molecules Article Beckmann Rearrangement of Ketoxime Catalyzed by N-methyl-imidazolium Hydrosulfate Hongyu Hu †, Xuting Cai †, Zhuying Xu, Xiaoyang Yan * and Shengxian Zhao * Xingzhi College, Zhejiang Normal University, Jinhua 321004, China; [email protected] (H.H.); [email protected] (X.C.); [email protected] (Z.X.) * Correspondence: [email protected] (X.Y.); [email protected] (S.Z.); Tel./Fax: +86-579-8229-1129 (X.Y. & S.Z.) † These authors contributed equally to this work. Received: 7 June 2018; Accepted: 14 July 2018; Published: 18 July 2018 Abstract: Beckmann rearrangement of ketoxime catalyzed by acidic ionic liquid-N-methyl- imidazolium hydrosulfate was studied. Rearrangement of benzophenone oxime gave the desirable ◦ product with 45% yield at 90 C. When co-catalyst P2O5 was added, the yield could be improved to 91%. The catalyst could be reused three cycles with the same efficiency. Finally, reactions of other ketoximes were also investigated. Keywords: Beckmann rearrangement; ketoxime; acidic ionic liquid; catalysis 1. Introduction Over the past years, amide derivatives have received much attention owing to their broad range of applications in many fields such as the pharmaceutical industry, chemical biology, the agrochemical industry, engineering plastics, and so on [1–6]. Various approaches have been developed for the synthesis of amide compounds including nucleophilic acyl substitution reactions with amines [7], Staudinger ligation [8], Schmidt reaction [9] and Beckmann rearrangement [10]. However, generations of large amounts of undesired by-products and corrosive phenomenon associated with common acid (H2SO4 and SOCl2) based on liquid phase protocols provide a challenging task for chemists to develop alternative methods [11,12]. A variety of alternative routes [13–16] based on organic and inorganic solid acids were developed. However, traditional methods often suffer from some drawbacks such as poor selectivity, harsh conditions, are not atom economic, or are not environmentally friendly. From the point of view of atom conversion efficiency, Beckmann rearrangement is a perfect way for construction of amides, in general sulfuric acid is most commonly used rearrangement catalyst in commercial production of amides. However, it brings equipment corrosion and environmental pollution problems. Recently, ionic liquids [17] have emerged as potential green alternatives to organic solvents due to their unique properties of low volatility, high polarity, good thermal stability, and excellent solubility [18–20]. Further, there are more potential capabilities as effective catalysts and reagents [13], as chemical transformations have also been explored. In order to develop a green pathway of amide synthesis, we report here a Beckmann rearrangement reaction catalyzed by N-methyl-imidazolium hydrosulfate ([HMIm]HSO4)[21] under solvent free conditions (Scheme1). Molecules 2018, 23, 1764; doi:10.3390/molecules23071764 www.mdpi.com/journal/molecules Molecules 2018, 23, 1764 2 of 9 Molecules 2018, 23, x FOR PEER REVIEW 2 of 9 HO O a N b O 1 R 2 R1 R2 1 2 N R R R H Molecules 2018, 23, x FOR 1PEERa- 1REVIEWk 2a-2o 3a-3o 2 of 9 HO O a N b O Scheme 1.1. SynthesisSynthesis of of amides. amides Reagents. Reagents and and conditions: conditions: (a) NH(a)2 1OH.HCl,NH2OH.HCl, NaOH, NaOH EtOH,, EtOH, H2O, reflux;H2O, 1 2 ◦ R 2 reflux(b) acidic; (b) ionicacidic liquid, ionic liquid, P2OR5,N P22,OR 905, NC,2, 90 6h. °C , 61 h. 2 N R R R H 2. Results 1a-1k 2a-2o 3a-3o 2. Results Scheme 1. Synthesis of amides. Reagents and conditions: (a) NH2OH.HCl, NaOH, EtOH, H2O, Beckmann rearrangement of benzophenone oxime catalyzed by [HMIm]HSO4 was carried out at 12 1200 ◦°CC over reflux 6 ; h(b without) acidic ionic any liquid, solvent, P2O5, N the2, 90 °C desired, 6 h. product,product, benzanilide,benzanilide, was obtained in moderate yield (45%).2. Results The co-catalystsco-catalysts suchsuch asas PP22OO55, FeCl33, ZnCl 2,, CuCl 2.2H.2H22OO,, an andd AlCl AlCl33 wwereere investigated investigated in this reaction system, the the yield was improved significantly significantly to 91% with P2O55.. However, However, i itt has been Beckmann rearrangement of benzophenone oxime catalyzed by [HMIm]HSO4 was carried out shown in the literature that the conversion is around 20% only when P2O5 is used as the sole shown inat the120 literature°C over 6 hthat without the conversionany solvent, the is around desired 20%product only, benzanilide when P2O, was5 is obtained used as in the moderate sole catalyst of catalyst of Beckmann rearrangement [15]. When CuCl2.2H2O was added, the yield was reduced to Beckmannyield rearrangement (45%). The co-catalyst [15].s When such as CuCl P2O5,2 FeCl.2H23,O ZnCl was2, added,CuCl2.2H the2O, yieldand AlCl was3 w reducedere investigated to 14%, in and the 14%,reverse andthis reaction reactionthe ofreverse system, benzophenone reactionthe yield was oximeof improvedbenzophenone was observed, significantly oxime benzophenone to 91% was with observed,P2O was5. However, regenerated. benzophenone it has been The results was rearegenerated. presentedshown The in Tabletheresults literature1. are presentedthat the conversion in Table is1. around 20% only when P2O5 is used as the sole catalyst of Beckmann rearrangement [15]. When CuCl2.2H2O was added, the yield was reduced to 14%, andTableTable the 1 1.. Effectreverse of coreaction co-catalyst-catalyst of onbenzophenone Beckmann rearrangement oxime was observed, in ionicionic liquid benzophenone systems.systems. was regenerated. The results are presented in Table 1. Entry Co-Catalyst Yield (%) Entry Co-Catalyst Yield (%) Table 1. Effect1 of co-catalyst on Beckmanna rearrangement in ioni45c liquid systems. 1 a 45 2 Entry CoP-Catalyst2O5 Yield (%)91 2a P2O5 91 3 1 FeCl 3 45 47 3 FeCl3 47 2 P2O5 91 4 4AlCl AlCl3 3 50 50 3 FeCl3 47 5 5ZnCl ZnCl2 2 53 53 64 AlCl CuCl3 ·2H O 50 14 b 6 CuCl2·2H2O 2 14 b 5 ZnCl2 53 Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO (11.4 mmol), and co-catalyst (8%), 90 ◦C, 6 h; Reaction conditions: Benzophenone oxime (9.52 mmol),2 [HMIm]HSO4 b4 (11.4 mmol), and co-catalyst a b 6 CuCl ·2H O 14 without co-catalyst;a benzophenone(%) wasb obtained. (8%), 90Reaction °C , 6 h; conditions without: Benzophenoneco-catalyst; boximeenzophenone (9.5 mmol),(%) [HMIm]HSO was obtain4 (11.4ed. mmol), and co-catalyst (8%), 90 °C , 6 h; a without co-catalyst; b benzophenone(%) was obtained. The effect of the amount of co co-catalyst-catalyst P2O5 onon reaction reaction was was investigated. investigated. The The reaction reaction yield yield was The effect of the amount of co-catalyst P2O5 on reaction was investigated. The reaction yield was improved when moremore co-catalystco-catalyst waswas added,added, and and the the best best yield yield was was around around 90% 90% when when the the amount amount of improved when more co-catalyst was added, and the best yield was around 90% when the amount P2O25 was5 higher than 8 mol %. The results are presented in Figure1. of P O ofwa Ps2O higher5 was higher than than8 mol 8 mol %. %.The The results results are are presentedpresented in in Figure Figure 1. 1. Figure 1. Effect of the amount of co-catalyst P2O5 on Beckmann rearrangement of benzophenone Figure 1. Effect of the amount of co-catalyst P O on Beckmann rearrangement of benzophenone oxime. Reaction conditions: Benzophenone oxime2 (9.55 mmol), [HMIm]HSO4 (11.4 mmol), 90 °C , 6 h. ◦ oxime. Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 90 C, 6 h. Figure 1. Effect of the amount of co-catalyst P2O5 on Beckmann rearrangement of benzophenone oxime. Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 90 °C , 6 h. Molecules 2018, 23, x FOR PEER REVIEW 3 of 9 Molecules 2018, 23, x FOR PEER REVIEW 3 of 9 MoleculesMolecules2018, 20123,8 1764, 23, x FOR PEER REVIEW 3 of 93 of 9 The influence of the reaction temperature on the yield was investigated subsequently. It was Molecules 2018,The 23Molecules, x influenceFOR 201 PEER8, 23, x REVIEW FORof thePEER reactionREVIEW temperature on the yield was investigated subsequently.3 of 9 3 of 9 It was Moleculesfound 2018,The 23 that, x influenceFOR 90 PEER°C is REVIEW theof the best reaction reaction temperature temperature. on The the results yield arewas presented investigated in Figure subsequently. 2. 3 of 9 It was foundThe influence that 90 °C of is the the reaction best reaction temperature temperature. on the The yield results was are investigated presented subsequently.in Figure 2. It was foundThe influence that 90 The◦C of isinfluence the bestreaction of reactionthe reaction temperature temperature. temperature on onthe The the yield resultsyield was was are investigatedinvestigated presented subsequently.in subsequently. Figure2 It. was It was The influencefound that of 90the °C reaction is the best reactiontemperature temperature. on the The yield results was are presented investigated in Figure subsequently. 2. It was found that 90 °C is the best reaction temperature. The results are presented in Figure 2. found that 90 °C is the best reaction temperature. The results are presented in Figure 2. Figure 2. Influence of the reaction temperature on Beckmann rearrangement of benzophenone oxime. Figure 2. InfluenceReaction conditions of the reaction：Benzophenone temperature oxime (9.5 on mmol), Beckmann [HMIm]HSO rearrangement4 (11.4 mmol), of 6 benzophenone h, co-catalyst oxime. ReactionFigure conditions:(P 2O. 5Influence 8%). Benzophenone of the reaction oxime temperature (9.5 mmol), on Beckmann [HMIm]HSO rearrangement4 (11.4 mmol), of benzophenone 6 h, co-catalyst oxime. Figure 2. Influence of the reaction temperature on Beckmann rearrangement of benzophenone oxime. (P2OReac5 8%).tion conditions：Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 6 h, co-catalyst ReactionThe conditionsrecycling performance：Benzophenone of ionic oxime liquid (9.5has themmol), most [HMIm]HSObenefits from 4 the(11.4 point mmol), of view 6 h of, co -catalyst Reaction conditions：Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 6 h, co-catalyst (P2O5 8%).