catalysts

Review Trifluoromethanesulfonic as Acylation Catalyst: Special Feature for C- and/or O-Acylation Reactions

Zetryana Puteri Tachrim, Lei Wang, Yuta Murai, Takuma Yoshida, Natsumi Kurokawa, Fumina Ohashi, Yasuyuki Hashidoko and Makoto Hashimoto * Graduate School of Agriculture, Hokkaido University, Kita 9, Nishi 9, Kita-ku, Sapporo 060-8589, Japan; [email protected] (Z.P.T.); [email protected] (L.W.); [email protected] (Y.M.); [email protected] (T.Y.); [email protected] (N.K.); [email protected] (F.O.); [email protected] (Y.H.) * Correspondence: [email protected]; Tel.: +81-11-7063849

Academic Editor: Andreas Pfaltz Received: 6 December 2016; Accepted: 18 January 2017; Published: 28 January 2017

Abstract: Trifluoromethanesulfonic acid (TfOH) is one of the superior catalysts for acylation. The catalytic activity of TfOH in C- and/or O-acylation has broadened the use of various substrates under mild and neat or forced conditions. In this review, the salient catalytic features of TfOH are summarized, and the unique controllability of its catalytic activity in the tendency of C-acylation and/or O-acylation is discussed.

Keywords: trifluoromethanesulfonic acid; triflic acid; Friedel–Crafts acylation; Fries rearrangement; condensation; O-acylation; C-acylation

1. Introduction The widely used C-acylation, Friedel–Crafts acylation [1,2] and Fries rearrangement [2] of aromatic compounds are efficient methods that result in satisfactory product yields. The fundamental feature of these reactions is the use of a homogeneous or heterogeneous Lewis or Brønsted acid that catalyzes the reaction of the acylating agent with the corresponding substrates. Conventionally, the Friedel–Crafts acylation of aromatic derivatives with acyl chloride or anhydrides requires at least 1 equiv. of AlCl3 [2,3]. Up to now, an improvement on this reaction is continuing at the time of writing this review. The Fries rearrangement, a typical rearrangement of a phenyl ester to o- or p-hydroxyphenyl , has been carried out with a number of that differ in their phenolic and [4]. When and phenol derivatives react with acylating reagents in the presence of appropriate catalyst, they can form aryl via C-acylation of the aromatic ring (Figure1a), as well as form phenyl esters via O-acylation (Figure1b). In the reaction, phenyl ester derivatives can also undergo Fries rearrangement (Figure1c). Direct phenol C-acylation and Fries rearrangement usually compete with one another, and are difficult to distinguish from their reaction mechanisms [5]. Many kinds of acid-promoted acylations have been developed in order to improve their reactivity and selectivity, and some of these activators have been applied to industrial processes [6,7]. A comparative study of the catalytic activities of various in acylation has demonstrated that trifluoromethanesulfonic acid (triflic acid, TfOH) is far superior to all other Lewis and Brønsted acids tested [8]. TfOH is a perfluoroalkanesulfonic acid [9] that is extremely thermostable and highly resistant to decomposition by aqueous bases [10]. The synthesis of this acid was first reported in 1954 [8,10]. Since then, the novel properties of TfOH have been developed for modern chemical applications [11]; thus, comprehensive discussions of its utilization in various reactions and applications have been published [5,8,9,11–13]. From the point of view of TfOH as a catalyst for C- or O-acylation, consideration of comprehensive substrates with the reaction condition are needed to achieve optimum conditions.

Catalysts 2017, 7, 40; doi:10.3390/catal7020040 www.mdpi.com/journal/catalysts Catalysts 2017, 7, x 2 of 27

Catalysts 2017, 7, 40 2 of 28 O-acylation, consideration of comprehensive substrates with the reaction condition are needed to achieve optimum conditions. Recently, the general trends for various substrates C- or O-acylation Recently,catalyzed the by generalTfOH are trends carried for various out, not substrates only byC the- or simpleO-acylation arenes catalyzed with ordinary by TfOH acyl are component carried out, notutilization, only by but the also simple with arenes extraordinary with ordinary substrates acyl component to achieve efficient utilization, reactions. but also Therefore, with extraordinary the use of substratesTfOH as a catalyst to achieve has efficientbroadened. reactions. In this review, Therefore, the catalytic the use ofactivity TfOH of as TfOH a catalyst in C- or has O-acylation broadened. is Indiscussed. this review, The therecent catalytic progress activity of TfOH of TfOH as a inpromisingC- or O-acylation catalyst for is discussed.both Friedel The–Crafts recent acylation progress and of TfOHthe Fries as arearrangement, promising catalyst where for esterificat both Friedel–Craftsion (O-acylation acylation) plays and an theimportant Fries rearrangement, role to connect where these esterificationtwo reactions( O(from-acylation) the point plays of view an important of phenol role and to phenol connect derivatives), these two reactions is described. (from Furthermore, the point of viewthe controllable of phenoland TfOH phenol catalytic derivatives), system for is described.C-acylation Furthermore, and/or O-acylation the controllable of various TfOH substrates catalytic is systemalso discussed for C-acylation in this review. and/or O-acylation of various substrates is also discussed in this review.

(a) Friedel–Crafts acylation (C-acylation)

Catalyst

(b) Esterification (c) Fries rearrangement (O-acylation) (C-acylation)

Types of acyl donors:

FigureFigure 1. 1.Schematic Schematic of of the the relationship relationship between betweenC- and C- Oand-acylations O-acylation of of phenol derivatives derivatives by catalyst. by Whencatalyst. reacted When with reacted acylating with acylating reagents inreagents the presence in the ofpresence catalyst, of phenolcatalyst, derivatives phenol derivatives can undergo can (a)undergo Friedel–Crafts (a) Friedel acylation–Crafts (acC-acylation)ylation (C- toacylation) form aryl to ketones form aryl or (b) ketonesO-acylation or (b) toO- formacylation phenyl to ester, form whichphenyl the ester, resulted which phenyl the resulted ester can phenyl also go ester through can also (c) Fries go through rearrangement (c) Fries to rearrangement form aryl ketones. to form aryl ketones. 2. General Features of the TfOH Catalytic System for C-Acylation 2. General Features of the TfOH Catalytic System for C-Acylation Carbon–carbon bond formation in Friedel–Crafts acylation (Figure1a) is one of the most important Carbon–carbon bond formation in Friedel–Crafts acylation (Figure 1a) is one of the most routes for preparing various ketones; especially in the synthesis of aryl ketones. In the case of the important routes for preparing various ketones; especially in the synthesis of aryl ketones. In the acylation of phenol, it has been extensively studied for o- or p-hydroxyphenyl ketones synthesis case of the acylation of phenol, it has been extensively studied for o- or p-hydroxyphenyl ketones and since it employs more readily available and less expensive raw materials, direct Friedel–Crafts synthesis and since it employs more readily available and less expensive raw materials, direct C-acylation might offer a convenient approach. Generally, the Friedel–Crafts acylation is carried Friedel–Crafts C-acylation might offer a convenient approach. Generally, the Friedel–Crafts out using acylating reagents such as acyl chlorides, carboxylic anhydrides or carboxylic acids in acylation is carried out using acylating reagents such as acyl chlorides, carboxylic anhydrides or the presence of a Lewis or Brønsted acid. TfOH possesses a large negative H0 value (−14.1) [9,14], carboxylic acids in the presence of a Lewis or Brønsted acid. TfOH possesses a large negative H0 which is stronger than other Lewis acids. Therefore, it is categorized as a and expected to be value (−14.1) [9,14], which is stronger than other Lewis acids. Therefore, it is categorized as a an effective catalyst for Friedel–Crafts C-acylation. A comparative study using , TfOH, superacid and expected to be an effective catalyst for Friedel–Crafts C-acylation. A comparative and three other perfluorinated sulfonic acids synthesized by Harmer et al. [15] in the acylation of study using sulfuric acid, TfOH, and three other perfluorinated sulfonic acids synthesized by anisole 1 (Figure2a) proved this expectation. Moreover, the Fries rearrangement of phenyl acetate Harmer et al. [15] in the acylation of anisole 1 (Figure 2a) proved this expectation. Moreover, the 2 (Figure2b) also shows high efficiency of TfOH utilization as a catalyst as it is 100 times stronger Fries rearrangement of phenyl acetate 2 (Figure 2b) also shows high efficiency of TfOH utilization as than sulfuric acid [13,16] and is a commercially available reagent which can be readily used for a catalyst as it is 100 times stronger than sulfuric acid [13,16] and is a commercially available reagent these reactions. which can be readily used for these reactions.

Catalysts 2017, 7, 40 3 of 28 Catalysts 2017, 7, x 3 of 27

Catalysts 2017, 7, x 3 of 27

HCF2CF2SO3H HCF2CF2SO3H

CF3HCFCF2SO3H CF3HCFCF2SO3H HCF2CF2SO3H HCF2CF2SO3H

HClCFCF2SO3H HClCFCF2SO3H CF3HCFCF2SO3H CF3HCFCF2SO3H

TfOH TfOH HClCFCF2SO3H HClCFCF2SO3H

H2SO4 H2SO4 TfOH TfOH

0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 H SO H SO 2 4Reactant Conversion (%) 1 → 3 2 4 Reactant Conversion (%) 2 → 4

0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 FigureFigure 2. Comparison 2. Comparison of of sulfuric sulfuric acid and and various various perfluorinated perfluorinated sulfonic sulfonic acids used acids as used catalysts as catalysts for Reactant Conversion (%) 1 → 3 Reactant Conversion (%) 2 → 4 for (a()a) the the acylation acylation ofof anisole 11; ;and and (b (b) )the the Fries Fries rearrangement rearrangement of phenyl of phenyl aceta acetatete 2. Data2. Datafrom from[15]. [15]. DashedFigureDashed lines 2. lines Comparison indicate indicate the theof reactant sulfuric reactant conversionacid conversion and various (%)(%) of perfluorinated the reaction reaction utilized sulfonic utilized by acids byTfOH. TfOH. used as catalysts for (a) the acylation of anisole 1; and (b) the Fries rearrangement of phenyl acetate 2. Data from [15]. A study in 1972 using a low proportion of TfOH (~1 wt %) for the acylation of p-xylene 5 with Dashed lines indicate the reactant conversion (%) of the reaction utilized by TfOH. Abenzoyl study chloride in 1972 6 using [3] found a low that proportion this acid produced of TfOH a higher (~1 wt yield %) for of product the acylation 7 in comparison of p-xylene with5 with 6 [3] found that this acid produced a higher yield of product 7 in comparison with otherA tested study catalysts,in 1972 using including a low the proportion conventional of TfOH catalyst (~1 wt AlCl %)3 for(Figure the acylation 3). Since ofthen, p-xylen the ecatalytic 5 with otherbenzoylactivity tested chloride ofcatalysts, TfOH 6 has[3] including found been extensivelythat the this conventional acid studied. produced In catalyst a recent higher AlCl decades, yield3 (Figureof product research3). Since7 into in comparison TfO then,H not the with onlycatalytic activityotherfocused of tested TfOH on determining catalysts, has been including extensively its optimal the proportion studied.conventional In for recent catalysthigh decades,efficiency AlCl3 (Figure researchacylations, 3). intoSince butTfOH alsothen, in notthe broadening catalytic only focused on determiningactivitythe utilization of TfOH its ofoptimal has vast been substrates,proportion extensively which for studied. high contribute In efficiency recent to decades, acylations, new synthetic research but intopathways, also TfO inH broadening not and only the the utilizationfocusedcomprehensive of on vast determining substrates, study of its suitable optimal which reaction contributeproportion conditions for to newhigh to efficiency synthetic optimize acylations, pathways, its application but and also exploitation. the in broadening comprehensive For studytheexample, of suitable utilization sterically reaction of vast hindered conditions substrates, aromatic to whichoptimize ketones contribute its application and to carboxylic new exploitation. synthetic acids can pathways, For undergo example, and either sterically the protodeacylation or decarboxylation, which are typically accompanied by side reactions in the hinderedcomprehensive aromatic ketones study of and suitable carboxylic reaction acids conditions can undergo to optimize either protodeacylation its application exploitation. or decarboxylation, For presence of TfOH (at 110 °C) [17]. As the direct mechanism of C-acylation is identical to that of other whichexample, are typically sterically accompanied hindered by aromatic side reactions ketones in the and presence carboxylic of TfOH acids (at can110 ◦ undergoC) [17]. As either the direct protodeacylationreactions, there is ora need decarboxylation, to examine the which selection are typically of aromatic accompanied compounds by used side in reactions these reactions in the mechanism of C-acylation is identical to that of other reactions, there is a need to examine the selection presence[18]. A summary of TfOH of(at th110e general°C) [17] .characteristics As the direct mechanismof the TfOH of catalytic C-acylation system is identical for C-acylation to that of in other this of aromatic compounds used in these reactions [18]. A summary of the general characteristics of the reactions,review is expectedthere is a to need discover to examine excellent the findings selection for of TfOH aromatic catalytic compounds activity inused the future.in these reactions TfOH[18] catalytic. A summary system of for theC general-acylation characteristics in this review of the is expectedTfOH catalytic to discover system excellent for C-acylation findings in forthis TfOH catalyticreview activity is expected in the to future. discover excellent findings for TfOH catalytic activity in the future.

100 6 h 90 80 100 70 6 h 10 h 90

(%Yield) 60

7 7 80 50 15 h 70 10 h 40

(%Yield) 60

7 7 30 50 15 h

Compound 20 40 10 30 0

Compound 20 TfOH FSO3H TsOH H2SO4 HClO4 TFAa HPOF2b AlCl3c SnCl4c TfOH FSO3H TsOH H2SO4 HClO4 TFA HPOF2 AlCl3 SnCl4 10 Figure 3. C-Acylation0 of p-xylene 5 with benzoyl chloride 6 at 138 °C using various catalysts. Data TfOH FSO3H TsOH H2SO4 HClO4 TFAa HPOF2b AlCl3c SnCl4c from [3]. The reaction timesTfOH areFSO indicated3H TsOH aboveH2SO the4 HClO bars.4 a 2.6TFA equivHPOF.; 2b 3.1AlCl equiv3 SnCl.; c4 2 equiv .

FigureFigure 3. C3.-Acylation C-Acylation ofof p--xylenexylene 5 5withwith benzoyl benzoyl chloride chloride 6 at 1386 at°C 138using◦C variou usings catalysts various. Data catalysts. from [3]. The reaction times are indicated above the bars. a 2.6 equiv.; b 3.1 equiv.; c 2 equiv. Data from [3]. The reaction times are indicated above the bars. a 2.6 equiv.; b 3.1 equiv.; c 2 equiv.

Catalysts 2017, 7, 40 4 of 28

2.1. TfOHCatalysts Catalytic 2017, 7, 40 Activity for Various Acyl Donors and Acyl Acceptors 4 of 27 A typical definition of the intermolecular C-acylation is the addition of acyl groups to aromatic 2.1.Catalysts TfOH 2017 Catalytic, 7, 40 Activity for Various Acyl Donors and Acyl Acceptors 4 of 27 derivatives, which is conducted by an activator. Conventional acylation includes the use of simple A typical definition of the intermolecular C-acylation is the addition of acyl groups to aromatic arenes2.1. (both TfOH electron-richCatalytic Activity and for electron-poor)Various Acyl Donors such and as Acyl , Acceptors toluene, and xylene, which act as derivatives, which is conducted by an activator. Conventional acylation includes the use of simple acyl acceptors, as well as typical acyl donors such as acyl chloride, carboxylic anhydride, esters, arenesA (bothtypical electron-rich definition of and the electron-poor) intermolecular such C-acylation as benzene, is the toluene, addition and of xylene, acyl groups which to act aromatic as acyl and carboxylicacceptors,derivatives, as acid.which well The asis conductedtypical TfOH acyl catalytic by donors an activator. system such as hasConventional acyl made chloride, the acylation explorationcarboxylic includes anhydride, of differentthe use esters, of acyl simple and donors morecarboxylicarenes feasible (both for acid. electron-richC-acylation, The TfOH and catalytic thus electron-poor) increasing system has thesuch made number as benzene, the exploration of potential toluene, of and donors different xylene, for acyl which this donors reaction. act as more acyl Direct C-acylationfeasibleacceptors, offor as aromaticC -acylation,well as compoundstypical thus increasingacyl donors using the such benzoic number as acyl acidof potentialchloride, esters isdonorscarboxylic extending for thisanhydride, this reaction. exploration esters, Direct and C series.- At 85acylationcarboxylic◦C, excess of acid. aromatic TfOH The (5 TfOH compounds equiv.) catalytic has using been system benzoic used hasfor acidmade direct esters the Cexploration is-acylation extending of ofthis different methyl exploration acyl benzoate donors series.8 Atmore(2 85 equiv.) and aromatic°feasibleC, excess for derivatives TfOH C-acylation, (5 equiv.)9– 16thus ,has thus increasing been forming used the for the number direct benzophenone C of-acylation potential derivativesof donors methyl for benzoate 17this–24 reaction.[ 819 (2]. equiv.) In Direct this and reaction, C- no furtheraromaticacylation electrophilic derivativesof aromatic 9 reactioncompounds–16, thus offorming using benzophenones benzoicthe benzophenone acid esters with derivatives theis extending aromatics 17 this–24 was exploration [19]. observed In this series.reaction, (Scheme At no85 1a). ° Evenfurther highlyC, excess electrophilic deactivated TfOH (5 equiv.) reaction nitrobenzene has of beenbenzophenones used15 and for direct benzotrifluoride with C the-acylation aromatics of16 methylwasacted observed benzoate as acyl (Scheme acceptors, 8 (2 equiv.) 1a). Even affording and highlyaromatic deactivated derivatives nitrobenzene 9–16, thus forming 15 and the benzotrifluoride benzophenone 16derivatives acted as 17acyl–24 acceptors, [19]. In this affording reaction, the no the corresponding three-substituted benzophenones 23 and 24 in high yield. Furthermore, the TfOH correspondingfurther electrophilic three-subs reactiontituted of benzophenones benzophenones with 23 andthe aromatics24 in high was yield. observed Furthermore, (Scheme the 1a). TfOH Even system can also catalyze the acylation of benzene 9 with diesters such as 1,4-dimethyl terephthalate systemhighly deactivatedcan also catalyze nitrobenzene the acylation 15 and of benzenebenzotrifluoride 9 with diesters 16 acted such as asacyl 1,4-dimethyl acceptors, affordingterephthalate the 25, which25corresponding, which results results inthree-subs in a a mixture mixturetituted containingcontaining benzophenones the the major major 23 products and products 24 in4-benzoyl high 4-benzoyl yield. methyl Furthermore, methyl benzoate benzoate 26 the and TfOH 1,4-26 and 1,4-dibenzoyldibenzoylsystem can benzenebenzene also catalyze 2727,, under under the acylationsimilar similar reaction of reaction benzene conditions conditions 9 with (i.e.,diesters (i.e.,reaction such reaction for as 81,4-dimethyl h) for (Scheme 8 h) (Scheme 1b).terephthalate 1b). 25, which results in a mixture containing the major products 4-benzoyl methyl benzoate 26 and 1,4- dibenzoyl benzene 27, under similar reaction conditions (i.e., reaction for 8 h) (Scheme 1b).

Scheme 1. C-Acylation of (a) methyl benzoate 8 to aromatic derivatives of 9–16; and (b) 1,4-dimethyl Scheme 1. C-Acylation of (a) methyl benzoate 8 to aromatic derivatives of 9–16; and (b) 1,4-dimethyl terephthalate 25 to benzene 9. Reagents and conditions: TfOH (5 equiv.), 85 °C, 0.5–8 h. terephthalate 25 to benzene 9. Reagents and conditions: TfOH (5 equiv.), 85 ◦C, 0.5–8 h. Scheme 1. C-Acylation of (a) methyl benzoate 8 to aromatic derivatives of 9–16; and (b) 1,4-dimethyl Efficientterephthalate 25 to benzene of reactions 9. Reagents involving and conditions:esters as acyl TfOH donors (5 equiv.), by using 85 °C, TfOH 0.5–8 h.have led to the use Efficientof TfOH catalysisfor the synthesis of reactions of β-amino involving aryl estersketone as derivatives acyl donors from by the using acyl TfOH donors have β-lactams led to the (28 use) of TfOH[20,21]. forEfficient the The synthesis TfOH-catalyzed catalysis of βof-amino reactions reaction aryl involving ketonebetween esters derivatives β-lactams as acyl 28 fromdonors and the arenesby acylusing 29 donors TfOHproduces haveβ-lactams the led desired to the (28 )[use β20- ,21]. The TfOH-catalyzedaminoof TfOH aryl for ketone the synthesis reaction derivatives betweenof β30-amino in moderateβ -lactamsaryl ketone to high28 derivativesand yields arenes (Scheme from29 produces 2).the Meanwhile, acyl donors the desired no β -lactamsreactionβ-amino was(28) aryl ketoneobserved[20,21]. derivatives The at roomTfOH-catalyzed30 temperaturein moderate reaction using to high otherbetween yields common β-lactams (Scheme catalysts 282). and Meanwhile,for arenesthe Friedel–Crafts 29 produces no reaction acylation, the wasdesired observedsuch β- asamino AlCl aryl3, methanesulfonic ketone derivatives acid 30(MSA), in moderate trifluoroacetic to high acid yields (TFA), (Scheme BF3·OEt 2). 2Meanwhile,, or SnCl2. Reflux no reaction conditions was at room temperature using other common catalysts for the Friedel–Crafts acylation, such as AlCl3, didobserved not produce at room the temperature desired β-amino using arylother ketone common compounds; catalysts thereffor theore, Friedel–Crafts utilization of acylation, TfOH for such this (MSA), trifluoroacetic acid (TFA), BF3·OEt2, or SnCl2. Reflux conditions did not reactionas AlCl3, atmethanesulfonic room temperature acid is (MSA), preferred. trifluoroacetic acid (TFA), BF3·OEt2, or SnCl2. Reflux conditions β producedid thenot desiredproduce the-amino desired aryl β-amino ketone aryl compounds; ketone compounds; therefore, theref utilizationore, utilization of TfOH of forTfOH this for reaction this at roomreaction temperature at room is temperature preferred. is preferred.

Scheme 2. C-Acylation of aromatic derivatives with β-lactams 28 as acyl donors. Reagents and

conditions: TfOH (1–2 equiv.), ClCH2CH2Cl, 0 °C to r.t., 15–30 min. Scheme 2. C-Acylation of aromatic derivatives with β-lactams 28 as acyl donors. Reagents and Scheme 2. C-Acylation of aromatic derivatives with β-lactams 28 as acyl donors. Reagents and ° conditions: TfOH (1–2 equiv.), ClCH2CH2Cl, 0 ◦C to r.t., 15–30 min. conditions: TfOH (1–2 equiv.), ClCH2CH2Cl, 0 C to r.t., 15–30 min.

CatalystsCatalysts 20172017,, 77,, 40x 55 ofof 2827

A recent study has reported the use of TfOH for the C-acylation of arenes with twisted 31–33A (Figure recent study4a) [22] has. The reported acylation theuse of benzene of TfOH 9 for with the twoC-acylation different of types arenes of with , twisted i.e., benzoyl amides 312,5–-33pyrrolidinedione(Figure4a) [ 22 ].31 Theand acylationbenzoyl 2,6 of-piperidinedione benzene 9 with two32, had different afforded types ketone of amide, product i.e., 34benzoyl in good 2,5-pyrrolidinedioneto excellent yields. Different31 and benzoyl to previous 2,6-piperidinedione amides-type of32 ,acyl had donor, afforded β- ketonelactams product 28 (Scheme34 in good2), that to excellentinvolved yields. the highly Different reactive to previous acyl carbonium amides-type ion of acyl intermediate donor, β-lactams [21], the28 acylation(Scheme2 ), of that arenes involved with thetwisted highly amides reactive 31– acyl33 occurred carbonium exclusively ion intermediate at the endothermic [21], the acylation N–CO of bond arenes. The with high twisted reactivity amides of 31the– 33twistedoccurred amide exclusively bond might at the be endothermictuned by N–C(O) N–CO bond bond. rotation, The high and reactivity selective ofN- theprotonation twisted amide of the bondamide might bond under be tuned acidic by conditions N–C(O) bond may rotation,enhance the and potential selective forN nucleophilic-protonation addition of the amide (Figure bond 4b). underTherefore, acidic the conditions selection of may the enhanceacid to promote the potential this reaction for nucleophilic is important. addition For example, (Figure4 acidb). Therefore,-catalyzed theacylation selection of ofbenzene the acid 9 towith promote benzoyl this 2,6 reaction-piperidinedione is important. 32 For is example, more efficient acid-catalyzed using TfOH acylation, which of benzeneresults in9 upwith to benzoyl90% yield 2,6-piperidinedione of ketone product32 34is (Figure more efficient 4c), than using the other TfOH, tested which catalysts, results insuch up toas 90%HBF4 yield, HCl, of TFA, ketone BF product3·Et2O, and34 (FigureTiCl4. Moreover,4c), than the the other TfOH tested catalytic catalysts, system such is also as HBF suitable4, HCl, for TFA, the BFacylation3·Et2O, of and benzene TiCl4. Moreover,with twisted the amides TfOH catalytic 33, in which system the is aromatic also suitable rings for carry the acylationvarious of benzene with(Figure twisted 4a). amides The mild33 , conditionin which the using aromatic TfOH rings as catalyst carry various is compatible substituents with (Figure the wide4a). The array mild of conditionfunctional using groups TfOH introduced as catalyst in is compatibletwisted amides with the33, wideindicated array byof functional up to a 70% groups yield introduced of ketone in twistedproduct amides 35. 33, indicated by up to a 70% yield of ketone product 35.

(a)

(b) (c) 100 (%)

32 32 80

from 60 34

40

20

Isolated yield of yield Isolated 0 TfOH OtherOther catalystacids

FigureFigure 4. 4. ((aa)) C--AcylationAcylation of benzene 9 with twisted amides 31–33 asas acyl acyl donor; donor; ( (bb)) proposed Proposed mechanismmechanism of Friedel–Crafts Friedel–Crafts acylation of benzene 9 withwith benzoylbenzoyl 2,6-piperidinedione 2,6-piperidinedione 32 byby N–C N–C cleavage;cleavage; (c ()c) comparison Comparison of TfOH of TfOH and other and catalysts other catalysts (HBF4, HCl, (HBF TFA,4, HCl, BF 3· TFA,Et2O, BFand3·Et TiCl2O,4 ) and utilization TiCl4) asutilization catalyst as for catalyst the C-acylation for the C-acylation of benzene of benzene9 with benzoyl9 with benzoyl 2,6-piperidinedione 2,6-piperidinedione32. Reagents 32. Reagents and ◦ conditions:and conditions: TfOH TfOH (1–3 (1 equiv.),–3 equiv.), 23 C, 23 15 C, h. 15 h.

TfOH-catalyzed aromatic acylation using β-lactams as the acyl donors has broadened the application of TfOH as a catalyst for intramolecular C-acylation. The typical Fries rearrangement of N-arylazetidinones 36 can be carried out using TfOH to produce quinolones 37 at excellent yields

Catalysts 2017, 7, 40 6 of 28

TfOH-catalyzed aromatic acylation using β-lactams as the acyl donors has broadened the application of TfOH as a catalyst for intramolecular C-acylation. The typical Fries rearrangement of N-arylazetidinones 36 can be carried out using TfOH to produce quinolones 37 at excellent yields (Table1, entry 1). Most protocols for quinoline-4-one synthesis require multistep procedures, a large amount of catalyst, and have low yields [23,24]; to address these limitations, TfOH has been utilized [25]. The rearrangement of trans-3-butadienyl-2-azetidinones 38 resulted in quinoline-4-ones 39 in moderateCatalystsCatalysts 20172017,,, 77 yields,,, 404040 CatalystsCatalysts (55%–65%; 2017 2017,, 7,,, 74040, 40 Table1, entry 2). Initial protonation of the starting66 ofof 2727 material 386 of6 can of27 27 lead to the generation of the carbenium ion intermediate, which can undergo the Fries rearrangement and (Table(Table 1,1, entryentry 1).1). (Table MostMost(Table protocol protocol1, 1, entry entry ss1). forfor1). Most quinoline-4-oneMostquinoline-4-one protocol protocols fors for synthesissynthesis quinoline-4-one quinoline-4-one requirerequire synthesismultistepmultistep synthesis require procedures,procedures, require multistep multistep aa largelarge procedures, procedures, a alarge large subsequentamountamount of oxidationof catalyst,catalyst,amountamount andand to havehave quinoline-4-onesof of catalyst, lowlowcatalyst, yieldsyields and and [23,24];[23,24]; have have low totolow39 addressaddressyields. yields However, [23,24]; thesethese[23,24]; limitations, limitations,to usingto address address TfOH theseTfOHTfOH these limitations, has has canlimitations, beenbeen simplify utilizedutilized TfOH TfOH has the has been rearrangementbeen utilized utilized process[25].[25]. under TheThe rearrangementrearrangement mild[25]. conditions[25]. The The ofof rearrangement transtransrearrangement-3-butadienyl-2-azetidinones-3-butadienyl-2-azetidinones to a one-step of of trans trans-3-butadienyl-2-azetidinones procedure.-3-butadienyl-2-azetidinones 3838 resultedresultedresulted ininin quinoline-4-onesquinoline-4-onesquinoline-4-ones 38 38 resultedresulted resulted inin in quinoline-4-onesquinoline-4-ones3939 quinoline-4-ones ininin 39 39 inin in moderate yields (55%–65%;moderatemoderate yields Table yields (55%–65%;1, (55%–65%; entry 2). TableInitialInitial Table 1, protonationprotonation 1, entry entry 2). 2). Initial Initialofof thethe protonation startingprotonationstarting materialmaterial of of the the 38starting38 starting cancancan leadleadlead material material 38 38 cancan can leadlead lead In Table1, the syntheses of 3-spirocycliquinon-4-ones involving intramolecular rearrangement toto thethe generationgeneration oftoofto thethe the carbeniumgenerationcarbenium generation ionofion of the intermediate,intermediate,the carbenium carbenium ionwhichwhich ion intermediate, intermediate, cancan undergoundergo which which thethe FriesFries can can undergo rearrangementrearrangement undergo the the Fries Fries andand rearrangement rearrangement and and of 3-spirocyclicsubsequentsubsequent oxidationoxidationβ-lactam,subsequentsubsequent toto quinoline-4-onesquinoline-4-ones whichoxidation oxidation areto to 39quinoline-4-ones39 quinoline-4-ones... used However,However,However, in usingusingusing the 39 39 . .TfOHsynthesesTfOHTfOH However,However,. However, cancancan simplifysimplify simplify usingusing using of TfOHTfOH important TfOHthethethe rearrangementrearrangement rearrangementcancan can simplifysimplify simplify heterocyclic thethe the rearrangementrearrangement rearrangement scaffolds, are described.process under Conditions mildprocessprocess conditions under under for to mild this amild one-step conditions synthesisconditions procedure. to to a usesaone-step one-step quinolones procedure. procedure. 40 and 41 which have been optimized InIn TableTable 1,1, thethe synthesessynthesesInIn Table Table of of1, 1, 3-spirocycliquinon-4-ones3-spirocycliquinon-4-onesthe the syntheses syntheses of of 3-spirocycliquinon-4-ones 3-spirocycliquinon-4-ones involvinginvolving intramolecularintramolecular involving involving rearrangementrearrangement intramolecular intramolecular rearrangement rearrangement by using a combination of 20 mol % TfOH and 30 mol % FeCl (Table1, entries 3 and 4) [ 26]. ofof 3-spirocyclic3-spirocyclic βof-lactam,-lactam,of 3-spirocyclic 3-spirocyclic whichwhich areareβ -lactam,β -lactam, usedused in inwhich whichthethe syntheses synthesesare are used used ofinof in importanttheimportant the syntheses syntheses heterocyclicheterocyclic of of important 3important scaffolds,scaffolds, heterocyclic heterocyclic areare scaffolds, scaffolds, are are Utilizationdescribed. of Conditions FeCl3described.described.without for this Conditions Conditions synthesis asynthesissynthesis Brønsted for usesuses usesfor this this quinolonesquinolones acidquinolones synthesissynthesis synthesis led to4040usesuses uses andandand only quinolonesquinolones quinolones4141 9%whichwhichwhich yield 40havehavehave 40 andand and frombeenbeenbeen 41 41 which whichoptimizedoptimizedoptimized which quinolones havehave have byby by beenbeen been 42optimizedoptimized optimizedand 43 byby by, along using a combinationusing of 20a combination mol % TfOH of and 20 mol30 mol % TfOH% FeCl and33 (Table 30 mol 1, entries% FeCl 3 (Table3and 4) 1,[26]. entries Utilization 3 and 4) [26]. Utilization with unreactedusing a combination startingusingusing of a20 material.acombination molcombination % TfOH Due of andof 20 20 mol to30 mol mol the % % TfOH % TfOH lower FeCl and 3and (Table(Table requisite30 30 mol mol 1,1, %entriesentries % FeCl FeCl amount 333 (Table andand (Table 4)4) 1, of[26].[26]. 1, entries entries Brønsted UtilizationUtilization 3 3and and 4) acid4) [26]. [26]. Utilization and Utilization the lower ofof FeClFeCl33 withoutwithoutwithout aaaof BrønstedBrønstedBrønstedof FeCl FeCl3 withoutwithout3 without acidacidacid ledledled aa BrønstedaBrønstedtototo Brønsted onlyonly 9%9% acidacid yieldacidyield ledled led fromfrom toto to only onlyquinolonesquinolones 9% 9% yield yield 42 42from from andandand quinolones 43 43quinolones,,, alongalongalong withwithwith 42 42 andand unreacted unreactedunreactedand 43 43,, alongalong, along withwith with unreactedunreacted unreacted reaction temperature required to effect high selectivity, TfOH is preferable to other acids such as TFA startingstarting material.material.starting DuestartingDue toto material. thethematerial. lowerlower Due Duerequisiterequisite to to the the amountamountlower lower requisite ofofrequisite BrønstedBrønsted amount amount acidacid of andandof Brønsted Brønsted thethe lowerlower acid acid reaction reactionand and the the lower lower reaction reaction for thesetemperaturetemperature reactions. requiredrequiredtemperaturetemperature toto effecteffect highrequiredhigh required selectivity,selectivity, to to effect effect TfOHTfOH high high isselectivity,is selectivity, preferablepreferable TfOH toTfOHto otherother is ispreferable acidspreferableacids suchsuch to astoas other TFAotherTFA acids forfor acids thesethese such such as as TFA TFA for for these these reactions.reactions. reactions.reactions. Table 1. The Fries rearrangement of various β-lactam derivatives upon intramolecular acylation Table 1. TheTheThe FriesFriesFries Table rearrangementrearrangementrearrangementTable 1. 1. TheThe The FriesFries Friesofofof variousvariousvariousrearrangementrearrangement rearrangement ββ-lactam-lactam ofof ofderivatives derivativesvariousvarious various β -lactam β uponupon-lactam intramolecularintramolecularderivatives derivatives upon upon acylationacylation intramolecular intramolecular acylation acylation acyl donors. Table 1. The Fries rearrangement of various β-lactam derivatives upon intramolecular acylation acylacyl donors.donors. acylacyl donors. donors.

EntryEntry EntryEntry YieldYield YieldYield Entry (Ref.) ββ-Lactamβ-Lactam-Lactam Derivatives Derivativesβ -Lactam-Lactamβ-Lactam Catalyst Catalyst DerivativesDerivatives Derivatives Catalyst(Amount)(Amount) (Amount) Catalyst Catalyst Catalyst Condition Condition (Amount)(Amount) (Amount) Condition Condition Condition Condition Product Product Product Product Product Product Yield (%) (Ref.)(Ref.) (Ref.)(Ref.)(Ref.) (%)(%) (%)(%)(%)

°° 2 2 ◦° ° ClCH222CH222Cl, 0 °C toClCH r.t.,ClCHClCH 2CH2CH2CH2Cl,2Cl,2Cl, 00 °0C Cto tor.t., r.t., r.t., 96%–96%– 96%–96%– 1 [201,121 [20,21][20,21]] 1 [20,21]1 [20,21] TfOHTfOH (1–2(1–2TfOH equiv.)equiv.) (1–2 equiv.)TfOHTfOH (1–2 (1–2 equiv.) equiv.) 96%–98% 1515 min.min. 1515 min.15 min. min. 98%98% 98%98%

2 2 °° ClCH2CH2Cl, 0 °C,°◦ 10–15 55%– ClCH22CH22Cl, 0 °C, 10–15ClCHClCHClCH 2CH22CHCH2Cl,2Cl,Cl, 0 °0C,0 C, 10–15C, 10–15 55%–55%– 55%–55%– 2 [2522] [25][25] 2 [25]2 [25] TfOHTfOH (~0.3(~0.3TfOH equiv.)equiv.) (~0.3 TfOH equiv.)TfOH (~0.3 (~0.3 equiv.) equiv.) 55%–65% min. 10–15min. min. 65%65% 65%65%

2020 molmol %% TfOH–TfOH– 2020 mol mol % %TfOH–° TfOH– Toluene,° 80 ◦C, 81%–81%– 81%–81%– 33 [26][26] 3 [26]3 [26] Toluene,Toluene, 8080 °C, 0.5–2.5Toluene, hToluene, 80 80 °C, °C, 0.5–2.5 0.5–2.5 h h 3 [26] 3 [26] 20 mol % TfOH–303 mol30 mol % FeCl% FeCl3 3 Toluene, 80 C, 0.5–2.5 h 93%81%–93% 3030 molmol %% FeClFeCl33 3030 mol mol % %FeCl FeCl3 3 0.5–2.5 h 93%93% 93%93%

2020 molmol %% TfOH–TfOH– 2020 mol mol % %TfOH– TfOH– ◦ 83%–83%– 83%–83%– 44 [26][26] 4 [26]4 [26] 20 mol % TfOH– 20Toluene,Toluene, mol % TfOH–8080 °°C, 3–4 h Toluene,Toluene,Toluene, 80 80 °C, °C, C,3–4 3–4 h h 83%– 83%– 4 [264] [26] 4 [26] 20 mol % TfOH–30 molToluene, % FeCl 80 3C,3 3–4 h Toluene, 80 C, 3–4 h 83%–85% 3030 molmol %% FeClFeCl333 3030 mol mol % %FeCl FeCl3 3 3–4 h 85%85% 85%85%

InIn 1986,1986, RobertsRoberts andandInIn 1986, Wells Wells1986, Roberts firstRobertsfirst usedused and and thethe Wells Wells TfOHTfOH first first caca usedtalytictalytic used the thesystemsystem TfOH TfOH inin ca cathethetalytictalytic acacylationylation system system ofof in electron-richelectron-richin the the ac acylationylation of of electron-rich electron-rich Inmetallocene 1986, Roberts and pyrenesmetallocenemetallocene and using Wells and andacetic pyrenes first pyrenes anhydride used using using the 44acetic44 acetic asasas TfOH ananananhydride anhydride acylacylacyl catalytic donordonordonor 44 44 as(Tableas(Table(Table as anan systeman acylacyl 2,2,2,acyl entriesentriesentries donordonor donor in 1 11 the(Table(Table andandand(Table acylation 2)2)2) 2,2, [27].[27].2,[27]. entriesentries entries 11 of 1andand and electron-rich 2)2) 2) [27].[27]. [27]. metalloceneTreatment and of excess pyrenesTreatmentTreatment acetic using anhydrideof of excess excess acetic acetic4444 acetic (~6(~6(~6 anhydride anhydride equiv.)equiv.)equiv.)anhydride withwithwith 44 44 44 1(~61(~61 (~6equiv.equiv.equiv. as equiv.)equiv.) equiv.) an ofofof acyl withwithTfOHTfOHTfOH with 1 donor1 atat1atequiv.equiv. equiv.roomroomroom (Tableofof temperaturetemperaturetemperatureof TfOHTfOH TfOH2 at,at at entries roomroom room temperaturetemperature temperature 1 and 2) [ 27]. improvedimproved thethe acylationacylationimprovedimprovedimproved ofof ferrocenesferrocenes thethe the acylationacylation acylation 4545 andandand ofof of ferrocenes ferrocenes 4646 ferrocenes ininin comparisoncomparisoncomparison 45 45 andand and 46withwithwith 46 inin in comparisonthecomparisonthethe comparison reactionreactionreaction usingwithusingwithusing with thethe approximatelyapproximately approximatelythe reactionreaction reaction usingusing using approximatelyapproximately approximately Treatment of excess 44 (~6 equiv.) with 1 equiv.°° of TfOH° ° at room temperature 11 equiv.equiv. ofof thethe conventionalconventional1 1equiv. equiv. of of catalystcatalystthe the conventional conventional AlClAlCl33 atatat roomroomroom catalyst catalyst temperaturetemperaturetemperature AlCl AlCl3 atat3 at roomroom [28][28]room[28] orortemperatureortemperature temperature atatat ~50~50~50 °C [29]. [28][28] [28] This oror or atat systemat ~50~50 ~50 °C C has[29]. [29]. This This system system has has improvedbeenbeen extendedextended the acylation forforbeen thethebeen use useextended ofextended ofof ferrocenes aa limitedlimited for for the the numbernumber use use45 of of and a ofof alimited possiblepossiblelimited46 numberin number acylationacylation comparison of of possible positions positionspossible acylation with acylationforfor metallocenesmetallocenes the positions positions reaction 47 47for for andandand metallocenes usingmetallocenes approximately 47 47 andand and 4848 [30].[30]. MonosubstitutionMonosubstitution4848 [30]. [30]. Monosubstitution ofofMonosubstitution anan acylacyl groupgroup atatof of thethean an acyltwo-positiontwo-position group at at (Table(Tablethe the two-position two-position 2,2, entriesentries 3 3(Table and and(Table 4)4) 2, occurs occurs2, entries entries◦ withwith 3 3and and 4) 4) occurs occurs with with 1 equiv. of the conventional catalyst AlCl3 at room temperature [28] or at ~50 C[29]. This system has thethe TfOHTfOH catalyticcatalyticthe system,thesystem, TfOH TfOH inincatalytic catalytic contrastcontrast system, system,toto thethe disubstitutionindisubstitution in contrast contrast to to the achievedachieved the disubstitution disubstitution withwith AlClAlCl achieved achieved33... PhenylPhenylPhenyl with withestersestersesters AlCl AlCl 49493 ..andandand 3PhenylPhenyl. Phenyl estersesters esters 49 49 andand and been extended for the use of a limited number of possible acylation positions for metallocenes 47 and 48 [30 ]. Monosubstitution of an acyl group at the two-position (Table2, entries 3 and 4) occurs with the TfOH catalytic system, in contrast to the disubstitution achieved with AlCl3. Phenyl esters 49 and 50 have also been used as acylating agents for metallocene (45, 46, and 51) and pyrene (52) (Table2, Catalysts 2017, 7, 40 7 of 28

CatalystsCatalysts 20172017,,, 77,,, 404040 77 ofof 2727 entries 5–8). The substituted aromatic derivative of phenyl p-methoxybenzoic acid (49), which is more 5050 havehavehave alsoalsoalso beenbeenbeen usedusedused asasas acylatingacylatingacylating agentsagentsagents forforfor metallocenemetallocenemetallocene (((4545,,, 4646,,, andandand 5151)) andand pyrenepyrene ((5252)) (Table(Table 2,2, electron-richentriesentries 5–8).5–8). thanTheThe substitutedsubstituted its corresponding aromaticaromatic derivativederivative phenyl benzoateofof phenylphenyl pp (-methoxybenzoic-methoxybenzoic50), had higher acidacid reactivity ((4949),), whichwhich in theisis moremore acylation of bothelectron-richelectron-rich ferrocene thanthan51 and itsits correspondingcorresponding pyrene 52 (Table phenylphenyl2, entries benzoatebenzoate 5 and ((5050),), 8). hadhad higherhigher reactivityreactivity inin thethe acylationacylation ofof bothboth ferroceneferrocene 5151 andandand pyrenepyrenepyrene 5252 (Table(Table(Table 2,2,2, entriesentriesentries 555 andandand 8).8).8). Table 2. TfOH-catalyzed acylation of electron-rich substrates using esters as acyl donors. TableTable 2.2. TfOH-catalyzedTfOH-catalyzedTfOH-catalyzed acylationacylationacylation ofofof electron-richelectron-richelectron-rich substratessubstrates usingusing estersesters asas acylacyl donors.donors. No. (Ref.) Acyl Donor Metallocene or Pyrene * Condition Product Yield No.No. (Ref.)(Ref.) Acyl Acyl DonorDonor Metallocene Metallocene oror PyrenePyrene ** Condition Condition Product Product YieldYield

1 [27] TfOH (1 equiv.), CH2Cl2, r.t. 65% 1 [1127 [27][27]] TfOHTfOHTfOH (1(1 equiv.),equiv.), (1 equiv.), CHCH222 CHClCl222,,, 2 r.t.r.t.r.t.Cl 2, r.t. 65% 65% 65% 65%

2 [27] TfOH (1 equiv.), CH2Cl2, r.t. 78% 2 [2227 [27][27]] TfOHTfOHTfOH (1(1 equiv.),equiv.), (1 equiv.), CHCH222 CHClCl222,,, 2 r.t.r.t.r.t.Cl 2, r.t. 78% 78% 78% 78%

3 [30] TfOH (1 equiv.), CH2Cl2, r.t. 91% 3 [3330 [30][30]] TfOHTfOHTfOH (1(1 equiv.),equiv.), (1 equiv.), CHCH222 CHClCl222,,, 2 r.t.r.t.r.t.Cl 2, r.t. 91% 91% 91% 91%

4 [30] TfOH (1 equiv.), CH2Cl2, r.t. 29% 4 [4430 [30][30]] TfOHTfOHTfOH (1(1 equiv.),equiv.), (1 equiv.), CHCH222 CHClCl222,,, 2 r.t.r.t.r.t.Cl 2, r.t. 29% 29% 29% 29%

42%42% (from(from42% 4949))) (from 49) 5 [31] TfOH (3 equiv.), CH2Cl2, r.t. 5 [5531 [31][31]] TfOHTfOHTfOH (3(3 equiv.),equiv.), (3 equiv.), CHCH222 CHClCl222,,, 2 r.t.r.t.r.t.Cl 2, r.t. 11%11% (from(from11% 5050))) (from 50)

6 [27] TfOH (1 equiv.), CH2Cl2, r.t. 62% 6 [6627 [27][27]] TfOHTfOHTfOH (1(1 equiv.),equiv.), (1 equiv.), CHCH222 CHClCl222,,, 2 r.t.r.t.r.t.Cl 2, r.t. 62% 62% 62% 62%

7 [27] TfOH (1 equiv.), CH2Cl2, r.t. 71% 7 [7727 [27][27]] TfOHTfOHTfOH (1(1 equiv.),equiv.), (1 equiv.), CHCH222 CHClCl222,,, 2 r.t.r.t.r.t.Cl 2, r.t. 71% 71% 71% 71%

Catalysts 2017, 7, 40 7 of 27

50 have also been used as acylating agents for metallocene (45, 46, and 51) and pyrene (52) (Table 2, entries 5–8). The substituted aromatic derivative of phenyl p-methoxybenzoic acid (49), which is more electron-rich than its corresponding phenyl benzoate (50), had higher reactivity in the acylation of both ferrocene 51 and pyrene 52 (Table 2, entries 5 and 8). Catalysts 2017, 7, 40 7 of 27 Table 2. TfOH-catalyzed acylation of electron-rich substrates using esters as acyl donors. 50 have also been used as acylating agents for metallocene (45, 46, and 51) and pyrene (52) (Table 2, No. (Ref.) Acyl Donor Metallocene or Pyrene * Condition Product Yield entries 5–8). The substituted aromatic derivative of phenyl p-methoxybenzoic acid (49), which is more electron-rich than its corresponding phenyl benzoate (50), had higher reactivity in the acylation of both ferrocene 51 and pyrene 52 (Table 2, entries 5 and 8). 1 [27] TfOH (1 equiv.), CH2Cl2, r.t. 65% Table 2. TfOH-catalyzed acylation of electron-rich substrates using esters as acyl donors.

No. (Ref.) Acyl Donor Metallocene or Pyrene * Condition Product Yield

1 [27] TfOH (1 equiv.), CH2Cl2, r.t. 65% 2 [27] TfOH (1 equiv.), CH2Cl2, r.t. 78%

2 [27] TfOH (1 equiv.), CH2Cl2, r.t. 78% 3 [30] TfOH (1 equiv.), CH2Cl2, r.t. 91%

Catalysts 2017, 7, 40 8 of 28

3 [30] TfOH (1 equiv.), CH2Cl2, r.t. 91%

4 [30] TfOH (1 equiv.), CH2Cl2, r.t. 29% Table 2. Cont.

Catalysts 2017, 7, 40 8 of 27 CatalystsNo.Catalysts (Ref.) 2017 2017, 7,, 740, 40 Acyl Donor Metallocene or Pyrene * Condition Product8 of8 of 27 27 Yield

4 [30] TfOH (1 equiv.), CH2Cl2, r.t. 42%27%27% (from 29% (from 27% 49 49) (from) 49) 58 [31] TfOH (3 equiv.), CH2Cl2, r.t. 27% (from 49) 8 [831 [31]8 ][31] TfOHTfOHTfOH (3 (3equiv.), (3 equiv.), equiv.), CH CH2Cl CH2Cl2, 2r.t.2,Cl r.t. 2, r.t. 11%7%7%7% (from (from(from (from 7%50 5050 50)) ) (from ) 50)

9 [31] TfOH (3 equiv.), CH2Cl2, r.t. 42% 10%–58% (from 49 ) 9 [95631 [31]9[31][27] ][31] TfOHTfOHTfOHTfOH (3(3(1 (3 equiv.),equiv.), (3 equiv.), equiv.), CHCH CH22Cl CHCl2Cl22,, r.t.2r.t.,Cl r.t. , r.t. 10%–58% 10%–58% 62% 10%–58% 2 2 11% (from 50)

10 [31] TfOH (3 equiv.), CH2Cl2, r.t. 45%–89% 10106 [1031 [27][31] ][31] TfOHTfOHTfOHTfOH (3(1 (3 equiv.),equiv.), (3 equiv.), equiv.), CHCH CH22Cl CHCl2Cl22,, r.t.2r.t.,Cl r.t. , r.t. 45%–89% 45%–89% 62% 45%–89% 7 [27] TfOH (1 equiv.), CH2Cl2,2 r.t. 2 71%

11 [31] TfOH (3 equiv.), CH2Cl2, r.t. 27%–47% 1111 [1131 [31] ][31] TfOHTfOHTfOH (3 (3equiv.), (3 equiv.), equiv.), CH CH2Cl CH2Cl2, r.t.2,Cl r.t. , r.t. 27%–47% 27%–47% 27%–47% 7 [27] TfOH (1 equiv.), CH2Cl2,2 r.t. 2 71%

12 [31] TfOH (3 equiv.), CH2Cl2, r.t. 30%–60% 1212 [31] [31] TfOHTfOH (3 (3equiv.), equiv.), CH CH2Cl2Cl2, r.t.2, r.t. 30%–60% 30%–60% 12 [31] TfOH (3 equiv.), CH2Cl2, r.t. 30%–60%

** Arrows*Arrows Arrows indicateindicate indicate thethe the acylationacylation acylation position.position. position. * Arrows indicate the acylation position. TheTheThe applicationapplication application ofof of functionalizedfunctionalized functionalized oror or biologicallybiologically biologically importantimportant important acidsacids acids oror or theirtheir their derivativesderivatives derivatives fromfrom from thethe the Friedel–CraftsFriedel–CraftsFriedel–CraftsThe application reactionreaction reaction of hashas functionalized has beenbeen been carriedcarried carried outout orout biologicallybyby by utilizingutilizing utilizing thethe the important so-calledso-called so-called activeactive acidsactive esters.esters. oresters. their TheseThese These derivatives estersesters esters ((53 53(53 from the and 54) are readily accessible, stable, and exhibit high electrophilic reactivity toward amino groups. Friedel–Craftsandand 54 54) are) are readily readily reaction accessible, accessible, has been stable, stable, carried and and exhibit exhibit out high by high utilizingelectrophilic electrophilic the reactivity reactivity so-called toward toward active amino amino esters. groups. groups. These esters TheThe TfOH TfOH system system has has also also been been used used to to catalyze catalyze the the direct direct acylation acylation of of the the electron-rich electron-rich aromatic aromatic (53Theand TfOH54) are system readily has accessible,also been used stable, to catalyze and exhibit the direct high electrophilicacylation of the reactivity electron-rich toward aromatic amino groups. ringsringsrings ferrocene ferrocene ferrocene 51 51 51 and and and pyrene pyrene pyrene 52 52 52 using using using tetrafluor tetrafluor tetrafluorophenylophenylophenyl esters esters esters 53 53 53 and and and N N N-hydroxysuccinimidyl-hydroxysuccinimidyl-hydroxysuccinimidyl esters esters esters The TfOH system has also been used to catalyze the direct acylation of the electron-rich aromatic rings 545454 [31].[31]. [31]. CompoundsCompounds Compounds 5353 53 werewere were foundfound found toto to bebe be lessless less reactivereactive reactive thanthan than thethe the NN N-hydroxysuccinimidyl-hydroxysuccinimidyl-hydroxysuccinimidyl estersesters esters 5454 54 ferrocene(Table(Table(Table 2,2, 512, entriesentries entriesand pyrene 9–12).9–12). 9–12). DespiteDespite Despite52 using thethe the tetrafluorophenyl useuse use ofof of anan an excessexcess excess ofof of thesethese estersthese esters,esters, esters,53 and thethe the acylationNacylation acylation-hydroxysuccinimidyl processprocess process waswas was observedobserved observed esters 54 [31]. Compoundstototo bebe be selectiveselective selective53 withoutwithoutwere without found formationformation formation to be ofof of lessthethe the diacylateddiacylated reactivediacylated thancompounds.compounds. compounds. the N -hydroxysuccinimidyl Nevertheless,Nevertheless, Nevertheless, acylationacylation acylation usingusing using esters thesethese these54 (Table 2, entriesestersestersesters 9–12). asas as electron-richelectron-rich electron-rich Despite thedonorsdonors donors use seemsseems ofseems an to excessto to bebe be ideniden iden oftical theseticaltical withwith with esters, thethe the process theprocess process acylation inducedinduced induced process usingusing using TfOHTfOH wasTfOH observedasas as thethe the to be selectivecatalyst.catalyst.catalyst. without AnotherAnother Another formation studystudy study foundfound found of thethatthat that diacylated acylationacylation acylation ofof of compounds. anan an electron-richelectron-rich electron-rich Nevertheless, acceptoracceptor acceptor usingusing using acylation aa a carboxyliccarboxylic carboxylic using acidacid acid these esters requires the combination TfOH and trifluoroacetic anhydride (TFAA) [32]. This study also claimed asrequires electron-richrequires the the combination combination donors seems TfOH TfOH toand and be trifluoroacetic trifluoroacetic identical with anhydride anhydride the process (TFAA) (TFAA) induced [32]. [32]. This This using study study TfOHalso also claimed claimed as the catalyst. thatthatthat efficientefficient efficient acylationacylation acylation hadhad had beenbeen been achievedachieved achieved duedue due toto to thethe the highhigh high reactivityreactivity reactivity ofof of thth thee eelectron-richelectron-rich electron-rich acceptorsacceptors acceptors Another study found that acylation of an electron-rich acceptor6 using a carboxylic acid requires the (e.g.,(e.g.,(e.g., ferroceneferrocene ferrocene 5151 51 andand and pyrenepyrene pyrene 5252 52,, which,which which are,are, are, respectively,respectively, respectively, 3.33.3 3.3 ×× × 1010 106 and6and and 220220 220 timestimes times moremore more reactivereactive reactive thanthan than combination TfOH and trifluoroacetic anhydride (TFAA) [32]. This study also claimed that efficient benzenebenzenebenzene 99 )9) [33].)[33]. [33]. WhenWhen When aa a stochiometricstochiometric stochiometric amam amountountount ofof of TFAATFAA TFAA isis is reactedreacted reacted withwith with carboxyliccarboxylic carboxylic acid,acid, acid, thethe the reactionreaction reaction acylationmixturemixturemixture hadwillwill will form form been form acyl acyl achievedacyl trifluoroacetate trifluoroacetate trifluoroacetate due to intermediate theintermediate intermediate high reactivitys.s. s.Next, Next, Next, these these ofthese the reactive reactive reactive electron-rich electrophiles electrophiles acceptors will will will react react react (e.g., with with with ferrocene 6 51 theandthethe aromaticaromatic pyrenearomatic compound52compound compound, which through are,through through respectively, aa a processprocess process that 3.3that that × usuallyusually usually10 and requiresrequires requires 220 times aa a strongstrong strong more acidacid acid reactive (TFA(TFA (TFA formedformed formed than benzene inin in thethe the 9)[33]. Whenreactionreactionreaction a stochiometric betweenbetween between carboxyliccarboxylic carboxylic amount acidacid acid of andandTFAA and TFAATFAA TFAA is reacted maymay may bebe be notwithnot not sufficientlysufficiently sufficiently carboxylic strongstrong strong acid, toto theto completecomplete complete reaction thethe the mixture reactionreaction reaction will form acyl[32]).[32]).[32]). trifluoroacetate Therefore,Therefore, Therefore, TfOHTfOH TfOH intermediates. isis is neededneeded needed inin in orderorder order Next, toto to aa cceleratetheseaccelerateccelerate reactive thethe the acylation.acylation. acylation. electrophiles Furthermore,Furthermore, Furthermore, will thereactthe the TfOH/TFAATfOH/TFAA TfOH/TFAA with the aromatic compoundcatalyticcatalyticcatalytic system throughsystemsystem can cancan a processalso alsoalso be bebe thatapplied appliedapplied usually to toto a a requiresa vast vastvast number numbernumber a strong of ofof acylation, acylation, acidacylation, (TFA such such formedsuch as asas the the inthe theacylation acylationacylation reaction of ofof between metallocenes with alkynoic acids which results in an acylated product that can undergo the carboxylicmetallocenesmetallocenes acid with andwith alkynoic TFAAalkynoic may acids acids be which notwhich sufficiently results results in in an strongan acylated acylated to completeproduct product that thethat reactioncan can undergo undergo [32 ]).the the Therefore, impressiveimpressive azide-alkyne azide-alkyne “click” “click” chemistry chemistry [34]. [34]. TfOHimpressive is needed azide-alkyne in order “click” to accelerate chemistry the [34]. acylation. Furthermore, the TfOH/TFAA catalytic system can also be applied to a vast number of acylation, such as the acylation of metallocenes with alkynoic

Catalysts 2017, 7, 40 9 of 28 acids which results in an acylated product that can undergo the impressive azide-alkyne “click” chemistryCatalysts 2017 [,34 7, ].40 9 of 27 Catalysts 2017, 7, 40 9 of 27 2.2. Use of Neat ReagentsReagents and Mild Conditions 2.2. Use of Neat Reagents and Mild Conditions The TfOH catalytic system has been of interest because of its two propertiesproperties that can enhance The TfOH catalytic system has been of interest because of its two properties that can enhance the reaction’sreaction’s efficiency:efficiency: (1) a -freesolvent-free reaction thatthat cancan bebe anan alternativealternative environment-friendlyenvironment-friendly the reaction’s efficiency: (1) a solvent-free reaction that can be an alternative environment-friendly organic synthetic pathway; (2) a mild conditions, which are advantageous to reactions of valuablevaluable organic synthetic pathway; (2) a mild conditions, which are advantageous to reactions of valuable heat-sensitive substrates. substrates. For For many many years, years, the the biot biotin–(strept)avidinin–(strept)avidin system system has has been been widely widely used used for heat-sensitive substrates. For many years, the biotin–(strept)avidin system has been widely used for forvarious various applications. applications. Biotin Biotin is a is complex a complex derivative derivative of of valeric acid that that possesses possesses a a high bindingbinding various applications. Biotin is a complex derivative of valeric acid that possesses a high binding affinityaffinity to avidin (a proteinprotein foundfound inin eggegg white)white) andand streptavidinstreptavidin (a proteinprotein foundfound inin StreptomycesStreptomyces affinity to avidin (a protein found in egg white) and streptavidin (a protein found in Streptomyces avidinni) [[35].35]. Previously, mixedmixed anhydrideanhydride generatedgenerated inin situsitu fromfrom biotinbiotin usingusing thethe TfOH/TFAATfOH/TFAA avidinni) [35]. Previously, mixed anhydride generated in situ from biotin using the TfOH/TFAA catalytic system system was was reported reported to to react react with with electr electron-richon-rich acyl acyl acceptors acceptors (ferrocene, (ferrocene, ruthenocene, ruthenocene, and catalytic system was reported to react with electron-rich acyl acceptors (ferrocene, ruthenocene, and andpyrene) pyrene) [33]. [ 33The]. Theselected selected arenes arenes are very are very reactive reactive in the in theFriedel–Crafts Friedel–Crafts acylation, acylation, thus thus providing providing an pyrene) [33]. The selected arenes are very reactive in the Friedel–Crafts acylation, thus providing an anopportunity opportunity for forusing using biotin biotin in these in these reactions. reactions. At present, At present, our ourlaboratory laboratory can canuse useneat neat TfOH TfOH for opportunity for using biotin in these reactions. At present, our laboratory can use neat TfOH for foracylation acylation reaction reaction using using acid acid chloride chloride of ofbiotin biotin 5555 asas an an acyl acyl donor. donor. It It is is estimated estimated that that the high acylation reaction using acid chloride of biotin 55 as an acyl donor. It is estimated that the high reactivity to acylation, which is the key role in this reaction, is not onlyonly duedue toto thethe reactivereactive skeletonskeleton reactivity to acylation, which is the key role in this reaction, is not only due to the reactive skeleton of the acyl acceptor, butbut alsoalso thethe properproper selectionselection of the acyl donor. As a result,result, the acid chloride of of the acyl acceptor, but also the proper selection of the acyl donor. As a result, the acid chloride of biotin 55 readilyreadily reactsreacts withwith thethe less-electron-richless-electron-rich acyl acceptor 56, formingforming acylated product 57 inin biotin 55 readily reacts with the less-electron-rich acyl acceptor 56, forming acylated product 57 in the presence ofof neatneat TfOH (Scheme3 3))[ [36].36]. FromFrom thethe pointpoint ofof viewview ofof fundamentalfundamental biologicalbiological activityactivity the presence of neat TfOH (Scheme 3) [36]. From the point of view of fundamental biological activity with the replacement of an avidin specificspecific bound compound, it suggests that aromatic derivatives of with the replacement of an avidin specific bound compound, it suggests that aromatic derivatives of acylated biotin have enough biologicalbiological activity against the biotin skeleton. Furthermore, the resulting acylated biotin have enough biological activity against the biotin skeleton. Furthermore, the resulting aromatic derivatives of of acylated acylated biotin biotin can can possibly possibly be be explored explored for for function functionalal bioanalysis-tag bioanalysis-tag in the in aromatic derivatives of acylated biotin can possibly be explored for functional bioanalysis-tag in the thefuture. future. future.

Scheme 3. CC-Acylation-Acylation of of aromatic aromatic derivatives derivatives using using acid acid chloride chloride of of biotin biotin 5555 asas an an acyl acyl donor. donor. Scheme 3. C-Acylation of aromatic derivatives using °acid chloride of biotin 55 as an acyl donor. Reagents and conditions: TfOH (>50 equiv.), −4040 to to 100 100 ◦C,C, ~1 ~1 h. h. Reagents and conditions: TfOH (>50 equiv.), −40 to 100 °C, ~1 h. The development of an efficient intramolecular Friedel–Crafts reaction of 1-(2- The development of an efficient intramolecular Friedel–Crafts reaction of 1-(2-isocyanatoethyl) isocyanatoethyl)benzeneThe development derivativesof an efficient 58 using TfOHintramolec as catalystular (SchemeFriedel–Crafts 4) [37] demonstratesreaction of the 1-(2-vast benzene derivatives 58 using TfOH as catalyst (Scheme4) [ 37] demonstrates the vast applications of isocyanatoethyl)benzeneapplications of the catalytic derivatives system based 58 using on TfOHneat TfOH. as catalyst In contrast (Scheme to 4)neat [37] TfOH demonstrates utilization, the other vast theapplications catalytic systemof the catalytic based on system neat TfOH. based In on contrast neat TfOH. to neat In TfOHcontrast utilization, to neat TfOH other utilization, catalysts such other as catalysts such as AlCl3, ZnCl2, TiCl4, or sulfuric acid require the use of an organic solvent for this AlCl , ZnCl , TiCl , or sulfuric acid require the use of an organic solvent for this intramolecular reaction. catalystsintramolecular3 such2 asreaction. 4AlCl3, ZnClThe high2, TiCl temperatures4, or sulfuric and acid reflux require conditions the use neededof an organic for these solvent catalysts for stillthis The high temperatures and reflux conditions needed for these catalysts still result in the low yield of intramolecularresult in the low reaction. yield of theThe desired high temperatures product 59 and and require reflux conditionsa long reaction needed time. for In these fact, undercatalysts certain still theresult desired in the product low yield59 ofand the require desired a longproduct reaction 59 and time. require In fact, a long under reaction certain time. conditions, In fact, theunder AlCl certain3 and conditions, the AlCl3 and ZnCl2 catalytic systems do not lead to the desired product 59. ZnClconditions,2 catalytic the systemsAlCl3 and do ZnCl not lead2 catalytic to the systems desired productdo not lead59. to the desired product 59.

Scheme 4. Intramolecular Friedel–Crafts reaction of 1-(2-iso-cyanatoethyl)benzene derivatives 58. SchemeReagents 4.4. and Intramolecular conditions: TfOH Friedel–Crafts Friedel–Crafts (>10 equiv.), reaction reaction 100 °C, of 1–2 1-(2- h. iso-cyanatoethyl)benzene derivatives derivatives 58.58. ° Reagents and conditions: TfOH (>10 equiv.), 100 ◦C, 1–2 h. Metal triflates can promote the acylation of benzene, chlorobenzene or fluorobenzene using benzoylMetal chloride triflates [38] can and promote the using acylation benzoic of be anhydridenzene, chlorobenzene [39]. This reaction or fluorobenzene is known usingto be benzoylcatalyzed chloride mainly by[38] TfOH and (either alcohol added using or benzoicreleased anhydrideat the onset [39]. of the This reactions); reaction therefore, is known a metal-to be catalyzedfree reaction mainly system by TfOHutilizing (either neat added TfOH oris streleasedill of interest. at the onsetThe synthesis of the reactions); of aryl keto therefore, α-amino a metal- acids freethrough reaction straightforward system utilizing and neatconvenient TfOH is methods still of interest. has attracted The synthesis more attention of aryl keto[12] αbecause-amino theseacids through straightforward and convenient methods has attracted more attention [12] because these

Catalysts 2017, 7, 40 10 of 28

Metal triflates can promote the acylation of benzene, chlorobenzene or fluorobenzene using benzoyl chloride [38] and alcohol using benzoic anhydride [39]. This reaction is known to be catalyzed mainly by TfOH (either added or released at the onset of the reactions); therefore, a metal-free reaction system utilizing neat TfOH is still of interest. The synthesis of aryl keto α-amino acids through straightforward and convenient methods has attracted more attention [12] because these compounds are convenient intermediates that can be directly converted into the desired α-amino acids. C-acylation involving the aromatic compounds and side chains of carboxylic derivatives is a potential pathway for the synthesisCatalysts of aryl2017, 7 keto, 40 α-amino acids that obviates the requirement of special reagents10 orof 27 precursors. This reaction may also be used for the asymmetric synthesis of α-amino acids. Therefore, due to these compounds are convenient intermediates that can be directly converted into the desired α-amino purposes, aspartic acid derivatives have become popular acyl donors and have been well studied. acids. C-acylation involving the aromatic compounds and side chains of carboxylic derivatives is a Homophenylalaninepotential pathway for or the bis-homophenylalanine, synthesis of aryl keto α-amino acids which that differ obviates in the the requirement addition of of special methylene or ethylene inreagents the side or precursors. chain of phenylalanine,This reaction may also is a be functional used for the biomolecule asymmetric synthesis and the of α asymmetric-amino acids. synthesis of both compoundsTherefore, due is to important. these purposes, One aspartic of the acid potential derivatives skeletons have become used popular in the acyl synthesis donors and of aryl keto have been well studied. α-amino acids is formed by using aspartic anhydride 60, which can undergo direct C-acylation to Homophenylalanine or bis-homophenylalanine, which differ in the addition of methylene or arenes 61 underethylene Friedel–Crafts in the side chain of conditions. phenylalanine, When is a functional AlCl3 wasbiomolecule used asand the the catalystasymmetric for synthesis the acylation of aspartic anhydridesof both compounds with arenes, is important. common One of organicthe potent solventsial skeletons such used as in CH the 2synthesisCl2 [40 ,of41 aryl] or keto MeNO α- 2 [41,42] were usedamino under acids reflux is formed for extended by using aspartic periods. anhydride When 60, organic which can solvent undergo was direct eliminated, C-acylation to arenes arenes in excess 61 under Friedel–Crafts conditions. When AlCl3 was used as the catalyst for the acylation of aspartic amount were used because of their low solubility to solve some aspartic acid derivatives. For example, anhydrides with arenes, common organic such as CH2Cl2 [40,41] or MeNO2 [41,42] were used >50 equiv.under of arenes reflux61 foris extended needed periods. to react When with organic aspartic solvent anhydride was eliminated,60 (Scheme arenes in5a) excess in order amount to produce aryl ketonewere62 usedor 63 because(wherein of their the low ratio solubility depends to solve on some the aspartic type of acid aspartic derivatives. anhydride For example, derivative >50 used in the reaction)equiv. of [43 arenes,44]. 61 Maintaining is needed to react the with ratio aspartic of asparticanhydride anhydride60 (Scheme 5a)60b in orderto 9 toat produce a 1:1 ratio,aryl as well ketone 62 or 63 (wherein the ratio depends on the type of aspartic anhydride derivative used in the as using AlClreaction)3 in [43,44]. CH2Cl Maintaining2 for 12 h the have ratio alsoof aspartic been anhydride shown to60b cause to 9 at noa 1:1 reaction ratio, as well and as theusing acyl donor remainedAlCl precipitated.3 in CH2Cl2 for This 12 h result have also implies been shown that theto cause full no dissolution reaction andof the this acyl systemdonor remained is essential and an excessprecipitated. amount of This arenes result is implies required that forthe thefull dissolution reaction. of Similarly, this system no is reactionessential and was an observedexcess when amount of arenes is required for the reaction. Similarly, no reaction was observed when the the conventional catalyst AlCl3 was replaced with TiCl4, sulfuric acid, or trifluoromethanesulfonic conventional catalyst AlCl3 was replaced with TiCl4, sulfuric acid, or trifluoromethanesulfonic anhydride (Tf O) [45]. anhydride2 (Tf2O) [45].

Scheme 5. C-Acylation of aromatic derivatives with aspartic acid derivatives 60 catalyzed by (a) Scheme 5. C-Acylation of aromatic derivatives with aspartic acid derivatives 60 catalyzed by conventional catalyst of AlCl3; (b) neat TfOH under mild conditions. C-Acylation of aromatic (a) conventionalderivatives catalyst also can of undergo AlCl3 with;(b )(c neat) aspartic TfOH acid underderivative mild 66a and conditions. glutamic acidC-Acylation derivative 66b of aromatic derivativescatalyzed also can by neat undergo TfOH under with mild (c) asparticconditions. acid Reagents derivative and conditions:66a and (i) AlCl glutamic3 (2.5–3 equiv.), acid derivative 0 °C 66b to r.t. or 50 °C, 3–72 h [43,44]; (ii) TfOH (>40 equiv.), 0 °C or r.t., 1 h [45,46]. catalyzed by neat TfOH under mild conditions. Reagents and conditions: (i) AlCl3 (2.5–3 equiv.), 0 ◦C to r.t. or 50 ◦C, 3–72 h [43,44]; (ii) TfOH (>40 equiv.), 0 ◦C or r.t., 1 h [45,46]. In contrast to other catalysts for the Friedel–Crafts acylation, TfOH can behave both as a catalyst and solvent because of its high dissolving capacity [12]. Aspartic anhydride derivatives 60b (1 equiv.)

Catalysts 2017, 7, 40 11 of 28

In contrast to other catalysts for the Friedel–Crafts acylation, TfOH can behave both as a catalyst and solvent because of its high dissolving capacity [12]. Aspartic anhydride derivatives 60b (1 equiv.) can dissolveCatalysts 2017 well, 7, 40 in TfOH, and the resulting homogenous system allows fast reaction with11 of benzene 27 9 (1 equiv.), thus forming 64 (major product) or 65 within only an hour (Scheme5b). Moreover, bothcan aspartic dissolve acid well derivative in TfOH, and66a the[45 ]resulting and glutamic homogenous acid derivativesystem allows66b fast[46 reaction] are also with potential benzene acyl donors9 (1 for equiv.), direct thusC-acylation forming 64 for(major the product) synthesis or 65 of within homophenylalanine only an hour (Scheme or bis-homophenylalanine. 5b). Moreover, both aspartic acid derivative 66a [45] and glutamic acid derivative 66b [46] are also potential acyl donors Neat TfOH can catalyze acylation of the aromatic derivatives 67 by the acyl donors 66 (Scheme5c) with for direct C-acylation for the synthesis of homophenylalanine or bis-homophenylalanine. Neat TfOH a good yield of acylated product 68 and a relatively short reaction time. Furthermore, this reaction is can catalyze acylation of the aromatic derivatives 67 by the acyl donors 66 (Scheme 5c) with a good environmentallyyield of acylated friendly product since 68 it and does a notrelatively use excess short reagent.reaction time. In the Furthermore, homogeneous this reaction reaction system,is acyl donorsenvironmentally66 can undergofriendly since acylation it does smoothly not use excess without reagent. any In hydrolysis the homogeneous and retain reaction its system, enantiomer skeletonacyl evendonors after 66 can the reaction.undergo acylation TfOH acts smoothly as a catalyst without and an solvent,y hydrolysis thus and enhancing retain its the enantiomer effectiveness and efficiencyskeleton even of synthesis after the reaction. of the aryl TfOH keto actsα as-amino a catalyst acids and by solvent, direct thusC-acylation. enhancing the effectiveness Photoaffinityand efficiency of labeling synthesis is of a the useful aryl keto biochemical α-amino acids technique by direct for C-acylation. investigating the structural and functionalPhotoaffinity relationships labeling between is a useful small biochemical biologically technique active compounds for investigating and biomoleculesthe structural and such as proteinsfunctional (enzymes), relationships RNA, andbetween DNA small [47, 48biologically]. In recent active years, compou our laboratorynds and biomolecules has developed such variousas proteins (enzymes), RNA, and DNA [47,48]. In recent years, our laboratory has developed various photophores such as phenylazide, phenyldiazirine, and benzophenone for use in this type of analysis. photophores such as phenylazide, phenyldiazirine, and benzophenone for use in this type of analysis. One of these potential photophores is directly constructed from the benzophenone moiety on One of these potential photophores is directly constructed from the benzophenone moiety on phenylalaninephenylalanine using using a Friedel–Crafts a Friedel–Crafts reaction. reaction. DueDue to the the low low solubility solubility of ofphenylalanine phenylalanine derivatives derivatives in organicin organic solvents solvents for for direct directC -acylationC-acylation [[49],49], neatneat TfOH TfOH was was used used [50]. [50 The]. The neat neat TfOH TfOH catalytic catalytic systemsystem enabled enabled the directthe direct construction construction of aof benzophenonea benzophenone moiety moiety onon opticallyoptically pure phenylalanine via stereocontrolledvia stereocontrolled Friedel–Crafts Friedel–Crafts acylation acylat (Schemeion (Scheme6a). When 6a). benzoyl When chloridebenzoyl 6chlorideand phenylalanine 6 and derivativesphenylalanine69a were derivatives used for 69a the were reaction used system,for the reaction a complex system, reaction a complex mixture reaction was mixture observed was with a low yieldobserved of the with desired a low yield product of the70a desired. When productN-protected 70a. When phenylalanine N-protected phenylalanine69b was used 69b to was suppress used any competingto suppress reactions, any competing it was found reactions, to increase it was the found product to increase yield withoutthe product any yield optical without loss (upanyto optical 40% yield loss (up to 40% yield of 70b was achieved with 98% ee). Here, benzoic anhydride [51] can also be of 70b was achieved with 98% ee). Here, benzoic anhydride [51] can also be used for the production used for the production of benzophenone derivatives via direct C-acylation. Reaction of this C N of benzophenonecompound with derivatives N-protectedvia direct -acylation. using neat Reaction TfOH resulted of this in compound a good yield with(86%) at-protected room phenethylaminetemperature. using neat TfOH resulted in a good yield (86%) at room temperature.

Scheme 6. TfOH-catalyzed Friedel–Crafts acylation for introducing photoreactive moiety of (a) Scheme 6. TfOH-catalyzed Friedel–Crafts acylation for introducing photoreactive moiety of benzophenone; (b) (3-trifluoromethyl)phenyldiazirinyl (TPD); (c) benzophenone containing TPD on (a) benzophenone; (b) (3-trifluoromethyl)phenyldiazirinyl (TPD); (c) benzophenone containing TPD on optically pure phenylalanine under mild conditions. Reagents and conditions: (i) TfOH (>50 equiv.), opticallyr.t. or pure 60–80 phenylalanine °C, 1–2 h or 10–12 under h; (ii) mild TfOH conditions. (>25 equiv.), Reagents 0 °C or 0 and°C to conditions: r.t., 2–3 h. (i) TfOH (>50 equiv.), r.t. or 60–80 ◦C, 1–2 h or 10–12 h; (ii) TfOH (>25 equiv.), 0 ◦C or 0 ◦C to r.t., 2–3 h.

Catalysts 2017, 7, 40 12 of 27 Catalysts 2017, 7, 40 12 of 28 The use of the (3-trifluoromethyl)phenyldiazirinyl (TPD) group as a photoreactive group in photoaffinityThe use labeling of the (3-trifluoromethyl)phenyldiazirinyl confers selectivity for probe activation (TPD) without group damaging as a photoreactive the peptides group and inproteins photoaffinity under radiation labeling confersof 350 selectivitynm wavelength for probe [48,52,53]. activation The without strategy damaging for the thesynthesis peptides of andhomophenylalanine proteins under or radiation bis-homophenylalanine of 350 nm wavelength containing [48, 52TPD,53 ].moiety The strategy starts with for the introduction synthesis of homophenylalanineof a TPD moiety in anisole or bis-homophenylalanine 71 into an aspartic acid containing analogue TPD66a [48] moiety or a startsglutamic with acid the analogue introduction 66b of[46] a (Scheme TPD moiety 6b). inIn anisolethis reaction,71 into high an aspartictemperatur acides analoguecan result66a in the[48 ]decomposition or a glutamic acidof the analogue starting 66bmaterial[46] (Scheme71 due to6b). the In thermolability this reaction,high of TPD temperatures under strongly can result acidic in conditions the decomposition [50,54]. A of temperature the starting ° materialof 0 C 71isdue optimal to the thermolabilityfor synthesis ofusing TPD underthese stronglyvaluable acidic heat-sensitive conditions aromatic [50,54]. A compounds. temperature ofFurthermore, 0 ◦C is optimal the forreaction synthesis between using 71 these andvaluable 66a did heat-sensitivenot proceed when aromatic neat compounds. TiCl4 was used, Furthermore, whereas theutilization reaction of between TfOH afforded71 and 66a thedid acylated not proceed product when 72a neat up to TiCl a 68%4 was yield. used, The whereas acylated utilization products of 72 TfOH are affordedintermediates the acylated that can product be reduced72a up toand a 68% deprotecte yield. Thed to acylated produce products the photoaffinity72 are intermediates labeling thatprobes can bebased reduced on homophenylalanine and deprotected to or produce bis-homophenylalanine the photoaffinity labeling derivatives. probes The based mild on conditions homophenylalanine offered by orTfOH bis-homophenylalanine catalysis can also be derivatives.applied to construct The mild no conditionst only one, offeredbut also by two TfOH kinds catalysis of photophores can also beto appliedintroduce to in construct one probe. not The only strategy one, but for also this two synthesis kinds ofis photophoresthe direct acylation to introduce of benzoyl in one chloride probe. Thecontaining strategy TPD for this73 synthesisand N-protected is the direct phenylalanine acylation of 69b benzoyl at room chloride temperature containing (Scheme TPD 73 and6c). NEnhancement-protected phenylalanine of this reaction69b wasat roomevidenced temperature by no decomposition (Scheme6c). Enhancement of the diazirine of this moiety reaction (product was evidenced74); and no by loss no decompositionof optical purity of the was diazirine observed moiety after (product the deprotection74); and no of loss product of optical 74 purityby NaOH was observed(99% ee). after the deprotection of product 74 by NaOH (99% ee).

2.3. Forced Conditions A bifunctional substratesubstrate forfor both both the the acylation acylation and and alkylation alkylation of of aromatic aromatic compounds compounds draws draws a lot a oflotattention of attention for for the the proposes proposes of usefulof useful cyclic cyclic aromatic aromatic ketones ketones formation formation [55 [55].]. The The process, process, known known as cyclicas cyclic acylalkylation, acylalkylation, can can be be formed formed by by the the TfOH TfOH catalytic catalytic system system under under forced forcedconditions. conditions. AA high temperature and excess catalyst suppresses the competitivecompetitive intermolecular reaction to make the cyclization possible.possible. The The reaction reaction between between aromatics aromatics75 with 75 unsaturatedwith unsaturated carboxylic carboxylic acids 76 catalyzedacids 76 bycatalyzed TfOH has by beenTfOH found has been to produce found1-indanone to produce ( n1-indanone= 0) or 1-tetralone (n = 0) (orn =1-tetralone 1) forms of (n77 =(Scheme 1) forms7)[ of55 77]. The(Scheme high temperature7) [55]. The (at high 80 ◦ C)temperature contributes to(at the 80 induction °C) contributes of the cyclic to acylalkylationthe induction inof this the reaction. cyclic Inacylalkylation comparison, in a lowthis temperaturereaction. In comparison, (at 20 ◦C) favors a low the temperature multiple terminals (at 20 °C) acylation favors ofthe the multiple alkyne moietyterminals and acylation carboxylic of the moiety alkyne of moiety unsaturated and carb carboxylicoxylic moiety acid 76 of. Moreover,unsaturated thiochroman-4-ones, carboxylic acid 76. whichMoreover, are valuable thiochroman-4-ones, synthons and which important are precursorsvaluable synthons in organic and syntheses, important are precursors generally synthesized in organic viasyntheses, a multistep are generally reaction; asynthesized one-pot approach via a multistep was uncovered reaction; through a one-pot the useapproach of TfOH was [56 uncovered]. One-pot cyclicthrough acylalkylation the use of TfOH of thiophenols [56]. One-pot78 and cyclic crotonic acylalkylation or methacrylic of acidthiophenols (79 or 80 78) under and microwavecrotonic or irradiationmethacrylic and acid in (79 the or presence 80) under of microwave excess TfOH irradiation gives good and yields in the of presence thiochroman-4-ones of excess TfOH81 and gives82 (Schemegood yields8). of thiochroman-4-ones 81 and 82 (Scheme 8).

Scheme 7. TfOH-catalyzed cyclic acylalkylationacylalkylation of aromatic derivatives (75) andand alkenylalkenyl carboxyliccarboxylic

acid derivatives (76)) underunder forcedforced conditions.conditions. ReagentsReagents andand conditions:conditions: TfOHTfOH (~5(~5 equiv.),equiv.), CHCH22ClCl22 or °◦ ClCH2CH22Cl,Cl, 80 80 C,C, 16–20 16–20 h. h.

Catalysts 2017, 7, 40 13 of 28 Catalysts 2017, 7, 40 13 of 27 Catalysts 2017, 7, 40 13 of 27

Scheme 8. TfOH-catalyzed cyclic acylalkylation of thiophenols (78) and crotonic or methacrylic acid Scheme 8. TfOH-catalyzed cyclic acyl acylalkylationalkylation of thiophenols ( 78) and crotonic or methacrylic acid (79 or 80) under forcedforced conditions.conditions. ReagentsReagents andand conditions:conditions: TfOHTfOH (~10(~10 equiv.), CHCH2Cl2,, Microwave Microwave (79 or 80) under forced conditions. Reagents and conditions: TfOH (~10 equiv.), CH22Cl22, Microwave (MW), 110–155 °◦C, 5 min. (MW), 110–155 °C, 5 min.

3. General General Features Features of of the the TfOH TfOH Catalytic Systems for O-Acylation Esterification,Esterification, ester ester condensation, condensation, or or so-called so-called OO-acylation-acylation feature feature is is clearly clearly identified identified as as the general utilization of carboxylic acids and and alcohols that that are are usually usually activated activated by by Brønsted Brønsted acids. acids. Thus, Thus, esterificationsesterifications dodo notnot require require superacid superacid catalysis catalysis [9 ].[9 Indeed,]. Indeed, typical typical superacids have have been been studied studied and andobserved observed as convenient as convenient catalyst catalyst which which can improvecan improve the methodthe method for directfor direct esterification, esterification, without without any anychanges changes of catalytic of catalytic activity activity even even for prolonged for prolonged reaction reaction times times [9,57]. [9,57]. This characteristicThis characteristic has thus has led thus to ledledan interest toto anan interestinterest in the in usein thethe of useuse TfOH ofof TfOHTfOH as a catalyst asas aa catalystcatalyst for O-acylation. forfor O-acylation. Rotaxanes are are molecules composed of of a linear dumbbell-shaped substituent substituent flanked flanked by by one one or or more macrocycles. For For many many years, years, chemists have have been intrigued by the challenge of synthesizing thesethese mechanicallymechanicallymechanically interlocked interlockedinterlocked molecules; molecules;molecules; traditional traditionaltraditional synthetic syntheticsynthetic methods methodsmethods can onlycancan produceonlyonly produceproduce poor yields poorpoor yieldsof rotaxanes of rotaxanes [58]. The [58]. selective The selectiveO-acylation O-acylation of diethanolamine of diethanolamine83 by aromatic 83 byby aromaticaromatic acid anhydride acidacid anhydrideanhydride84 was 84carried waswas carriedcarried out in the outout presence inin thethe presencepresence of 1.5 equiv.ofof 1.51.5 equiv.equiv. of TfOH ofof TfOH and dibenzo-24-crown-8 and dibenzo-24-crown-8 to afford to afford [2]rotaxane [2]rotaxane85 at ◦ ° 850 atCat (Scheme00 °C (Scheme9). The 9). useThe of use TFA of andTFA MSAand MSA did not did allow not allow the formation the formation of 85 ofand 85 andand only onlyonly formed formedformed the thetheesterification esterificationesterification product productproduct from fromfrom starting startingstarting material materialmaterial83 83. Relative.. RelativeRelative to toto the thethe acidity acidityacidity of ofof other otherother catalysts,catalysts,catalysts, TfOHTfOH isis sufficientsufficient for the protection of the aminoamino groupgroup viavia protonationprotonation andand esterification.esterification. Thus, the TfOH catalytic system enables high production yields ofof 85 at low temperaturetemperature [[59].[59].59].

O O O O

O O O O Ar O O Ar HO OH (ArCO) O Ar O N O Ar HO N OH (ArCO)2O N N 2 O H2 O H O H2 O H O O O O CH 83 84 O O CH3 83 84 O O 3 Ar = Ar = 85 84% 85 84% CH3 CH3 Scheme 9. Selective TfOH-catalyzed O-acylation of diethanolamine 83 for the synthesis of [2] Scheme 9.9. SelectiveSelective TfOH-catalyzed TfOH-catalyzedO -acylationO-acylation of diethanolamineof diethanolamine83 for 83 the for synthesis the synthesis of [2]rotaxane of [2] rotaxane 85. Reagents and conditions: TfOH (1.5 equiv.), dibenzo-24-crown-8, CH2Cl2, 0 °C, 6 h. rotaxane 85. Reagents and conditions: TfOH (1.5 equiv.), dibenzo-24-crown-8, CH◦ 2Cl2, 0 °C, 6 h. 85. Reagents and conditions: TfOH (1.5 equiv.), dibenzo-24-crown-8, CH2Cl2, 0 C, 6 h.

TfOH as an efficient catalyst in the esterification reaction was also studied by Shibata et al. [60]. TfOH as an efficient catalyst in the esterification reaction was also studied by Shibata et al. [60]. Reactions between various benzoic acid derivatives (86) and octan-1-ol (87) were carried out using a Reactions between various benzoic acid derivatives (86) and octan-1-ol (87) were carried out using a catalytic amount of TfOH in 1,1,1,3,3-pentafluorobutane as a solvent. The unique properties of TfOH make it a more active catalyst than ; thus, 0.2 mol % of TfOH is sufficient for the excellent conversion of the reactants to 88 (Scheme(Scheme 10a).10a). ThisThis conditioncondition isis alsoalso suitablesuitable forfor thethe O-acylation of

Catalysts 2017, 7, 40 14 of 28 catalytic amount of TfOH in 1,1,1,3,3-pentafluorobutane as a solvent. The unique properties of TfOH make it a more active catalyst than sulfonic acid; thus, 0.2 mol % of TfOH is sufficient for the excellent Catalysts 2017, 7, 40 14 of 27 conversion of the reactants to 88 (Scheme 10a). This condition is also suitable for the O-acylation of eithereither the the diacid diacid89 89with with an an alcohol alcohol87 87(Scheme (Scheme 10 b),10b), or or the the diol diol90 90with with carboxylic carboxylic acid acid91 91(Scheme (Scheme 10 c). Both10c). of Both these of reactants these reactants were converted were converted to their to diesters,their diesters,92 or 9392 ,or respectively, 93, respectively, with with excellent excellent yields withoutyields thewithout need the for need extended for extended reaction reaction times. times.

SchemeScheme 10. 10.TfOH-catalyzed TfOH-catalyzed ester condensation condensation of of (a) ( abenzoic) benzoic acid acid derivatives derivatives 86 and86 octan-1-oland octan-1-ol 87; 87;((bb) )diacid diacid 8989 andand alcohol alcohol 8787; (c;() cdiol) diol 90 90andand carboxylic carboxylic acid acid 91. Reagents91. Reagents and conditions: and conditions: TfOH TfOH(0.2 ° (0.2mol mol %), %), 1,1,1,3,3-pentafluorobutane, 1,1,1,3,3-pentafluorobutane, 80 80C, ◦18C, h. 18 h.

4. Special Features of TfOH in Selective C- and/or O-Acylations 4. Special Features of TfOH in Selective C- and/or O-Acylations C- and/or O-acylations using various substrates naturally depend on the acyl donor and acceptor C O used.- and/orBoth reactions-acylations can be using controlled various by substrates changing naturally the reaction depend temperature, on the acyl which donor is andinherently acceptor used.related Both to reactions the reaction can betime. controlled The catalyst, by changing and sometimes the reaction the solvent, temperature, also plays which an isimportant inherently role related in to thethese reaction reactions. time. One The of the catalyst, unique and characteristics sometimes of the TfOH solvent, as a alsocatalyst plays is that an importantconditions rolefor TfOH- in these reactions.catalyzed One acylation of the unique may be characteristics determined and of TfOHadjusted as to a catalystincrease is the that reaction’s conditions selectivity. for TfOH-catalyzed Denoting acylationinto this may term, be itdetermined can be mentioned and adjusted as a “special” to increase catalytic the feature reaction’s of TfOH. selectivity. For example, Denoting TfOH into can this term,be used it can in be the mentioned transacylation as a “special”and deacylation catalytic between feature several of TfOH. types For of example,hindered TfOHacetophenones can be used and in theanisole transacylation 1 at 70 °C and in the deacylation presence of between imidazolium-based several types ioni ofc hindered liquids [61]. acetophenones The high yield and conversion anisole 1 at 70 (>98%◦C in thefor presenceone moiety of imidazolium-basedof acyl group in hindered ionic liquids acetophenones), [61]. The highhigh yieldselectivity, conversion minimal (>98% side for onereactions, moiety of and acyl the group obviated in hindered use of excess acetophenones), TfOH illustrate high its selectivity, superiority minimal over other side acids reactions, utilized and in the obviatedthese reactions. use of excess TfOH illustrate its superiority over other acids utilized in these reactions. TheThe selective selective intramolecular intramolecular cyclic cyclic acylationacylation ofof the 2-arylphenoxyacetic acid acid 9494, which, which contains contains twotwo phenyl phenyl ring ring moieties moieties (which (which areare denoteddenoted asas ringsrings A A and and B, B, Figure Figure 5)5)[ [62],62], is is another another unique unique characteristiccharacteristic of of the the TfOH TfOH catalytic catalytic system. system. CyclicCyclic acylation of of the the carboxylic carboxylic moiety moiety of of 9494 intointo ring ring A A to formto form arylcoumaranone arylcoumaranone95 95or or ring ring B toB to form form dibenzoxepine dibenzoxepine96 96can can be be controlled controlled (Figure (Figure5). 5). Under Under the actionthe action of the strongof the strong acid TfOH, acid TfOH, the intermediate the intermediate of mixed of mixed anhydride anhydride with 94withcan 94 form can andform then and furtherthen further transformed into an ionic intermediate by removing the possible leaving group as –OTf. This transformed into an ionic intermediate by removing the possible leaving group as –OTf. This ionic ionic intermediate exhibits the less steric hindrance; therefore, the formation of 95 or 96 is achievable, intermediate exhibits the less steric hindrance; therefore, the formation of 95 or 96 is achievable, depending upon the conditions. A low temperature is preferred for the selective formation of 95 depending upon the conditions. A low temperature is preferred for the selective formation of 95 (Figure 5a) using a similar amount of TfOH (30 equiv.) added dropwise. Meanwhile, under the same (Figure5a) using a similar amount of TfOH (30 equiv.) added dropwise. Meanwhile, under the temperature, utilization of a low amount of TfOH (10 equiv.) can result in the formation of 96 same(Figure temperature, 5b). utilization of a low amount of TfOH (10 equiv.) can result in the formation of 96 (Figure5b).

Catalysts 2017, 7, 40 15 of 28 Catalysts 2017, 7, x 15 of 27 Catalysts 2017, 7, 40 15 of 27

(a) (b) 100% 100%

80% 80%

60% 60% Proportion Proportion 40% 40%

20% 20%

0% 0% 35 25 15 0 0a to 25 10 20 30 40 (T oC) (Equiv.)a

aTfOH was drop wise added at 0 °C and then the reaction mixture was stirred at 25 oC

Compound 95 Compound 96

Figure 5.5. Intramolecular cyclic acylation of 2-arylphenoxyacetic2-arylphenoxyacetic acid 94. Dependence of 95 and 96 Figure 5. Intramolecular cyclic acylation of 2-arylphenoxyacetic acid 94. Dependence of 95 and 96 formation on (a) temperature andand ((b)) numbernumber ofof equivalentsequivalents ofof TfOH.TfOH. DataData fromfrom [[62].62]. formation on (a) temperature and (b) number of equivalents of TfOH. Data from [62]. The derivatization of O- and C-arylglycoside is hampered by the low solubility of the The derivatizationderivatization of ofO - andO- andC-arylglycoside C-arylglycoside is hampered is hampered by the lowby solubilitythe low ofsolubility the unprotected of the unprotected aromatic glycosides in the reaction medium and the competitive deglycosidation under aromaticunprotected glycosides aromatic inglycosides the reaction in the medium reaction andmedium the competitiveand the competitive deglycosidation deglycosidation under acidicunder acidic conditions for O-glycosides. TfOH was found to easily dissolve the carbohydrates without conditionsacidic conditions for O-glycosides. for O-glycosides. TfOH wasTfOH found was tofound easily to dissolve easily dissolve the carbohydrates the carbohydrates without without causing causing their decomposition. The low solubility of unprotected aromatic glycosides can be overcome theircausing decomposition. their decomposition. The low The solubility low solubility of unprotected of unprotected aromatic aromatic glycosides glycosides can be overcome can be overcome by using by using TfOH as a Friedel–Crafts acylation promoter. This technique can be extended to other TfOHby using as aTfOH Friedel–Crafts as a Friedel–Crafts acylation promoter. acylation This promoter. technique This can technique be extended can tobe other extended reactions to other such reactions such as direct acylation of O- and C-arylglycosides. The Friedel–Crafts acylation of the asreactions direct acylationsuch as direct of O- andacylationC-arylglycosides. of O- and C The-arylglycosides. Friedel–Crafts The acylation Friedel–Crafts of the aromaticacylation moiety of the aromatic moiety and O-acylation of the glucose moiety of aryl glycoside is dependent upon the andaromaticO-acylation moiety ofand the O glucose-acylation moiety of the of arylglucose glycoside moiety is of dependent aryl glycoside upon theis dependent proportion upon of TfOH the proportion of TfOH used [63]. The reaction of phenyl-β -D-glucoside 97 with 98 in usedproportion [63]. The of TfOH reaction used of [63]. phenyl- Theβ reaction-D-glucoside of phenyl-97 withβ-D acetyl-glucoside chloride 97 with98 in acetyl the presence chloride of98 excess in the the presence of excess TfOH (16 equiv.) can result in the production of 98 with good yield (Scheme TfOHpresence (16 of equiv.) excess can TfOH result (16 in equiv.) the production can result of 98in withthe production good yield of (Scheme 98 with 11 good). In this yield case, (Scheme the excess 11). 11). In this case, the excess TfOH promotes not only the Friedel–Crafts acylation of the aromatic TfOHIn thispromotes case, the excess not only TfOH the Friedel–Craftspromotes not acylationonly the Friedel–Crafts of the aromatic acylation moiety, butof the also aromatic the O-acylation moiety, moiety, but also the O-acylation of the glucose moiety. Treatment of 97 with 1.6 equiv. of TfOH, ofbut the also glucose the O-acylation moiety. Treatment of the glucose of 97 with moiety. 1.6 equiv.Treatment of TfOH, of 97 produces with 1.6 equiv. only the of per-TfOH,O-acetylated produces produces only the per-O-acetylated compound 100, indicating that the O-acylation is faster than the compoundonly the per-100O,-acetylated indicating thatcompound the O-acylation 100, indicating is faster that than the the O Friedel–Crafts-acylation is faster acylation. than Thisthe Friedel– result is Friedel–Crafts acylation. This result is supported by the re-treatment of 100 with a large amount of supportedCrafts acylation. by the This re-treatment result is ofsupported100 with aby large the re-treatment amount of TfOH, of 100 which with affordeda large amount an ~90% of yield TfOH, of TfOH, which afforded an ~90% yield of the Friedel–Crafts product 99. thewhich Friedel–Crafts afforded an product~90% yield99. of the Friedel–Crafts product 99.

Scheme 11. Dependence of the proportion of TfOH on C- and/or O-acylations of Scheme 11. Dependence of the proportion of TfOH on CC- and/or O-acylations of phenyl-β-D-glucoside Schemephenyl-β 11.-D-glucosideDependence 97. of Reagents the proportion and conditions: of TfOHon Acetyl- and/or chloride-acylations 98 (solvent), of phenyl- 0 C, 10 min.- -glucoside 97.. Reagents and conditions: Acetyl chloride 98 (solvent), 0 ◦°C, 10 min. The Friedel–Crafts C-acylation of phenol derivatives and acetyl agents and the Fries The Friedel–Crafts C-acylation of phenol derivatives and acetyl agents and the Fries rearrangement of phenyl ester derivatives via an appropriate catalyst are useful approaches to the rearrangement of phenyl ester derivatives via an appropriate catalyst are useful approaches to the synthesis of o- or p-hydroxyaryl ketones [1,2]. In these reactions, TfOH may act as both catalyst and synthesis of o- or p-hydroxyaryl ketones [1,2]. In these reactions, TfOH may act as both catalyst and

Catalysts 2017, 7, 40 16 of 28

The Friedel–Crafts C-acylation of phenol derivatives and acetyl agents and the Fries rearrangementCatalysts 2017, 7, 40 of phenyl ester derivatives via an appropriate catalyst are useful approaches to16 the of 27 synthesis of o- or p-hydroxyaryl ketones [1,2]. In these reactions, TfOH may act as both catalyst and solvent,solvent, resulting resulting in in high high efficiencies efficiencies of of these these reactions. reactions. When When phenol phenol101 101was was reacted reacted with with 1 1 equiv. equiv. ofof acetyl acetyl chloride chloride98 98using using an an excess excess of of neat neat TfOH TfOH (>30 (>30 mmol), mmol),p -hydroxyphenylp-hydroxyphenyl ketone ketone102 102was was formedformed (Scheme (Scheme 12 12a)a) [64 [64].]. Despite Despite the the reaction reaction being being conducted conducted at at room room temperature, temperature, the the reaction reaction waswas relatively relatively fast fast and and had had excellent excellent yield. yield. Under Under the the same same conditions, conditions, neat neat TfOH TfOH can can also also be be used used inin the the Fries Fries rearrangement rearrangement of of phenyl phenyl acetate acetate2 2to to produce producep -hydroxyphenylp-hydroxyphenyl ketone ketone102 102(Scheme (Scheme 12 12b).b). InIn contrast contrast to to the the conventional conventional Fries Fries rearrangement, rearrangement, which which usually usually involves involves heating heating the the reaction reaction mixturemixture to 80–180to 80–180◦C[ °2C], [2], the Friesthe Fries rearrangement rearrangement of phenyl of phenyl acetate acetate2 occurs 2 occurs at room at temperature room temperature under theunder mild the conditions mild conditions offered byoffered TfOH. by TheTfOH. appropriate The appropriate conditions conditions for catalysis for catalysis using neatusing TfOH neat TfOH can alsocan be also applied be applied to direct toC -acylationdirect C-acylation of acyl chlorides of acyl havingchlorides various having side various chains toside phenol chains derivatives. to phenol Theirderivatives. application Their to theapplication Fries rearrangement to the Fries rearra of variousngement phenyl of various carboxylate phenyl derivatives carboxylate also derivatives results in highalso yield. results in high yield.

(a) C-acylation

(i)

(b) Fries (i) rearrangement

(c) O-acylation

(ii)

SchemeScheme 12. 12.Controllable Controllable TfOH-catalyzed TfOH-catalyzedC- and C- Oand-acylations O-acylations of phenol of phenol101. Under 101. neat Under TfOH, neat phenol TfOH, 101phenolcan undergo 101 can (a undergo) C-acylation (a) C and-acylation phenyl and acetate phenyl2 can acetate undergo 2 can (b) Friesundergo rearrangement. (b) Fries rearrangement. Meanwhile, underMeanwhile, limited proportionunder limited of TfOH, proportion phenol of101 TfOH,can undergophenol 101 (c) Ocan-acylations. undergo Reagents(c) O-acylations. and conditions: Reagents

(i)and Neat conditions: TfOH (3 mL), (i) Neat 1 equiv. TfOH acetyl (3 mL), chloride 1 equiv.98 acetyl, r.t., 1chloride h; (ii) 1% 98 TfOH, r.t., 1 (inh; (ii) CH 1%3CN), TfOH 3 equiv. (in CH acetyl3CN), 3 chlorideequiv. 98acetyl, r.t., chloride 1 h. 98, r.t., 1 h.

The mixed carboxylic trifluoromethanesulfonic anhydride is formed from the reaction of TfOH The mixed carboxylic trifluoromethanesulfonic anhydride is formed from the reaction of TfOH with acyl chloride [65] or carboxylic acid [66,67]. It is known as an extremely powerful acylating agent with acyl chloride [65] or carboxylic acid [66,67]. It is known as an extremely powerful acylating [65,67]; its reaction with toluene is highly selective when a bulky side chain is used [67]. The TfOH agent [65,67]; its reaction with toluene is highly selective when a bulky side chain is used [67]. The TfOH catalytic system for acylation of m-cresol 103 using either acetyl chloride 98 (Scheme 13a) or acetic catalytic system for acylation of m-cresol 103 using either acetyl chloride 98 (Scheme 13a) or 104 (Scheme 13b) has been found to have similar yields of the isomeric products (105a/105b ratio acid 104 (Scheme 13b) has been found to have similar yields of the isomeric products (105a/105b of 1.4–2:1) [64]. This result indicates that the acylation of phenolic compounds with either acetyl ratio of 1.4–2:1) [64]. This result indicates that the acylation of phenolic compounds with either acetyl chloride 98 or acetic acid 104 have the same active species that plays an important role in exceeding chloride 98 or acetic acid 104 have the same active species that plays an important role in exceeding the the reaction. When m-tolyl acetate 106 was reacted with TfOH (Scheme 13c), both the Fries reaction. When m-tolyl acetate 106 was reacted with TfOH (Scheme 13c), both the Fries rearrangement rearrangement and hydrolysis were observed. Even though the Fries rearrangement of 106 was and hydrolysis were observed. Even though the Fries rearrangement of 106 was reported to be faster reported to be faster than the reaction of m-cresol 103 and acetic acid 98 in an hour, after 16 h reaction than the reaction of m-cresol 103 and acetic acid 98 in an hour, after 16 h reaction at room temperature at room temperature the yield of the products was almost the same. These results indicate the yield of the products was almost the same. These results indicate competition between the Fries competition between the Fries rearrangement and hydrolysis of m-tolyl acetate 106. However, the rearrangement and hydrolysis of m-tolyl acetate 106. However, the hydrolyzed acyl donor again hydrolyzed acyl donor again underwent a Friedel–Crafts type reaction with m-cresol 103 over an underwent a Friedel–Crafts type reaction with m-cresol 103 over an extended period [64]. extended period [64].

Catalysts 2017, 7, 40 17 of 28 Catalysts 2017, 7, 40 17 of 27

Scheme 13. TfOH-catalyzed synthesis of hydro hydroxyarylxyaryl ketone from acylation of (a) m-cresol 103 with acetyl chloride 98;(; (b) m-cresol 103 with acetic acid 104; and (c) Fries rearrangement of m-tolyl acetate 106.. Reagents andand conditions:conditions: Neat TfOH (3 mL), r.t.,r.t., 1616 h.h.

When phenol derivatives were reacted with a selected acyl donor using a catalyst, direct C- When phenol derivatives were reacted with a selected acyl donor using a catalyst, direct acylation was achieved and the O-acylation for the formation of phenyl ester derivatives was also C-acylation was achieved and the O-acylation for the formation of phenyl ester derivatives was observed (Scheme 12). A catalytic amount of TfOH in CH3CN (1%) used in the room-temperature also observed (Scheme 12). A catalytic amount of TfOH in CH3CN (1%) used in the room-temperature reaction between phenol 101 and acetyl chloride 98 afforded phenyl acetate 2 in excellent yields reaction between phenol 101 and acetyl chloride 98 afforded phenyl acetate 2 in excellent yields (Scheme 12c) [64]. Increasing the proportion of acetyl chloride 98 (3 equiv.) resulted in a quantitative (Scheme 12c) [64]. Increasing the proportion of acetyl chloride 98 (3 equiv.) resulted in a quantitative yield of phenyl acetate 2. A high proportion of the acylating agent was utilized to prevent other yield of phenyl acetate 2. A high proportion of the acylating agent was utilized to prevent other reactions when the available TfOH in the reaction system was very low. The interaction between reactions when the available TfOH in the reaction system was very low. The interaction between CH3CN, which also functions as a solvent, and TfOH has already been studied and a wide variety of CH3CN, which also functions as a solvent, and TfOH has already been studied and a wide variety of complicated structures that can be formed according to the ratio of the two compounds are known complicated structures that can be formed according to the ratio of the two compounds are known [68]. [68]. A previous study suggested that an excess amount of neat TfOH, acting as both catalyst and A previous study suggested that an excess amount of neat TfOH, acting as both catalyst and solvent, solvent, can catalyze the direct C-acylation of phenol 101 with acetyl chloride 98. This study showed can catalyze the direct C-acylation of phenol 101 with acetyl chloride 98. This study showed that the that the unique properties of TfOH, which depends on its proportion, affects the phenol 101 acylation unique properties of TfOH, which depends on its proportion, affects the phenol 101 acylation process process and can be controlled for C- or O-acylated product synthesis [64]. However, O-acylated and can be controlled for C- or O-acylated product synthesis [64]. However, O-acylated product product of phenyl acetate 2 is also can be followed by the Fries rearrangement to p-hydroxyaryl of phenyl acetate 2 is also can be followed by the Fries rearrangement to p-hydroxyaryl ketones, ketones, which are known as useful reactants and/or intermediates for the manufacture of which are known as useful reactants and/or intermediates for the manufacture of agrochemicals agrochemicals and pharmaceuticals. and pharmaceuticals. Direct C-acylation of naphthol 107 with acetyl chloride 98 and acetic acid 104, as well as the Fries Direct C-acylation of naphthol 107 with acetyl chloride 98 and acetic acid 104, as well as the rearrangement of naphtyl acetate 108 can be conducted by using the TfOH catalytic system (Table 3). Fries rearrangement of naphtyl acetate 108 can be conducted by using the TfOH catalytic system Kobayashi et al. [69] reported that the direct acylation of naphthol 107 required the use of 20% TfOH (Table3). Kobayashi et al. [ 69] reported that the direct acylation of naphthol 107 required the use of in a toluene–nitromethane (6.7:1) solution and a temperature of 100 °C (Table 3, entry 1). As 20% TfOH in a toluene–nitromethane (6.7:1) solution and a temperature of 100 ◦C (Table3, entry 1). mentioned above, catalysis by 1% TfOH in CH3CN at room temperature produces product 108 (Table As mentioned above, catalysis by 1% TfOH in CH3CN at room temperature produces product 108 3, entry 2). In a study of thermodynamic analysis of phenol 101 acylation with acetic acid 104 by (Table3, entry 2). In a study of thermodynamic analysis of phenol 101 acylation with acetic acid Sobrinho et al. [70], they found that temperature played an important role in determining the 104 by Sobrinho et al. [70], they found that temperature played an important role in determining acylation product; phenyl acetate 2 is favored over hydroxyphenyl ketone derivatives at high the acylation product; phenyl acetate 2 is favored over hydroxyphenyl ketone derivatives at high temperature (>800 K). The product distribution was also very clear in which ~100% formation of temperature (>800 K). The product distribution was also very clear in which ~100% formation of hydroxyphenyl ketone derivatives were selective when the temperature was up to 800 K. Therefore, hydroxyphenyl ketone derivatives were selective when the temperature was up to 800 K. Therefore, when the utilization of a limited proportion of TfOH was applied to naphthol 107 at a high when the utilization of a limited proportion of TfOH was applied to naphthol 107 at a high temperature, temperature, the two parallel pathways that resulted in the production of hydroxyaryl ketones [71,72] the two parallel pathways that resulted in the production of hydroxyaryl ketones [71,72] might might be pursued (the solvent effect, however, is not discussed here). First is the direct C-acylation be pursued (the solvent effect, however, is not discussed here). First is the direct C-acylation of of phenolic compound. Second is the O-acylation of phenolic compounds, which form the ester as an phenolic compound. Second is the O-acylation of phenolic compounds, which form the ester as an intermediate, and directly transform to hydroxyaryl ketones via the Fries rearrangement. Neat TfOH can also smoothly catalyze the direct C-acylation of naphthol 107 and the Fries rearrangement of 108,

Catalysts 2017, 7, 40 18 of 28 intermediate, and directly transform to hydroxyaryl ketones via the Fries rearrangement. Neat TfOH Catalysts 2017, 7, 40 18 of 27 can alsoCatalystsCatalysts smoothlyCatalysts 2017 2017, 7, 402017,, 7 catalyze,, 4040,, 7 ,, 4040 the direct C-acylation of naphthol 107 and the Fries rearrangement18 of18 27 of 18 27 of of 27108 , which affords good yields of the two isomers 109 and 110 (Table3, entries 3 and 4). In summary, which affords good yields of the two isomers 109 and 110 (Table 3, entries 3 and 4). In summary, the the controllabilitywhichwhich whichaffords affords affords good of good TfOH yields good yields catalysisyieldsof the of the twoof thetwo inisomers two directisomers isomers 109C 109- and and/or 109 and 110 and 110 (TableO 110 (Table-acylations (Table3, entries 3, entries 3, entries 3 canand 3 and be 4).3 and In4). exploited summary, In4). summary, In summary, to the obtain the the the controllabilitycontrollability of TfOHof TfOH catalysis catalysis in directin direct C- Cand/or-- and/orand/or O-acylations O-acylations-acylations can cancan be beexploitedbe exploitedexploited to obtaintoto obtainobtain the thethe desiredcontrollabilitycontrollability aromaticcontrollability productsof TfOHof TfOHof TfOHcatalysis from catalysis catalysis thermolabile in directin directin directC- Cand/or substrates,- and/orC- and/or O-acylations O-acylations anO-acylations approach can can be can beexploited that exploitedbe wouldexploited to obtainto be obtainto of obtainthe interest the the for desireddesireddesireddesired aromatic aromatic aromaticaromatic products products productsproducts from from thermolabile fromfrom thermolabile thermolabilethermolabile substr substr ates,substrsubstrates, anates,ates, anapproach approachanan approachapproach that that would thatthat would would wouldbe ofbe interestofbebe interest ofof interestinterest for for forfor further study. furtherfurtherfurtherfurther study. study. study.study.

Table 3. C- and/or O-acylations of naphthol 107 and the Fries arrangement of naphthol acetate 108. TableTable 3.TableC -3.Table and/or C 3.- and/or C -3. and/or CO- -acylationsOand/or-acylations O-acylations O-acylations of naphthol naphthol of naphthol of naphthol 107107 107andand 107and the and andthe theFries Friesthethe arrangement FriesFries arrangement arrangement arrangementarrangement of naphthol of naphtholof ofof naphtholnaphthol acetate acetate acetateacetate108 acetate .108 .108 108.. . No. Acyl No. No. No. Substrate AcylAcyl Acyl Condition Product Yield (%) No. (Ref.)(Ref.) SubstrateSubstrate SubstrateSubstrate Acyl DonorDonor ConditionCondition ConditionCondition ProductProduct Product ProductYield Yield (%) Yield (%) (%) (%) (Ref.)(Ref.) (Ref.) DonorDonor Donor

20 mol % TfOH in toluene– 20 mol20 mol%20 TfOH20 mol% molTfOH % in TfOH %toluene– in TfOH toluene– in toluene– in 1 [69] nitromethane solution (6.7:1), 1 [691 ][69]1 [69]1 [69] nitromethanenitromethanenitromethanetoluene–nitromethane solution solution solution (6.7:1), (6.7:1), (6.7:1), 100 °C, 6 h solution100 100°C, (6.7:1), 6°C,100 h 6 °C, h 100 6 h ◦C, 6 h

44% 44%44% 44% 44%

2 [64] 1% TfOH in CH33CN, r.t., 1 h 2 [642 ][64]2 [64]2 [64] 1% TfOH1%1% TfOH1% TfOH in TfOH CH in in3CHCN, in CH3 CN,CH r.t.,3CN,3 CN,1r.t., h r.t., 1r.t., h 11 hh

3 equiv. 33 equiv. 3 equiv. 3 equiv. quant. quant.quant. quant.quant.

3 [64] Neat TfOH (3 mL), r.t., 1 h 3 [643 ][64]3 [64]3 [64] NeatNeat NeatTfOHNeat TfOH TfOH(3 TfOH mL), (3 (3mL), r.t.,(3 mL), mL), 1r.t., h r.t., 1r.t., h 11 hh

1.5 equiv. 1.5 equiv.1.5 1.5 equiv.1.5 equiv. (27%)(27%) (27%)(27%) (27%) (60%) (60%)(60%) (60%)(60%)

4 [64] - Neat TfOH (3 mL), r.t., 1 h 4 [644 ][64]4 [64]4 [64] - - - Neat Neat NeatTfOH Neat TfOH TfOH (3 TfOH mL), (3 (3mL), r.t.,(3 mL), mL), 1r.t., h r.t., 1r.t., h 1 1 hh

(27%)(27%)(27%)(27%) (27%)(27%) (27%) (60%) (60%)(60%) (60%)(60%)

TheThe applicationsTheThe applications applicationsapplications of controlled of controlled ofof controlledcontrolled TfOH-catalyzed TfOH-catalyzed TfOH-catalyzedTfOH-catalyzed C- and/orC- and/or CC-- and/orand/or O-acylations O-acylations OO-acylations-acylations of phenol of phenol ofof phenolphenol 101 101 are 101 101 areshowed areareshowed showedshowed The applications of controlled TfOH-catalyzed C- and/or O-acylations of phenol 101 are showed in Schemein Schemeinin SchemeScheme 14 14[64,73]. [64,73].1414 [64,73].[64,73]. In aIn previous aInIn previous aa previousprevious section, section, section,section, the thusee ththuse eofe use useneatof neatofof TfOH neatneat TfOH TfOHTfOHunder under underundermild mild conditions mildmild conditions conditionsconditions in thein the inin thethe in Schemeacylationacylationacylation acylation14 of[ 64aromatic of, 73aromatic ofof]. aromaticaromatic Inderivatives aderivatives previous derivativesderivatives using using section, acylating usingusing acylating acylatingacylating theagent agent use 66 agentagent (Scheme of66 (Scheme 66 neat66 (Scheme(Scheme 5c) TfOH 5c)is discussed. 5c)5c)is underdiscussed. isis discussed.discussed. When mild When When1When conditions equiv. 1 equiv. 11 equiv.equiv.of of in ofof the acylationacylatingacylating ofacylatingacylating aromatic agent agent 66 agentagent is derivatives66 reacted is 6666 reacted isis reactedreacted with with using phenol withwith phenol acylating phenolphenol 101 101 under 101 101under agent underunderneat neat TfOH 66 neatneat TfOH(Scheme atTfOHTfOH room at room atat5 temperature, roomroomc) temperature, is discussed. temperature,temperature, the the C When-acylation thetheC-acylation CC-acylation-acylation 1 equiv. of acylatingproduct,product, agentproduct,product, benzyl benzyl66 benzylisbenzyl ca reactedrbonyl carbonyl cacarbonyl rbonylderivative with derivative derivativederivative phenol 111 111, is101 111,observed111 is observed,, under isis observedobserved inneat good in good ininTfOH yield. goodgood yield. Theyield.yield. at The room Fries TheThe Fries rearrangement temperature, FriesFries rearrangement rearrangementrearrangement step the step canC stepstep-acylation can cancan also be conducted from the phenyl ester 112 by the use of neat TfOH to produce two C-acylated product,alsoalso benzylbealso beconducted conductedbecarbonyl conducted from from derivative thefrom the phenyl thephenyl phenyl ester111 ester, 112 isester 112 observedby 112 bythe thebyuse theuse inof usegoodneatof neatof TfOH yield.neat TfOH TfOHto Theproduceto produceto Fries produce two rearrangementtwo C -acylatedtwo C-acylated C-acylated step isomersisomersisomers 111 111 (o- (or(o-- poror-position p-position-position with withwith ratio ratioratio of 1.4:1 ofof 1.4:11.4:1 for forforcompound compoundcompound 111a 111a and andand 9:1 9:19:1for forforcompound compoundcompound 111b 111b). O).).- O-- can alsoisomersisomers beisomers conducted 111 111 (o- 111(oro- p or(-positiono from- p or-position p-position the with phenyl with ratio with ratio of ester ratio 1.4:1of 1.4:1 112of for 1.4:1 forbycompound forcompound the compound use 111a of 111a neat and 111a and TfOH9:1 and 9:1for for9:1compound to produceforcompound compound 111b two 111b). 111bOC).--acylated O).- O- acylationacylationacylationacylation can can be can can proceededbe proceeded bebe proceededproceeded in thein the reactioninin thethereaction reactionreaction between between betweenbetween 3 equiv. 3 equiv. 33 equiv.equiv.of acylatingof acylating ofof acylatingacylating agent agent 66agentagent and66 and 6666 phenol andand phenol phenolphenol 101 101 by 101 101by byby isomers 111using(o- diluted or p-position TfOH in CH with3CN ratio (3%–5%) of 1.4:1 at room for temperature, compound producing111a and the 9:1 phenyl for ester compound 112 in good111b ). usingusing dilutedusing diluted diluted TfOH TfOH inTfOH CH in CH3 inCN CH3CN (3%–5%)3CN (3%–5%) (3%–5%) at room at room at temperature, room temperature, temperature, producing producing producing the the phenyl thephenyl phenyl ester ester 112 ester 112 in good 112in good in good O-acylationyield.yield. Theyield.yield. can The O -acylationTheThe beO-acylation proceeded OO-acylation-acylation product product productproduct in can the can also reaction cancan also undergo alsoalso undergo undergoundergo between the theFries thetheFries 3arrangement FriesFries equiv. arrangement arrangementarrangement of acylatingto the to the regioisomerstoto thetheregioisomers agent regioisomersregioisomers66 111and 111, with 111,111 phenol with ,, withwith 101 isolation yields and proportions identical to those of the direct Friedel–Crafts C-acylation products. by usingisolationisolation dilutedisolation yields yields TfOH yieldsand and proportions in and proportions CH proportions3CN identical (3%–5%) identical identical to thoseto at those roomto ofthose theof temperature, the directof thedirect Friedel–Craftsdirect Friedel–Crafts Friedel–Crafts producing C-acylation C-acylation the C-acylation phenyl products. products. products. ester 112 in goodCompound yield.CompoundCompoundCompound The 111O -acylation111 can 111 111can then cancan then undergo productthenthen undergo undergoundergo reduction can reduction alsoreductionreduction and undergo and deprotonation andand deprotonation thedeprotonationdeprotonation Fries to arrangement opticallyto opticallytoto opticallyoptically pure pure to multifunctional purepure the multifunctional regioisomersmultifunctionalmultifunctional 111 , products, homophenylalanine or bis-homophenylalanine derivatives (>99% ee), which can be used with isolationproducts,products,products, yieldshomophenylalanine homophenylalanine homophenylalanine and proportions or bis-homophenylalanor identical bis-homophenylalanor bis-homophenylalan to thoseine of inederivatives the inederivatives direct derivatives Friedel–Crafts(>99% (>99% (>99%ee), ee), which ee), whichC whichcan-acylation can be can usedbe usedbe products. used for forforfurther furtherfurther analytical analyticalanalytical studies. studies.studies. Hence, Hence,Hence, the thetheTfOH TfOHTfOH cata catacatalyticlyticlytic system systemsystem has hashas a number aa numbernumber of functions, ofof functions,functions, acting actingacting not not not Compoundfor forfurther furtherfor111 further analyticalcan analytical analytical then studies. studies. undergo studies. Hence, Hence, reductionHence, the the TfOH theTfOH cataTfOH and catalytic deprotonationcatalytic systemlytic system system has has a number hasa to number a optically number of functions, of functions, of pure functions, acting multifunctional acting notacting not not onlyonly asonlyonly aas catalyst a asas catalyst aa catalystcatalyst but but also but butalso as also also aas solvent. a asas solvent. aa solvent.solvent. Furthermore, Furthermore, Furthermore,Furthermore, it can it can be itit cancan controlledbe controlled bebe controlledcontrolled for forthe forthe fordesired thethedesired desireddesired C- and/orC- and/or CC-- and/orand/or O- O- OO-- products, homophenylalanine or bis-homophenylalanine derivatives (>99% ee), which can be used acylationsacylationsacylationsacylations products products productsproducts synthesis. synthesis. synthesis.synthesis. for further analytical studies. Hence, the TfOH catalytic system has a number of functions, acting not only as a catalyst but also as a solvent. Furthermore, it can be controlled for the desired C- and/or O-acylations products synthesis.

Catalysts 2017, 7, 40 19 of 28 Catalysts 2017, 7, 40 19 of 27

Scheme 14. Controllable C-- and/or OO-acylations-acylations of of phenol phenol 101101 catalyzedcatalyzed by by TfOH. Reagents and conditions: (i) neat TfOH, r.t., 1 h; (ii) neat TfOH, r.t., 2 h or 16 h; (iii) 3%–5% TfOH (in CH3CN), r.t., conditions: (i) neat TfOH, r.t., 1 h; (ii) neat TfOH, r.t., 2 h or 16 h; (iii) 3%–5% TfOH (in CH3CN), r.t., 30 min or 1 h.

5. Multifunctional Features of Deuterated TfOH (TfOD) Even though catalytic catalytic amounts amounts of of TfOH TfOH are are known known to to enable enable selective selective OO- and/or- and/or C-acylationC-acylation in organicin organic solvents, solvents, the the solubility solubility of ofsome some substrates substrates such such as as amino amino acids, acids, which which was was previously mentioned above, should be taken intointo consideration.consideration. Selection Selection of of suitable conditions for these reactions isis necessary,necessary, especially especially the the reactions reactions for opticallyfor optically active active amino amino acids. acids. Several Several plausible plausible routes routesusing varioususing various active species active [species65–67] for[65–67] aromatic for aromatic acylation acylation exist (Scheme exist 15 (Scheme). The mixed 15). The carboxylic mixed carboxylictrifluoromethanesulfonic trifluoromethanesulfonic anhydride mayanhydride be obtained may bybe treatmentobtained ofby TfOH treatment with acylof TfOH chloride with [65 acyl] or chloridecarboxylic [65] acid or [carboxylic66,67]. The acid acylation [66,67]. pathway The acylat forion an pathway acyl donor for in an the acyl form donor of alkyl in the carboxylic form of alkyl acid 113carboxylicor acyl chlorideacid 113114 or canacyl produce chloride several 114 species.can produce When several mixed, carboxylicspecies. When trifluoromethanesulfonic mixed, carboxylic trifluoromethanesulfonicanhydride is deprotonated anhydride and is115 deprotonatedmay be formed and (Scheme ketene 15115a). may Next, be if noformed proton (Scheme is eliminated 15a). Next,during if theno process,proton is the eliminated dissociated during acyl carbonium the process, ion the116 dissociatedseems more acyl reliably carbonium formed. ion (Scheme 116 seems 15b). Anothermore reliably possible formed. species (Scheme is the protonated 15b). Another carbonyl possible ofthe species mixed is anhydridethe protonated117 (Scheme carbonyl 15 ofc), the in mixed which anhydridethe detailed 117 spectroscopy (Scheme 15c), has beenin which studied. the Ascertainingdetailed spec whichtroscopy intermediate has been hasstudied. formed Ascertaining is a crucial whichstep in intermediate preventing thehas formation formed is of a acrucial racemic step adduct in preventing during acylation. the formation One ofof thea racemic advantages adduct of 2 duringTfOH potential acylation. features One of arethe the advantages2H-labelling of TfOH experiments potential by features using deuterated are the H-labelling TfOH (TfOD). experiments The use byof TfODusing asdeuterated a catalyst, TfOH solvent, (TfOD). and sourceThe use of of deuterium TfOD as ina catalyst, /deuterium solvent, and source (H/D) of exchange deuterium in inthe hydrogen/deuterium direct C-acylation of aromatic(H/D) exchange substrates in providesthe direct insight C-acylation into the of mechanismsaromatic substrates of these reactions.provides insightDeuterium into incorporationthe mechanisms at theof theseα-proton reactions. of carbonyl Deuterium during incorporation TfOD-catalyzed at the reaction α-proton between of carbonyl acyl duringdonor and TfOD-catalyzed substrate indicates reaction the formationbetween acyl of the donor intermediate and substrate ketene indicates115. Otherwise, the formation non-deuterium of the intermediateincorporation ketene at the α115-proton. Otherwise, of carbonyl non-deuterium indicates formation incorporation of either at the the acyl α-proton cabonium of ioncarbonyl116 or indicatesprotonated formation carbonyl of of either mixed the anhydride acyl cabonium117. ion 116 or protonated carbonyl of mixed anhydride 117.

Catalysts 2017, 7, 40 20 of 28 Catalysts 2017, 7, 40 20 of 27 Catalysts 2017, 7, 40 20 of 27

Scheme 15. Plausible acylation routes of benzene 9 with alkyl carboxylic acid 113 or acyl chloride 114 Scheme 15. Plausible acylation routes of benzene 9 with alkyl carboxylic acid 113 or acyl chloride 114 via formation of (a) ketene 115;(; (b)) acylacyl carboniumcarbonium ion 116;; oror ((cc)) protonatedprotonated carbonylcarbonyl ofof anhydrideanhydride via formation of (a) ketene 115; (b) acyl carbonium ion 116; or (c) protonated carbonyl of anhydride mixture 117.. mixture 117. TfOD catalysis of the direct C-acylation of toluene 118 and glutamic acid derivatives 66b has TfOD catalysis catalysis of of the the direct direct C-acylationC-acylation of oftoluene toluene 118118 andand glutamic glutamic acid acid derivatives derivatives 66b 66bhas been previously established (Scheme 16) [74]. The deuterium incorporation was observed only on the hasbeen been previously previously established established (Scheme (Scheme 16) [74]. 16 The)[ 74deuterium]. The deuterium incorporation incorporation was observed was only observed on the aromatic protons (68%–75% deuterium incorporation) at a fine yield (94%) of the acylated product onlyaromatic on theprotons aromatic (68%–75% protons deuterium (68%–75% incorporation) deuterium incorporation)at a fine yield (94%) at a fineof the yield acylated (94%) product of the 119. The active species in the typical Friedel–Crafts acylation/electrophilic aromatic substitution is acylated119. The productactive species119. The in activethe typical species Friedel–Crafts in the typical acylation/electrophilic Friedel–Crafts acylation/electrophilic aromatic substitution aromatic is very important, especially the N-alkylated α-amino acids that behave as acyl donors. If the substitutionvery important, is very especially important, the especially N-alkylated the Nα-alkylated-amino acidsα-amino that acidsbehave that as behave acyl donors. as acyl donors.If the deprotonation of the α-proton of the carbonyl favors ketene species 115 (Scheme 15a), racemization Ifdeprotonation the deprotonation of the α of-proton the α of-proton the carbonyl of the favors carbonyl ketene favors species ketene 115 (Scheme species 11515a),(Scheme racemization 15a), can occur because of the loss of optical purity of the α-. Experiments for elucidating racemizationcan occur because can occur of the because loss of of optical the loss purity of optical of the purity α-amino of the acid.α-amino Experiments acid. Experiments for elucidating for reaction mechanisms using catalysis by TfOD have revealed intramolecular cyclization of methyl- elucidatingreaction mechanisms reaction mechanisms using catalysis using by catalysis TfOD have by TfOD revealed have intramolecular revealed intramolecular cyclization cyclization of methyl- of cyano-3-arylpropionate and non-deuterium incorporation of the α-proton of the recovered starting methyl-cyano-3-arylpropionatecyano-3-arylpropionate and non-deuterium and non-deuterium incorporation incorporation of the α-proton of the α of-proton the recovered of the recovered starting material was observed [75]. These findings suggest that acid-catalyzed deprotonation of the α-proton startingmaterial materialwas observed was observed [75]. These [75 findings]. These suggest findings that suggest acid-catalyzed that acid-catalyzed deprotonation deprotonation of the α-proton of the of methyl-cyano-3-arylpropionate does not reach equilibrium even under strongly acidic conditions. αof-proton methyl-cyano-3-arylpropionate of methyl-cyano-3-arylpropionate does not reach does eq notuilibrium reach equilibrium even under even strongly under acidic strongly conditions. acidic In conclusion, in the reaction process, the exclusion of the loss α-proton is feasible. A similar tendency conditions.In conclusion, In conclusion,in the reaction in the process, reaction the process, exclusion the of exclusion the loss ofα-proton the loss isα feasible.-proton is A feasible. similar tendency A similar has also been observed in the intramolecular cyclization of 3-nitro-3-phenylpropionate, which found tendencyhas also been has observed also been in observed the intramolecular in the intramolecular cyclization of cyclization 3-nitro-3-phenylpropionate, of 3-nitro-3-phenylpropionate, which found no contribution of proton elimination during the reaction [76]. In the TfOD-catalyzed acylation of whichno contribution found no of contribution proton elimination of proton during elimination the reaction during [76]. the reaction In the TfOD-catalyzed [76]. In the TfOD-catalyzed acylation of toluene 118 with glutamic acid derivatives 66b, the deuterium incorporation occurred only at acylationtoluene 118 oftoluene with glutamic118 with glutamicacid derivatives acid derivatives 66b, the66b deuterium, the deuterium incorporation incorporation occurred occurred only only at aromatic protons, indicating the absence of α-proton deprotonation and that formation of ketene 115 ataromatic aromatic protons, protons, indicating indicating the the absence absence of α of-protonα-proton deprotonation deprotonation and and that that formation formation of ketene of ketene 115 formations was not possible. 115formationsformations was was not notpossible. possible.

Scheme 16. TfOD-catalyzed C-acylation of toluene 118 and glutamic acid derivatives 66b. Reagents Scheme 16. TfOD-catalyzed C-acylation of toluene 118 and glutamic acid derivatives 66b. Reagents Schemeand conditions: 16. TfOD-catalyzed TfOD, r.t., 1 h.C -acylation of toluene 118 and glutamic acid derivatives 66b. Reagents and conditions: TfOD, r.t., 1 h.

H/D exchange methods can generally be divided into those utilizing D2O as the deuterium H/D exchange methods can generally be divided into those utilizing D2O as the deuterium source,H/D those exchange involving methods the addition can generally of an beacid divided or base, into and those those utilizing using Dmetal-promotedO as the deuterium H/D source, those involving the addition of an acid or base, and those using metal-promoted2 H/D source,exchange. those Commonly, involving theheterogeneous addition of ancatalytic acid or systems base, and are those frequently using metal-promoted used under harsh H/D conditions exchange. exchange. Commonly, heterogeneous catalytic systems are frequently used under harsh conditions Commonly,and followed heterogeneous by dehalogenation, catalytic systems hydrogenation, are frequently hydrolysis, used under as harshwell conditionsas epimerization and followed and and followed by dehalogenation, hydrogenation, hydrolysis, as well as epimerization and byracemization dehalogenation, [77,78].hydrogenation, Since a homogenous hydrolysis, system asis preferable well as epimerization in H/D exchange, and racemizationespecially in the [77 case,78]. racemization [77,78]. Since a homogenous system is preferable in H/D exchange, especially in the case Sinceof optically a homogenous active amino system acids, is preferablethe organic in solvent H/D exchange,must consider especially no observation in the case of ofamino optically acid of optically active amino acids, the organic solvent must consider no observation of amino acid activeracemization amino during acids, thethe organicreaction. solvent A study must thatconsider used a D no2O/D observation2SO4 system of found amino that acid conditions racemization will racemization during the reaction. A study that used a D2O/D2SO4 system found that conditions will lead to either partial or complete racemization of phenylalanine H/D exchange, which is indicated by lead to either partial or complete racemization of phenylalanine H/D exchange, which is indicated by the exchange of α-protons [79]. Deuterated TFA (TFA-d) is appropriate for slow H/D exchange [80], the exchange of α-protons [79]. Deuterated TFA (TFA-d) is appropriate for slow H/D exchange [80],

Catalysts 2017, 7, 40 21 of 28

during the reaction. A study that used a D2O/D2SO4 system found that conditions will lead to Catalystseither partial 2017, 7, 40 or complete racemization of phenylalanine H/D exchange, which is indicated by21 of the 27 exchange of α-protons [79]. Deuterated TFA (TFA-d) is appropriate for slow H/D exchange [80], but its butapplication its application to aromatic to aromatic amides andamides and [81amines] is less [81] effective is less foreffective more electron-poorfor more electron-poor substrates substratessuch as acetophenone such as acetophenone and its derivatives and its derivatives [82]. In Scheme [82]. In 17 Scheme, a comparison 17, a comparison can be made can be between made phenylalaninebetween phenylalanine120 and 120 tyrosine and tyrosine121 treated 121 treated with TFA- withd TFA-[82]d and [82] TfOD and TfOD [74,83 [74,83].]. It shows It shows that that the thearomatic aromatic proton proton deuterium deuterium incorporation incorporation is generally is generally larger larger when TfODwhen isTfOD used. is Thus, used. the Thus, absence the absenceof α-proton of α exchange-proton exchange with TfOD with indicates TfOD indicates no loss ofno optical loss of purity optical of purity amino of acids. amino On acids. the basisOn the of basisthe time of the dependence time dependence of H/D exchangeof H/D exchange using TfOD using as TfOD monitored as monitored by mass by spectroscopy, mass spectroscopy, the favored the favoredsites for sites H/D for exchange H/D exchange can be summarized can be summarized as the o-position as the o-position with respect with to respect the hydroxyl to the grouphydroxyl on grouptyrosine on > thetyrosine hydrogen > the atoms hydrogen of phenylalanine atoms of phenylalanine > the m-position > the with m-position respect to with the hydroxyl respect to group the hydroxylon tyrosine. group on tyrosine.

Scheme 17.17. H/DH/D exchange exchange in in phenylalanine phenylalanine 120120, ,tyrosine tyrosine 121121,, and phenylalaninephenylalanine derivativesderivatives containing TPD ( 122). Numbers Numbers in in brackets brackets give give the the percentage percentage of of deuterium deuterium in in the the side side chain chain sites. sites. Reagents and conditions: (i) TFA- d,, 110 ◦°CC 16 h, [82]; [82]; (ii) TfOD, TfOD, r.t., r.t., 1 h or 12 h [74,83]; [74,83]; (iii) TfOD, 0 °C,◦C, 5 h [83]. [83].

As mentionedmentioned previously, previously, TfOH TfOH can can be usedbe used in mild in reactionmild reaction conditions conditions for C-acylation for C-acylation synthesis synthesisof probes containingof probes valuablecontaini heat-sensitiveng valuable photophoresheat-sensitive for photophores photoaffinity for labeling photoaffinity (Scheme 6).labeling TfOD was(Scheme thus 6). also TfOD used inwas H/D thus exchange also used for aromaticin H/D exchange amino acids for oraromatic peptides amino containing acids photophores.or peptides Thecontaining special photophores. feature utility The of specia TfODl feature under utility mild conditionsof TfOD under for H/Dmild conditions exchange for of phenylalanineH/D exchange ofderivatives phenylalanine containing derivatives photophores containing has photophore been establisheds has been [83]. established In this system, [83]. In the this phenylalanine system, the phenylalaninederivative containing derivative TPD containing (122; Scheme TPD 17) ( can122; dissolve Scheme well 17) incan TfOD, dissolve and well the low in TfOD, temperature and the allows low temperature allows H/D exchange of these valuable heat-sensitive photophores. The selective aromatic-protons deuterium incorporation by TfOD in the synthesis of other important photophores based on benzophenone derivatives via direct C-acylation of an aromatic substrate and benzoyl chloride has also been studied [84]. Fast H/D exchanges that occur only on the aromatic protons of the substrate is proposed from the exclusion of benzyl carbonium ion formation from benzoyl

Catalysts 2017, 7, 40 22 of 28

H/D exchange of these valuable heat-sensitive photophores. The selective aromatic-protons deuterium incorporation by TfOD in the synthesis of other important photophores based on benzophenone derivatives via direct C-acylation of an aromatic substrate and benzoyl chloride has also been studied [84]. Fast H/D exchanges that occur only on the aromatic protons of the substrate is proposed from the exclusion of benzyl carbonium ion formation from benzoyl chloride. Intramolecular H/D exchanges between benzene and TfOD via 1,2-hydride shifts, that have been previously studied, are known to occur rapidly at room temperature [85]. However, aromatic-protons H/D exchange on the substrates containing photophores can contribute to comprehensive photoaffinity labeling studies in the future. H/D exchange can be used not only in investigations of reaction mechanisms, but also for selective protonation/deuteration, which can greatly simplify the spectra of even the largest protein moieties [86]. Several simple exchange techniques for the selective deuteration of aromatic amino acids have been developed [79,86,87], yet α-amino acids are known to interfere in these methods because of their solubility in many organic solvents [83,88,89]. The substrate solubility in the homogenous catalytic system for H/D exchanges influences the rate of hydride transfer between the substrate and its deuterated derivative, which can be analyzed from isotopolog distributions obtained by mass spectroscopy. For example, the low solubility of isobutene in D2SO4 can limit hydride transfer to the gas–liquid interface. Thus, the cation solvated in the acid has a long residence time, which undergoes repeated deprotonation and reprotonation, in turn leading to fast H/D exchange before hydride transfer. In contrast, the solubility of isobutane in TfOD is much higher; as a result, hydride transfer may occur in the liquid phase [90] and result in fast H/D exchange. This example is in agreement with the high dissolving capacity of TfOH [12]. Therefore, TfOD can be used to dissolve most α-amino acid derivatives and H/D exchange study can be broadened into peptides utilization. According to Wishart et al. [86], there are several criteria that must be fulfilled for improving the selectivity of deuteration of aromatic amino acids. First, the solubility of very hydrophobic amino acids must be enhanced in order to increase their labeling efficiency. Second, the labeling efficiency must not be lost and amino acid decomposition must not occur. Third, the methodological improvements should make large-scale protonation and deuteration of aromatic amino acids accessible and affordable to any well-equipped biochemistry laboratory, and finally, the method must provide significant savings in time and contribute to greater laboratory safety. The simple, safe, and high product yield of this process, as well as its ability to produce non-racemic deuterated amino acids, can be achieved because of the unique properties of TfOD as discussed above. Rapid room-temperature H/D exchange with peptides without any stereochemical changes has been achieved by controlling the amount of TfOD [74]. Leucine enkephalin 123 (Tyr-Gly-Gly-Phe-Leu/YGGFL) is a pentapeptide with two aromatic rings (tyrosine and phenylalanine; Scheme 18) that has been studied by mass spectrometry [91,92]. Leucine enkephalin 123 has been previously shown to undergo H/D exchange with ND3 [93] in the gas phase [94]. Additionally, a homogenous system may be obtained using TfOD (as shown by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy). In this system, leucine enkephalin 123 can dissolve well in TfOD even at low temperatures. Within 9 h at room temperature, four and five exchanges sites were observed. Characterizations of deuterated leucine-enkephalin 123 via digestion with chymotrypsin have shown that the favored H/D exchange sites in the order of most to least favorable are as follows: the 3-position of tyrosine > phenylalanine > 2-position of tyrosine (Scheme 18). TfOD catalytic systems may also be utilized in the development of H/D exchange methods, which may extend the application of H/D exchange to a vast range of substrates, including compounds that are valuable, heat-sensitive, and sparingly soluble in many organic solvents. Catalysts 2017, 7, 40 23 of 28 Catalysts 2017, 7, 40 23 of 27

Scheme 18.18. TfOD-catalyzed H/D exchange exchange with with leucin leucinee enkephalin enkephalin (Tyr-Gly (Tyr-Gly-Gly-Phe-Leu,-Gly-Phe-Leu, YGGFL) 123123 andand itsits characterizationcharacterization byby digestiondigestion with chymotrypsin. Reagents and conditions conditions:: (i) (i) TfOD, TfOD, r.t., r.t., 9 h; (ii) chymotrypsin [[71].71].

6. Conclusions 6. Conclusions In general, the catalytic features of TfOH have contributed largely to increase the effectiveness In general, the catalytic features of TfOH have contributed largely to increase the effectiveness and efficiency of acid-promoted C- and/or O-acylations. The roles of TfOH as both catalyst and and efficiency of acid-promoted C- and/or O-acylations. The roles of TfOH as both catalyst and solvent solvent have broadened its utilization towards various substrates. Moreover, the amenability of the have broadened its utilization towards various substrates. Moreover, the amenability of the neat neat catalytic systems under mild reaction conditions makes it useful for valuable heat-sensitive catalytic systems under mild reaction conditions makes it useful for valuable heat-sensitive substrates. substrates. TfOH can also be used in any reaction that requires forced conditions. The special features TfOH can also be used in any reaction that requires forced conditions. The special features of TfOH of TfOH enable the control of C- and/or O-acylations of phenol derivatives, which are dependent enable the control of C- and/or O-acylations of phenol derivatives, which are dependent upon the upon the proportion of TfOH used; exploiting such characteristics is thus a useful approach to proportion of TfOH used; exploiting such characteristics is thus a useful approach to increasing the increasing the selectivity of these reactions. The construction of a metal-free TfOH catalytic system selectivity of these reactions. The construction of a metal-free TfOH catalytic system through the through the development of a solvent-free and highly selective synthesis may enhance the efficiency development of a solvent-free and highly selective synthesis may enhance the efficiency of direct of direct catalytic acylation, thus possibly providing economic and environmental benefits. catalytic acylation, thus possibly providing economic and environmental benefits. Acknowledgments: Zetryana Puteri Tachrim thanks LPDP (Indonesia Endowment Fund for Education) for Acknowledgments:financial support. PartZetryana of this work Puteri was Tachrim performed thanks un LPDPder the (Indonesia Cooperative Endowment Research Program Fund for of Education) the Network for financial support. Part of this work was performed under the Cooperative Research Program of the Network Joint Joint Research Center for Materials and Devices. Research Center for Materials and Devices. Author Contributions:Contributions:Zetryana Zetryana Puteri Puteri Tachrim, Tachrim, Lei Wang,Lei Wang, Yuta Murai,Yuta TakumaMurai, Takuma Yoshida andYoshida Makoto and Hashimoto Makoto designedHashimoto the designed experiments; the Zetryanaexperiments; Puteri Zetryana Tachrim, Puteri Lei Wang, Tachrim, Yuta Murai,Lei Wang, Takuma Yuta Yoshida, Murai, Natsumi Takuma Kurokawa, Yoshida, FuminaNatsumi OhashiKurokawa, and MakotoFumina HashimotoOhashi and performedMakoto Hashim the experiments;oto performed Zetryana the experiments; Puteri Tachrim, Zetryana Lei Wang,Puteri YutaTachrim, Murai, Lei Takuma Wang, Yuta Yoshida, Murai, Yasuyuki Takuma Hashidoko Yoshida, andYasuyuki Makoto Hashidoko Hashimoto and analyzed Makoto theHashimoto data; Zetryana analyzed Puteri the Tachrimdata; Zetryana and Makoto Puteri HashimotoTachrim and wrote Makoto the paper.Hashimoto wrote the paper. Conflicts of Interest: The authors declare no conflicts of interest. Conflict of Interest: The authors declare no conflicts of interest. References References and note 1. Olah, G.A. Friedel–Crafts and Related Reactions; Interscience Publishers-John Wiley & Sons, Inc.: London/Beccles, 1. Olah, G.A. Friedel–Crafts and Related Reactions; Interscience Publishers-John Wiley & Sons, Inc.: UK, 1963; Volume 1. London/Beccles, UK, 1963; Volume 1. 2. Olah, G.A. Friedel–Crafts and Related Reactions; Interscience Publishers-John Wiley & Sons, Inc.: London/Beccles, 2. Olah, G.A. Friedel–Crafts and Related Reactions; Interscience Publishers-John Wiley & Sons, Inc.: UK, 1964; Volume 3, Part 1. London/Beccles, UK, 1964; Volume 3, Part 1. 3. Effenberger, F.; Epple, G. Catalytic Friedel–Crafts acylation of aromatic compounds. Angew. Chem. Int. Ed. Effenberger, F.; Epple, G. Catalytic Friedel–Crafts acylation of aromatic compounds. Angew. Chem. Int. Ed. 3. 1972, 11, 300–301. [CrossRef] 1972, 11, 300–301. 4. Olah, G.A.; Arvanaghi, M.; Krishnamurthy, V.V. Heterogeneous catalysis by solid superacids. 17. Polymeric

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