Beckmann Rearrangement of Ketoxime Catalyzed by N-Methyl-Imidazolium Hydrosulfate

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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 oxime of 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 presented that 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.. Effect reverse of co reactionco-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; b oximeenzophenone (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 conditions recycling performance：Benzophenone of ionic oxime liquid (9.5has themmol), most [HMIm]HSO benefits 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%). (Penvironmental2O5 8%). protection. During the reaction workup, the white product was precipitated out Figure 2(.P Influence2O5 8%). of the reaction temperature on Beckmann rearrangement of benzophenone oxime. FigureThe 2. recycling whenInfluence ice water of performance the was reaction added, aftertemperature of filtration, ionic liquid onthe Beckmannmother has liquid the rearrangement mostwas evaporated beneﬁts of in frombenzophenone a vacu theum, and point ionic oxime of view. of Reaction conditions：Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 6 h, co-catalyst Theliquid recycling was recovered： performance and could be ofreused ionic for liquidthree times. has The the results most4 are benefits presented fromin Table the 2. point of view of environmentalReactionThe conditions recycling protection.Benzophenone performance During oxime the of reactionionic (9.5 mmol), liquid workup, [HMIm]HSOhas the the most white (11.4 benefits product mmol), from 6 was h, cothe precipitated-catalyst point of view out of (P2O5 8%The). recycling performance of ionic liquid has the most benefits from the point of view of (P2environmentalO5 8%). protection. During the reaction workup, the white product was precipitated out whenenvironmental ice water was protectionadded,Table after 2.. Effect During ﬁltration, of ionic the liquid the reaction motherrecycling workup,on liquid Beckmann was the rearrangement evaporated white product. in a vacuum, was precip anditated ionic out whenenvironmental ice water was protection added,. Duringafter filtration, the reaction the mother workup, liquid the was white evaporated product in was a vac precipuum,itated and ionic out liquidThewhen wasrecycling ice recovered water performance was and added, could of after be ionic reused filtration, liquid for three hasthe motherthe times. most Theliquid benefits results was areevaporatedfrom presented the point in ina vac Table of u viewum2. , andof ionic Theliquidwhen recycling icewas water recovered performance wasReaction added, and Turn could of after ionic be filtration, reusedP liquid2O5/% hasforthe three mothertheConversion mosttimes. liquid benefits/ %The was results evaporatedfromYield are/ %the presented point in a vac of in u view umTable, andof 2. ionic environmentalliquid was protection recovered. During and1 could the be reaction reused8 workup,for three times. the91 white The results product91 are was presented precipitated in Table out 2. environmentalliquid was protection recoveredTable. During2. andEffect could of the ionic be reaction reused liquid recycling workup,for three on times. the Beckmann white The results product rearrangement. are was presented precipitated in Table out 2. when ice water was added, after2 filtration, the1 mother liquid9 1was evaporated90 in a vacuum, and ionic when ice water was added,Table after3 2 filtration,. Effect of i onicthe0.5 motherliquid recycling liquid90 was on Beck evaporatedmann rearrangement88 in a vacuum. , and ionic liquid was recovered and couldTable 2be. Effect reused of iforonic three liquid times. recycling The on results Beckmann are presented rearrangement in Table. 2. liquid was recoveredReactionReaction and conditions could Turn: beBenzophenone reused P2 forO 5 oxime/% three (9.5 times. mmol), Conversion/% The [HMIm]HSO results4 are(11.4 presented mmol), Yield/% 90 °C in, 6Table h; 2. Reaction Turn P2O5/% Conversion/% Yield/% ConversionReaction was determined Turn by Gas CPhromatography2O5/% (GC) Conversionusing internal st/andard% method.Yield /% TableReaction1 2. Effect1 Turn of ionic liquid 8P 2rOecycling85 /% on BeckConversion 91mann91 r earrangement/% 91. Yield91 /% Table 22. Effect1 of ionic liquid 1 recycling8 on Beck 91mann91 r earrangement 90. 91 In order to explore21 the scope and limitations18 of this reaction,9911 we extended the procedure9091 to Reaction Turn32 P2O5/% 0.5 1 Conversion 90/%91 Yield 88/% 90 various aryl-substituted2 and alkyl2 -5substituted1 ketoximes. In general,91 the reaction proceeded90 easily Reaction Turn3 P O /% 0.5 Conversion/%90 Yield◦ /% 88 Reactionunder conditions: the1 best conditions Benzophenone3 and the oxime8 amide (9.5 0.5products mmol), [HMIm]HSO were isolated91 4 in(11.490 excellent mmol), yields 9091C, and 6 h;high88 Conversion purity. was determinedReactionThe results by Gas1 conditions are Chromatography presented: Benzophenone in Table (GC)8 3. using oxime internal (9.5 standard mmol),91 method. [HMIm]HSO4 9(11.41 mmol), 90 °C , 6 h; Reaction 2 conditions : Benzophenone1 oxime (9.5 mmol),91 [HMIm]HSO4 90(11.4 mmol), 90 °C , 6 h; ConversionReaction 2 conditions was determined: Benzophenone by1 G as C hromatography oxime (9.5 mmol),91 (GC) [HMIm]HSO using internal4 90 (11.4st andard mmol), method. 90 °C , 6 h; Conversion was determined by Gas Chromatography (GC) using internal standard method. ConversionTable3 3 .was Formation determined of amides by0.5 ( 3aG –a3so )C fromhromatography ketoxime (290a–2o (GC)) in theusing presence internal of ionic88 st andard liquid and m ethod. In order to explore3 the scope and0.5 limitations of this reaction,90 we extended88 the procedure to various Reaction conditionsco-catalyst: BenzophenoneP2O5. oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 90 °C , 6 h; aryl-substitutedReactionIn conditions order and to: alkyl-substituted exploreBenzophenone the scope oxime ketoximes. and (9.5 limitations mmol), In general, [HMIm]HSO of this the reaction, reaction4 (11.4 weproceeded mmol), extended 90 easily°C , the 6 underh procedure; the to ConversionIn order was determined to explore by the Ga s scope Chromatography1 and limitations (GC) using of this internal 2 reaction, standard we extendedmethod. the procedure to ConversionvariousIn order arylwasCompd- determinedsubstituted to explore. by and the Ga s scopealkyl CRhromatography - substituted and limitations (GC)ketoximes. using of this iRnternal In reaction, general, standard we the extendedmYield reactionethod. % theproceeded procedure easily to bestvarious conditions aryl and-substituted the amide and products alkyl-substituted were isolated ketoximes. in excellent In general, yields and the high reaction purity. proceeded The results easily various aryl-substituted and alkyl-substituted ketoximes. CInH 3general, the reaction proceeded easily under the best3a conditions and the amideOCH3 products were isolated in excellent91 yields and high purity. areIn presented under order the to inexplorebest Table conditions 3 the. scope and and the limitations amide products of this were reaction, isolated we in extended excellent the yields procedure and high to purity. In Theunder order results the to explorebest are conditionspresented the scope inand Table and the limitations 3.amide products of this were reaction, isolated we in extended excellent the yields procedure and high to purity. variousThe aryl results-substituted are presented and alkyl in- substitutedTable 3. ketoximes. In general, the reaction proceeded easily variousThe aryl results-substituted are3b presented and alkyl in- substitutedTable 3.C H3 ketoximes. In general, the reaction 90proceeded easily under theTable best 3. conditionsFormation and of amides the amide (3a–3o products) from ketoxime were isolated (2a–2o) in in excellent the presence yields of ionicand high liquid purity. and under theco-catalyst bestTable conditions P 3. OFormation. and the of amides amide (3aproducts–3o) from were ketoxime isolated (2a in–2o excellent) in the presence yields and of ionichigh liquidpurity. and The results areTable presented 32. Formation3c5 in Table of amides 3. (3a–3o) from ketoxime (2a–2o) in the presence90 of ionic liquid and The results areco-catalyst presented P2O 5in. Table 3. Molecules 2018,co 23-,catalyst x FOR PEER P2O 5REVIEW. 4 of 9 co-catalyst P2O5. 1 2 Compd. R 1 R 2 Yield % Table 3. FormationCompd. of amides (3a–3oR) 1 from ketoxime (2a–2o) in the presenceR2 of ionic liquid Yield and % Table 3. FormationCompd. of amides (3a–3oR) 1 from ketoxime (2a–2o) in the presenceR2 of ionic liquid Yield and % co-catalyst P2O5. CH3 CH3 co-catalyst3d P2O3a5. F OCH3 CH3 9189 91 3a OCH3 3 91 Compd. 3a R1 3 R2 Yield % 91 Compd. R1 Br R2 Yield % 3b CH3 CH3 90 3a 3b OCH3 CH CH 9091 90 3a3e 3b OCH CH3 3 9818 90 3 3

3c 90 3b 3c CH3 90 90 3b 3c CH3 9090 90 3f NO 86 2

3c 90 3c 90 3g 91

3h 89

3i Cl 85

3j 84

3k OCH3 90

52 3l(3l’) 28 ( ) ( )

3m 89

3n CF3 82

3o Caprolactam 85

Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), catalyst (P2O5 8%), 90 °C , 6 h.

3. Experimental Section All melting points were determined using a YRT-3 Digital Melting Point Apparatus (Tianjin, China). All melting points were uncorrected. All new compounds were characterized by HRMS-EI(M+), 1H and 13C-NMR spectra were recorded in CDCl3 or DMSO-d6 on a Bruker AV 600 MHz or Bruker AV 400 MHz instrument. HRMS spectra were obtained on an Agilent 6230 mass spectrometer.

3.1. Synthesis of N-methyl-imidazolium Hydrosulfate ([HMIm]HSO4) N-Methylimidazole (8.2 g, 0.10 mol) was cooled down to 0 °C and concentrated sulfuric acid (10.0 g) was added dropwise. After addition, the solution was stirred 24 h at room temperature, a transparent viscous liquid (17.6 g) was obtained. Yield: 99%; IR (cm−1): 3345, 3150, 2870, 1447, 1337, 1221, 1048, 1082, 887.

3.2. General Procedures for Synthesis of Oxime Substrates 2a–2o Ketone (0.027 mol) and hydroxylamine hydrochloride (3.0 g, 0.043 mol) were dissolved in EtOH (10 mL) and H2O (20 mL). To the mixture was added NaOH (5.5 g, 0.137 mol). The reaction mixture was heated under reflux and the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled down to room temperature,

Molecules 2018, 23, x FOR PEER REVIEW 3 of 9

The influence of the reaction temperature on the yield was investigated subsequently. It was 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. Reaction conditions：Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 6 h, co-catalyst

(P2O5 8%).

The recycling performance of ionic liquid has the most benefits from the point of view of environmental protection. During the reaction workup, the white product was precipitated out when ice water was added, after filtration, the mother liquid was evaporated in a vacuum, and ionic liquid was recovered and could be reused for three times. The results are presented in Table 2.

Table 2. Effect of ionic liquid recycling on Beckmann rearrangement.

Reaction Turn P2O5/% Conversion/% Yield/% 1 8 91 91 2 1 91 90 3 0.5 90 88

Reaction conditions: Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), 90 °C , 6 h; Conversion was determined by Gas Chromatography (GC) using internal standard method.

In order to explore the scope and limitations of this reaction, we extended the procedure to various aryl-substituted and alkyl-substituted ketoximes. In general, the reaction proceeded easily under the best conditions and the amide products were isolated in excellent yields and high purity. The results are presented in Table 3.

Table 3. Formation of amides (3a–3o) from ketoxime (2a–2o) in the presence of ionic liquid and co-catalyst P2O5.

Compd. R1 R2 Yield % Molecules 2018, 23, 1764 4 of 9 CH3 3a OCH3 91

Molecules 2018, 23, x FOR PEER REVIEW Table 3. Cont. 4 of 9 MoleculesMolecules 2013b8, 23 , 201x FOR8, 23 PEER, x FOR REVIEW PEER REVIEW CH 3 90 4 of 9 4 of 9 MoleculesMolecules 2018, 23, 201x FOR8, 23 PEER, x FOR REVIEW PEER REVIEW 4 of 9 4 of 9 MoleculesMolecules 2018, 23, 201x FOR8, 23 PEER, x FOR REVIEW PEER REVIEW 4 of 9 4 of 9 MoleculesMolecules 2018, 23, 201x FOR8, 23 PEER, x FOR REVIEW PEER REVIEW 4 of 9 4 of 9 MoleculesMolecules 2018, 23, 201x FOR8, 23 PEER, x FOR REVIEW PEER REVIEW 4 of 9 4 of 9 MoleculesMolecules 2018, 23, 201x FOR8, 23 PEER, x FOR REVIEW PEER REVIEW CH CH3 4 of 9 4 of 9 MoleculesMolecules 2013d3c8, 23 , 201x FOR3d8, 23 PEER, x FOR REVIEW PEER REVIEW F F CH3 CH3 899089 894 of 9 4 of 9 MoleculesMolecules 2013d8,, 23 ,, 201xx FORFOR3d8, 23 PEERPEER, x FOR REVIEWREVIEW PEER REVIEW F F CH3 3 89 894 of 9 4 of 9 MoleculesMolecules 2018, 23, 201x FOR3d8, 23 PEER, x FOR REVIEW PEER REVIEW CH3 CH3 894 of 9 4 of 9 MoleculesMolecules 2013d8, 23 , 201x FOR3d8, 23 PEER, x FOR REVIEW PEER REVIEW F F CH3 CH3 89 894 of 9 4 of 9 3d 3d F BrF CH3 CH3 89 89 3d 3d BrF BrF CH3 CH3 89 89 3d 3d BrF BrF CH3 CH3 89 89 3d 3d3e BrF BrF CH3 CH3 89 889 3d3e 3d3e BrF BrF CH3 CH3 88898 898 3d3e 3d3e BrF BrF CH3 CH3 889 898 3d3e 3d3e BrF BrF 898 889 3e 3e Br Br 88 88 3e 3e Brr Br 88 88 3e 3e Br Br 88 88 3e 3e Br Br 88 88 3e 3e3f NO 2 88 8868 3e3f 3e3f NO 2 NO 2 8868 8868 3e3f 3e3f NO 2 NO 2 868688 8868 3f 3f NO 2 NO 2 86 86 3f 3f NO 2 NO 2 86 86 3f 3f NO 2 NO 2 86 86 3f 3g3f NO 2 NO 2 86 9186 3g3f 3g3f NO2 NO2 8691 9186 3g3f 3g3f NO2 N O2 8691 8691 3g3f 3g3f N O2 N O2 919186 8691 3g3f 3g3f N O2 N O2 8691 9186 3g 3g 91 91 3g 3h3g 91 8991 3h3g 3h3g 9189 8991 3g3h 3g3h 9189 9189 3h3g 3g3h 8991 9189 3h3g 3h3g 899189 8991 3h 3h 89 89 3h 3h3i C l 89 8895 3h3i 3h3i C l C l 8985 8895 3h3i 3h3i C l C l 8985 8985 3h3i 3h3i C l C l 8895 8985 3h3i 3h3i C l C l 8985 8895 3i 3i Cl Cl 8585 85 3i 3j3i C l C l 85 845 3i3j 3j3i Cl Cl 854 845 3i3j 3i3j Cll Cl 854 854 3j3i 3i3j Cl Cl 845 854 3i3j 3j3i Cl Cl 854 845 3j 3j OCH 84 84 3k3j 3k3j OCH OCH 3 848904 9084 3k3j 3k3j OCH 3 OCH 3 9084 8904 3j 3j OCH 3 OCH 3 84 84 3k3j 3k3j OCH 3 OCH 3 9084 8904 3k3j 3k3j 3 OCH 3 8904 9084 3k 3k OCH 3 3 90 90 3k 3k OCH 3 OCH 3 9052 5290 3k 3k OCH3 OCH3 905290 5290 3k 3k ’ OCH3 OCH3 90 9052 3k ’ 3l3k(3l ’) OCH3 OCH 5290 9052 3l(3l’) 3l(3l ) OCH OCH3 52 52 3l3k(3l ) 3l3k(3l ’) 3 3 5290 5290 3l(3l’) 3l(3l’) 52 2852 3l(3l’) 3l(3l’) 5228 2852 3l(3l’) 3l(3l’) ( ) ( ) 525228 5228 3l(3l’) 3l(3l’) ( ( ) ) ( ( ) ) 28 28 3l(3l’) 3l(3l’) ( ( ) ) ( ( ) ) 5228 5228 3l((3l’’)) 3l3l(3l(3l’)) ( ( ) ) ( ( ) ) 28 28 ’ ’ ( ( ) ) ( ( ) ) 28 3l(3l’) 3l(3l’) ( ( ) ) ( ( ) ) 28 3l3m(3l ) 3l3m(3l ) ( ( ) ) ( ( ) ) 2889 8928 3m 3m ( ( ) ) ( ( ) ) 282889 2889 3m 3m (( ( )) ) (( ( )) ) 8928 2889 3m 3m ( ( ) ) 2889 8928 3m 3m ( ( ) ) ( ( ) ) 89 89 3m 3m CF 3 89 89 3m3n 3m3n CF 3 CF 3 8982 8289 3m3n 3m3n CF 3 CF 3 8982 8982 3m 3m3m3n CF 3 CF 3 8989 8982 3m3n 3m3n CF 3 CF 3 8982 8289 3n 3n3o Caprolactam CF 3 CF 3 82 8582 3n3o 3n3o Caprolactam Caprolactam CF3 CF3 8285 8582 3n3o 3n3o Caprolactam Caprolactam CF3 CF3 8582 8285 3n3oReaction 3n3o conditions: Benzophenone Caprolactam oxime (9.5Caprolactam mmol), [HMIm]HSO CF C4F (11.4 mmol), catalyst8582 (P85822O 5 8%), Reaction3nReaction conditions3n conditions: Benzophenone: Benzophenone oxime (9.5 oxime mmol), (9.5 [HMIm]HSOmmol), [HMIm]HSO4 (11.43 mmol),4 (11.43 catalystmmol), catalyst(P822O 5 8% (P82),2 O 5 8%), 3o 3o Caprolactam Caprolactam C4F3 CF3 852 5 85 Reaction3o3nReaction conditions3n3o conditions: Benzophenone: Benzophenone oxime (9.5Caprolactam oxime mmol), (9.5Caprolactam [HMIm]HSOmmol), [HMIm]HSO CF (11.43 mmol),C4F (11.4 catalystmmol), catalyst(P8582O 8% (P8285),2 O 5 8%), Reaction90 °C , 3n3o6 90Reactionh conditions. °C , 3n3o6 h conditions. : Benzophenone: Benzophenone oxime (9.5Caprolactam oxime mmol), (9.5Caprolactam [HMIm]HSOmmol), [HMIm]HSO 4 (11.4 mmol),4 (11.43 catalystmmol), catalyst(82P85822O 5 8% (P8582),2 O 5 8%), 90Reaction °C , 3o6 Reaction90h conditions. °C , 3o6 h conditions. : Benzophenone: Benzophenone oxime (9.5Caprolactam oxime mmol), (9.5Caprolactam [HMIm]HSOmmol), [HMIm]HSO 4 (11.4 mmol),4 (11.4 catalystmmol), catalyst(P852O 5 8% (P85),2 O 5 8%), Reaction90 °C , 3o6 90Reactionh conditions. °C , 3o6 h conditions. : Benzophenone: Benzophenone oxime (9.5Caprolactam oxime mmol), (9.5Caprolactam [HMIm]HSOmmol), [HMIm]HSO 4 (11.4 mmol),4 (11.4 catalystmmol), catalyst(P852O 5 8% (P85),2 O 5 8%), Reaction90 °C , 3o6 Reaction90h conditions. °C , 3o6 h conditions. : Benzophenone: Benzophenone oxime (9.5Caprolactam oxime mmol), (9.5Caprolactam [HMIm]HSOmmol), [HMIm]HSO 4 (11.4 mmol),4 (11.4 catalystmmol), catalyst(P852O 5 8% (P85),2 O 5 8%), 90Reaction °C , 3o6 90Reactionh conditions. °C , 3o6 h conditions. : Benzophenone: Benzophenone oxime (9.5Caprolactam oxime mmol), (9.5Caprolactam [HMIm]HSOmmol), [HMIm]HSO 4 (11.4 mmol),4 (11.4 catalystmmol), catalyst(P852O 5 8% (P85),2 O 5 8%), 3. ExperimentalReaction90 3.°C Experimental, 6 Reaction90h conditions. °C ,Section 3o6 h conditions. :: BenzophenoneSection : Benzophenone oxime (9.5(9.5 oxime mmol),Caprolactammmol), (9.5 [HMIm]HSO[HMIm]HSOmmol), [HMIm]HSO44 (11.4(11.4 mmol),mmol),4 (11.4 catalystcatalystmmol), catalyst(( 85P22O55 8% (P)),,2 O5 8%), 3. Experimental90Reaction 3.°C Experimental, 6 Reaction90h conditions. °C Section, 6 h conditions. : BenzophenoneSection : Benzophenone oxime (9.5 oxime mmol), (9.5 mmol),[HMIm]HSO [HMIm]HSO4 (11.4 mmol),4 (11.4 mmol),catalyst catalyst(P2O5 8% (P),2 O5 8%), 3. Experimental90Reaction 3.°C Experimental,, 6 90Reactionh conditions.. °C Section, 6 h conditions. : BenzophenoneSection : Benzophenone oxime (9.5 oxime mmol), (9.5 [HMIm]HSOmmol), [HMIm]HSO4 (11.4 mmol),4 (11.4 catalystmmol), catalyst(P2O5 8%◦ (P),2 O5 8%), 3. Experimental3.Reaction Experimental conditions: Section Section Benzophenone oxime (9.5 mmol), [HMIm]HSO4 (11.4 mmol), catalyst (P2O5 8%), 90 C, 6 h. 3. Experimental90All 3.°C melting Experimental, 6 90Allh. °C melting Section,, points6 h.. Sectionpoints were determined were determined using ausing YRT -a3 YRTDigital-3 DigitalMelting Melting Point Apparatus Point Apparatus (Tianjin, (Tianjin, 3. ExperimentalAll3. melting ExperimentalAll melting Sectionpoints Sectionwere points determined were determined using a using YRT -a3 DigitalYRT-3 DigitalMelting Melting Point Apparatus Point Apparatus (Tianjin, (Tianjin, 3.China). ExperimentalAllChina).3. melting AllExperimentalAll melting melting All Sectionpoints melting points Sectionwerepoints determined points werewere determineduncorrected.were using uncorrected. ausing YRT All -a3 new YRTDigital All - compounds3 new DigitalMelting compounds Melting Point were Apparatus Point characterized were Apparatus characterized (Tianjin, by (Tianjin, by 3.China). Experimental3.All Experimental3.China). melting AllExperimentalAll melting melting All Sectionpoints Section melting points Sectionwere points determined points werewere determineduncorrected.were using uncorrected. ausing YRT All -a3 new DigitalYRT All - compounds3 new DigitalMelting compounds Melting Point were Apparatus Point characterized were Apparatus characterized (Tianjin, by (Tianjin, by 3. ExperimentalAll3. melting ExperimentalAll melting Sectionpoints1 Sectionwerepoints determined13 were determined using ausing YRT -a3 DigitalYRT-3 DigitalMelting 3Melting Point Apparatus Point6 Apparatus (Tianjin, (Tianjin, 3.China). ExperimentalAllHRMSChina).3. melting AllExperimentalAll melting- EI(M+) melting1 All Sectionpoints melting , 1 points H13Sectionwerepoints and determined points 13werewere C-NMR determineduncorrected.were spectra using uncorrected. were ausing YRT All rec -a3 new orded YRTDigital All - compounds 3 newin Digital3Melting CDCl compounds 3Melting orPoint wereDMSO6 Apparatus Point characterized were-d6 onApparatus characterizeda (Tianjin,Bruker by (Tianjin,AV 600 by China).HRMSAll-HRMSChina). EI(M+) melting AllAll melting- ,EI(M+) 1melting All Hpoints and melting , 1pointsH 13werepointsC and-NMR determined points 13werewereC spectra-NMR determineduncorrected.were spectra were using uncorrected. rec were ausing orded YRT All rec -a3 newin orded YRTDigital AllCDCl - compounds 3 newin DigitalMelting CDClor DMSO compounds Melting orPoint were-DMSOd onApparatus Point characterizeda were-d Bruker onApparatus characterizeda (Tianjin, BrukerAV 600 by (Tianjin,AV 600 by China).HRMS-China).HRMS EI(M+) All melting-, EI(M+) 1 AllH and melting , points13HC and-NMR pointswereC spectra-NMR uncorrected.were spectra were uncorrected. rec wereorded All rec newinorded AllCDCl compounds newin3 orCDCl DMSO compounds3 or were-DMSOd6 on characterizeda were-d Bruker6 on characterizeda BrukerAV 600 by AV 600 by HRMSAll-MHzHRMSEI(M+)All meltingAll meltingor-,EI(M+) meltingBruker Hpoints and, points 1 HAVwerepointsC and- NMR400 weredetermined 13were CMHz spectra-NMR determineddetermined instrument. spectra were using rec werea using ordedHRMSYRT rec --a3 ina orded DigitalYRTspectra CDCl YRT-3-3 in Digital3 Melting wereorCDCl Digital DMSO obtained3Melting orPoint Melting-DMSOd6 onApparatus Pointon a-d Brukeran Point6 onApparatus Agilent a (Tianjin, Bruker ApparatusAV 6230600 (Tianjin, AV mass 600 China).MHzAll orMHzChina). melting AllBrukerAll or melting melting1 BrukerAll AVpoints melting400 1 points 13AVpointswere MHz 400 determinedpoints 13wereinstrument.were MHz determined uncorrected.wereinstrument. using HRMSuncorrected. ausing HRMSYRTspectra All -a3 new YRTDigitalspectra Allwere - compounds3 new Digitalobtained3 Meltingwere compounds obtained3Melting Point on were an6 Apparatus Point Agilenton characterized were an6 Apparatus Agilent characterized6230 (Tianjin, mass 6230 by (Tianjin, mass by MHzHRMSChina).All or-China).HRMSMHz EI(M+) meltingBruker AllAll or melting- ,EI(M+) 1melting AllBrukerH AVpoints and melting400 , 1 points 13HAVwere pointsCMHz and-NMR 400 determined points 13wereinstrument.were CMHz spectra-NMR determined uncorrected.wereinstrument. spectra were using HRMSuncorrected. rec were ausing orded HRMSYRTspectra All rec -a3 newin orded DigitalYRTspectra AllwereCDCl - compounds3 newin obtainedDigital Melting wereorCDCl DMSO compounds obtainedMelting or Point on were-DMSOd an onApparatus AgilentPoint on characterizeda were-d Brukeran onApparatus Agilent characterized6230a (Tianjin,BrukerAV mass 6006230 by (Tianjin,AV mass 600 by China).HRMSMHz(Tianjin, or-spectrometer.China).MHzHRMS EI(M+) AllBruker China). or melting- ,EI(M+) 1 AllBrukerHAV and melting400 All , 1 points13HAV CMHz meltingand- NMR400 points 13wereinstrument. CMHz spectra- pointsNMR uncorrected.wereinstrument. spectra were HRMSuncorrected. rec uncorrected. were orded HRMSspectra All rec newinorded spectra AllwereCDCl All compounds newin obtained3 new wereorCDCl DMSO compounds compounds obtained3 or on were -DMSOd an6 on Agilent on characterized a were- wered Brukeran6 on Agilent characterized 6230a BrukerAV mass 6006230 by AV mass 600 by HRMSMHzChina).spectrometer. or-China).spectrometer.HRMSMHz EI(M+) Bruker All or melting- ,EI(M+) 1 AllBrukerHAV and melting400 , 1 pointsH13AV CMHz and- NMR400 points 13wereinstrument. CMHz spectra-NMR uncorrected.wereinstrument. spectra were HRMSuncorrected. rec were orded HRMSspectra All rec newinorded spectra AllwereCDCl compounds newin obtained3 wereorCDCl DMSO compounds obtained3 or on were-DMSOd an6 on Agilenton characterized werea-d Brukeran6 on Agilent characterized6230a BrukerAV mass 6006230 by AV mass 600 by spectrometer.China).HRMS-HRMSChina).spectrometer. EI(M+) All melting- ,EI(M+) 11 AllH and melting , 1 points13H13C and-NMR points13wereC spectra-NMR uncorrected.were spectra were uncorrected. rec wereorded All rec newinorded AllCDCl compounds newin3 orCDCl DMSO compounds3 or were-DMSOd6 on characterizeda were-d Bruker6 on characterizeda BrukerAV 600 by AV 600 by HRMSMHzspectrometer.by or HRMS-EI(M+),--HRMSMHzEI(M+) Bruker or -,,EI(M+) BrukerHAV and 400, 1 HHAV CMHz andand--NMR 400 13instrument. CC-NMRMHz spectra-NMR instrument. spectra spectrawere HRMS rec were were orded HRMSspectra rec recorded inorded spectra wereCDCl in obtained33 wereorCDCl DMSO obtained3 or oron --DMSO DMSO-dd an66 on Agilenton a-d Brukeran6 onon Agilent 6230a a Bruker BrukerAV mass 6006230 AV AV mass 600 MHz orMHzspectrometer. Bruker or 1 BrukerAV 4001 13AV MHz 400 13instrument. MHz instrument. HRMS HRMSspectra spectra were obtained3 were obtained33 on an6 Agilenton an66 Agilent 6230 mass 6230 mass spectrometer.MHzHRMS or-HRMSMHzspectrometer.EI(M+) Bruker or -EI(M+), 1 BrukerHAV and 400, 1H13AV CMHz and- NMR400 13instrument. CMHz -spectraNMR instrument. spectra were HRMS rec were orded HRMSspectra rec inorded spectra wereCDCl in obtained3 wereCDClor DMSO obtained or on -DMSOd an6 on Agilenton a-d Brukeran on Agilent 6230a BrukerAV mass 6006230 AV mass 600 MHzspectrometer.HRMS or-3.1.MHzspectrometer.HRMSEI(M+) Bruker Synthesis or -,EI(M+) BrukerHAV and of 400, N HAV -CMHzm and-ethyl NMR400 instrument.instrument. -CMHzimidazolium spectra-NMR instrument. spectra were HRMS Hydrosulfate rec were orded HRMSspectra rec ([HMIm]HSOinorded spectra wereCDCl in obtained wereorCDCl DMSO4) obtained3 or on -DMSOd an on Agilenton a-d Brukeran6 on Agilent 6230a BrukerAV mass 6006230 AV mass 600 spectrometer.3.1.600 SynthesisMHz3.1.spectrometer. Synthesis or orof NBruker Bruker-m ethylof N AV AV-mimidazoliumethyl 400 400 -MHzimidazolium MHz Hydrosulfate instrument. instrument. Hydrosulfate ([HMIm]HSO HRMS HRMS ([HMIm]HSO spectra spectra4) were were4) obtained obtained on on an an Agilent Agilent 6230 6230 mass 3.1.MHzspectrometer. Synthesis orMHzspectrometer.3.1. Bruker Synthesis orof N BrukerAV-methyl of 400 N AV -MHzimidazoliummethyl 400 instrument. -MHzimidazolium Hydrosulfate instrument. HRMS Hydrosulfate ([HMIm]HSO HRMSspectra ([HMIm]HSO spectra were4) obtained were4) obtained on an Agilenton an Agilent 6230 mass 6230 mass spectrometer.3.1.mass Synthesisspectrometer.3.1. spectrometer. Synthesis of N-methyl of N-imidazoliummethyl-imidazolium Hydrosulfate Hydrosulfate ([HMIm]HSO ([HMIm]HSO4) 4) 3.1.spectrometer. Synthesisspectrometer.3.1. SynthesisN of- M Nethylimidazole-methyl of N-imidazoliummethyl- imidazolium(8.2 gHydrosulfate, 0.10 Hydrosulfatemol) ([HMIm]HSOwas cool ([HMIm]HSOed down4) to4 )0 °C and concentrated sulfuric acid 3.1.spectrometer. SynthesisN-3.1.spectrometer.Methylimidazole SynthesisN of- M Nethylimidazole-methyl of N- imidazoliumm(8.2ethyl g,- imidazolium(0.108.2 gHydrosulfatemol), 0.10 was Hydrosulfatemol) cool ([HMIm]HSOwased cooldown ([HMIm]HSOed todown4 )0 °C to and4 )0 °C concentrated and concentrated sulfuric sul acidfuric acid 3.1. SynthesisN-3.1.Methylimidazole SynthesisN of-M Nethylimidazole-methyl of N- imidazoliumm(8.2ethyl g,- imidazolium0.10(8.2 gHydrosulfatemol), 0.10 was Hydrosulfatemol) cool ([HMIm]HSOwased cooldown ([HMIm]HSOed todown4 )0 °C to and4 )0 °Cconcentrated and concentrated sulfuric sul acidfuric acid 3.1.(10.0 Synthesis Ng)-(10.03.1.M wasethylimidazole Synthesis N g) addedof-M wasNethylimidazole-m ethyl addeddropwise.of N- mimidazolium(8.2 ethyldropwise. g After,- imidazolium0.10(8.2 addition,g Hydrosulfatemol)After, 0.10 was addition,Hydrosulfatemol) the cool ([HMIm]HSO wassolutioned the cooldown ([HMIm]HSOsolutioned was todown4 )0st irred°Cwas to and4 )st024 irred °C concentratedh andat 24room concentratedh at temperature room sulfuric temperature sul acid,f urica acid, a 3.1.(10.03.1. Synthesis Ng)- Synthesis3.1.(10.0M wasethylimidazole Synthesis N g) addedof-M wasN ofethylimidazole--m N-methyl-imidazolium ethyl addeddropwise.of N-- imidazoliummimidazolium(8.2 ethyldropwise. g After,- imidazolium0.10(8.2 addition,gHydrosulfate mol)After, 0.10 Hydrosulfate was addition,Hydrosulfatemol) the cool ([HMIm]HSO ([HMIm]HSOwassolutioned ([HMIm]HSO the cooldown ([HMIm]HSO solution edwas todown44 ))st0 irred4°Cwas) to and4 )st024 irred °C concentratedh andat 24room concentratedh at temperature room sulfuric temperature sul acid,f urica acid, a 3.1. SynthesisN-3.1.(10.0Methylimidazole Synthesis Ng) of-M wasNethylimidazole-m ethyladdedof N- mimidazolium(8.2 ethyldropwise. g,- imidazolium0.10(8.2 g Hydrosulfatemol)After, 0.10 was addition,Hydrosulfatemol) cool ([HMIm]HSOwased the cooldown ([HMIm]HSO solutioned todown4 )0 °Cwas to and4 )st0 irred °Cconcentrated −1and 24 concentratedh at room sulfuric temperature sul acidfuric acid, a 3.1.(10.0transparent Synthesis Ng)-transparent(10.03.1.M wasethylimidazole Synthesis N viscousg) addedof-M wasNethylimidazole-m viscous ethyldropwise.addedliquidof N- imidazoliumm(8.2 ethyldropwise.(17.6liquid g After,- imidazolium0.10(g)8.2 (17.6 was addition,g Hydrosulfatemol)After, g)0.10obtained waswas addition,Hydrosulfatemol) the obtainedcool. ([HMIm]HSO wasYield:solutioned the cooldown. 99([HMIm]HSO Yield:solution ed%was ; to downIR 4 99)st0 (cm irred%°Cwas ; to −IRand1):4 )st0 24 (cm3345, irred °C concentratedh − 1andat): 3150, 243345,room concentratedh 2870,at 3150,temperature room sul 1447, 2870,furic temperature sul1337, acid1447,,f urica 1337, acid, a transparent(10.0 Ng)-(10.0transparentM wasethylimidazole N viscousg)added-M wasethylimidazole viscous dropwise.addedliquid (8.2 (17.6dropwise.liquid g After, g)0.10(8.2 (17.6 was addition,g mol)After, 0.10g)obtained waswas addition,mol) the obtainedcool. wasYield:solutioned the cooldown. 99 Yield:solution ed%was ; todownIR 99st0 (cm irred%°Cwas ;to −◦IR1and): st0 243345,(cm irred °C concentratedh −and1at ):3150, 24room3345, concentratedh 2870,at 3150,temperature room sul 1447, 2870,furic temperature sul1337, acid1447,,f urica 1337, acid, a (10.0transparent Ng)--1221,(10.0M Nwasethylimidazole-Methylimidazole N viscousg)1048,added-M wasethylimidazole 1082, dropwise.addedliquid 887. ((8.2 (17.6dropwise. (8.2 g After,, 0.10g)( g,8.2 was 0.10 addition,g mol)After, 0.10obtained mol) was addition,mol) was the cool. wasYield: cooledsolutioned the cooldown 99 solution down ed%was ; to downIR 0st to(cm irred°Cwas 0 to −and1C): st0 243345,and irred °C concentratedh −and1at concentrated 3150, 24room concentratedh 2870,at temperature room sul 1447, sulfuricffuric temperature sul1337, acid,f uric acida acid, a (10.0transparent1221, N g)1048,-1221,(10.0transparentM wasethylimidazole 1082, N viscousg)1048,added-M wasethylimidazole 887. 1082, viscous dropwise.addedliquid 887. (8.2 (17.6dropwise.liquid g After, (g)0.108.2 (17.6 was gaddition, mol)After, 0.10g)obtained waswas addition,mol) the obtainedcool. wasYield:solutioned the cooldown. 99 Yield:solutioned %was ; todownIR 99st0 (cm irred%°Cwas ;to −IR1and): 0st 243345,(cm irred°C concentratedh − and1at): 3150, 243345,room concentratedh 2870,at 3150,temperature room sul 1447, 2870,furic temperature sul1337, acid1447,f, urica 1337, acid, a transparent1221,(10.0 N g)1048,-transparent(10.01221,M wasethylimidazole 1082, Nviscous g)1048,added-M was ethylimidazole887. 1082, viscous addeddropwise.liquid 887. (8.2 (17.6dropwise.liquid g After, g)0.10(8.2 (17.6 was addition,g mol)After, g)0.10obtained waswas addition,mol) the obtainedcool. wasYield:solutioned the cooldown. 99 Yield:solution ed%was ; todownIR 99st0 (cm irred%°Cwas ; to −IR1and): st0 243345,(cm irred °C concentratedh −1andat ):3150, 243345,room concentratedh 2870,at 3150,temperature room sul 1447, 2870,furic temperature sul1337, acid1447,,f urica 1337, acid, a (10.0transparent1221,(10.0(10.0 g)g)1048,(10.0transparent1221, waswas g) was1082, viscous g)1048,addedadded was added 887. 1082, viscous dropwise.addeddropwise.liquid dropwise.887. (17.6dropwise.liquid AfterAfter g) (17.6 Afterwas addition,addition, After g)obtained addition, was addition, thetheobtained. Yield:solutionsolution the the solution. 99 Yield:solution %waswas; IR 99st wasst (cm irredirred%was; − stirredIR1): st 2424(cm3345,irred hh − 241atat): 3150, 24room3345,room h ath 2870,at room 3150,temperaturetemperature room 1447, temperature,2870, temperature 1337, 1447,,, a 1337,, a 1221,transparent(10.0 g)1048,(10.0transparent1221, was 1082, viscousg)1048,added was 887. 1082, viscous addeddropwise.liquid 887. dropwise.(17.6liquid After g) (17.6 was addition, After g)obtained was addition, theobtained. Yield:solution the. 99 Yield:solution %was; IR 99st (cm irred%was; −IR1): st 24−(cm3345,irred h− 1at): 3150, 243345,room h 2870,at 3150,temperature room 1447, 2870, temperature 1337, 1447,, a 1337,, a 1221,(10.0transparenta transparent g)1048,3.2transparent1221,(10.0 was. General1082, viscousg)1048,added was viscous887. 1082, Procedures viscous dropwise.addedliquid 887. liquid dropwise.(17.6liquid for After (17.6 g)Synthesis (17.6 was g)addition, After was g)obtained ofwas obtained.addition,Oxime theobtained. Yield: solutionSubstrates Yield:the. 99 Yield:solution %was 99%; ;2a IR –99st 2(cm IR oirred%was (cm; −−IR11): st 24(cm3345,irred1 ):h− 3345,1at): 3150, 243345,room 3150,h 2870,at 3150,temperature room 2870, 1447, 2870, temperature 1447, 1337, 1447,, 1337,a 1337,, a transparent1221,3.2. General 1048,transparent3.21221,. General 1082, Proceduresviscous 1048, 887. 1082, Proceduresviscous liquid for 887. Synthesis (17.6liquid for g)Synthesis (17.6 ofwas Oxime g)obtained ofwas SubstratesOxime obtained. Yield: Substrates 2a. –99Yield:2o% ;2a IR –99 2(cmo% ; −IR1): 3345,(cm−1 ):3150, 3345, 2870, 3150, 1447, 2870, 1337, 1447, 1337, 3.21221,transparent. General 1048,transparent1221,3.2. General1082, Procedures viscous1048, 887. 1082, Proceduresviscous liquid for 887. Synthesis (17.6liquid for g)Synthesis (17.6 ofwas Oxime g)obtained ofwas SubstratesOxime obtained. Yield: Substrates 2a. –99Yield:2o% ;2a IR –99 2(cmo% ; −IR1): (cm3345,−1): 3150, 3345, 2870, 3150, 1447, 2870, 1337, 1447, 1337, 1221,transparent3.21221,. General 1048,1221,transparent 1048, 1082, Procedures viscous1048, 1082, 887. 1082, viscous 887.liquid for 887. Synthesis (17.6liquid g) (17.6 ofwas Oxime g)obtained was Substrates obtained. Yield: 2a. –99Yield:2o% ; IR 99 (cm%; IR): 3345,(cm ):3150, 3345, 2870, 3150, 1447, 2870, 1337, 1447, 1337, 1221,3.2. General 1048, 1082,Procedures 887. for Synthesis of Oxime Substrates 2a–2o 3.21221,. GeneralK 1048,etone1221,3.2. General1082,ProceduresK 1048,(etone0.027 887. 1082,Procedures (mol0.027 for )887. Synthesisand mol forhydroxylamine) Synthesisand of Oximehydroxylamine of SubstratesOxime hydrochloride Substrates 2ahydrochloride–2o 2a (3.0–2o g, (0.0433.0 g , mol0.043) were mol ) dissolvedwere dissolved in in 3.2. GeneralKetone3.2. General Procedures K(etone0.027 Procedures mol(0.027 for) Synthesisand mol forhydroxylamine) Synthesisand of Oximehydroxylamine of SubstratesOxime hydrochloride Substrates 2ahydrochloride–2o 2a (3.0–2o g , (0.0433.0 g , mol0.043) were mol )dissolved were dissolved in in 3.2. GeneralKetoneEtOH3.2. General ProceduresK ((10etone0.027 mL) Procedures mol(0.027 andfor) Synthesisand Hmol2 O forhydroxylamine )(20 Synthesisand ofmL) Oximehydroxylamine. To of SubstratestheOxime hydrochloride mixture Substrates hydrochloride2a –w2aso 2a added(3.0–2o g , NaOH (0.0433.0 g , mol(5.0.0435 )g, were 0.137mol )dissolved molwere). dissolvedThe in reaction in 3.2EtOH. GeneralK etone(10EtOH3.2 .mL) General Procedures K ((10etone0.027 and mL) Procedures Hmol(0.027 2 andOfor) (20 Synthesisand Hmol mL)2 O forhydroxylamine )(20 .Synthesisand To ofmL) Oximethehydroxylamine. Tomixture of SubstratestheOxime hydrochloride mixture w Substratesas hydrochloride2aadded –w2aso 2a addedNaOH(3.0–2o g , NaOH ((0.0435.3.05 g, g , 0.137mol(5.0.0435 )g, weremol 0.137mol). )dissolved The molwere reaction). dissolvedThe in reaction in 3.2EtOH. GeneralK (10etone3.2EtOH .mL) GeneralProcedures K( etone(100.027 and mL) Procedures Hmol(0.0272 Oandfor )(20 Synthesisand Hmol mL)2 O forhydroxylamine )(20 .Synthesisand To ofmL) Oximethehydroxylamine. Tomixture of SubstratesOximethe hydrochloride mixture w Substratesas 2ahydrochlorideadded –w2oas 2a NaOHadded(3.0–2o g , NaOH((0.0435.3.05 g, g , 0.137mol(0.0435.5 )g, weremol 0.137mol). )dissolvedThe weremol reaction). dissolvedThe in reaction in 3.2EtOH. GeneralK (10etone3.2mixtureEtOH ..mL) General ProceduresK ((10etone0.027 and was mL) Procedures H mol(heated0.0272 andOfor )(20 Synthesisand Hmol mL)under2 Ofor hydroxylamine )(20 .Synthesisand To ofmL)reflux Oximethehydroxylamine. Tomixture ofand SubstratesOximethe hydrochloridethe mixture w Substrates reaas hydrochloride2acaddedtion –w2aso was 2a addedNaOH(3.0– 2monitoredo g , NaOH((0.0435.3.05 g, g , 0.137mol(by0.0435.5 thin )g, weremol 0.137mol layer). )dissolvedThe weremol chromatography reaction). dissolvedThe in reaction in mixtureEtOHK (10etonemixtureEtOH was mL)K ((10etoneheated0.027 and was mL) H mol( heated0.027under2 Oand )(20 and Hmol mL)refluxunder2O hydroxylamine )(20 .and To andmL)reflux thehydroxylamine .the Tomixture and reathe hydrochloridethec mixturetion w reaas was hydrochloridecaddedtion w monitoredas was addedNaOH(3.0 monitored g , NaOH(by(5.0.0433.05 thin g, g , 0.137mol(by 0.0435.layer5 thin )g, molwere 0.137molchromatography layer). ) dissolvedThe weremol chromatography reaction). dissolvedThe in reaction in EtOHmixtureK etone(10(EtOHmixtureTLC was mL) K ) (.(etone(10 heated0.027After and was mL) H mol completion( heated0.027under2 Oand) )(20 and Hmol mL)refluxunder2O hydroxylamine ) (20 of.and To the andmL)reflux the hydroxylaminereaction, .the Tomixture and reathe hydrochloridethec mixturetion w reaction reaas was hydrochloridecaddedtion w monitoredas mixture was addedNaOH((3.0 monitored g was ,, NaOH (by(0.0435.3.05 cooledthin g, g , 0.137mol(by 0.0435.layer5 downthin ))g, weremol 0.137molchromatography layer )to. )dissolvedThe roomweremol chromatography reaction). temperature, dissolvedThe in reaction in EtOH(TLCK) .(10etone (EtOHmixtureAfterTLC mL)K ) (completion.etone(10 0.027After and was mL) H (completionmolheated0.0272 andO ) (20 ofand H molthe mL)under2O hydroxylamine) reaction, (20 of.and To the mL)reflux thehydroxylamine reaction,. theTomixture and reactionthe hydrochloridethethe mixture w reaction reaas mixture hydrochloridecaddedtion was mixture was was addedNaOH(3.0 monitoredcooled g was , NaOH ((5.0.0433.05 cooleddown g, g , 0.137mol(by0.0435. 5 todownthin )g, roommolwere 0.137mol layer )to. ) temperature,dissolvedThe roomweremol chromatography reaction). temperature, dissolvedThe in reaction in mixture(EtOHTLCK) .(10etone AftermixtureEtOH( TLCwas mL) K) completion(.(10heatedetone 0.027After and was mL) H mol(completion heated0.027under2 andO ) (20 ofand H mol the mL)refluxunder2O hydroxylamine reaction,) (20 of.and To the andmL)reflux the hydroxylaminereaction, . the the Tomixture and reaction reathe hydrochloridethec themixturetion w reaction reaas mixture was hydrochloridecaddedtion w monitoredas mixture was was addedNaOH(3.0 monitoredcooled g was, NaOH(by(0.0435.3.05 cooleddownthin g, g , 0.137mol(by 5.0.043layer 5to downthin )g, roomweremol 0.137molchromatography layer )to. )temperature,dissolvedThe roommolwere chromatography reaction). temperature, dissolvedThe in reaction in EtOHmixture(TLC) .(10 EtOHmixture(AfterTLC was mL)) completion.(10heated Afterand was mL) H completion heatedunder2 2Oand (20of H the mL)refluxunder2O reaction, (20of.. ToTo the andmL)reflux thethe reaction, . the the Tomixturemixture and reaction reathe thec themixturetion ww reaction reaas mixture was caddedtion w monitoredas mixture was wasaddedNaOH monitoredcooled was NaOH((by5.5 cooleddown thing, 0.137(by 5.layer 5to downthin g, roommol 0.137chromatography layer ))to.. temperature,The roommol chromatography reaction). temperature,The reaction (mixtureEtOHTLC) .(10 EtOHAftermixture(TLC was mL)) completion.(10heated After and was mL) H completion heatedunder 2andO (20of H the mL)refluxunder2O reaction, (20of. To themL)andreflux the reaction, . thethe Tomixture and reactionthe rea thec themixturetion w reaction reaas mixture was caddedtion w monitoredas mixture was wasaddedNaOH monitoredcooled was NaOH(by5.5 cooleddownthin g, 0.137(by 5.layer 5to down thing, roommol 0.137chromatography layer )to. temperature,The roommol chromatography reaction). temperature,The reaction mixture(EtOHTLC) .(10 mixtureAfter(EtOH TLC was mL)) completion .heated(10 After and was mL) H completion heatedunder2 Oand (20of H the mL)refluxunder2O reaction, (20of. To the andmL)reflux the reaction, . the the Tomixture and reaction rea reathe thecthe tionmixturetion w reaction reaas mixture was was caddedtion w monitoredas mixture was wasaddedNaOH monitoredcooled was NaOH(by5.5 cooleddownthin thing, 0.137(by 5.layerlayer 5to downthin g, roommol 0.137chromatographychromatography layer )to. temperature,The roommol chromatography reaction). temperature,The reaction (mixtureTLC). mixture(AfterTLC was) completion. heatedAfter was completion heatedunder of the underreflux reaction, of theandreflux reaction, thethe and reaction rea thecthetion reaction rea mixture wasction monitored mixture was was monitoredcooled was by cooleddownthin by layer to downthin room chromatography layer to temperature, room chromatography temperature, mixture( TLC). (mixtureAfterTLC was) completion.heated After was completion heatedunder of therefluxunder reaction, of the andreflux reaction, thethe and reaction rea thecthetion reaction rea mixture wasction monitored mixture waswas monitoredcooled was by cooleddownthin by layer to downthin room chromatography layer to temperature, room chromatography temperature, ( (TLC)).. After( TLC) completion. After completion of thethe reaction, of the reaction, thethe reactionreaction the reaction mixturemixture mixture waswas cooledcooled was cooleddowndown toto down roomroom to temperature,temperature, room temperature, (TLC). ( AfterTLC) .completion After completion of the reaction, of the reaction, the reaction the reaction mixture mixture was cooled was cooleddown to down room to temperature, room temperature, ( TLC). After (TLC) completion. After completion of the reaction, of the reaction, the reaction the reaction mixture mixture was cooled was cooleddown to down room to temperature, room temperature,

Molecules 2018, 23, 1764 5 of 9

3.2. General Procedures for Synthesis of Oxime Substrates 2a–2o Ketone (0.027 mol) and hydroxylamine hydrochloride (3.0 g, 0.043 mol) were dissolved in EtOH (10 mL) and H2O (20 mL). To the mixture was added NaOH (5.5 g, 0.137 mol). The reaction mixture was heated under reﬂux and the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled down to room temperature, to the reaction mixture were added concentrated hydrochloric acid (15 mL) and water (100 mL). The solid was ﬁltered off and recrystallized from EtOH, affording the products 2a–2o.

◦ 1 2a: White solid, Yield: 91%. m.p.: 87.6–88.7 C; H-NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.9 Hz, 2H), 13 6.93 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.30 (s, 3H); C-NMR (100 MHz, CDCl3) δ 160.5, 155.6, 129.0, 127.4, 113.9, 55.3, 13.3.

◦ 1 2b: White solid, Yield: 93%. m.p.: 88.0–89.0 C; H-NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.2 Hz, 2H), 13 7.22 (d, J = 8.0 Hz, 2H), 2.39(s, 3H), 2.31 (s, 3H); C-NMR (100 MHz, CDCl3) δ 156.0, 139.3, 133.7, 129.3, 126.0, 21.3, 12.3.

◦ 1 2c: White solid, Yield: 90%. m.p.: 51.7–53.0 C; H-NMR (600 MHz, CDCl3) δ 7.68–7.64 (m, 2H), 13 7.44–7.40 (m, 3H), 2.35(s, 3H); C-NMR (150 MHz, CDCl3) δ 156.1, 136.5, 129.3, 128.5, 126.1, 12.3. ◦ 1 2d: White solid, Yield: 70%. m.p.: 74.0–76.0 C; H-NMR (600 MHz, DMSO-d6) δ 11.21 (s, 1H), 7.76–7.59 13 1 (m, 2H), 7.22–7.19 (m, 2H), 2.14 (s, 3H); C-NMR (150 MHz, DMSO-d6) δ 162.4 (d, JCF = 245.5 Hz), 4 3 2 152.1, 133.5 (d, JCF = 3.0 Hz), 127.6 (d, JCF = 8.3 Hz), 115.2 (d, JCF = 21.5 Hz), 11.9. ◦ 1 2e: White solid, Yield: 91%. m.p.: 141.0–142.0 C; H-NMR (600 MHz, DMSO-d6) δ 11.40 (s, 1H), 7.80 (t, J = 1.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.34 (dd, J = 11.1, 4.6 Hz, 1H), 2.14 (s, 13 3H); C-NMR (150 MHz,DMSO-d6) δ 151.9, 139.3, 131.3, 130.6, 128.1, 124.6, 121.8, 11.4. ◦ 1 2f: Yellow solid, Yield: 90%. m.p.: 172.0–173.0 C; H-NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 13 8.28—8.18 (m, 2H), 7.96–7.88 (m, 2H), 2.21 (s, 3H); C-NMR (100 MHz, DMSO-d6) δ 157.1, 152.5, 148.3, 131.9, 131.8, 16.6.

◦ 1 2g: White solid, Yield: 95.6%. m.p.: 129.6–131.0 C; H-NMR (600 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.42–7.27 (m, 5H), 3.04–2.85 (m, 1H), 1.75–1.66 (m, 2H), 1.64–1.50 (m, 6H); 13C-NMR (150 MHz, DMSO-d6) δ 158.6, 135.8, 128.3, 128.2, 128.1, 45.2, 30.3, 24.9. ◦ 1 2h: White solid, Yield: 60%. m.p.: 92.0–93.0 C; H-NMR (600 MHz, DMSO-d6) δ 11.40 (s, 1H), 7.48–7.44 13 (m, 2H), 7.43–7.40 (m, 1H), 7.387.37 (m, 5H), 7.30–7.25 (m, 2H); C-NMR (150 MHz, DMSO-d6) δ 155.2, 136.8, 133.5, 128.88, 128.86, 128.40, 128.36, 128.2, 127.0.

◦ 1 2i: White solid, Yield: 87.5%. m.p.: 134.0–136.0 C; H-NMR (600 MHz, CDCl3) δ 7.48 (d, J = 8.6 Hz, 13 2H), 7.43–7.37 (m, 4H), 7.36–7.31 (m, 2H); C-NMR (150 MHz, CDCl3) δ 156.1, 135.9, 135.5, 134.3, 130.8, 130.4, 129.1, 128.8, 128.7.

◦ 1 2j: White solid, Yield: 88.5%. m.p.: 131.0–132.0 C; H-NMR (600 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.43–7.38 (m, 2H), 7.38–7.32 (m, 2H), 7.28 (dd, J = 12.3, 5.4 Hz, 2H), 7.19 (dd, J = 12.3, 5.4 Hz, 2H); 13 1 1 C-NMR (150 MHz, DMSO-d6) δ 162.6 (d, JCF = 244.6 Hz), 161.9 (d, JCF = 244.6 Hz), 153.4, 133.2, 3 3 2 2 131.3 (d, JCF = 8.2 Hz), 129.5, 129.1 (d, JCF = 8.2 Hz), 115.4 (d, JCF = 22.6 Hz), 115.2 (d, JCF = 22.3 Hz). ◦ 1 2k: White solid, Yield: 87.5%. m.p.: 129.0–130.0 C; H-NMR (400 MHz, DMSO-d6) δ 11.1 (s, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 13 3.76 (s, 3H); C-NMR (100 MHz, DMSO-d6) δ 159.8, 159.1, 154.4, 130.7, 129.7, 128.6, 125.6, 113.7, 113.4, 55.2, 55.1.

◦ 1 2l: Light yellow solid, Yield: 87.9%. m.p.:155.0–160.0 C; (isomer 1): H-NMR (600 MHz, DMSO-d6) δ 11.27(s, 1H), 7.38–7.34 (m, 4H), 7.29–7.24 (m, 3H), 7.00 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H); (isomer 2): 1 H-NMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.46–7.43 (m, 2H), 7.42–7.38 (m, 3H), 7.30 (d, J = 8.8 Hz, Molecules 2018, 23, 1764 6 of 9

13 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H); (isomer 1): C-NMR (100 MHz, DMSO-d6) δ 159.85, 154.85, 13 137.32, 130.74, 129.22, 128.32, 128.29, 128.12, 113.80, 55.20; (isomer 2): C-NMR (100 MHz, DMSO-d6) δ 159.20, 154.80, 133.82, 128.87, 128.76, 128.29, 127.32, 125.37, 113.46, 55.15.

◦ 1 2m: Yield: 94.0%. m.p.: 84–86 C; H-NMR (600 MHz, DMSO-d6) δ 8.81 (brs, 1H), 7.30–7.18 (m, 5H), 13 2.83 (t, J = 8.2 Hz, 2H), 2.51 (t, J = 8.2 Hz, 2H), 1.91 (s, 3H); C-NMR (150 MHz, DMSO-d6) δ 157.9, 141.0, 128.4, 128.3, 126.1, 37.7, 32.6,13.8.

◦ 1 2n: Yield: 90.0%. m.p.: 79–81 C; H-NMR (600 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.73–7.16 (m, 5H); 13 2 1 C-NMR (150 MHz, DMSO-d6) δ145.2 (q, JCF = 30.0), 130.6, 129.0, 128.9, 127.2, 121.6 (q, JCF3 = 271.5). ◦ 1 2o: Yield: 85.5%. m.p.: 89–91 C; H-NMR (600 MHz, DMSO-d6) δ 2.48 (dd, J = 6.8, 5.3, 2H), 2.48 (m, 13 2H), 1.76–1.45 (m, 6H); C-NMR (150 MHz, DMSO-d6) δ 157.1, 31.6, 26.6, 25.4, 25.2, 23.8.

3.3. General Procedures for the Synthesis of Amides 3a–3o

To a solution of the oxime substrates 2a–2o (9.50 mmol) in (HMIm)HSO4 (2.05 g, 11.4 mmol), the ◦ co-catalyst P2O5 (0.15 g, 1.0 mmol) was added. Then the solution was heated to 90 C and the reaction was monitored by TLC. After completion of the reaction, the mixture was extracted with ethyl acetate (50 mL) twice, and the combined organic phase was washed with the aqueous solution of sodium bicarbonate and brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford a residue, which was puriﬁed by column (ethyl acetate: petroleum ether = 1:4) to afford the products 3a–3o.

◦ 1 3a [22]: White solid, Yield: 91%. m.p.: 127.0–128.0 C; H-NMR (600 MHz, DMSO-d6) δ 9.80 (brs, 1H), 7.51–7.46 (m, 2H), 7.20 (d, J = 7.9 Hz, 1H), 6.89–6.84 (m, 2H), 3.71 (s, 3H), 2.01 (s, 3H); 13C-NMR (150 MHz, DMSO-d6) δ 168.2, 155.5, 133.0, 121.0, 114.2, 55.6, 24.3; HRMS(+): calcd. for C9H11NO2 + + [M + H] 166.0863, found 166.0859; calcd. for C9H11NO2Na [M + Na] 188.0682, found 188.0682. ◦ 1 3b [22]: White solid, Yield: 90%. m.p.: 149.0–150.0 C; H-NMR (600 MHz, DMSO-d6) δ 9.84 (s, 1H), 13 7.46 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 2.24 (s, 3H), 2.02 (s, 3H); C-NMR (150 MHz, DMSO-d6) + δ 173.2, 142.1, 137.0, 134.1, 124.2, 29.2, 25.6; HRMS(+): calcd. for C9H11NO [M + H] 150.0913, found + 150.0912; calcd. for C9H11NONa [M + Na] 172.0733, found 172.0741. ◦ 1 3c [23]: White solid, Yield: 90%. m.p.: 108.5–110.0 C; H-NMR (600 MHz, DMSO-d6) δ 9.93 (brs, 1H), 7.58 (dd, J = 1.0, 8.5 Hz, 2H), 7.29 (dd, J = 7.5, 8.4 Hz, 2H), 7.08–6.91 (m, 1H), 2.05 (s, 3H); 13C-NMR + (150 MHz, DMSO-d6) δ 168.7, 139.8, 129.1, 123.4, 119.4, 24.5; HRMS(+): calcd. for C8H9NO [M + H] + 136.0757, found 136.0755; calcd. for C8H9NONa [M + Na] 158.0576, found 158.0572. ◦ 1 3d [24]: Light yellow solid, Yield: 89%. m.p.: 153–155 C; H-NMR (600 MHz, DMSO-d6) δ 9.99 (brs, 13 1H), 7.87–7.47 (m, 2H), 7.12 (t, J = 8.99 Hz, 2H), 2.04 (s, 3H); C-NMR (150 MHz, DMSO-d6) δ 168.6, 1 4 3 2 158.3.8 (d, JCF = 237.0 Hz), 136.2 (d, JCF = 1.5 Hz), 121.1 (d, JCF = 7.5 Hz), 115.2 (d, JCF = 22.5 Hz), + 24.3; HRMS(+): calcd. for C8H8FNO [M + H] 154.0663, found 154.0665; calcd. for C8H8FNONa [M + Na]+ 176.0482, found 176.0481.

◦ 1 3e [25]: White solid, Yield: 88%. m.p.: 87.0–89.0 C; H-NMR (600 MHz, DMSO-d6) δ 10.11 (brs, 1H), 7.95 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.27–7.23 (m, 1H), 7.22–7.19 (m, 1H), 2.05 (s, 3H); 13C-NMR (150 MHz, CDCl3) δ 169.1, 141.3, 131.1, 126.0, 122.0, 121.7, 118.1, 24.5; HRMS(+): calcd. for C8H8BrNO + + [M + H] 213.9862, found 213.9860; calcd. for C8H8BrNONa [M + Na] 235.9681, found 235.9681. ◦ 1 3f [25]: Yellow solid, Yield: 86%. m.p.: 214.0–215.0 C; H-NMR (600 MHz, DMSO-d6) δ 10.57 (s, 1H), 13 8.21 (d, J = 9.2 Hz, 2H), 7.82 (d, J = 9.4 Hz, 2H), 2.12 (s, 3H); C-NMR (150 MHz, DMSO-d6) δ 169.8, + 145.9, 142.3, 125.4, 119.0, 24.7; HRMS(+): calcd. for C8H8N2O3 [M + H] 181.0608, found181.0610; + Calcd. for C8H8N2O3Na [M + Na] 203.0433, found 203.0437. ◦ 1 3g: White solid, Yield: 91%. m.p.: 160.0–161.0 C; H-NMR (600 MHz, DMSO-d6) δ 8.29 (d, J = 7.0 Hz, 1H), 7.88–7.80 (m, 2H), 7.54–7.49 (m, 1H), 7.48–7.42 (m, 2H), 4.46–3.96 (m, 1H), 1.96–1.81 (m, 2H), Molecules 2018, 23, 1764 7 of 9

13 1.74–1.64 (m, 2H), 1.60–1.43 (m, 4H); C-NMR (150 MHz, DMSO-d6) δ 166.4, 135.3, 131.4, 128.6, + 127.7, 51.4, 32.6, 24.1; HRMS(+): calcd. for C12H15NO [M + H] 190.1226, found 190.1228; calcd. for + C12H15NO Na [M + Na] 212.1046, found 212.1044. ◦ 1 3h [23]: White solid, Yield: 89%. m.p.: 162.6–163.0 C; H-NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.99–7.92 (m, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.63–7.58 (m, 1H), 7.57–7.51 (m, 2H), 7.36 (t, J = 7.9 Hz, 2H), 13 7.15–7.07 (m, 1H); C-NMR (100 MHz, DMSO-d6) δ 166.0, 139.6, 135.5, 132.0, 129.1, 128.9, 128.1, 124.1, + 120.8; HRMS(+): calcd. for C13H11NO [M + H] 198.0913, found 198.0913; calcd. for C13H11NONa [M + Na]+ 220.0733, found 220.0733.

◦ 1 3i [25]: White solid, Yield: 85%. m.p.: 210.0–212.0 C; H-NMR (600 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.02–7.96 (m, 2H), 7.86–7.79 (m, 2H), 7.66–7.59 (m, 2H), 7.45–7.39 (m, 2H); 13C-NMR (150 MHz, DMSO-d6) δ 165.0, 138.4, 137.0, 133.8, 130.1, 129.0, 127.9, 122.4; HRMS(+): calcd. for C13H9Cl2NO + + [M + H] 266.0134, found 266.0129; calcd. for C13H9Cl2NONa [M + Na] 287.9953, found 287.9951. ◦ 1 3j [26]: Light yellow solid, Yield: 84%. m.p.: 183–185.0 C; H-NMR (600 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.04–8.02 (m, 2H), 7.82–7.72 (m, 2H), 7.37 (t, J = 8.8 Hz, 2H), 7.19 (t, J = 8.8 Hz, 2H); 13C-NMR 1 1 (150 MHz, DMSO-d6) δ 164.3, 164.1 (d, JCF = 249.5 Hz), 158.3 (d, JCF = 240.3 Hz), 135.4, 131.2, 130.4 (d, 3 3 2 2 JCF = 9.0 Hz), 122.2 (d, JCF = 7.8 Hz), 115.3 (d, JCF = 22.4 Hz), 115.2 (d, JCF = 22.8 Hz); HRMS(+): + + calcd. for C13H9F2NO [M + H] 234.0725, found 234.0727; calcd. for C13H9F2NONa [M + Na] 256.0544, found 256.0546.

◦ 1 3k [26]: Light yellow solid, Yield: 90%. m.p.: 204.0–205.0 C; H-NMR (600 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 13 3.87 (s, 3H), 3.81 (s, 3H); C-NMR (150 MHz, DMSO-d6) δ 164.5, 161.7, 155.4, 132.4, 129.4, 127.1, 121.9, + 113.7, 113.5, 55.4, 55.2; HRMS(+): calcd. for C15H15NO3 [M + H] 258.1125, found 258.1127; calcd. for + C15H15NO3Na [M + Na] 280.0944, found 280.0946. 3l [25] (N-(4-Methoxyphenyl)benzamide): Light yellow solid, Yield: 52%. M.p.: 156.5–159.5 ◦C; 1H-NMR (600 MHz, DMSO-d6) δ 10.07 (s, 1H), 7.95 (d, J = 9.2 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 13 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H), 3.84 (s, 3H); C-NMR (100 MHz, DMSO-d6) δ 164.94, 161.91, 139.36, 131.40, 129.61, 128.58, 123.45, 120.37, 113.62, 55.45; HRMS(+): calcd. for C14H13NO2 + + [M + H] 228.1019, found 228.1020; calcd. for C14H13NO2Na [M + Na] 250.0838, found 250.0838; 1 (4-Methoxy-N-phenylbenzamide): Light yellow solid, Yield: 28% H-NMR (600 MHz, DMSO-d6) δ 10.12 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 8.8 Hz, 2H), 13 6.93 (d, J = 9.0 Hz, 2H), 3.74 (s, 3H); C-NMR (100 MHz, DMSO-d6) δ 165.14, 155.58, 135.07, 132.24, + 128.37, 127.56, 127.00, 122.02, 113.76, 55.20. HRMS(+): calcd. for C14H13NO2 [M + H] 228.1019, found + 228.1020; calcd. for C14H13NO2Na [M + Na] 250.0838, found 250.0838. ◦ 1 3m [27]: Yield: 89%. m.p.: 113–114 C; H-NMR (600 MHz, DMSO-d6) δ 7.34–7.30 (m, 2H), 7.26–7.21 13 (m, 3H), 3.85–3.77 (m, 2H), 2.84–2.74 (m, 2H), 2.29 (s, 3H); C-NMR (150 MHz, DMSO-d6) δ 173.4, + 139.0, 129.3, 129.0, 126.9, 46.4, 34.8, 26.6. HRMS(+): calcd. for C10H13NO [M + H] 164.1070, found + 164.1071; calcd. for C10H13NONa [M + Na] 186.0889, found 186.0884. ◦ 1 3n [28]: Yield: 82%. m.p.: 84–87 C; H-NMR (600 MHz, DMSO-d6) δ 11.26 (brs, 1H), 7.70 (dd, 13 J = 0.83, 8.53 Hz, 2H), 7.43–7.38 (m, 2H), 7.24–7.20 (m, 1H), C-NMR (150 MHz, DMSO-d6) δ 155.0 (q, 2 1 + JCF = 36.0), 136.8, 129.4, 126.0, 121.5, 116.3 (q, JCF3 = 286.5). HRMS(+): calcd. for C8H6F3NO [M + H] + 190.0474, found 190.0472; calcd. for C8H6F3NONa [M + Na] 212.0294, found 212.0296. ◦ 1 3o [29]: Yield: 85%. m.p.: 68–71 C; H-NMR (600 MHz, DMSO-d6) δ 7.41 (brs, 1H), 3.05 (dd, J = 5.87, 10.09 Hz, 2H), 2.38–2.13 (m, 2H), 1.66 (q, J = 5.87 Hz, 2H), 1.56–1.46 (m, 4H); 13C-NMR (150 MHz, + DMSO-d6) δ 177.4, 41.9, 36.9, 30.5, 30.3, 23.4, HRMS(+): calcd. for C6H11NO [M + H] 114.0913, found + 114.0910; calcd. for C6H11NONa [M + Na] 136.0733, found136.0734. Molecules 2018, 23, 1764 8 of 9

4. Conclusions In conclusion, we successfully demonstrated an efﬁcient approach for the synthesis of amide derivatives via Beckmann rearrangement of ketoxime by using Brønsted acidic ionic liquid N-methyl-imidazolium hydrosulfate as an environmental friendly catalyst and solvent. The best reaction condition is: reaction temperature 90 ◦C, reaction time 6 h, solvent N-methyl-imidazolium hydrosulfate 10 grams, co-catalyst P2O5 8 mol %. Ionic liquid can be reused three times. The procedure can be extended to various symmetrical and unsymmetrical aryl-substituted and alkyl-substituted ketoxime substrates. The aryl group migration products are sole products for unsymmetrical aryl alkyl substituted amides.

Author Contributions: H.H., X.Y., and S.Z. conceived and designed the experiments; X.C. and Z.X. performed the experiments; H.H. analyzed the data; and H.H. wrote the paper. Funding: The project was supported by the Zhejiang province ecology first-class discipline and Zhejiang Provincial Department of Education general research projects (Y201636410). Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors.

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