with aliphatic acid anhydrides produced 3-acylindoles in good yields Table 3 , entries 19— In addition, N -acylated byproducts were slightly decreased in comparison with electron-rich indoles, but 2-acylindoles were obtained in small amounts Table 3 , entries 19— A variety of aliphatic acid anhydrides have been tested.
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Good yields were obtained for both straight-chain and branched-chain acid anhydrides. Effects due to steric hindrance do not play a role as pivalic acid anhydride is also reactive in general Table 3. The use of microwave irradiation is probably very important in the case of pivalic acid anhydride as pivaloyl chloride under Friedel-Crafts conditions are known to lead to decarbonylation [ 50 ].
The reaction has also been tested using conventional heating for 5 min. The regioselectivity was worse and much longer times are needed.
Advances in Friedel-Crafts Acylation Reactions
Looking at regioselectivity in general, it is seen from Table 1 that the catalyst has little influence. From Table 2 , most solvents give good regioselectivity. It is hard to find a common factor for those conditions. From Table 3 , it is seen that pivalic acid anhydride and 2-methylpropionic acid anhydride give rise to more 2-substitution than straight chain acid anhydrides and so does benzoic acid anhydride.
A comparison of entries 23 and 34 shows that the reason is not purely steric. More important seems to be the nature of the substitutent in the 5-position. As the three mentioned acylium ions are more stable than those of straight chain acylium ions, it appears that a higher yield of the 2-isomer is caused by a combination of a small steric effect, electronic influence of the 5-position and the stability of the acylium ion. Table 3. Other conditions were tested to obtain the best yield. After the first use, the recovered catalytic system was tested in four consecutive runs without significant loss of catalytic activity in propionylation of indole and 5-bromoindole Scheme 1.
After workup, the ionic liquid containing metal triflate is dried under vacuum before the next use. Scheme 1.
Indoles, acid anhydrides and metal triflates were purchased from Sigma-Aldrich St. Solvents were obtained from Labscan Bangkok, Thailand and Chemsol Hochiminhcity, Vietnam and also directly used without purification. Silica gel was from Merck Darmstadt, Germany.
Catalytic Friedel–Crafts Acylation Reactions - Arene Chemistry - Wiley Online Library
Microwave irradiation was performed in a CEM Discover BenchMate apparatus Matthews, NC, USA which allows microwave synthesis with safe pressure regulation using a 10 mL pressurized glass tube with Teflon-coated septum and vertically-focused IR temperature sensor controlling reaction temperature. Flash column chromatography was performed on silica gel Merck. A 10 mL glass vessel suited for the monomode microwave oven was charged with 1 mmol substrate, 1 mmol acid anhydride, 0. Next, the vessel was sealed with a Teflon cap and irradiated in a monomode microwave oven at many different reaction conditions temperature and time to find the optimal condition.
The organic layer was dried over MgSO 4 , filtered, and the solvent was removed by a rotary evaporator. This procedure was also carried out in the monomode microwave oven using indole or 5-bromoindole. This recycled system was used for four consecutive runs and it can be noticed that the isolated yield of product only decreased slightly after each run. This is a simple, straightforward and environmentally benign method to prepare 3-acylindoles in high yields, high regioselectivity and in short reaction times. Tran, H. Tran designed and performed the experiments; P.
Hansen and M. Do analyzed the spectra and data; P. Hansen and T.