The Beneficial Sinergy of MW Irradiation and Ionic Liquids in Catalysis of Organic Reactions

catalysts

Review The Beneﬁcial Sinergy of MW Irradiation and Ionic Liquids in Catalysis of Organic Reactions

Barbara Floris, Federica Sabuzi, Pierluca Galloni and Valeria Conte * ID

Dipartimento di Scienze e Tecnologie Chimiche, Università degli Studi di Roma “Tor Vergata”, via della Ricerca Scientiﬁca snc, 00133 Rome, Italy; ﬂ[email protected] (B.F.); [email protected] (F.S.); [email protected] (P.G.) * Correspondence: [email protected]; Tel.: +39-06-72594014

Received: 26 July 2017; Accepted: 23 August 2017; Published: 1 September 2017

Abstract: The quest for sustainable processes is becoming more and more important, with catalysis playing a major role in improving atom economy and reducing waste. Organic syntheses with less need of protecting/de-protecting steps are highly desirable. The combination of microwave irradiation, as energy source, with ionic liquids, as both solvents and catalysts, offered interesting solutions in recent years. The literature data of the last 15 years concerning selected reactions are presented, highlighting the importance of microwave (MW) technology coupled with ionic liquids.

Keywords: catalysis; microwave; ionic liquids; C–C bond formation; oxidation

1. Introduction Twenty years have elapsed since the publication of the seminal book by Anastas and Warner [1], where principles of Green Chemistry were formulated and presented in a systematic discussion. Since then, the idea of “eco-friendly” or “sustainable” ways to obtain and to transform chemicals has increasingly spread among the scientific community [2]. Catalysis is an important tool for the development of sustainable processes; among the other ones, alternative energy sources (as provided by microwave heating) and alternative solvents (for example, ionic liquids, ILs) are of major importance. Microwave irradiation rapidly gained importance and was widely applied as a “green” way to provide the necessary energy to reactions. In 2002, a book appeared [3] containing many examples of applications to organic synthesis, followed in 2006 by an increased second edition. In addition, ILs were the object of a book that became a two-volume set after few years [4]. Since then, reviews appeared discussing several aspects of both microwave (MW) and ILs topics, separately (see, for example [5–11]) and together (for selected examples, see [12–16]). Nowadays, the use of ILs is quite diffuse, but a brief illustration of their characteristics may be useful for people not yet familiar with them. According to the generally accepted definition [4], Ionic Liquids are salts that are liquid at room temperature (or, at least, below 100 ◦C). They are non-volatile and non-flammable, which make them interesting substitutes for volatile organic solvents. Their properties depend on the nature of both cation and anion, thus giving access to a large number of compounds, often tailor-made, on the basis of reaction requirements. Moreover, depending on their miscibility or non-miscibility with water or organic solvents, they can be easily recycled, simply by distilling off (or filtering) the reaction product at the end of the reaction, washing with water, drying and reusing them. Generally, catalysts remain in the IL phase, so that addition of reagents allows a second reaction run. Thus, on the basis of their properties, ILs are considered “green solvents”. They are commercially available, with prices that became accessible with time, although purity is still a crucial item. Therefore, it is advisable to prepare them by known, simple, and reproducible procedures, rather than to buy commercial products [4].

Catalysts 2017, 7, 261; doi:10.3390/catal7090261 www.mdpi.com/journal/catalysts CatalystsCatalysts 20172017,, 77,, 261 261 22 of of 56 57

One of us became involved in MW‐assisted reactions in ILs since 2003, investigating oxidation of electrophilicOne of us became alkenes involved by inhydrogen MW-assisted peroxide reactions in in ILspresence since 2003, of investigatinga base [17]. oxidation ILs with1of electrophilic‐butyl‐3‐methylimidazolium alkenes by hydrogen cation peroxide and different in presence counteranions of a base were [17]. used. ILs with1-butyl-Generally, epoxides3-methylimidazolium formed quantitatively cation and within different few minutes counteranions at room were temperature. used. Generally, The sustainability epoxides formed of the reactionquantitatively was granted within few by minutes the safe at and room inexpensive temperature. oxidant, The sustainability by the non of‐ thevolatile reaction solvents, was granted and, moreover,by the safe by and the inexpensive extraction oxidant,of the organic by the product, non-volatile performed solvents, with and, supercritical moreover, bycarbon the extraction dioxide. Later,of the screening organic product, the oxidation performed of different with supercritical substrates with carbon H2O dioxide.2 and VVO Later, complexes screening in ILs, the we oxidation found V thatof different MW irradiation substrates had with a beneficial H2O2 and effect V O in complexes oxidation inof ILs,organic we foundsulfides that [18], MW where irradiation a significant had a improvementbeneficial effect in inthe oxidation rate of ofreaction organic and sulfides an increase [18], where in selectivity a significant have improvement been observed, in the when rate hydrophobicof reaction and ILs an were increase used in in combination selectivity have with been MW observed, activation. when A completely hydrophobic different ILs were reaction used we in investigatedcombination was with the MW C–C activation. bond formation A completely in ferrocene different reactionFriedel‐Craft we investigated acylation [19]. was theAcylation C–C bond of ferroceneformation with in ferrocene carboxylic Friedel-Craft anhydrides, acylation catalyzed [19 by]. Acylation Sc(OTf)3 in of bmimTf ferrocene2N with occurred carboxylic with high anhydrides, yields andcatalyzed excellent by Sc(OTf)selectivity3 in bmimTf(Scheme2 N1). occurred MW heating with highdecreased yields andreaction excellent times selectivity from 50 (Schemeto 60 min1). (conventionalMW heating decreased heating) to reaction 1.5–4.5 timesmin. from 50 to 60 min (conventional heating) to 1.5–4.5 min.

O O O MW, 105-120°C 2-5 min O Fe isolated yield >99%

Fe 10% mol Sc(OTf)3, bmimNTf2 O N O O O O + O O O O S S + Fe N F C N CF Fe 3 - 3 O bmimNTf2 isolated yield 84% 13%

Scheme 1. Ferrocene Friedel‐Craft acylation in bmimNTf2, under microwave (MW) irradiation. Scheme 1. Ferrocene Friedel-Craft acylation in bmimNTf2, under microwave (MW) irradiation.

After almost a decade, we are interested in examining the state of the art as to the combination After almost a decade, we are interested in examining the state of the art as to the combination of of MW as the heating source and ionic liquids as solvents. Considering the literature of the last MW as the heating source and ionic liquids as solvents. Considering the literature of the last 15 years 15years only, the number of publication is impressive, amounting to more than five hundred. About only, the number of publication is impressive, amounting to more than five hundred. About 20% of 20% of them use the combination ILs/MW to transform biomasses or biomolecules (see, for example, them use the combination ILs/MW to transform biomasses or biomolecules (see, for example, [20–24]), [20–24]), a few papers used MW irradiation to facilitate the IL synthesis (e.g., [25,26]), some recent a few papers used MW irradiation to facilitate the IL synthesis (e.g., [25,26]), some recent paper used paper used ILs for the MW‐assisted formation of nanoparticles to be used successively (for example, ILs for the MW-assisted formation of nanoparticles to be used successively (for example, [27–32]), [27–32]), and the large majority of reports deal with organic synthesis, with ILs acting as solvents and the large majority of reports deal with organic synthesis, with ILs acting as solvents and/or and/or as catalysts. Many organic reactions have been performed combining ILs and MW as catalysts. Many organic reactions have been performed combining ILs and MW irradiation: irradiation: esterification of alcohols [33] and of carboxylic acids [34–36], formation of esterification of alcohols [33] and of carboxylic acids [34–36], formation of diphenylmethyl ethers diphenylmethyl ethers from alcohols [37], Michael addition of sulfonamides [38,39], asymmetric from alcohols [37], Michael addition of sulfonamides [38,39], asymmetric organocatalysis [40] or organocatalysis [40] or thiol‐ene “click” reaction [41], to cite only a few. thiol-ene “click” reaction [41], to cite only a few. In this review, we will focus our attention on oxidation and C–C bond formation reactions, In this review, we will focus our attention on oxidation and C–C bond formation reactions, published between 2002 and the beginning of 2017 that benefited from the combined use of published between 2002 and the beginning of 2017 that benefited from the combined use of microwaves microwaves and ionic liquids. Moreover, carbon dioxide functionalization, a hot topic nowadays, and ionic liquids. Moreover, carbon dioxide functionalization, a hot topic nowadays, will be considered. will be considered. Structures and abbreviations of ionic liquids reported in the review are collected in Figure1. Structures and abbreviations of ionic liquids reported in the review are collected in Figure 1.

Catalysts 2017, 7, 261 3 of 57 Catalysts 2017, 7, 261 3 of 56

Cations of the Imidazolium-based ILs

N N N N N N + + + N N + + + + N N N + N N N N N i bmim bdmim emim hmim C7mim omim bmim bnmim

N + N

ovim SO3H SO H 3 N H O SO H Acidic ILs 3 + N N + N OH N N + + + N (pSO3H)2im N N N pSO3Hmim bSO3Hmim Hmim HO2CC1mim SO3H

Functionalyzed ILs ONO CN OH NH2 N N N O O N + N + + N + + N + N N N N O O N O O ONObmim HO eCNeOHim H2NC2mim HOC2mim KEtEmim KMeEmim

O O Supported ILs Si

O O N n OH N + + N N PEG pim p mim n Si Cations of Pyridinium-based ILs

N N N N N + + + + + + N bupy bumpy bnpy mbupy 3-Mebupy opy

Acidic ILs OH SO H N SO H 3 + N 3 N O + +

mCO2Hpy pSO3Hpy bSO3Hpy

Supported ILs O N n OH +

PEGnpy

Cations of Alylammonium-based ILs

H N + N+ SO H N+ N+ 3

Et3NH Bu4N Et3PrSO3H Aliquat OH OH N + N+

BuMe2NCH2CH2OH EtMe2NCH2CH2OH

O HO3S SO3H + + N N N N + + N + bmpyr ompyr (bSO3H)2m2cyu oepip

Figure 1. StructuresStructures and abbreviations of ionic liquids (ILs) encountered in the review.

2. Oxidation Reactions 2. Oxidation Reactions Different functional groups have been oxidized in ILs with MW assistance. H2O2 is one of the Different functional groups have been oxidized in ILs with MW assistance. H2O2 is one of the “greenest” oxidant, considering that it reduces to water, but also other primary oxidants have been “greenest” oxidant, considering that it reduces to water, but also other primary oxidants have been used. Hydrogen peroxide needs an activator, either acid or metal‐based. In the latter case, the choice of metal is important to ensure sustainability of the process.

Catalysts 2017, 7, 261 4 of 57

used.Catalysts Hydrogen 2017, 7, 261 peroxide needs an activator, either acid or metal-based. In the latter case, the choice4 of 56 of metal is important to ensure sustainability of the process. Alcohols—Primary andand secondary secondary benzylic benzylic alcohols alcohols were were oxidized oxidized to the correspondingto the corresponding carbonyl derivativescarbonyl derivatives using KIO using4 as the KIO primary4 as the oxidant, primary tetraethylammonium oxidant, tetraethylammonium bromide (Et 4bromideNBr) as ionic(Et4NBr) liquid, as irradiatedionic liquid, with irradiated MW without with MW any without other solvent any other [42], assolvent illustrated [42], as in illustrated Scheme2. in Scheme 2.

primary benzyl alcohols MW, °C not indicated 1-6 min OH O KIO4

Et4NBr X X isolated yield 70-98% X = H, 2-MeO, 3-MeO, 3,4-(MeO)2, 2,5-(MeO)2, 4-Me, 3-Cl, 4-Cl, 3-NO2, 4-NO2

secondary benzyl alcohols MW, °C not indicated 4-5 min

Cl KIO4 KIO4 MW, 3 min Et4NBr O OH Et4NBr

O X X

Cl X = H, 4-Cl isolated yield 80-90% isolated yield 97%

Scheme 2. Oxidation of primary and secondary benzyl alcohols, with KIO4, Et4NBr, and MW heating Scheme 2. Oxidation of primary and secondary benzyl alcohols, with KIO4, Et4NBr, and MW heating[42]. [42].

The selectivity is excellent, because carboxylic acids were never detected and competition The selectivity is excellent, because carboxylic acids were never detected and competition experiments showed high substrate selectivity. Even more important, blank experiments experiments showed high substrate selectivity. Even more important, blank experiments demonstrated demonstrated that oxidation without Et4NBr does not occur at all, while scarce oxidation products that oxidation without Et NBr does not occur at all, while scarce oxidation products were observed were observed after conventional4 heating, even with prolonged reaction times. Therefore, the after conventional heating, even with prolonged reaction times. Therefore, the combination IL/MW combination IL/MW is necessary to make the reaction efficient (although, strictly speaking, Et4NBr is is necessary to make the reaction efficient (although, strictly speaking, Et NBr is nor a real IL, since nor a real IL, since it should be liquid at ambient temperature or below 1004 °C). The same reaction it should be liquid at ambient temperature or below 100 ◦C). The same reaction resulted much less resulted much less efficient with other alkyl alcohols. efficient with other alkyl alcohols. Immobilized IL on AuNP was an efficient catalyst in oxidation of benzyl alcohol by H2O2 in Immobilized IL on AuNP was an efficient catalyst in oxidation of benzyl alcohol by H O in water [43]. The rationale of the method was to prepare polymeric materials based on poly(ionic2 2 water [43]. The rationale of the method was to prepare polymeric materials based on poly(ionic liquid)s, liquid)s, to give the so‐called “supported ionic liquid‐like phases” (SILLPs). They combine the to give the so-called “supported ionic liquid-like phases” (SILLPs). They combine the characteristics of characteristics of ILs with those of polymers, in particular the ability to stabilize metal nanoparticles. ILs with those of polymers, in particular the ability to stabilize metal nanoparticles. Thus, stable AuNPs Thus, stable AuNPs of different sizes were prepared, taking advantage of the ability of supported of different sizes were prepared, taking advantage of the ability of supported ILs to absorb inorganic ILs to absorb inorganic or organic anions from a solution. AuNPCs–SILLPs were used to efficiently or organic anions from a solution. AuNPCs–SILLPs were used to efficiently catalyze the oxidation of catalyze the oxidation of 1‐phenylethanol in water, with H2O2 as the primary oxidant and MW 1-phenylethanol in water, with H O as the primary oxidant and MW irradiation as energy source. irradiation as energy source. While2 with2 conventional heating the catalytic efficiency is higher with While with conventional heating the catalytic efficiency is higher with low-size AuNP [44], here the low‐size AuNP [44], here the authors found that higher yields were obtained with the largest authors found that higher yields were obtained with the largest AuNPs. A polystyrene-divinylbenzene AuNPs. A polystyrene‐divinylbenzene resin was used for a Merrifield‐type linking of imidazolium resincation was with used different for a Merrifield-type anions (Scheme linking 3). The of anion imidazolium influenced cation the turnover with different frequency, anions with (Scheme the best3). −1 − The anion influenced the turnover frequency, with the best TOF (1383 h ) obtained when BF4 was TOF (1383 h−1) obtained when BF4− was the anion. the anion.

Interestingly, lignin-derived bio-oils, obtained bya) AuCl pyrolysis- or MW heating, containing N 4 N several benzyl alcohol functionalities, are reportedN to undergo aerobic oxidationAu(0) [45] catalyzed by Cl + + + N b) NaBH Cl- N oxidovanadium or copper complexes in ILs. However,Cl- N the paper4 is centered mainly on bio-oils and therefore it willP not be discussed further. SIILP AuNP-SIILP

OH O MW, 150°C 0.25 mol% AuNP-SIILP + H2O2 H O 2 yield 70%

Catalysts 2017, 7, 261 4 of 56

Alcohols—Primary and secondary benzylic alcohols were oxidized to the corresponding carbonyl derivatives using KIO4 as the primary oxidant, tetraethylammonium bromide (Et4NBr) as ionic liquid, irradiated with MW without any other solvent [42], as illustrated in Scheme 2.

primary benzyl alcohols MW, °C not indicated 1-6 min OH O KIO4

Et4NBr X X isolated yield 70-98% X = H, 2-MeO, 3-MeO, 3,4-(MeO)2, 2,5-(MeO)2, 4-Me, 3-Cl, 4-Cl, 3-NO2, 4-NO2

secondary benzyl alcohols MW, °C not indicated 4-5 min

Cl KIO4 KIO4 MW, 3 min Et4NBr O OH Et4NBr

O X X

Cl X = H, 4-Cl isolated yield 80-90% isolated yield 97%

Scheme 2. Oxidation of primary and secondary benzyl alcohols, with KIO4, Et4NBr, and MW heating [42].

The selectivity is excellent, because carboxylic acids were never detected and competition experiments showed high substrate selectivity. Even more important, blank experiments demonstrated that oxidation without Et4NBr does not occur at all, while scarce oxidation products were observed after conventional heating, even with prolonged reaction times. Therefore, the combination IL/MW is necessary to make the reaction efficient (although, strictly speaking, Et4NBr is nor a real IL, since it should be liquid at ambient temperature or below 100 °C). The same reaction resulted much less efficient with other alkyl alcohols. Immobilized IL on AuNP was an efficient catalyst in oxidation of benzyl alcohol by H2O2 in water [43]. The rationale of the method was to prepare polymeric materials based on poly(ionic liquid)s, to give the so‐called “supported ionic liquid‐like phases” (SILLPs). They combine the characteristics of ILs with those of polymers, in particular the ability to stabilize metal nanoparticles. Thus, stable AuNPs of different sizes were prepared, taking advantage of the ability of supported ILs to absorb inorganic or organic anions from a solution. AuNPCs–SILLPs were used to efficiently catalyze the oxidation of 1‐phenylethanol in water, with H2O2 as the primary oxidant and MW irradiation as energy source. While with conventional heating the catalytic efficiency is higher with low‐size AuNP [44], here the authors found that higher yields were obtained with the largest AuNPs. A polystyrene‐divinylbenzene resin was used for a Merrifield‐type linking of imidazolium

Catalystscation with2017, 7different, 261 anions (Scheme 3). The anion influenced the turnover frequency, with the5 best of 57 TOF (1383 h−1) obtained when BF4− was the anion.

a) AuCl - N 4 N N Au(0) Cl + + + N b) NaBH Cl- N Cl- N 4 P SIILP AuNP-SIILP

Catalysts 2017, 7, 261 5 of 56 OH O MW, 150°C Scheme 3. AuNPs–supported ionic0.25 mol%liquid AuNP-‐like SIILPphases (SILLPs) as catalyst in 1‐phenylethanol + H2O2 oxidation with H2O2 and MW heating [43].H O 2 yield 70% Interestingly, lignin‐derived bio‐oils, obtained by pyrolysis or MW heating, containing several Scheme 3. AuNPs–supported ionic liquid-like phases (SILLPs) as catalyst in 1-phenylethanol oxidation benzyl alcohol functionalities, are reported to undergo aerobic oxidation [45] catalyzed by oxidovanadiumwith H2O2 and or MW copper heating complexes [43]. in ILs. However, the paper is centered mainly on bio‐oils and therefore it will not be discussed further. AliphaticAliphatic alcohols alcohols are are more more difﬁcult difficult toto oxidizeoxidize thanthan benzyl ones. ones. An An accurate accurate screening screening on on cyclohexanol oxidation showed that it can be selectively oxidized by H2O2 with different catalysts in cyclohexanol oxidation showed that it can be selectively oxidized by H2O2 with different catalysts in the presence of ILs [46], Scheme 4. The screening examined different catalysts (H2WO4 resulted the the presence of ILs [46], Scheme4. The screening examined different catalysts (H 2WO4 resulted the bestbest one), one), the the inﬂuence influence of of the the amounts amounts of of oxidant, oxidant, catalyst catalyst and and ionic ionic liquid, liquid, and and thethe naturenature andand role of of ILs (considering both the cation and the anion). Imidazolium‐ ([omim]NTf2), pyridinium‐ ILs (considering both the cation and the anion). Imidazolium- ([omim]NTf2), pyridinium- ([opy]NTf2), ([opy]NTf2), and alkylammonium salts ([oepip]NTf2, [ompyr]NTf2, AliquatCl—also known as and alkylammonium salts ([oepip]NTf2, [ompyr]NTf2, AliquatCl—also known as Aliquat336—and Aliquat336—and AliquatNTf2) were used. Structures are reported in Figure 1. The authors AliquatNTf ) were used. Structures are reported in Figure1. The authors concluded that ILs act concluded2 that ILs act as phase‐transfer catalysts. Finally, MW irradiation was compared to as phase-transfer catalysts. Finally, MW irradiation was compared to conventional heating and conventional heating and resulted in reduced reaction times (from 90 min to 2.5 min, with Aliquat resulted in reduced reaction times (from 90 min to 2.5 min, with Aliquat 336; with sonication, 7.5 min 336; with sonication, 7.5 min were necessary). Other cycloalkanols resulted less reactive than werecyclohexanol. necessary). However, Other cycloalkanols with all cycloalkanols, resulted lessthe corresponding reactive than cycloalkanones cyclohexanol. constituted However, withmore all cycloalkanols,than 99% of the obtained corresponding products. cycloalkanones constituted more than 99% of the obtained products.

OH OH OH

OH O 2.4% mol H2WO4, 6.8% mol [omim]NTf2 H O + 2 2 O O 90 °C, 1h O

1 equiv 2 equiv isolated yield 79%

48% 65% 69%

Scheme 4. Oxidation of cycloalkanols with H2O2 [46]. Scheme 4. Oxidation of cycloalkanols with H2O2 [46].

Alcohols were converted into oximes by reaction with hydroxylamine hydrochloride in ILs Alcohols were converted into oximes by reaction with hydroxylamine hydrochloride in ILs with with MW irradiation [47]. Among the investigated ILs, 1‐methylimidazolium nitrate, [Hmim]NO3, MWgave irradiation the best results [47]. Among (Scheme the 5). investigated ILs, 1-methylimidazolium nitrate, [Hmim]NO3, gave the bestThe results scope (Scheme or the reaction5). is wide and, according to the authors, the protocol presents attractive featuresThe scope such or as the reduced reaction reaction is wide times, and, accordinghigh yields to and the authors,economic the viability protocol of presentsthe ionic attractiveliquid. featuresMoreover, such the as reduced IL could reaction be reused times, at least high three yields times, and with economic limited viability activity of reduction. the ionic liquid. Moreover, the IL couldOxidative be reused amidation at least of threealcohols times, was with reported limited using activity tert‐ reduction.butylhydroperoxide (THBP) as the oxidant,Oxidative task‐specific amidation ILs, ofwith alcohols cations wasbearing reported the –SO using3H functionalitytert-butylhydroperoxide and polyoxometalate (THBP) anions, as the oxidant,as catalysts, task-speciﬁc under ILs,MW with‐assisted cations and bearing solvent‐ thefree –SO conditions3H functionality [48]. A wide and polyoxometalaterange of alcohols anions,and asamines catalysts, were under used, MW-assisted the IL catalyst and could solvent-free be recycled conditions six times, [48 ].maintaining A wide range good of activity, alcohols and and when amines werecomparison used, the with IL catalyst conventional could be heating recycled was six possible, times, maintainingMW conditions good gave activity, better andyields when in addition comparison to withreduced conventional reaction times. heating One was example possible, is shown MW conditionsin Scheme 6. gave better yields in addition to reduced reaction times. One example is shown in Scheme6.

Catalysts 2017, 7, 261 6 of 57 Catalysts 2017, 7, 261 6 of 56 Catalysts 2017, 7, 261 6 of 56

MW, 80°C MW, 80°C 2.5 min 2.5 min [Hmim]NO OH [Hmim]NO 3 NOH OH . 3 NOH + H2NOH. HCl + H2NOH HCl

isolated yield, 95% isolated yield, 95%

NOH NOH NOH NOH NOH NOH NOH NOH O O O N O 2N 3 min, yield 93% 2 2.5 min, yield 95% 6 min, yield 85% 3 min, yield 97% 3 min, yield 93% 2.5 min, yield 95% 6 min, yield 85% 3 min, yield 97%

NOH O NOH NOH NOH O NOH NOH NOH O NOH O 3 min, yield 97% 5 min, yield 89% 2.5 min, yield 99% 2.5 min, yield 96% 3 min, yield 97% 5 min, yield 89% 2.5 min, yield 99% 2.5 min, yield 96%

O O NOH NOH NOH Se NOH NOH Se NOH 2.5 min, yield 96% 3 min, yield 97% 3 min, yield 94% 2.5 min, yield 96% 3 min, yield 97% 3 min, yield 94%

O O O O O NOH O NOH NOH NOH O 4.5 min, yield 92% O O O O O 4.5 min, yield 92% 4 min, yield 94% O 4 min, yield 94% O

Scheme 5. Synthesis of benzaldehyde oxime in [Hmim]NO3 [47]. Scheme 5. Synthesis of benzaldehyde oxime in [Hmim]NO3 [47].[47].

O O NH NH 2 OH 2 TBHP N OH + TBHP NH + H isolated yield isolated yield

[pSO3Hpy]3PW12O40 86% MW, 90°C [pSO3Hpy]3PW12O40 86% MW, 90°C 1 h [p py] PMo O 1 h SO3H 3 12 40 75% [pSO3Hpy]3PMo12O40 75%

[pSO3Hmim]3PW12O40 79% [pSO3Hmim]3PW12O40 79%

[pSO3Hmim]3PMo12O40 66% [pSO3Hmim]3PMo12O40 66%

[Et3PrSO3H]3PW12O40 65% [Et3PrSO3H]3PW12O40 65% [Et Pr ] PMo O [Et 3Pr SO3H] 3PMo 12O 40 54% 3 SO3H 3 12 40 54% Scheme 6. Oxidative amidation of phenylmethanol with tert‐butylhydroperoxide (THBP) under MW Scheme 6. Oxidative amidation of phenylmethanol with terttert‐-butylhydroperoxidebutylhydroperoxide (THBP) under MW irradiation, with task‐specific IL catalysts [48]. irradiation, with task-speciﬁctask‐specific IL catalysts [[48].48]. The same research group applied the procedure to oxidative amidation of aldehydes with The same research group applied the procedure to oxidative amidation of aldehydes with N‐heteroarylaminesThe same research [49]. group The results applied are the in procedure line with tothose oxidative obtained amidation with alcohols of aldehydes and the withbest N‐heteroarylamines [49]. The results are in line with those obtained with alcohols and the best Ncatalyst-heteroarylamines was again 1‐(3 [49‐sulfopropyl)pyridiniumphosphotungstate.]. The results are in line with those obtained with alcohols and the best catalyst was again 1‐(3‐sulfopropyl)pyridiniumphosphotungstate. catalystAlkenes was again—The 1-(3-sulfopropyl)pyridiniumphosphotungstate. alkene epoxidation was obtained with TBHP, using CpMo(CO)3CH3 as the Alkenes—The alkene epoxidation was obtained with TBHP, using CpMo(CO)3CH3 as the catalystAlkenes precursor,—The alkeneat 55 epoxidation°C [50]. Interestingly, was obtained the withstudy TBHP, compared using CpMo(CO)the reaction3CH output3 as the in catalyst precursor, at 55 ◦°C [50]. Interestingly, the study compared the reaction output in catalystconventional precursor, solvents at (1,2 55‐dichloroethane,C[50]. Interestingly, toluene, hexane) the study with compared that in biphasic the reaction liquid‐liquid, output using in conventional solvents (1,2‐dichloroethane, toluene, hexane) with that in biphasic liquid‐liquid, using conventional1‐butyl‐3‐methylimidazolium solvents (1,2-dichloroethane, tetrafluoroborate, toluene, hexane)[bmim]BF with4. thatMoreover, in biphasic conventional liquid-liquid, oil using‐bath 1‐butyl‐3‐methylimidazolium tetrafluoroborate, [bmim]BF4. Moreover, conventional oil‐bath 1-butyl-3-methylimidazoliumheating was compared with MW tetraﬂuoroborate, irradiation. From [bmim]BF the comprehensive4. Moreover, conventional screening, oil-bathMW irradiation heating heating was compared with MW irradiation. From the comprehensive screening, MW irradiation emerged as the most efficient heating, shortening reaction times without affecting selectivity, which emerged as the most efficient heating, shortening reaction times without affecting selectivity, which

Catalysts 2017, 7, 261 7 of 57

Catalysts 2017, 7, 261 7 of 56 was compared with MW irradiation. From the comprehensive screening, MW irradiation emerged aswas the most100% efﬁcientepoxide from heating, cyclooctene. shortening Efficiency reaction was times enhanced without by affectingmicrowave selectivity, absorbing which solvents, was 100%such epoxide as bmimBF from cyclooctene.4. Another EfﬁciencyMo catalyst was enhancedwas tested by microwave for cyclooctene absorbing epoxidation, solvents, such i.e., as bmimBFpyimMo(CO)4. Another4(where Mo pyim catalyst is N was‐(propyl) tested‐2‐pyridylmethanimine) for cyclooctene epoxidation, and the immobilized i.e., pyimMo(CO) version4(where of it, pyimgrafted is N -(propyl)-2-pyridylmethanimine)on mesoporous silica MCM‐41 [51]. and However, the immobilized in this example, version MW of it,heating grafted was on used mesoporous only to silicaprepare MCM-41 the catalyst, [51]. However, whereas [bmim]BF in this example,4 was used MW in heatingthe subsequent was used cyclooctene only to prepare epoxidation. the catalyst, whereasAn [bmim]BF interesting4 was oxidation used in theof terminal subsequent alkenes cyclooctene to aldehydes epoxidation. by ammonium persulfate was reportedAn interesting [52]; a palladacycle oxidation complex of terminal was the alkenes catalyst to and aldehydes [bmim]BF by4 the ammonium solvent ( persulfate was reportedScheme [52]; a 7 palladacycle). complex was the catalyst and [bmim]BF4 the solvent (Scheme7).

MW, 70°C 15 min (NH4)2S3O8 0.5% mol Pd(II) cat. O O N [bmim]BF4, H2O Pd X X Cl selectivity >99% S yield, 86-91% Pd(II) cat.

X = 4-Cl, 4-NO2, 4-Me, 4-OMe, 3-Cl, 2-Cl

SchemeScheme 7. 7.Pd-catalyzed Pd‐catalyzed MW-assisted MW‐assisted oxidation oxidation ofof styrenes to aldehydes in in IL IL [52]. [52].

The reaction was highly selective in IL solvent, where only traces of ketone were observed, at The reaction was highly selective in IL solvent, where only traces of ketone were observed, at variance with organic solvents, where phenylpropanone formed in amounts up to 25–40%. In the varianceabsence with of Pd(II) organic catalyst solvents, no oxidation where phenylpropanonewas observed. MW formed heating inmade amounts the reaction up to 25–40%.to complete In in the absence15 min of at Pd(II) 70 °C catalystwith 89% no yield, oxidation while wasconventional observed. heating MW heatingrequired made 24 h, with the reaction yield decreasing to complete to ◦ in73%. 15 min at 70 C with 89% yield, while conventional heating required 24 h, with yield decreasing to 73%.Alkanes—Alkyl substituted aromatics were oxidized by aqueous TBHP in the presence of small amountAlkanes of —AlkylbmimBF substituted4, under microwave aromatics irradiation were oxidized [53]. No by aqueousother catalyst TBHP was in the necessary. presence Toluene of small amountand substituted of bmimBF 4methylbenzenes, under microwave were irradiation transformed [53]. in No the other corresponding catalyst was necessary.benzoic acids, Toluene while and substitutedaromatic compounds methylbenzenes with other were alkyl transformed groups were in the oxidized corresponding to ketones benzoic (Scheme acids, 8). Without while aromatic the IL, compoundsthe reaction with was other much alkyl less groupsefficient, were requiring oxidized higher to ketones temperatures (Scheme and8). prolonged Without the reaction IL, the times, reaction to wasgive much lower less yields. efﬁcient, No experiment requiring higher was performed temperatures with conventional and prolonged heating. reaction times, to give lower yields.Finally, No experiment a recent was report performed illustrated with cyclohexane conventional oxidation heating. at 50 °C, under MW irradiation, by ◦ H2Finally,O2 and aFeCl recent2(tpm) report catalyst illustrated [54] (tpm cyclohexane = hydrotris oxidation‐(pyrazol at‐ 501‐yl)methane).C, under MW A irradiation,variety of reaction by H2O 2 andconditions FeCl2(tpm) were catalyst investigated, [54] (tpm varying = hydrotris-(pyrazol-1-yl)methane). the solvent, the reaction time, A variety without of or reaction with additives conditions were(pyrazinecarboxylic investigated, varying acid, the nitric solvent, acid, the potassium reaction time, carbonate). without At or withthe end additives of the (pyrazinecarboxylic reaction, before acid,workup, nitric acid,triphenylphosphine potassium carbonate). was added At theto reduce end of the the eventually reaction, before formed workup, cyclohexyl triphenylphosphine hydroperoxide wasto added cyclohexanol. to reduce Although the eventually the best formed overall cyclohexyl product yield hydroperoxide (28% in 1 h) to was cyclohexanol. obtained in AlthoughMeCN with the bestpyrazinecarboxylic overall product yield acid (28% as additive, in 1 h) was the obtainedauthors prefer in MeCN the reaction with pyrazinecarboxylic in IL, because the acid relative as additive, ratio thealcohol:ketone authors prefer can the be reaction tuned changing in IL, because the anion the of relative IL (Scheme ratio 9). alcohol:ketone Moreover, higher can be catalyticactivities tuned changing theunder anion additive of IL (Scheme‐free conditions9). Moreover, were higherachieved catalyticactivities and the catalyst undercould be additive-free re‐used in several conditions catalytic were cycles, especially in bmimBF4 (13 runs), maintaining its activity and selectivity. achieved and the catalyst could be re-used in several catalytic cycles, especially in bmimBF4 (13 runs), maintaining its activity and selectivity.

Catalysts 2017, 7, 261 8 of 56

Catalysts 2017, 7, 261 MW, 150°C 8 of 57 O Catalysts 2017, 7, 261 70% aq. THBP 60 min 8 of 56 CH3 2% mol bmimBF4 OH MW, 150°C O homemade70% simultaneous aq. THBP cooling 60 min X CH unit3 with 7 psi compress air X 2% mol bmimBF4 OH homemade simultaneous cooling conversion 39 -71% X = H,X 2-Cl, 3-Cl, 4-Cl, 4-Br, 2-NO2 X unit with 7 psi compress air with X = 4-OEt and no IL, conversion 80% conversion 39 -71% X = H, 2-Cl, 3-Cl, 4-Cl, 4-Br, 2-NO2 with X = 4-OEt and Ono IL, conversion 80% 70% aq. THBP MW, 130°C CH 3 O OH 30 min 2% mol bmimBF4 70% aq. THBP MW, 130°C CH O O 3 simultaneous cooling OH 30 min C 2% mol bmimBF4 C O O OH simultaneous cooling C OH C conversion 29 -39% OH OH conversion 29 -39%

MW, 170-180°C MW, 170-180°C 30 min 30 min

O O O OO O O O

yield, 77% yield, 83% yield, 98% yield, 53% yield, 77% yield, 83% yield, 98% yield, 53% Scheme 8. Oxidation of methyl, dimethyl, and alkyl benzenes with aqueous TBHP and [bmim]BF4 SchemeScheme 8. 8.Oxidation Oxidation of of methyl, methyl, dimethyl, dimethyl, and and alkyl alkyl benzenes benzenes with with aqueous aqueous TBHP TBHP and and [bmim]BF [bmim]BF4 4 under MW heating [53]. underunder MW MW heating heating [53 [53].].

MW, 50°C PPh3 PPh 6 MW,h 50°C 3 6 h OOH OH O H2O2 OOH+ OH+ O H2O2 FeCl2(tpm) bmimX + + FeCl (tpm) - -2 X = BF4 , N(CN)bmimX2 relative amount 1 : 10.8 with bmimN(CN)2 4.6 : 1 with bmimBF - - 4 X = BF4 , N(CN)2 relative amount 1 : 10.8 with bmimN(CN)2 4.6 : 1 with bmimBF overall yields, 15-19% 4 Scheme 9. Cyclohexane oxidation by H2O2, catalyzed overallby FeCl yields,2(tpm), 15-19%in ILs, under MW irradiation [54]. Scheme 9. Cyclohexane oxidation by H2O2, catalyzed by FeCl2(tpm), in ILs, under MW irradiation Scheme 9. Cyclohexane oxidation by H2O2, catalyzed by FeCl2(tpm), in ILs, under MW irradiation [54]. [54].Sulfides —Oxidation of organic sulfides is a very easy reaction that generally does not require harsh conditions. However, this is not the case of thiophene and related sulfur‐containing SulfidesheteroaromaticSulfides—Oxidation—Oxidation compounds. of of organic organic Their sulfides difficult sulfides is oxidation a veryis a very easy requires easy reaction reactionconditions that generally that under generally which does not alsodoes require alkenes not require harsh conditions.harshare conditions.oxidized. However, This However, thismakes is notthe usethis the of caseis oxidative not of thiophene the desulfurization case andof thiophene related of fuels sulfur-containing (ODS)and relatednot practicable, sulfur heteroaromatic ‐since,containing compounds.heteroaromaticfor a valuable Their compounds. fuel, difficult alkenes oxidation shouldTheir difficultremain requires unaltered. oxidation conditions Thus, requires under taking which conditionsadvantage also alkenes of under the chemoselectivity arewhich oxidized. also alkenes This shown by oxido vanadium(V) salen and salophen complexes, able to catalyze sulfides oxidation makesare oxidized. the use ofThis oxidative makes desulfurizationthe use of oxidative of fuels desulfurization (ODS) not practicable, of fuels (ODS) since, not for practicable, a valuable fuel,since, alkeneswith should H2O2, remainbut almost unaltered. inert towards Thus, takingalkene advantageoxidation, ofdibenzotiophene the chemoselectivity was oxidized shown to by the oxido for a valuable fuel, alkenes should remain unaltered. Thus, taking advantage of the chemoselectivity vanadium(V)shown by oxido salen andvanadium(V) salophen complexes,salen and ablesalophen to catalyze complexes, sulfides able oxidation to catalyze with Hsulfides2O2, but oxidation almost inert towards alkene oxidation, dibenzotiophene was oxidized to the corresponding sulfone, while with H2O2, but almost inert towards alkene oxidation, dibenzotiophene was oxidized to the cyclooctene, chosen as model of alkenes, remained unaffected [55,56] (Scheme 10). Catalysts 2017, 7, 261 9 of 56 Catalysts 2017, 7, 261 9 of 56 corresponding sulfone, while cyclooctene, chosen as model of alkenes, remained unaffected [55,56] Catalystscorresponding2017, 7, 261 sulfone, while cyclooctene, chosen as model of alkenes, remained unaffected [55,56]9 of 57 (Scheme 10). (Scheme 10).

0.05 mol [VO(salophen)CF3SO3 0.05 mol [VO(salophen)CF3SO3 + + H2O2 + + + H2O2 + S H2O/bmimPF6 S S H2O/bmimPF6 S DBT COT 60 °C, 24 h O O DBT COT 60 °C, 24 h O O 1 equiv. 1 equiv 4 equivs. DBTSO2 1 equiv. 1 equiv 4 equivs. DBTSO2 62% DBT conversion 62% DBT conversion Scheme 10. Selective oxidation of dibenzothiophene by H2OO2, ,in in the the presence presence of of cyclooctene cyclooctene [55,56]. [55,56]. Scheme 10. Selective oxidation of dibenzothiophene by H22O2, in the presence of cyclooctene [55,56].

Reduced reaction times to minutes were obtained substituting external heating (oil bath) with Reduced reaction times toto minutesminutes werewere obtainedobtained substitutingsubstituting externalexternal heatingheating (oil bath)bath) withwith MW irradiation [57]. A three‐phase system was implemented for VO(V)‐catalyzed desulfurization of MW irradiationirradiation [[57].57]. AA three-phasethree‐phase system system was was implemented implemented for for VO(V)-catalyzed VO(V)‐catalyzed desulfurization desulfurization of of a a model fuel: an organic phase containing benzine, cyclooctene and dibenzothiophene, an aqueous modela model fuel: fuel: an an organic organic phase phase containing containing benzine, benzine, cyclooctene cyclooctene and dibenzothiophene, and dibenzothiophene, an aqueous an aqueous phase phase containing H2O2, and the IL phase with the catalyst. At the end of the reaction, containingphase containing H2O2, and H2O the2, ILand phase the withIL phase the catalyst. with Atthe the catalyst. end of theAt reaction,the end dibenzothiophene of the reaction, dibenzothiophene sulfone was in IL, while unreacted cyclooctene was in the upper benzine phase. sulfonedibenzothiophene was in IL, while sulfone unreacted was in IL, cyclooctene while unreacted was in cyclooctene the upper benzine was in phase.the upper benzine phase. A similar rationale led to the recently reported extractive catalytic oxidative desulfurization A similarsimilar rationalerationale ledled toto thethe recentlyrecently reportedreported extractiveextractive catalyticcatalytic oxidativeoxidative desulfurizationdesulfurization (ECODS) process of diesel fuel model [58] that used H2O2 as the primary oxidant, a task‐specific IL (ECODS)(ECODS) processprocess ofof dieseldiesel fuelfuel modelmodel [[58]58] thatthat usedused HH22OO22 as the primary oxidant, a task-speciﬁctask‐specific IL ([mCO2Hpy]HSO4) as the extractant solvent, and VO(acac)2 as the catalyst. Microwave irradiation was ([m([mCO2HCO2Hpy]HSOpy]HSO4)4 )as as the the extractant extractant solvent, solvent, and and VO(acac) VO(acac)22 asas the the catalyst. catalyst. Microwave Microwave irradiation was used both for the IL synthesis and for the oxidation reaction (Scheme 11). used bothboth forfor thethe ILIL synthesissynthesis andand forfor thethe oxidationoxidation reactionreaction (Scheme(Scheme 1111).).

MW MW MW 5 MW min 5 min OH OH 5 min OH OH 5 min N OH - N Cl OH N Cl + N + + Cl- + Cl + O H SO + O O O H2 SO4 O N O 2 4 N [m py]HSO [mCO2Hpy]Cl [mCO2H py]HSO4 [mCO2Hpy]Cl CO2H 4

MW, 80°C MW, 3.5 min80°C 3.5 min H O , VO(acac) H2 O2 , VO(acac)2 Commercial Diesel Fuel 2 2 2 + Commercial Diesel Fuel + [m py]HSO [mCO2H py]HSO4 S S CO2H 4 S S O O O O O O H2O H2O, H2SO4 H2O H2O, H2SO4

removal efficiency 86.7% 99.1% removal efficiency 86.7% 99.1% Scheme 11. MW‐assisted extractive catalytic oxidative desulfurization by H2O2 in IL [58]. Scheme 11. MW‐assisted extractive catalytic oxidative desulfurization by H2O2 in IL [58]. Scheme 11. MW-assisted extractive catalytic oxidative desulfurization by H2O2 in IL [58]. 3. Carbon‐Carbon Bond Formation 3. Carbon‐Carbon Bond Formation 3. Carbon-Carbon Bond Formation 3.1. Transition Metal‐Catalyzed C–CCoupling Reactions 3.1. Transition Metal-CatalyzedMetal‐Catalyzed C–CCouplingC–CCoupling ReactionsReactions Reactions catalyzed by transition metals (in primis palladium) that lead to C–C bond formation Reactions catalyzed by transition metals (in primis palladium) that lead to C–C bond formation are ofReactions the utmost catalyzed importance by transition in organic metals synthesis (in primis and itpalladium) is not surprising that lead that to the C–C problem bond formation to make are of the utmost importance in organic synthesis and it is not surprising that the problem to make themare of more the utmostsustainable importance received inattention, organic considering synthesis and in particular it is not the surprising use of microwave that the problem activation to them more sustainable received attention, considering in particular the use of microwave activation [59].make Palladium them more‐catalyzed sustainable alkoxycarbonylation received attention, reaction considering was recently in particular reviewed the considering, use of microwave among activation[59]. Palladium [59]. Palladium-catalyzed‐catalyzed alkoxycarbonylation alkoxycarbonylation reaction was reaction recently was recentlyreviewed reviewed considering, considering, among improvements, the use of alternative solvents (ILs, scCO2) and MW heating [60]. It is worth marking improvements, the use of alternative solvents (ILs, scCO2) and MW heating [60]. It is worth marking theamong asymmetric improvements, Pd(II)‐catalysedoxycarbonylation the use of alternative solvents of racemic (ILs, pent scCO‐4‐ene2) and‐1,3‐diol MW by heating kineticresolution [60]. It is the asymmetric Pd(II)‐catalysedoxycarbonylation of racemic pent‐4‐ene‐1,3‐diol by kineticresolution inworth ILs using marking a chiral the asymmetric ligand for palladium. Pd(II)-catalysedoxycarbonylation MW irradiation was used of to racemic shorten pent-4-ene-1,3-diol reaction time [61]. byA in ILs using a chiral ligand for palladium. MW irradiation was used to shorten reaction time [61]. A selectionkineticresolution of transition in ILs metal using‐catalyzed a chiral coupling ligand for reactions palladium. are considered MW irradiation in the following. was used to shorten selection of transition metal‐catalyzed coupling reactions are considered in the following. reactionSuzuki time‐Miyaura [61]. Areaction selection—Palladium of transition‐catalyzed metal-catalyzed C–C coupling coupling reaction reactions between are aromatic considered halides in Suzuki‐Miyaura reaction—Palladium‐catalyzed C–C coupling reaction between aromatic halides andthe following.areneboronic acids has been considered one of the most versatile approaches among the and areneboronic acids has been considered one of the most versatile approaches among the crossSuzuki-Miyaura‐coupling reactions. reaction Several—Palladium-catalyzed modifications of the C–C original coupling protocol reaction were between aimed aromatic at improving halides it andcross areneboronic‐coupling reactions. acids hasSeveral been modifications considered oneof the of original the most protocol versatile were approaches aimed at improving among the it cross-coupling reactions. Several modiﬁcations of the original protocol were aimed at improving

Catalysts 2017, 7, 261 10 of 57

Catalysts 2017, 7, 261 10 of 56 it not only from the scientiﬁc point of view, but also considering sustainability problems, that led to environmentallynot only from the friendly scientific Suzuki point of aryl-aryl view, but couplingalso considering reaction, sustainability as reviewed problems, in 2005 that [62 led]. to Good resultsenvironmentally were obtained friendly in water Suzuki [63], aryl where‐aryl aryl coupling bromides reaction, reacted as reviewed with benzeneboronic in 2005 [62]. Good acid results in a few minuteswere (1–5 obtained min), in with water a benzimidazole-oxime[63], where aryl bromides Pd(II)-complex reacted with benzeneboronic as catalyst and acid MW in a few irradiation. minutes The same(1–5 system min), was with used a benzimidazole in the Heck‐oxime reaction Pd(II) (‐videcomplex infra as) of catalyst aryl and and heteroarylMW irradiation. bromides, The same such as 2-acetyl-5-bromobenzofuransystem was used in the [64Heck]. reaction (vide infra) of aryl and heteroaryl bromides, such as 2‐acetyl‐5‐bromobenzofuran [64]. In more recent examples, it was performed using as catalysts Pd complexes of imidazolium-type In more recent examples, it was performed using as catalysts Pd complexes of cations and 2-propanol/water as reaction medium [65]. It was shown that Pd(0) nanoparticles form in imidazolium‐type cations and 2‐propanol/water as reaction medium [65]. It was shown that Pd(0) solution,nanoparticles but they actform mainly in solution, as a source but they of catalytically act mainly activeas a source soluble of palladium catalytically species. active Thesoluble reaction ◦ gavepalladium high yields species. under The moderate reaction heatinggave high (40–70 yields underC) with moderate a variety heating of aromatic (40–70 °C) halides with a (Scheme variety 12). Conventionalof aromatic and halides MW (Scheme heating 12). were Conventional compared; and the MW latter heating resulted were compared; in halved the reaction latter resulted times with analogousin halved yields. reaction times with analogous yields.

 or MW Br B(OH)2 40°C

[IM]2PdCl4 + iPrOH,H O 2 X X yields 67 - >99% (, 2h) 64 - >99% (MW, 0.5 h)

X = H; 4-NO2; 4-OMe; 2-OMe; 4-Me; 4-Br; 4-CHO; 2-Me,4-NO2; 3-NO2,6-Me; 2-CN,6-Me

 or MW Cl B(OH)2 70°C

[IM]2PdCl4 + iPrOH X X yields 20 - 71% (, 24h) 6 - 58% (MW, 6 h) X = H; 2-NO2; 3-NO2; 2-Me,6-NO2; 2-Me; 4-Me

+ IM = O O N N N N N + + + + N N N N N bcpim bmim dmiop mioe

+ N + N N + N N N

HIMes HISMes HiPr

N O O N N O O N + + + + N N N N mdim dmdim

Scheme 12. Palladium‐catalyzed Suzuki‐Miyaura reaction catalyzed by Pd‐IL complexes [65]. Scheme 12. Palladium-catalyzed Suzuki-Miyaura reaction catalyzed by Pd-IL complexes [65]. The use of nanoparticles has become increasingly diffused in catalysis, because NPs allow very Theeasy userecovery of nanoparticles of the catalyst, has thus become rendering increasingly transformations diffused eco‐friendly. in catalysis, because NPs allow very easy recovery of the catalyst, thus rendering transformations eco-friendly. The combination MW/ILs was used to prepare heterogeneous catalysts, efﬁcient in Suzuki-Miyaura reaction performed under conventional heating [66]. Only in a second paper the Catalysts 2017, 7, 261 11 of 56 Catalysts 2017, 7, 261 11 of 57 The combination MW/ILs was used to prepare heterogeneous catalysts, efficient in Suzuki‐Miyaura reaction performed under conventional heating [66]. Only in a second paper the · reaction was performed in water underunder MWMW irradiationirradiation [[67].67]. Halloysite, Halloysite, Al Al2Si2Si2O2O5(OH)5(OH)4∙2H4 2H2O,2 O,a naturallya naturally occurring occurring aluminosilicatealuminosilicate nanoclay nanoclay with with a tubular a tubular shape, shape, was functionalized was functionalized on the externalon the externalsurface by surface MW-assisted by MW grafting‐assisted of (3-sulfanylpropyl)trimethoxysilane,grafting of (3‐sulfanylpropyl)trimethoxysilane, thus allowing thus anchoring allowing of anchoringvinylimidazoliumionic of vinylimidazoliumionic liquids by a thiol-eneliquids by reaction. a thiol‐ene Two reaction. types of Two Hallosyte types nanoof Hallosyte tubules nano were preparedtubules were and prepared used in coupling and used reaction, in coupling as shown reaction, in Schemes as shown 13 in and Scheme 14. 13 and Scheme 14.

MW, 80°C MW, 50°C 1 h MW, 50°C 1 h 1 h N + N X- - - - O N X X- = Br-, NTf2-, BF4- O O O X = Br , NTf2 , BF4- toluene O Si SH HNT Si HNT + O Si SH HNT Si HNT O AIBN O O SH

O O O O O O O HNT Si a) PdCl2, NaCl, H2O O HNT Si 2 2 Si O HNT Si O b) NaBF , EtOH - - b) NaBF4, EtOH O X- S X- 4 N S N + N N + HNT-IL1-Pd + HNT-IL1-Pd Pd(0)

B(OH) Br B(OH)2 2 1% mol HNT-IL1-Pd EtOH,H2O EtOH,H2O + K2CO3 2 3 X X 50°C, 19 h 50°C, 19 h yields 66 - 92%

X = 3-OMe, 4-OMe, 3-COMe, 4-COMe, 4-NH2, 4-CHO MW, 120°C 2 1% mol HNT-IL-Pd MW, 120°C 10 min conversion, 25 - >99% K2CO3 10 min 2 3 Scheme 13. Hallosyte nano tubules (HNT) functionalized with ILs ILs used used to to stabilize stabilize Pd Pd nanoparticles, nanoparticles, ecoeco-friendly‐friendly catalysts in MW-assistedMW‐assisted SuzukiSuzuki reactionreaction [[67].67]. First-generationFirst‐generation HNT-IL-PdHNT‐IL‐Pd catalystcatalyst [[67].67].

O O O O HNT Si + HNT Si + O O O O O O HNT Si N HNT Si N click reaction O N click reaction O O N O N N H O N N N HN O N N N N O N N O N N O O O O O O O O O O O O O O O O O O O O O O HNT Si HNT Si O Br O Br N N N N a) PdCl , NaCl, H O N + N N a) PdCl2, NaCl, H2O N + O N + 2 2 N O N + N O O O O O b) NaBF , EtOH O O O b) NaBF4, EtOH O 4 O O O O O HNT Si HNT Si O O Pd(0) N - Pd(0) N Br- N N N + Br N N N + O N + - N O N + Br- HNT-IL2-Pd N O Br HNT-IL2-Pd O O O O O O O O O

B(OH) Br B(OH)2 2 0.1% mol HNT-IL2-Pd EtOH,H2O EtOH,H2O + K2CO3 K2CO3 X X X X = 3-OMe, 4-OMe, 3-COMe, 4-COMe, 4-NO2, 4-CHO X yields 66 - 92% 2 MW, 120°C yields 66 - 92% MW, 120°C conversion, 25 - >99% 10 min

Scheme 14. Hallosyte nano tubules (HNT) functionalized with ILs used to stabilize Pd nanoparticles, Scheme 14. Hallosyte nano tubules (HNT) functionalized with ILs ILs used used to to stabilize stabilize Pd Pd nanoparticles, nanoparticles, eco‐friendly catalysts in MW‐assisted Suzuki reaction [67]. Second‐generation HNT‐IL‐Pd catalyst ecoeco-friendly‐friendly catalystscatalysts in in MW-assisted MW‐assisted Suzuki Suzuki reaction reaction [67 ].[67]. Second-generation Second‐generation HNT-IL-Pd HNT‐IL catalyst‐Pd catalyst [67]. [67].

Catalysts 2017, 7, 261 12 of 57 Catalysts 2017,, 7,, 261 12 of 56

The second second generation generation HNT HNT-IL2-Pd‐IL2‐Pd catalyst catalyst is is definitely definitely more more troublesome troublesome to prepare to prepare than than the thefirst first generation generation catalyst, catalyst, but but it has it has the the advantage advantage that that could could be be used used in in five five consecutive runsruns maintaining high efficiency, efficiency, whilewhile HNT-IL1-PdHNT‐IL1‐Pd catalystcatalyst lostlost somesome efficiencyefficiency in thethe secondsecond and third run (86% (86% and and 85% 85% conversion conversion from from 95% 95% in inthe the first first run) run) and and became became scarce scarce after after the fourth the fourth run (27% run (27%conversion). conversion). An originaloriginal and veryvery efficientefficient catalystcatalyst waswas recently developeddeveloped preparingpreparing a supportedsupported ionicionic liquid‐like phase (SILLP) covalently linking a C60‐IL hybrid to silica‐based solid supports [68,69] liquid-likeliquid‐like phase (SILLP)(SILLP) covalentlycovalently linkinglinking aa CC6060‐-ILIL hybrid to silica-basedsilica‐based solid supports [[68,69]68,69] (Scheme(Scheme 1515).). This SILLP is able toto immobilizeimmobilize and stabilize palladium nanoparticles inin a system thatthat waswas dubbeddubbed by by the the authors authors as “aas sort “a ofsort matryoshka” of matryoshka” system. system. The silica The catalysts silica catalysts are highly are recyclable highly withrecyclable no leaching with no above leaching the limit above of the detection limit of (0.5 detection ppm). (0.5 ppm).

MW 120°C 3 min B(OH)2 3 min B(OH)2 Br Br 0.001% mol C60-IL-PdNP + 60 + K2CO3 K2CO3 1:1 v/v H2O-EtOH 1:1 v/v H2O-EtOH O conv., >99% O O conv., >99% yield, 99% (runs from 1 to 10) TON 100,000 TOF (h-1) 3,640,000 TOF (h-1) 3,640,000 Scheme 15.15. Example of the MW-irradiatedMW‐irradiated Suzuki reaction catalyzed by PdNPs in C60-ILC60‐IL hybridhybrid supported on mesoporous silicasilica [[68,69].68,69].

Heck reaction—Palladium‐catalyzed vinylation of aryl halides or triflates has been investigated Heck reactionreaction—Palladium-catalyzed—Palladium‐catalyzed vinylation vinylation of of aryl aryl halides halides or or triflates triflates has has been been investigated investigated in in a variety of non‐conventional systems, from supercritical fluids to ionic liquids, from fluorous ain variety a variety of non-conventional of non‐conventional systems, systems, from from supercritical supercritical fluids fluids to ionic to liquids,ionic liquids, from fluorous from fluorous media media to aqueous solvents, and with a variety of energy sources (microwave, ultrasound, high tomedia aqueous to aqueous solvents, solvents, and with and a variety with of a energyvariety sources of energy (microwave, sources ultrasound,(microwave, high ultrasound, pressure), high as a pressure), as a consequence of its synthetic value [70]. Interestingly, with the aid of microwaves, consequencepressure), as of a itsconsequence synthetic value of its [70 synthetic]. Interestingly, value [70]. with Interestingly, the aid of microwaves, with the highlyaid of regioselectivemicrowaves, highly regioselective internal Heck arylation of hydroxyalkyl vinyl ethers by aryl halides could be internalhighly regioselective Heck arylation internal of hydroxyalkyl Heck arylation vinyl ethers of hydroxyalkyl by aryl halides vinyl could ethers be performedby aryl halides in the could “green” be performed in the “green” solvent water [71]. solventperformed water in the [71]. “green” solvent water [71]. Considering ILs and MW together, in 2002 it was reported that 4‐bromomethoxybenzene Considering ILsILs and and MW MW together, together, in 2002 in 2002 it was it reportedwas reported that 4-bromomethoxybenzene that 4‐bromomethoxybenzene reacted reacted quite easily with butyl propenoate when treated with palladium catalysts in IL and with quitereacted easily quite with easily butyl with propenoate butyl propenoate when treated when with treated palladium with catalystspalladium in ILcatalysts and with in MWIL and heating with MW heating (Scheme 16), even without addition of phosphine ligands [72], in more eco‐friendly (SchemeMW heating 16), even(Scheme without 16), additioneven without of phosphine addition ligands of phosphine [72], in moreligands eco-friendly [72], in more conditions eco‐friendly than conditions than the usual ones. theconditions usual ones. than the usual ones.

MW, 180°C Br MW, 180°C 4545 minmin O O PdCl2 oror Pd(OAc)Pd(OAc)2 + O 2 2 O O [bmim]PF6, Et3N O [bmim]PF6, Et3N O GC yield, 43-99% O O GC yield, 43-99%

Scheme 16. Palladium‐catalyzed Heck reaction of aryl bromides in [bmim]PF6 with MW heating [72]. Scheme 16. Palladium‐catalyzed Heck reaction of aryl bromides in [bmim]PF6 with MW heating [72]. Scheme 16. Palladium-catalyzed Heck reaction of aryl bromides in [bmim]PF6 with MW heating [72].

The same research group succeeded in alkenylating the generally sluggish aryl chlorides, that The same research group succeeded in alkenylating the generally sluggish aryl chlorides, that reacted in the air, in a mixture of 1,4‐dioxane‐IL, with MW heating [73]. The reaction worked well reacted in the air, in a mixture of 1,4-dioxane-IL, with MW heating [73]. The reaction worked not only with the most reactive electron‐poor aryl chlorides, but also with electron‐rich substrates, wellsimply not varying only with reaction the mosttimes. reactive [bmim]PF electron-poor6 was used aryl with chlorides, 10 mol but% tri( alsot‐butyl)phosphonium with electron-rich simply varying reaction times. [bmim]PF6 was used with 10 mol % tri(t‐butyl)phosphonium substrates,tetrafluoroborate, simply varying(t‐Bu)3PH]BF reaction4, times.with the [bmim]PF so 6 calledwas used “Herrmann’s with 10 mol palladacycle”, % tri(t-butyl) tetrafluoroborate, (t‐Bu)3PH]BF4, with the so called “Herrmann’s palladacycle”, phosphonium tetraﬂuoroborate, (t-Bu) PH]BF , with the so called “Herrmann’s palladacycle”, trans‐di(μ‐acetato)bis[o‐(di‐o‐tolylphosphino)benzyl]3 4 ‐dipalladium(II) as catalyst. Reaction times trans-di(µ-acetato)bis[o-(di-o-tolylphosphino)benzyl]-dipalladium(II) as catalyst. Reaction times varied varied from 30 min for the reactive halides to 60 min for the electron rich ones (Scheme 17). from 30 min for the reactive halides to 60 min for the electron rich ones (Scheme 17).

Catalysts 2017, 7, 261 13 of 57 Catalysts 2017, 7, 261 13 of 56

"Herrmann's palladacycle" [(t-Bu)3PH]BF4, Cy3NMe MW, 180°C [bmim]PF6-dioxane 60 min air atm.

Cl Cl Cl Cl

O O

O O O O Bu Bu Bu Bu O O O O yield 60% 85% 85% 80% O

"Herrmann's palladacycle" [(t-Bu)3PH]BF4, Cy3NMe MW, 180°C [bmim]PF6-dioxane 40-60 min air atm.

Cl Cl Cl Cl Cl CF3

N N

CF3 N

O Bu O O Bu N Bu O O Bu Bu O O O O yield 90% 91% 88% 85% 81% O O

"Hermann's palladacycle" [(t-Bu)3PH]BF4, Cy3NMe [bmim]PF6-dioxane MW, 180°C 30 min air atm.

Cl Cl Cl Cl Cl

CN CF3 O O O O Bu Bu Bu Bu Bu O O O O O O O O O O

O O NC O F3C O yield 93% 94% 95% 90% 80%

Scheme 17. Palladium‐catalyzed Heck reaction of aryl chlorides in [bmim]PF6‐dioxane with MW Schemeheating 17. [73].Palladium-catalyzed Heck reaction of aryl chlorides in [bmim]PF6-dioxane with MW heating [73].

Butyl propenoate was used as vinylating agent of aryl iodides in a Heck reaction in [omim]BF4

withButyl a simple propenoate Pd/C catalyst was used (3 mol as vinylating %), that could agent be of recycled aryl iodides up to in five a Heck times reaction with scarce in [omim]BF loss of 4 withactivity a simple [74]. Pd/CMW irradiation catalyst (3 made mol reaction %), that times could very be recycled short (0.5 up min), to ﬁve but timesyields with were scarce not always loss of activitysatisfactory; [74]. MW moreover, irradiation aryl halides made were reaction inert times in these very conditions. short (0.5 min), but yields were not always satisfactory;Instead, moreover, Heck alkenylation aryl halides was were successfully inert in these achieved conditions. on aryl iodides, bromides and chlorides, usingInstead, an ortho Heck‐palladated alkenylation complex was successfullyin non‐aqueous achieved ionic onliquid, aryl iodides,such as bromidesBu4NBr, Bu and4NCl, chlorides, and [bmim]Br [75]. Other conditions being equal, Bu4NBr gave the best conversion of halides and using an ortho-palladated complex in non-aqueous ionic liquid, such as Bu4NBr, Bu4NCl, and therefore was the solvent of choice for the reaction screening. Conventional heating and MW heating

Catalysts 2017, 7, 261 14 of 57

[bmim]Br [75]. Other conditions being equal, Bu4NBr gave the best conversion of halides and Catalysts 2017, 7, 261 14 of 56 therefore was the solvent of choice for the reaction screening. Conventional heating and MW heating werewere compared, compared, with with the the latter latter favoring favoring thethe reaction in in terms terms of of reduced reduced reaction reaction times, times, thanks thanks to to microwave-absorbingmicrowave‐absorbing nature nature of of Bu Bu44NBr.NBr. SelectedSelected results are are presented presented in in Scheme Scheme 18. 18 .

O O O , 1.5 h, 93% isolated yield O O MW, 1 min,94% isolated yield NH O Pd 2 Br Br Br  or MW Pd O Bu4NBr, AcONa, 0.1-0.2% mol o-cyclopalladate 130°C H2N

O o-cyclopalladate , 1.5 h, 96% isolated yield MW, 1 min,94% isolated yield

time, 0,5-7 h, isolated yield 65-96% () other ArBr = 4-CHO, 4-CN, 4-COMe, 3-Cl, 1-bromonaphthalene, 9-bromophenanthrene time, 1-12 min, isolated yield 83-94% (MW) O O , 1 h, 93% isolated yield O O MW, 4 min,93% isolated yield

O I SOCl2 Bu NBr, AcONa, 0.1-0.2% mol o-cyclopalladate  or MW 4 130°C O O MW,130°C

, 2 h, 95% isolated yield MW,12 min,95% isolated yield O

O O O O O O MW, 4 min 90% isolated yield O Cl Bu4NBr, AcONa, 0.1-0.2% mol o-cyclopalladate MW,130°C 4 min, 93% 5 min, 90%

MW, 6 min 90% isolated yield 20-.25 min other ArCl = 4-COMe, 4-COMe 80-82%

SchemeScheme 18. 18.Palladium-catalyzed Palladium‐catalyzed Heck reaction of of aryl aryl halides halides in in Bu Bu4NBr4NBr [75]. [75 ].

Regioselectivity was discussed in detail in a study that examined the Heck reaction in Regioselectivity was discussed in detail in a study that examined the Heck reaction in DMSO/[bmim]BF4, with MW as heating source [76]. It was observed that regioselectivity was higher DMSO/[bmim]BF , with MW as heating source [76]. It was observed that regioselectivity was in IL solvent and 4that MW heating reduced the reaction time from hours to minutes. As the catalyst, higher in IL solvent and that MW heating reduced the reaction time from hours to minutes. Pd2(dba)3 was used together with a sugar‐derived phosphine ligand (methyl As4,6 the‐O‐ catalyst,benzylidene Pd‐23(dba)‐deoxy3 ‐was3‐(diphenylphosphino) used together with‐α‐D‐ aaltropyranoside). sugar-derived phosphine ligand (methyl 4,6-O-benzylidene-3-deoxy-3-(diphenylphosphino)-MW‐assisted Heck reaction wasα- D-altropyranoside).performed using the IL 1‐(2MW-assisted‐cyanoethyl)‐3 Heck‐(2‐hydroxyethyl) reaction was‐1H performed‐imidazol‐3 using‐ium thetetrafluoroborate IL 1-(2-cyanoethyl)-3-(2-hydroxyethyl)- as solvent, ligand and 1Hbase,-imidazol-3-ium i.e., an efficient, tetrafluoroborate air stable and phosphine as solvent, free ligand catalytic and system base, (PdCl i.e., an2 was efficient, the precursor air stable of the and phosphineactual catalyst) free catalytic [77]. A variety system of (PdCl substrates,2 was with the precursordifferent electronic of the actual and steric catalyst) effects, [77 ].were A varietytreated of substrates,under these with conditions. different Significant electronic andresults steric are effects, collected were in Scheme treated 19. under these conditions. Significant resultsA are collecteddifferent inapproach Scheme 19was. used by other researchers, that focused on new N‐phenylbenimidazoliumA different approach salts wasas ILs, used while commercial by other Pd(OAc) researchers,2 was the that catalyst focused [78]. Actually, on new N-phenylbenimidazoliumthe salts are not liquid and salts were as used ILs, in while 2 mol commercial % amounts, Pd(OAc) in solvents2 was as DMF the catalyst‐H2O or [EtOH78]. Actually,‐H2O. theThe salts system are not was liquid used andboth werein Heck used and in in 2 Suzuki mol %‐ amounts,Miyaura reactions in solvents on halopyridines. as DMF-H2O MW or EtOH-H heating2 O. Thewas system determinant was used to obtain both in good Heck results: and in there Suzuki-Miyaura are examples reactions of reactions on halopyridines.not occurring at MW all under heating wasconventional determinant heating to obtain that became good results: practicable there with are MW examples irradiation. of reactions Reaction not conditions occurring are at reported all under conventionalin Scheme 20. heating that became practicable with MW irradiation. Reaction conditions are reported in Scheme 20.

Catalysts 2017, 7, 261 15 of 56 Catalysts 2017, 7, 261 15 of 57 Catalysts 2017, 7, 261 15 of 56

MW, 100°C 5 min MW, 100°C I 0.2% mol PdCl2 5 min O O + 0.2% mol PdCl I [e e im]BF 2 + O CN OH 4 R O O [e e im]BF O R CN OH 4 R E O O R isolated Eyield, 81-88% R = H, 4-COMe, 4-CO2Et, 4-OMe isolated yield, 81-88% R = H, 4-COMe, 4-CO Et, 4-OMe 2 MW, 100°C MW, 5-10 100°C min Br 0.2% mol PdCl2 O 5-10 min Br+ 0.2% mol PdCl2 O O O + [eCNeOHim]BF4 R [e e im]BF O CN OH 4 R E O R O O R E isolated yield, 68-72% R = H, 4-COMe, 4-OMe, 2-CO2Me isolated yield, 68-72% R = H, 4-COMe, 4-OMe, 2-CO2Me

MW, 100°C MW, 100°C I I 5 min 0.2%0.2% mol mol PdCl PdCl2 5 min + 2 + R [e[eCNeOHe im]BFim]BF4 R CN OH 4 E R R E R = 4-COMe, 4-CO Et, 4-OMe isolatedisolated yield,yield, 80-85%80-85% R = 4-COMe, 4-CO2 2Et, 4-OMe

MW,MW, 100°C 100°C I I 5-10 5-10 min min 0.2%0.2% mol mol PdCl PdCl22 + + [e e im]BF RR [eCNCNeOHOHim]BF44 R R E 2 isolated yield, 65-72% R =R H, = 4-COMe,H, 4-COMe, 4-OMe, 4-OMe, 2-CO 2-CO2MeMe isolated yield, 65-72%

CNCN N +N + N N HO eCNeOHim HO e e im CN OH

SchemeScheme 19. 19.MW-assisted, MW‐assisted, phosphine phosphine and and base base free Heck reaction reaction in in task task-speciﬁc‐specific IL IL[77]. [77 ]. Scheme 19. MW‐assisted, phosphine and base free Heck reaction in task‐specific IL [77].

, MW, 80°C yield, 9% (), 63% (MW) N  , MW, 10 min 80°C yield, 9% (), 63% (MW) N 10 min Br Heck Br Heck N 1% mol Pd(OAc)2, 2% mol [PhRbzim]X, 1:1 v/v DMF-H2O, K2CO3 yield, 11% (), 76% (MW)

1% mol Pd(OAc)2, 2% mol [PhRbzim]X, 1:1 v/v DMF-H2O, K2CO3 yield, 11% (), 76% (MW) N Suzuki-Miyaura , MW, 100°C 10 min Suzuki-Miyaura N , MW, 100°C B(OH)2 10 min N B(OH)2

Y R = Et, allyl, CH=CHOCH2CH2-, Y NCCH2CH2CH2-, R = Et, allyl, CH=CHOCH2CH2-, Cl CH2 NCCH2CH2CH2-, N - CH X X Cl= Cl, Br, I 2 + Y = H, Cl N N X- X = Cl, Br, I [PhRbzim]X + R Y = H, Cl N [PhRbzim]X R Scheme 20. Example of MW‐assisted Pd‐catalyzed Heck and Suzuki‐Miyaura reactions of 2‐bromopyrimidine [78]. SchemeScheme 20.20. ExampleExample of of MW MW-assisted‐assisted Pd Pd-catalyzed‐catalyzed Heck Heck and and Suzuki Suzuki-Miyaura‐Miyaura reactions reactions of of 2-bromopyrimidine2‐bromopyrimidine [ [78].78].

Catalysts 2017, 7, 261 16 of 57 Catalysts 2017, 7, 261 16 of 56 Catalysts 2017, 7, 261 16 of 56 Catalysts 2017, 7, 261 16 of 56 AnAn unusual unusual Heck-type Heck‐‐typetype alkenylation alkenylation waswas obtained directly directly fromfrom from aryl aryl alcohols alcohols insteadinstead instead of alkenes, of alkenes, An unusual Heck‐type alkenylation was obtained directly from aryl alcohols instead of alkenes, ininin a one-pota one‐‐pot reaction reactionreaction that thatthat was was assisted assisted byby ILsILsILs andand MW [79].[79]. [79]. This This procedure procedure avoided avoided prone prone toto to in a one‐pot reaction that was assisted by ILs and MW [79]. This procedure avoided prone to polymerizationpolymerization alkene alkene reagents, reagents,reagents, diddid notnot require inertinert atmosphere, atmosphere, and and could could be be applied applied toto toa wide a wide polymerization alkene reagents, did not require inert atmosphere, and could be applied to a wide rangerangerange of of substrates substratessubstrates (Scheme (Scheme(Scheme 21 21).). range of substrates (Scheme 21).

MW, 150°C MW, 15 min150°C MW, 15 min 150°C O OH O OH 15 min O OH I PdCl2(PPh3)2 I PdCl2(PPh3)2 I PdCl2(PPh3)2 + HCO2Na, piperidine, LiCl + HCO2Na, piperidine, LiCl O + HCO Na,[hmim]Br piperidine, LiCl O 2 [hmim]Br O [hmim]Br isolated yield, 78% isolated yield, 78% isolated yield, 78% N + N + N N+ N hmim N hmim hmim Scheme 21. IL‐ and MW‐assisted Heck‐type alkenylation of aryl alcohols [79]. SchemeScheme 21. 21.IL- IL‐ andand MW-assisted MW‐assisted Heck-typeHeck‐type alkenylation alkenylation of of aryl aryl alcohols alcohols [79]. [79 ]. Scheme 21. IL‐ and MW‐assisted Heck‐type alkenylation of aryl alcohols [79]. Sonogashirareaction—The Pd‐‐catalyzed coupling reactionreaction of aryl chlorides and terminalterminal alkynes SonogashirareactionSonogashirareaction—The—The Pd-catalyzed Pd‐catalyzed coupling coupling reaction of of aryl aryl chlorides chlorides and and terminal terminal alkynes alkynes was accomplished inin 10 min using MW heating [80][80] and worked well also intramolecularly,intramolecularly, leadingleading waswas accomplished accomplished in in 10 10 min min using using MW MW heating heating [[80]80] andand worked well well also also intramolecularly, intramolecularly, leading leading toto one‐‐pot synthesissynthesis of indolesindoles [81].[81]. However, thethe procedures were farfar fromfrom being sustainable,sustainable, sincesince to one-potto one‐pot synthesis synthesis of of indoles indoles [ 81[81].]. However, However, thethe proceduresprocedures were far far from from being being sustainable, sustainable, since since itit was necessary toto use phosphines, organic solvents,solvents, copper compounds, and a base. Instead,Instead, thethe it wasit was necessary necessary to to use use phosphines, phosphines, organic organic solvents, solvents, coppercopper compounds, and and a a base. base. Instead, Instead, the the Sonogashira reactionreaction was made more eco‐‐friendlyfriendly when tetrabutylammoniumtetrabutylammonium acetate was Sonogashira reaction was made more eco‐friendly when tetrabutylammonium acetate was Sonogashiraintroducedintroduced reaction as an activator was made [82][82] more inin a eco-friendly copper‐‐freefree when system,system, tetrabutylammonium with complete substratesubstrate acetate disappearance was introduced introduced as an activator [82] in a copper‐free system, with complete substrate disappearance aswithin an activator 15 min [ (Scheme(Scheme82] in a copper-free22). system, with complete substrate disappearance within 15 min (Schemewithin 22 15). min (Scheme 22). MW, 110°C MW, 110°C 15 min MW, 15 min 110°C 15 min N N N 10% mol PdCl2(PCy3)2 N N I 10% mol PdCl2(PCy3)2 N I + 10% mol PdCl (PCy ) + 2 3 2 N I N-methylpyrrolidone N R N + R N-methylpyrrolidone N R N R N-methylpyrrolidone N R R [Bu4N]OAc [Bu4N]OAc [Bu4N]OAc yield, 70-95% yield, 70-95% yield, 70-95%

R = 4-OH, 4-OMe, 4-Me, 3-Me, 4-Ph, 3-Ph, 4-F, 3-F, 3-Br, 3-NH2, 3-(3-pyridyl), 4-(N-piperidyl), 4-diethylamino R = 4-OH, 4-OMe, 4-Me, 3-Me, 4-Ph, 3-Ph, 4-F, 3-F, 3-Br, 3-NH2, 3-(3-pyridyl), 4-(N-piperidyl), 4-diethylamino SchemeR = 4-OH, 22. MW-irradiated 4-OMe, 4-Me, 3-Me, Pd-catalyzed, 4-Ph, 3-Ph, amine4-F, 3-F, and 3-Br, copper-free 3-NH2, 3-(3-pyridyl), Sonogashira 4-(N-piperidyl), reaction with 4-diethylamino ammonium Scheme 22. MW‐irradiated Pd‐catalyzed, amine and copper‐free Sonogashira reaction with saltScheme activator 22. [82 MW]. ‐irradiated Pd‐catalyzed, amine and copper‐free Sonogashira reaction with ammoniumScheme 22. salt MW activator‐irradiated [82]. Pd‐catalyzed, amine and copper‐free Sonogashira reaction with ammonium salt activator [82]. ammonium salt activator [82]. Allylic alkylation—Efﬁcient allylic alkylation was performed in tailor-made ILs, with Pd catalysts Allylic alkylation—Efficient allylic alkylation was performed inin tailortailor‐‐made ILs,ILs, with Pd havingAllylic phosphine-imidazoline alkylation—Efficient ligands allylic and alkylation MW heating was [performed83]. The accurate in tailor investigation‐made ILs, consideredwith Pd catalysts having phosphine‐‐imidazolineimidazoline ligandsligands and MW heating [83].[83]. The accurate investigationinvestigation differentconsideredcatalysts catalysts, having different differentphosphine catalysts, ILs,‐imidazoline different MW irradiation, ILs, ligands MW irradiation,and recycling, MW heating andrecycling, enantioselectivity. [83]. and The enantioselectivity. accurate The investigation best resultsThe considered different catalysts, different ILs, MW irradiation, recycling, and3 enantioselectivity. The arebestconsidered shown results in Schemearedifferent shown 23 catalysts, .in The Scheme actual different 23. catalyst The ILs, actual is MW formed catalyst irradiation, in situ,is formed recycling, by the in [Pd( situ, andη by-allyl)Cl] enantioselectivity. the [Pd(2 precursorη3‐allyl)Cl] The and2 best results are shown in Scheme 23. The actual catalyst is formed in situ, by the [Pd(η3‐allyl)Cl]2 3 a phosphine-imidazolineprecursorbest results and are a shownphosphine in ligand Scheme‐imidazoline in IL23. (preferably, The ligand actual in [bdmim]BFcatalyst IL (preferably, is formed). The [bdmim]BF in reaction situ, by4 also). the The occurred[Pd( reactionη ‐allyl)Cl] at also room 2 precursor and a phosphine‐imidazoline ligand in IL (preferably,4 [bdmim]BF4). The reaction also precursor and a phosphine‐imidazoline ligand in IL (preferably, [bdmim]BF4). The reaction also temperature,occurred at butroomroom heating temperature,temperature, increased but enantioselectivity.heating increasedincreased enantioselectivity. occurred at room temperature, but heating increased enantioselectivity. O O MW, 45°C O O MW, 45°C O O O O 1 h O O MW, 1 h 45°C O 2% mol [Pd(3-C H )Cl] O O O O 2% mol [Pd(3-C3 H5 )Cl]2 O O 1 h O 3 5 2 O O O + 2% mol4.4% [Pd( mol3-C L H )Cl] O 4.4% mol L3 5 2 O + O O + 4.4%BSA mol L O BSA O O [bdmim]BF rac O [bdmim]BFBSA 4 L = rac O 4 R L = HN [bdmim]BF4 R rac ee 90% L = HN ee 90%R HN (conv., 99%) N (conv.,ee 90% 99%) N (conv., 99%) N PPh2 PPh2 PPh 2

Scheme 23. Pd-catalyzed MW-assisted asymmetric allylic alkylation in IL [83].

Catalysts 2017, 7, 261 17 of 56

Catalysts 2017, 7, 261 17 of 57 Scheme 23. Pd‐catalyzed MW‐assisted asymmetric allylic alkylation in IL [83].

Cyanation of aryl and vinyl halides —Although with a less wide scope, this reaction is important to prepare arylaryl and arylvinyl nitriles, useful synthones in organic synthesis. Moreover, cyanide sources are notorious toxic compounds,compounds, thusthus renderingrendering advisableadvisable anyany newnew eco-friendlyeco‐friendly procedure.procedure. 4 6 The non-toxicnon‐toxic potassiumpotassium hexacyanoferrate(II),hexacyanoferrate(II), K4[Fe(CN)[Fe(CN)6],], was was used used as as cyanide source in a palladium-catalyzedpalladium‐catalyzed reactionreaction of of several several aryl andaryl arylvinyland arylvinyl bromides, bromides, in ionic liquidin ionic under liquid microwave under irradiationmicrowave [ 84irradiation] (Scheme [84] 24). (Scheme These conditions 24). These had conditions the advantage had the not advantage only to reduce not only the reactionto reduce time, the butreaction also totime, make but product also to make separation product and separation catalyst recycle and catalyst easier. recycle easier.

MW 14-34 min PdCl2 Ar Br + K4[Fe(CN)6] Ar CN [bmim]BF4 isolated yields, 44-84%

Ar Br = Br O Br

O2N Br Br Br Br

Br Br

Br Br Br

Br Br Br Br Br

N N N Br Br

MW Ar PdCl2 Ar 12-40 min + K4[Fe(CN)6] Br CN [bmim]BF4 isolated yields, 31-76%

Br Br Br O Br Br

O O O Br Br

Br Br Br Cl Cl O Cl

Scheme 24. Pd‐catalyzed MW‐assisted cyanation of aryl and arylvinyl bromides in [bmim]BF4 [84]. Scheme 24. Pd-catalyzed MW-assisted cyanation of aryl and arylvinyl bromides in [bmim]BF4 [84].

Ullmann reaction—A “green” catalyst was prepared treating graphene oxide (GO) with CuSO4 Ullmann reaction—A “green” catalyst was prepared treating graphene oxide (GO) with CuSO and and then reducing with ascorbic acid. The resulting Cu nanoparticles on reduced graphene oxide4 then reducing with ascorbic acid. The resulting Cu nanoparticles on reduced graphene oxide (RGO), (RGO), Cu NPs@RGO, were used to catalyze the Ullmann homocoupling reaction (Scheme 25) [85]. Cu NPs@RGO, were used to catalyze the Ullmann homocoupling reaction (Scheme 25)[85]. MW MW irradiation was used with different solvents, ILs included. Optimized conditions were aryl irradiation was used with different solvents, ILs included. Optimized conditions were aryl iodides iodides (or areneboronic acids) as the substrates, 10 mol % CuNPs@RGO catalyst, (or areneboronic acids) as the substrates, 10 mol % CuNPs@RGO catalyst, 1-butyl-3-methylpyridinium 1‐butyl‐3‐methylpyridinium bis(trifluormethylsulfonyl)imide and H2O (2:1 ratio) as solvent, and 30 bis(triﬂuormethylsulfonyl)imide and H O (2:1 ratio) as solvent, and 30 min MW irradiation. Aryl min MW irradiation. Aryl bromides were2 less reactive, but still interesting yields were obtained bromides were less reactive, but still interesting yields were obtained (78–91%). (78–91%).

Catalysts 2017, 7, 261 18 of 57 Catalysts 2017, 7, 261 18 of 56 Catalysts 2017, 7, 261 18 of 56

MW X 30 MW min X 30 min 10% molCuNPs@RGO 2 10% molCuNPs@RGO 2 [bumpy]NTf2/H2O 2:1 R [bumpy]NTf /H O 2:1 R R R 2 2 R R yields, 90-97% (ArI), 78-91% (ArBr), 90-95% (ArB(OH)2) yields, 90-97% (ArI), 78-91% (ArBr), 90-95% (ArB(OH)2)

X = I, Br, B(OH)2 X = I, Br, B(OH)2 R = H, 4-NO2, 4-CHO, 4-OMe, 4-Me, 4-CN, 4-CF3, 2-NO2 N R = H, 4-NO , 4-CHO, 4-OMe, 4-Me, 4-CN, 4-CF , 2-NO + N 2 3 2 + bumpy bumpy

SchemeScheme 25.25. MW-promotedMW‐promoted UllmannUllmann reactionreaction catalyzedcatalyzed byby CuCu nanoparticlesnanoparticles onon reducedreduced graphenegraphene Scheme 25. MW‐promoted Ullmann reaction catalyzed by Cu nanoparticles on reduced graphene oxide,oxide, inin IL/HIL/H2OO[ [85].85]. oxide, in IL/H2O [85]. 3.2. Friedel‐Crafts Aromatic Substitutions 3.2.3.2. Friedel-Crafts Friedel‐Crafts Aromatic Aromatic Substitutions Substitutions Acylation Reactions—It is well known that Friedel‐Crafts acylation is a powerful method to AcylationAcylation Reactions Reactions—It—It is wellis well known known that that Friedel-Crafts Friedel‐Crafts acylation acylation is a powerful is a powerful method tomethod prepare to prepare aromatic ketones, but is far from being a “green” procedure, because it requires chlorinated aromaticprepare aromatic ketones, butketones, is far but from is beingfar from a “green” being a procedure, “green” procedure, because it because requires it chlorinated requires chlorinated solvents andsolvents a more and than a more stoichiometric than stoichiometric amount of amount the “catalyst” of the AlCl “catalyst”. Therefore, AlCl3. attemptsTherefore, have attempts been made have solvents and a more than stoichiometric amount of the “catalyst”3 AlCl3. Therefore, attempts have been made to achieve a sustainable electrophilic acylation. Following the finding of metal triflates tobeen achieve made a to sustainable achieve a electrophilicsustainable electrophilic acylation. Following acylation. theFollowing finding the of metalfinding triflates of metal that, triflates still that, still maintaining strong Lewis acid character, are water resistant [86], some of them were used maintainingthat, still maintaining strong Lewis strong acid Lewis character, acid are character, water resistant are water [86 resistant], some of [86], them some were of used them as were catalysts used as catalysts in IL solvents. inas IL catalysts solvents. in IL solvents. TheThe acylationacylation of of ferrocene, ferrocene, already already discussed discussed in introduction in introduction [19], showed [19], showed that Sc(OTf) that ,Sc(OTf) Y(OTf) 3, The acylation of ferrocene, already discussed in introduction [19], showed that3 Sc(OTf)33, andY(OTf) Yb(OTf)3, and ,Yb(OTf) could be3, could used in be 10 used mol in % 10 amount mol % in amount bmimNTf in bmimNTfand was2and improved was improved by MW heating.by MW Y(OTf)3, and3 Yb(OTf)3, could be used in 10 mol % amount in bmimNTf2 2and was improved by MW Later,heating. Bi(OTf) Later, wasBi(OTf) used3 was to efficiently used to acylateefficiently methoxybenzene acylate methoxybenzene with different with carboxylic different anhydrides carboxylic heating. Later,3 Bi(OTf)3 was used to efficiently acylate methoxybenzene with different carboxylic oranhydrides chlorides inor bmimPFchlorides [in87 ]bmimPF (Scheme6 [87]26a). (Scheme MW irradiation 26a). MW efficiently irradiation accelerated efficiently the accelerated acylation with the anhydrides or chlorides6 in bmimPF6 [87] (Scheme 26a). MW irradiation efficiently accelerated the acylation with yields generally increased. yieldsacylation generally with yields increased. generally increased. a) O O a) X O O R O X R O R O R 0.5% mol Bi(OTf)3 , 80°C, 30 min R O R 0.5% mol Bi(OTf) , 80°C, 30 min + 3 or + or MW, or 5 min or [bmim]PF6 O [bmim]PF MW, 5 min O 6 X X R Cl yields 22 - 94% () R Cl yields 1722 -- >99%94% (MW) () 17 - >99% (MW)

X = OMe, SMe, 1,2(OMe)2, 1,3(OMe)2, 1,4(OMe)2, 1,4(OMe)Me RX == Me,OMe, t-Bu, SMe, Ph 1,2(OMe)2, 1,3(OMe)2, 1,4(OMe)2, 1,4(OMe)Me R = Me, t-Bu, Ph

b) b) MW, 80-140°C MW, 15-30 80-140°C min 15-30 min O O O O O O O O O 0.5% mol Bi(OTf)3 O Cl 0.5% mol Bi(OTf) + Cl 3 + + [bmim]PF6 [bmim]PF + 6 O O 5 : 95 5 : 95 isolated overall yield 94% isolated overall yield 94% Scheme 26. MW‐assisted Friedel‐Craft acylation of aromatic compounds in [bmim]PF6. (a) acylation Scheme 26. MW‐assisted Friedel‐Craft acylation of aromatic compounds in [bmim]PF6. (a) acylation Schemeof aromatic 26. MW-assistedethers by acyl Friedel-Craft anhydrides or acylation chlorides of [87], aromatic (b) benzoylation compounds of in methoxybenzene [bmim]PF6.(a) acylation [88]. ofof aromatic aromatic ethers ethers by by acyl acyl anhydrides anhydrides or or chlorides chlorides [ 87[87],], ( b(b)) benzoylation benzoylation of of methoxybenzene methoxybenzene [ 88[88].]. The attention was then focused on MW‐assisted benzoylation of aromatic compounds that was The attention was then focused on MW‐assisted benzoylation of aromatic compounds that was explored with a variety of substrates, evidencing the product distribution and the high yields [88] explored with a variety of substrates, evidencing the product distribution and the high yields [88] (Scheme 26b). (Scheme 26b).

Catalysts 2017, 7, 261 19 of 57

The attention was then focused on MW-assisted benzoylation of aromatic compounds that was exploredCatalysts 2017 with, 7, 261 a variety of substrates, evidencing the product distribution and the high yields19 of 56 [88 ] (Scheme 26b). AA screening screening ofof catalyticcatalytic efficiencyefficiency of various metal metal triflates triflates was was performed performed investigating investigating acetylationacetylation ofof 1,3,5-trimethylbenzene1,3,5‐trimethylbenzene with acetic anhydride [89]. [89]. Among Among the the 14metal 14metal triflates triflates examined, In(OTf)3 gave the best results, being superior also to the above discussed Bi(OTf)3 catalyst. examined, In(OTf)3 gave the best results, being superior also to the above discussed Bi(OTf)3 1‐isobutyl‐3‐methylimidazolium dihydrogen phosphate, [ibmim]H2POi 4 was the solvent of choice catalyst. 1-isobutyl-3-methylimidazolium dihydrogen phosphate, [ bmim]H2PO4 was the solvent and the reaction was applied to a wide range of aromatic compounds. The combination carboxylic of choice and the reaction was applied to a wide range of aromatic compounds. The combination anhydride/[ibmim]H2PO4/In(OTf)3/MW gave good performances and the catalyst could be easily carboxylic anhydride/[ibmim]H PO /In(OTf) /MW gave good performances and the catalyst could recycled. 2 4 3 be easily recycled. Considering the pharmaceutical importance of tetralone derivatives, such as donepezil Considering the pharmaceutical importance of tetralone derivatives, such as donepezil hydrochloride, a “green” intramolecular Friedel‐Craft acylation was carried out with Tb(OTf)3 hydrochloride, a “green” intramolecular Friedel-Craft acylation was carried out with Tb(OTf) catalyst, catalyst, in ILs (bmim or bupy triflates), under MW irradiation, directly from carboxylic acid3 [90] in ILs (bmim or bupy triflates), under MW irradiation, directly from carboxylic acid [90] (Scheme 27). (Scheme 27). Tb(OTf)3 emerged as the catalyst of choice after a screening of 19metal triflates; Tb(OTf)moreover,3 emerged it could as be the recovered catalyst of and choice re‐used after athree screening times, of with 19metal only triflates;slight decrease moreover, in itproduct could be recoveredisolated yield. and re-used three times, with only slight decrease in product isolated yield.

MW, 80°C MW, 100°C 20 min 20 min N N N - + - + Br + Br TfO N N LiOTf N

[bmim]Br [bmim]OTf yield 96%

MW, 220°C 30 min O O

Tb(OTf)3 OH + H2O [bmim]OTf yield 89% O O O O Tb(OTf)3 OH + H2O [bmim]OTf O O yield 91%

O OH Tb(OTf)3 + H2O [bmim]OTf yield 82%

Scheme 27. Intramolecular Friedel‐Craft acylation to tetralones catalyzed by Tb(OTf)3 in [bmim]OTf, Scheme 27. Intramolecular Friedel-Craft acylation to tetralones catalyzed by Tb(OTf) in [bmim]OTf, under MW irradiation [90]. 3 under MW irradiation [90].

Another metal triflate, Y(OTf)3, was the best catalyst for regioselective 3‐acylation of indoles [91].Another MW irradiation metal triﬂate, and IL Y(OTf) solvent3, was ([bmim]BF the best4) catalyst contributed for regioselective to obtain high 3-acylation yields in few of indoles minutes [91 ]. MW(Scheme irradiation 28). Moreover, and IL solventto further ([bmim]BF improve 4sustainability) contributed of to the obtain reaction, high it was yields not in necessary few minutes to (Schemeprotect the28). heterocyclic Moreover, NH, to further thus eliminating improve sustainability the protection‐ ofdeprotection the reaction, steps, it was in agreement not necessary with to protectthe eighth the heterocyclic principle of NH,Green thus Chemistry eliminating [1]. the protection-deprotection steps, in agreement with the eighth principle of Green Chemistry [1].

Catalysts 2017, 7, 261 20 of 57 Catalysts 2017, 7, 261 20 of 56

MW, 80°C 5 min O R O O O 0.1% mol Y(OTf)3 + + [bmim]BF R OH N R O R 4 N H H

R = Me isolated yield 88% R = Et 92% R = Pr 88% R = i-Pr 91% R = t-Bu 89% R = Ph 78%

Br O Br Cl F

N N N N N N H H H H H H

O O O O O O R R R R R Br R O Br Cl F

N N N N N N H H H H H H R yield R yield R yield R yield R yield R yield

Me 79% Me 79% Me 83% Me 79% Et 82% Et 72% Et 80% Et 78% Et 85% Et 82% t-Bu 65% t-Bu 82% Pr 79% Pr 80% Pr 78% Pr 80% i-Pr 80% i-Pr 78% i-Pr 80% i-Pr 79% t-Bu 83% t-Bu 79% t-Bu 80% t-Bu 65% MW, 80 -110°C Ph 83% Ph 78% Ph 75% Ph 77% 5 -15 min

3 4 Scheme 28.28. MWMW-assisted‐assisted Y(OTf)3 catalyzedcatalyzed indole acylation in [bmim]BF 4 [91].[91].

The recovery of yttrium triflate in [bmim]BF4 was simple: after product extraction, the ionic The recovery of yttrium triﬂate in [bmim]BF was simple: after product extraction, the ionic liquid liquid containing metal triflate was dried under 4vacuum and reused. Differently substituted indoles containing metal triﬂate was dried under vacuum and reused. Differently substituted indoles were were also acylated in good yields and only few percents of N‐acylindoles were occasionally also acylated in good yields and only few percents of N-acylindoles were occasionally observed. observed. Aromatic Substitutions by elecrophilic aldehydes. The condensation of indoles with Aromatic Substitutions by elecrophilic aldehydes. The condensation of indoles with benzenecarbaldehyde was reported to be catalyzed by 1-benzyl-3-methyl imidazolium hydrogen benzenecarbaldehyde was reported to be catalyzed by 1‐benzyl‐3‐methyl imidazolium hydrogen sulphate, [bnmim]HSO4, and improved by MW irradiation, in terms of higher yields and reduced sulphate, [bnmim]HSO4, and improved by MW irradiation, in terms of higher yields and reduced reaction time [92] (Scheme 29a). reaction time [92] (Scheme 29a). IL acted as an acid catalyst and MW heating shortened reaction times. A variety of aromatic IL acted as an acid catalyst and MW heating shortened reaction times. A variety of aromatic aldehydes were used, with yields in the range 81–95% and reaction times varying from 5 to 19 min aldehydes were used, with yields in the range 81–95% and reaction times varying from 5 to 19 min and the catalyst could be used in four consecutive runs, with negligible loss of activity. and the catalyst could be used in four consecutive runs, with negligible loss of activity. Also [bmim]Br was found to catalyze reaction of aldehydes with indoles, probably behaving as Also [bmim]Br was found to catalyze reaction of aldehydes with indoles, probably behaving as both acid and base catalyst [93] (Scheme 29b). A wide range of aldehydes was reacted and, once again, both acid and base catalyst [93] (Scheme 29b). A wide range of aldehydes was reacted and, once the combination IL/MW was decisive in increasing yield and reducing reaction times, with the bonus again, the combination IL/MW was decisive in increasing yield and reducing reaction times, with the of easy recovery and recycling. bonus of easy recovery and recycling.

Catalysts 2017, 7, 261 21 of 57 Catalysts 2017, 7, 261 21 of 56

MW, 5 min a)

R O 0.5 equiv. [bnmim]HSO4 + N H R N N H H 2 equiv. 1 equiv. yield 93% (R=H)

MW, 150°C b) 8 min

O [bmim]Br + N H N N H H 2 equiv. 1 equiv. yield 95%

Ar [bmim]Br + Ar O N H N N H H

NO2 CN MW, 150°C O N Ar = 2 Me 6 -21 min

O HO Cl isolated yield, 81-97%

N O N H

Scheme 29. Formation of bis‐indolylmethanes by MW‐assisted electrophiilic substitution catalyzed Scheme 29. Formation of bis-indolylmethanes by MW-assisted electrophiilic substitution catalyzed by by [bnmim]HSO4 (a) [92] and [bmim]Br (b) [93]. [bnmim]HSO4 (a)[92] and [bmim]Br (b)[93]. Later, the synthesis of aryl(bis‐3,3′‐indolyl)methanes was obtained in good yields with a variety 0 of aldehydes,Later, the synthesis ammonium of‐ aryl(bis-3,3based ionic -indolyl)methanesliquids and microwave was obtainedheating [94]. in good Mild yieldsreaction with conditions a variety ofwere aldehydes, accompanied, ammonium-based according to ionic the authors, liquids by and simple microwave product heating recovery [94 and]. Mild recycle reaction of ammonium conditions weresalts. accompanied, When the indole according 3‐position to the was authors, occupied by by simple a methyl product group, recovery the reaction and recycle worked of as ammonium well and salts.aryl Whenor alkyl(2,2 the indole′‐bis‐3‐ 3-positionmethylindolyl)methanes was occupied were by a methylprepared group, (Scheme the 30). reaction worked as well and aryl or alkyl(2,20-bis-3-methylindolyl)methanes were prepared (Scheme 30).

Catalysts 2017, 7, 261 22 of 57 Catalysts 2017, 7, 261 22 of 56

a) MW, 5 min

0.5 equiv. [R NH ]HSO X O O 2 2 4 + or or N H X N N N N H H H H 2 equiv. 1 equiv. isolated yield 85-99% isolated yield 95%

X = H, 4-Cl. 4-Me, 4-OH, 2-NO2, 2-OMe, 3-NO2

H H H H H H N N N [R2NH2] = + + +

O 0.5 equiv. [R2NH2]HSO4 + N N N H H H X

2 equiv. 1 equiv. isolated yield 90 ->99% X

X = H, 4-Me, 4-OH, 4-OMe, 4-NO2, 2-OMe, 3,4(OMe)2, 2,5(OH)(OMe)

Scheme 30. MW-assisted dialkylammonium hydrogensulfate-catalyzed reaction of aldehydes with Scheme 30. MW‐assisted dialkylammonium hydrogensulfate‐catalyzed reaction of aldehydes with indole (a) and 3-methylindole (b)[94]. indole (a) and 3‐methylindole (b) [94].

AA relatedrelated reaction,reaction, thatthat probablyprobably goes through electrophilic electrophilic aromatic aromatic substitution, substitution, formed formed triphenylmethanetriphenylmethane and and phthalein phthalein with with catalysis catalysis by by Brønsted Brønsted acid acid ionic ionic liquids liquids and and heating heating by by MW MW [95 ] (Scheme[95] (Scheme 31). 31). MWMW heating heating was was more more efficient efficient than than conventional conventional one, one, reducing reducing reaction reaction time time from from hours hours to to few minutes.few minutes. The work The work up was up easy,was easy, reaction reaction rates rates were were fast, fast, reaction reaction conditions conditions were were mild, mild, yields yields were good,were andgood, ILs and could ILs be could reused: be thereused: combination the combination IL/MW gaveIL/MW facile gave access facile to familiesaccess to of families compounds of importantcompounds in dyesimportant chemistry in dyes and chemistry biologically and activebiologically [95]. active [95]. AlkylationAlkylation ReactionsReactions—Friedel-Craft—Friedel‐Craft alkylation alkylation is is scarcely scarcely used used in in organic organic synthesis, synthesis, because because generallygenerally it it is is affected affected byby polysubstitutedpolysubstituted by by-products,‐products, since since the the more more alkyl alkyl groups groups are are introduced, introduced, thethe moremore reactivereactive is is the the aromatic aromatic compound. compound. Nevertheless, Nevertheless, an interesting an interesting report reportappeared appeared in 2013, in 2013,where where indium(III) indium(III) triflate triflate catalyzed catalyzed alkylation alkylation of benzenes of benzenes by alcohols by alcohols in IL solvents in IL solvents with MW with MWirradiation irradiation [96]. [Noticeably,96]. Noticeably, only monoalkylated only monoalkylated benzenes benzenes were obtained were obtained (Scheme (Scheme32) with benzyl,32) with benzyl,tertiary, tertiary, and secondary and secondary (but not (but primary) not primary) alcohols alcoholsas alkylating as alkylating agents, thus agents, suggesting thus suggesting the possible the possibleintermediacy intermediacy of carbocations. of carbocations. A phosponium A phosponium-based‐based IL, IL, trihexyl(tetradecyl)phosphonium trihexyl(tetradecyl)phosphonium bis(trifluoromethanesulfonyl)imide, [thtdp]NTf2, and the imidazolium‐based [emim]NTf2 were bis(trifluoromethanesulfonyl)imide, [thtdp]NTf2, and the imidazolium-based [emim]NTf2 were examinedexamined as as solvents, solvents, withwith thethe latter giving the best best results; results; energy energy-efficient‐efficient heating heating was was provided provided byby MWs. MWs.

Catalysts 2017, 7, 261 23 of 57 Catalysts 2017, 7, 261 23 of 56

OH N MW, 2 min O

+ O 5% mol N HSO4 H

HO OH N N yield, 80% yield, 97%

triphenylmethanes synthesized with yields (time in parenthesis)

N N N N N N HO OH N N 78% (2 min) 87% (3 min) 86% (2 min) 84% (2 min) 88% (5 min)

HO O OH O OH + O N HSO4 H MW, 2 min O + O 5% mol OH O yield, 89% O phthaleins synthesized with yields (time in parenthesis)

HO O OH HO O OH

N O N HO O OH

HO OH O O O O O O HO O O O2N O O O 80% (5 min) 86% (2 min) 97% (2 min) 78% (3 min)

HO O OH HO O OH HO O OH H H H H H H N N N N N N O O O N N N N N N

O O O

NH2 O HO 79% (5 min) 74% (5 min) 78% (5 min)

Scheme 31. MW‐activated acid IL‐catalyzed synthesis of triphenylmethanes and phthaleins [95]. Scheme 31. MW-activated acid IL-catalyzed synthesis of triphenylmethanes and phthaleins [95].

Catalysts 2017, 7, 261 24 of 57

Catalysts 2017, 7, 261 24 of 56

OH OH

[emim]NTf2 yield 77% yield 76%

yield <5% yield 8% (at 70°C) MW, 120°C 1.5 h

Me Me Me

OH + + overall yield, Me 52%

[emim]NTf2 2 : 41 : 17 Me Me Me OH overall yield, + + 55%

91 : 8 : 1

O O O

OH + + overall yield, O 58%

[emim]NTf2 56 : 42 : 2 O O O OH

+ + overall yield, 73%

88 : 11 : 1 OH

Cl Cl Cl Cl

+ + overall yield, 61% [emim]NTf2

58 : 40 : 2

Scheme 32. MW‐assisted In(OTf)3 catalyzed aromatic alkylation of benzenes with alcohols in Scheme 32. MW-assisted In(OTf)3 catalyzed aromatic alkylation of benzenes with alcohols in [emim]NTf2 [96]. [emim]NTf2 [96].

Catalysts 2017, 7, 261 25 of 57

Catalysts 2017, 7, 261 25 of 56 3.3. C–CBond Formation with C-Nucleophilic Reagents 3.3. C–CBond Formation with C‐Nucleophilic Reagents Aldol-type reactions—It is well known that the aldol reaction is one of the most powerful tool for theAldol construction‐type reactions of C–C—It bonds is well and known it is that considered the aldol relatively reaction is environmentally one of the most powerful benign, being tool for also highlythe construction atom-economic. of C–C However, bonds and due it to is the considered need of strongrelatively bases environmentally or acids, the “green” benign, aspect being canalso be highly atom‐economic. However, due to the need of strong bases or acids, the “green” aspect can be improved, as discussed in a 2004 review [97]. Catalysis, biocatalysis, and alternative solvents, among improved, as discussed in a 2004 review [97]. Catalysis, biocatalysis, and alternative solvents, among which task-speciﬁc ionic liquids (TSILs) [98–100], have been the object of following research. Even a which task‐specific ionic liquids (TSILs) [98–100], have been the object of following research. Even a MW-assisted aldol reaction was carried on in absence of solvents [101]. MW‐assisted aldol reaction was carried on in absence of solvents [101]. The possibility to use together an alternative power source as MW and alternative solvents The possibility to use together an alternative power source as MW and alternative solvents as asILs ILs was was explored explored in in the the aldol aldol condensation condensation reactions reactions of of aryl aryl aldehydes aldehydes with with acetone acetone [102]. [102 ]. TetralkylammoniumTetralkylammonium and and tetrabutylphosphonium tetrabutylphosphonium salts were were prepared prepared and and used, used, with with encouraging encouraging resultsresults (Scheme (Scheme 33 33).). The The functionalized functionalized ILsILs acted as both both solvents solvents and and the the reaction reaction did did not not require require anyany strong strong acid acid or or base base to to catalyze catalyze the the aldol aldol condensation. condensation. Aldehydes with with electron electron-withdrawing‐withdrawing substituentssubstituents were—as were—as expected—more expected—more reactive reactive thanthan the electron electron-rich‐rich ones. ones. The The system system was was effective effective alsoalso in in the the nitro-aldol nitro‐aldol condensation condensation (Henry(Henry reaction).reaction). MW MW heating heating was was confirmed conﬁrmed to toprovide provide rate-enhancementrate‐enhancement with with respect respect to to conventional conventional heating.heating.

O MW, 80°C 30 min 50 wt.% [Et N][ C SO ] O 4 EtNH 3 3 O H O + 2 R R + N N SO- conv. 88 ->99% H 3 yield, 87-98% R = H, 4-OMe, 4-Me, 2-Cl, 3-Br [Et4N][EtNHC3SO3]

MW, 80°C 30 min

O 50 wt.% [Bu4N][im], H2O + NO 2 NO2 R R N conv. >99% P yield, 87-98% + N R = H, 4-OMe, 4-Me, 2-Cl -

Scheme 33. MW‐assisted aldol (top) and nitro‐aldol (bottom) reactions with ILs catalytic systems Scheme 33. MW-assisted aldol (top) and nitro-aldol (bottom) reactions with ILs catalytic systems [102]. [102].

TheThe condensation condensation of arylof aryl aldehydes aldehydes with with nucleophilic nucleophilic enolates enolates was exploited was exploited to prepare to prepare bioactive heterocyclicbioactive heterocyclic compounds, compounds, such as chromanone such as chromanone and thiochromanone and thiochromanone derivatives, inderivatives, a MW-irradiated in a process,MW‐irradiated catalyzed process, by ILs withcatalyzed a basic by anionILs with [103 a ]basic (Scheme anion 34 [103]). (Scheme 34). TheThe basic basic [bmim]OH [bmim]OH IL IL catalyzed catalyzed the the synthesissynthesis of 3 3-styrylchromones‐styrylchromones from from 3‐ 3-formylchromonesformylchromones andand a carbaniona carbanion precursor, precursor, under under MW MW irradiationirradiation [[104]104] (Scheme 35).35). The The authors authors pointed pointed at atthe the advantagesadvantages of of the the method method (easy (easy work-up, work‐up, shortshort reaction times, times, satisfactory satisfactory yields, yields, reusable reusable catalyst) catalyst) andand at at the the cytotoxicity cytotoxicity of of products. products. The condensation of aryl aldehydes was achieved also with Brønsted acid ILs, giving xantenedione derivatives [105] (Scheme 36), in a process made fast by MW irradiation. In such reaction, products were simply isolated by ﬁltration and the catalyst reused without treatment, although a dramatic drop in yield was reported from the second run (from 97% to 9%). However, a direct comparison of yields is difﬁcult, because also the reaction time changed (from 10 to 1 min).

Catalysts 2017, 7, 261 26 of 56

MW, 3 min

O O Cl Catalysts 2017, 7, 261 Cl [bmim]CF3CO2 26 of 57 O Catalysts 2017,, 7,, 261 + 26 of 56 O O yield, 76% (79% with [bmim]OH) MW,MW, 33 minmin O O O O O MW, Cl Cl 2,5-4 min O ClCl [bmim]CF[bmim]CF3COCO2 Cl Cl [bmim]CF3CO2 O + + or O O O X O [bmim]OH O X yield, 76% (79% with [bmim]OH) yields, 76-88%yield, with 76% [bmim]CF (79% with3CO [bmim]OH)2 79-88% with [bmim]OH) X = 2-Cl, 4-Cl, 2,4-Cl2, 3-NO2, 4-NO2, 4-OMe O O O MW,MW, 2,5-4 min O Cl [bmim]CF CO Cl 2,5-4 MW, min O Cl [bmim]CF3CO2 3 min + O O or X O Cl O X O Cl [bmim]OH[bmim]OH[bmim]CF3CO2 X yields, 76-88% with [bmim]CF CO + yields, 76-88% with [bmim]CF3CO2 X =O 2-Cl, 4-Cl, 2,4-Cl , 3-NO , 4-NO , 4-OMe 79-88%79-88% withwith [bmim]OH)[bmim]OH)S O X = 2-Cl, 4-Cl, 2,4-Cl2, 3-NO2, 4-NO2, 4-OMeS yield, 87% Scheme 34. MW‐irradiated condensation of aryl aldehydes with chromanones MW,MW, and 3 min O 3 min thiochromanones, catalyzed by ILs [103].O O Cl [bmim]CF CO Cl O Cl [bmim]CF3CO2 + MW, O S O O S S 5-15O min yield, 87% yields, 34-57% O2N Scheme 34. MW‐irradiated condensation of aryl aldehydes with chromanones and Scheme 34.34.MW-irradiated MWO ‐irradiated condensation condensation of aryl aldehydesof aryl withaldehydes chromanones with andchromanones thiochromanones,NO and O 2 catalyzedthiochromanones, by ILs [103 catalyzed]. by ILs [103]. O [bmim]OH MW, O MW, X O 5-15 min X O N yields, 34-57% O2N O2N NO O NO2 O yields, 54-70%O 2 O HO [bmim]OH Scheme 35.O MW‐irradiated [bmim]OH‐catalyzed formation of 3‐styrylchromones [104]. X O X The condensation of aryl aldehydes was achieved also with Brønsted acid ILs, giving O2N xantenedione derivatives [105] (Scheme2 36), in a process made fast by MW irradiation. In such O yields, 54-70% reaction, products were simply isolated by filtration and the catalyst reused without treatment, HO although a dramatic drop in yield was reported from the second run (from 97% to 9%). However, a Scheme 35. MW‐irradiated [bmim]OH‐catalyzed formation of 3‐styrylchromones [104]. direct comparisonScheme 35. of yieldsMWMW-irradiated‐irradiated is difficult, [bmim]OH-catalyzed[bmim]OH because‐catalyzed also the formation reaction time of 3-styrylchromones3‐styrylchromones changed (from [[104].10104 to]. 1 min).

The condensation of aryl aldehydes was achieved also with Brønsted acid ILs, giving xantenedione derivatives [105] (Scheme 36), in a process made fast by MWMW, 100°Cirradiation. In such 10 min reaction, products were simply isolated by filtration and theO catalystO reused without treatment, 5% mol [(p ) im]OTf although a dramatic dropO in yield was reportedSO from3H 2 the second run (from 97% to 9%). However, a direct comparison of yields+ 2is difficult, because also the reaction time changed (from 10 to 1 min). O O O yield, 97%

HO S SO H 3 3 MW, 100°C N + N MW, 100°C O O 1010 minmin (pSO3H)2im

5% mol [(pSO3H)2im]OTfim]OTf O SO3H 2 Scheme 36. MW‐assisted,+ 2 Brønsted acid IL‐catalyzed condensation of benzenecarbaldehyde with Scheme 36. MW-assisted,O Brønsted acidO IL-catalyzed condensationO of benzenecarbaldehyde with 1,3‐cyclohexanedione [105].O O 1,3-cyclohexanedione [105]. yield, 97%

SO H HO3S SO3H 3 N + N 3 The reaction was extendedN N to substituted aldehydes and diketones, with yields in the range (pSO3H)2imim 90–97%. SO3H 2 Scheme 36. MW‐assisted, Brønsted acid IL‐catalyzed condensation of benzenecarbaldehyde with 1,3‐cyclohexanedione [105].

Catalysts 2017, 7, 261 27 of 56

Catalysts 2017, 7, 261 27 of 57 CatalystsThe 2017reaction, 7, 261 was extended to substituted aldehydes and diketones, with yields in the27 ofrange 56 90–97%. BenzoinThe reaction condensationcondensation was extended—Benzene—Benzene to substituted carbaldehyde carbaldehyde aldehydes underwent underwent and diketones, benzoin benzoin condensation with yieldscondensation in in the 1-octyl-3- range in 90–97%. methyl1‐octyl‐3 imidazolium‐methyl imidazolium bromide bromide that acted that also acted as catalyst also as undercatalyst MW under [106 MW] (Scheme [106] (Scheme 37a) as well37a) as Benzoin condensation—Benzene carbaldehyde underwent benzoin condensation in ultrasoundwell as ultrasound [107] irradiation. [107] irradiation. 1‐octyl‐3‐methyl imidazolium bromide that acted also as catalyst under MW [106] (Scheme 37a) as Similar resultsresults were were obtained obtained by by another another research research group group that that used used MW MW irradiation irradiation also also in the in ILsthe well as ultrasound [107] irradiation. preparationILs preparation [108 [108]] (Scheme (Scheme 37b). 37b). Similar results were obtained by another research group that used MW irradiation also in the ILs preparation [108] (Scheme 37b). a) O MW, 150°C 2 MW, 80°C 4 min 60 min a) O MW, 150°C 2 MW, 80°C 4 min [omim]Br [omim]OTf 60 min MeONa DBU [omim]Br [omim]OTf O MeONa DBU O OH isolated yield, 83% isolated yield, 72% OH isolated yield, 83% isolated yield, 72%

b) X MW, 80°C O b) X 60 min MW, 80°C DBU O O 60 min 2 DBU O [omim]OTf OH 2 X X [omim]OTf OH X X GC yields, 47-92% X = H, 4-Me, 4-OMe, 4-Cl, 3-Me, 3-OMe GC yields, 47-92% X = H, 4-Me, 4-OMe, 4-Cl, 3-Me, 3-OMe Scheme 37. MW‐ and base‐promoted benzoin condensation with 1‐octyl‐3‐methyl imidazolium Scheme 37. MW- and base-promoted benzoin condensation with 1-octyl-3-methyl imidazolium bromideScheme ( a37.) [106] MW and‐ and triflate base (‐bpromoted) [108]. benzoin condensation with 1‐octyl‐3‐methyl imidazolium bromidebromide (a ()[a)106 [106]] and and triﬂate triflate ( b(b)[) 108[108].].

A further development was the preparation of diarylglycolic acids in [bmim]BF4 and KOH, A further development was the preparation of diarylglycolic acids in [bmim]BF and4 KOH, with with MWA further heating development [109]. Likely, was KOH the shouldpreparation deprotonate of diarylglycolic the imidazolium acids in salt,[bmim]BF forming4 and the KOH, actual MWwith heating MW heating [109]. Likely, [109]. Likely, KOH should KOH should deprotonate deprotonate the imidazolium the imidazolium salt, forming salt, forming the actual the actual catalyst. catalyst. This one‐pot procedure resulted easy and efficient and was applied to substituted aromatic Thiscatalyst. one-pot This procedure one‐pot procedure resulted easy resulted and efﬁcient easy and and efficient was applied and was to applied substituted to substituted aromatic aromatic aldehydes, aldehydes, with results summarized in Scheme 38. withaldehydes, results summarized with results summarized in Scheme 38 in. Scheme 38. O O MW, 60°C HO MW, 60°C HO OH 25 min 20% mol [bmim]BF OH 25 min O 20% mol [bmim]BF4 2 O 4 2 1 equiv. KOH 1 equiv. KOH isolated yield, 74% isolated yield, 74%

,-diarylglycolic acids prepared with isolated yields (time in parenthesis) ,-diarylglycolic acids prepared with isolated yields (time in parenthesis)

O O OO O OO O O HO HO HO HO HO HO OHOH HO OHOH HO OH HO OHOH HO OHOH

O O Cl Cl Br Br O N NO O O Cl Cl Br Br O2N2 NO2 2 78%78% (25 (25 min) min) 76% 76% (25 (25 min) min) 80% (20 min) 78% 78% (20 (20 min) min) 78%78% (25 (25 min) min)

O O OO O OO O O O HOOHO HOHO OHOH HHOO OHOH HO OHOH HHOO OHOH OHOH ClCl ClCl BrBr BrBr

O N NO O O O2N 2 NO2 2

81%81% (20 (20 min) min)77%77% (25 (25 min) min) 75% (5 min)min) 76% 76% (25 (25 min) min) 73% 73% (25 (25 min) min)

4 SchemeScheme 38. 38. MW MW‐‐heatedheated synthesissynthesis of diarylglycolic acids acids in in [bmim]BF [bmim]BF [109].4 [109]. Scheme 38. MW-heated synthesis of diarylglycolic acids in [bmim]BF4 [109].

MoritaMorita‐Baylis‐Baylis‐Hillman‐Hillman reactionreaction—DABCO—DABCO‐catalyzed C–CC–C bondbond formationformation betweenbetween an an alkene alkene Morita-Baylis-Hillman reaction—DABCO-catalyzed C–C bond formation between an alkene bearing bearingbearing an an electron electron‐withdrawing‐withdrawing substituentsubstituent and an electrophilicelectrophilic carboncarbon could could be be performed performed in in an electron-withdrawing substituent and an electrophilic carbon could be performed in water

Catalysts 2017, 7, 261 28 of 57 Catalysts 2017, 7, 261 28 of 56 containing IL, only if MW heating was provided [110]. Under conventional heating, no reaction waterCatalysts containing 2017, 7, 261 IL, only if MW heating was provided [110]. Under conventional heating,28 of 56 no occurredreaction occurred in 3 h, while in 3 with h, while MW irradiation with MW the irradiation product formedthe product almost formed quantitatively almost (isolatedquantitatively yield, >97%)(isolatedwater within containingyield, 3–7 >97%) min, IL, within only that arrived3–7if MW min, heating at that 20–40 arrived was s, ifprovided at the 20–40 reaction s,[110]. if the is Under carriedreaction conventional on is carried under 40on heating, psiunderpressure. 40no psi Nucleophilicpressure.reaction Nucleophilicoccurredα,β-unsaturated in 3 α h,,β‐ whileunsaturated esters with are MW less esters irradiation reactive, are butless the the reactive,product reaction formedbut still the gives almost reaction satisfactory quantitatively still yields,gives evensatisfactory(isolated with the yield, yields, sterically >97%) even within crowded with the3–7 t sterically-butylmin, that ester arrivedcrowded (Scheme at t20–40‐butyl 39). s, ester if the (Scheme reaction is39). carried on under 40 psi pressure. Nucleophilic α,β‐unsaturated esters are less reactive, but the reaction still gives satisfactory yields, even with the sterically crowded t‐butyl ester (Scheme 39). MW, 150°C OH 2 min CN O [bmim]PF6 -H2O 1:50 v/v MW, 150°C + CN OH isolated yield, >97% 2 min O N 2 equiv DABCO 2 O2N CN O [bmim]PF6 -H2O 1:50 v/v + CN OHisolatedO yield, >97% O N 2 equiv DABCO 2 O2N O O OH O O N MW, 150°C O O 2 isolated yield,O 90% O [bmim]PF6 -H2O 1:50 v/v 60 min OH O O O2N isolated yield, 90% MW, 150°C [bmim]PF2 equiv DABCO -H O 1:50 v/v O2N O 6 2 60 min O O OH O 2 equiv DABCO O2N O N O O O 2 isolated yield, 77% O N O 2 isolated yield, 77% Scheme 39.39. TheThe MW MW-promoted‐promoted DABCO DABCO catalyzed catalyzed Morita Morita-Baylis-Hillman‐Baylis‐Hillman reaction reaction in water‐[bmim]PF6 [110]. water-[bmim]PFScheme 39. 6 The[110 ]. MW‐promoted DABCO catalyzed Morita‐Baylis‐Hillman reaction in water‐[bmim]PF6 [110]. The reaction was tested with good results also varying the aldehyde. The reaction was tested with good results also varying the aldehyde. KnoevenagelThe reaction reaction was tested—In order with goodto solve results the scarcealso varying sustainability the aldehyde. of catalysts used in Knoevenagel Knoevenagel reaction—In order to solve the scarce sustainability of catalysts used in Knoevenagel reaction,Knoevenagel that is the reaction C–C —Inbond order formation to solve between the scarce aldehydes sustainability and of active catalysts methylene used in Knoevenagelcompounds, a reaction, that is the C–C bond formation between aldehydes and active methylene compounds, a range rangereaction, of homogeneous that is the C–C and bond heterogeneous formation betweencatalysts aldehydeshave been and applied active with methylene varying compounds, results. Among a of homogeneous and heterogeneous catalysts have been applied with varying results. Among them, them,range the of functionalized homogeneous andionic heterogeneous liquid [bmim]OH catalysts was have chosen been to applied catalyze with the varying reaction, results. because Among it can the functionalized ionic liquid [bmim]OH was chosen to catalyze the reaction, because it can provide providethem, the functionalizednecessary basic ionic environment, liquid [bmim]OH beside wasthe chosenionic one to catalyze[111]. The the section reaction, was because performed it can in the necessary basic environment, beside the ionic one [111]. The section was performed in absence absenceprovide of the other necessary solvents, basic underenvironment, grinding, beside conventional the ionic one heating, [111]. The and section microwave was performed irradiation in of other solvents, under grinding, conventional heating, and microwave irradiation conditions. The conditions.absence ofThe other first solvents, method underrequired grinding, longer conventionalreaction time heating, than the and other microwave two and irradiation yields are ﬁrst method required longer reaction time than the other two and yields are comparable in all cases. comparableconditions. in The all cases.first methodSelected required examples longer are shown reaction in Schemetime than 40. the other two and yields are Selectedcomparable examples in all are cases. shown Selected in Scheme examples 40. are shown in Scheme 40.

MW CN MW30-120 s O [bmim]OH CN 30-120 s O+ NC CN [bmim]OH + CN NC CN CN R R R R isolated yield, 83-91% isolated yield, 83-91% R = H, 2-Cl, 4-Cl, 4-OH, 4-Me, 4-NMe2, 3-NO2 R = H, 2-Cl, 4-Cl, 4-OH, 4-Me, 4-NMe2, 3-NO2

MW MW 15-12015-120 s s O CNCN O OO [bmim]OH ++ NCNC [bmim]OH R OO O O R RR O O isolatedisolated yield, yield, 85-96% 85-96% R R= 4-Cl,= 4-Cl, 4-OH, 4-OH, 4-Me, 4-Me, 4-NMe 4-NMe22, ,3-NO 3-NO22

MW MW CN 60-90 60-90 s s OO NH CN NH22 ++ NCNC [bmim]OH[bmim]OH R OO O NH R R O NH2 R 2 isolated yield, 74-94% isolated yield, 74-94% R = H, 2-Cl, 4-Cl, 4-OH, 4-Me, 4-NMe R = H, 2-Cl, 4-Cl, 4-OH, 4-Me, 4-NMe 2 2 Scheme 40. MW‐promoted IL‐catalyzed Knoevenagel reaction [111]. Scheme 40. MWMW-promoted‐promoted IL-catalyzedIL‐catalyzed Knoevenagel reaction [[111].111].

Catalysts 2017, 7, 261 2929 of of 56 57

An application of MW‐assisted Knoevenagel reaction to the synthesis of heterocyclic compoundsAn application was also of reported MW-assisted [112]. Knoevenagel Coumarin reactionderivatives to the were synthesis prepared of heterocyclic in high yields, compounds in the determinantwas also reported presence [112 of]. imidazolium Coumarin derivatives‐based IL that were rendered prepared fast in highan otherwise yields, in sluggish the determinant reaction (Schemepresence 41). of imidazolium-based IL that rendered fast an otherwise sluggish reaction (Scheme 41).

O K2CO3 MW, [bmim]Br 2 min X OH

O O O O O NC O O O O

O O CN O

X O O X O O X O O yields, 70-87% yields, 79-82% yields, 72-85%

X = H, 4-OH, 4-Et2N, 3-OMe X = H, 4-OH X = H, 4-OH, 4-Et2N, 3-OMe

OH K CO MW, 2 3 2 min [bmim]Br

O O O O O NC O O O O

O O CN O O O O O O O yield, 87% yield, 91% yield, 89%

SchemeScheme 41. 41. MWMW-assisted‐assisted Knoevenagel synthesis of coumarins in IL [112]. [112].

Michael reaction—This well‐known and versatile conjugated addition could not escape the Michael reaction—This well-known and versatile conjugated addition could not escape the attention of research aimed at applying modern eco‐friendly procedures. Solvent‐free metal‐ attention of research aimed at applying modern eco-friendly procedures. Solvent-free metal- catalyzed Michael addition of β‐ketoesters to enones was accomplished in tailor made IL, catalyzed Michael addition of β-ketoesters to enones was accomplished in tailor made IL, 1‐butyl‐3‐methylimidazolium tetrachloroferrate, with MW irradiation [113]. The IL acted as iron 1-butyl-3-methylimidazolium tetrachloroferrate, with MW irradiation [113]. The IL acted as iron catalyst and the system could be reused, after removal of products by distillation. The synthesis of catalyst and the system could be reused, after removal of products by distillation. The synthesis of [bmim]FeCl4 was straightforward, simply mixing commercial solid [bmim]Cl with FeCl3∙6H2O and [bmim]FeCl was straightforward, simply mixing commercial solid [bmim]Cl with FeCl ·6H O and removing the4 resulting upper aqueous phase (Scheme 42). 3 2 removing the resulting upper aqueous phase (Scheme 42). Although not pertinent here (because a bond different from C–C is also formed), aza‐Michael Although not pertinent here (because a bond different from C–C is also formed), aza-Michael reaction has to be mentioned, because the pharmaceutically important family of N‐alkyl reaction has to be mentioned, because the pharmaceutically important family of N-alkyl sulfonamides sulfonamides could be prepared in ILs under MW heating, with green and reusable catalysts MgO could be prepared in ILs under MW heating, with green and reusable catalysts MgO [38] and ZnO [39]. [38] and ZnO [39]. Moreover, the addition of imidazole to cyclohex‐2‐en‐1‐one, followed by Moreover, the addition of imidazole to cyclohex-2-en-1-one, followed by lipase-catalyzed kinetic lipase‐catalyzed kinetic resolution, led to optically active ILs [114]. resolution, led to optically active ILs [114].

Catalysts 2017, 7, 261 30 of 57 Catalysts 2017, 7, 261 30 of 56

1% mol [bmim]FeCl4 O O

MW, 125°C H MW,125°C 15 min 90 min O O O O O O O O isolated yield, 94% isolated yield, 91% O O

O O O O O O MW, 125°C + 30 min O O isolated yield,89% 94% (, 24 h)

O O O O MW, 125°C + O 30 min O O O isolated yield,71% 72% (, 24 h)

O O MW,125°C O 90 min O

H O O O O O O O O O O O O O

O isolated yield, 79% isolated yield, 88% isolated yield,52% 48% (, 24 h)

Scheme 42. MW‐heated iron‐catalyzed Michael addition in [bmim]FeCl4 IL [113]. Scheme 42. MW-heated iron-catalyzed Michael addition in [bmim]FeCl4 IL [113].

Stetter reaction—1,4‐Bifunctional compounds, key intermediates in organic synthesis, can be Stetter reaction—1,4-Bifunctional compounds, key intermediates in organic synthesis, can be obtained by this reaction, that was investigated in the intramolecular version using IL solvents and obtained by this reaction, that was investigated in the intramolecular version using IL solvents and microwave irradiation, since ILs only were not much efficient [115]. Among the tested ILs, microwave irradiation, since ILs only were not much efﬁcient [115]. Among the tested ILs, [bmim]BF4 [bmim]BF4 allowed best results; 3‐ethyl‐5‐(2‐hydroxyethyl)‐4‐methylthiazolium bromide was used allowed best results; 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide was used as the catalyst, as the catalyst, with best performances observed when it was 15 mol %. A number of aldehydes were with best performances observed when it was 15 mol %. A number of aldehydes were reacted, reacted, producing a library of substituted chroman‐4‐ones (Scheme 43). producing a library of substituted chroman-4-ones (Scheme 43). Intramolecular Stetter reaction was performed under MW irradiation, either solventless or in ILs, with thiazolium-based ionic liquids that, in turn, were prepared by a one-pot, solvent-free, MW-assisted reaction (Scheme 44)[116].

Catalysts 2017, 7, 261 31 of 56

MW, 80°C O 5 min Catalysts 2017, 7, 261 31 of 57 O O Catalysts 2017, 7, 261 O 15% mol catalyst O 31 of 56

Et3N, [bmim]BF4 O O O MW, 80°C N + O isolated yied, 98% H O 5 min Br- S O O O 15% mol catalyst O catalyst

Et3N, [bmim]BF4 O Synthesized chroman-4-ones with isolated yields (reaction time, 5-20 min): O O N + O O isolated yied, 98% O HO - O O O Br S Cl O Br O O O catalyst O 94% O 75%O 84% Synthesized chroman-4-ones with isolated yields (reaction time, 5-20 min):

O O O O O O O O OO O O O O Cl O Br O O O O O O O O O O O 94% 75%O 84% 83% 89% 85%

O O O O O O O O Scheme 43. MW assisted intramolecular Stetter reaction in [bmim]BF4 [115]. O O O O O O Intramolecular Stetter83% reaction was performed89% under MW irradiation,85% either solventless or in

ILs, with thiazolium‐based ionic liquids that, in turn, were prepared by a one‐pot, solvent‐free, Scheme 43. MW assisted intramolecular Stetter reaction in [bmim]BF4 [115]. MW‐assisted reactionScheme (Scheme 43. MW assisted44) [116]. intramolecular Stetter reaction in [bmim]BF4 [115].

Intramolecular Stetter reaction was performed underMW, 150°C MW irradiation, either solventless or in ILs, with thiazolium‐based ionic liquids that, in turn, 90 were min prepared by a one‐pot, solvent‐free, N NaBF MW‐assisted reaction (Scheme 44) [116]. 4 + I no solvent S N + - BF4 MW, 150°CS [othyaz]BF 90 min 4 isolated yield, 93% N NaBF4 conv. 100% + I no solvent S N + - BF4 S O O [othyaz]BF O O O 4 O isolated yield, 93% 15% mol [othyaz]BF4 X MW, 80°C conv. 100% 30 min 0.15 equiv. Et N 3 O O in [omim]BF , conv. 100%, isolatedO yield,O 96% O O 4 O O without solvent, conv. 100%, isolated yield, 85% 15% mol [othyaz]BF4 X MW, 80°C MW, 100°C, 20 min, 30 min no solvent, conv. 100%, isolated yield, 97% 0.15 equiv. Et N (conventional3 heating isolatedO yield, 77%) O in [omim]BF , conv. 100%, isolatedO O yield, 96% O O 4 O O without solvent, conv. 100%, isolated yield, 85% MW, 100°C 15% mol [othyaz]BF4 X X MW, 100°C, 20 min, 20 min no solvent, conv. 100%, isolated yield, 97% 0.15 equiv. Et N (conventional3 heating isolatedO yield, 77%) O isolated yield, 82-97%O O X = Me,O OMe,O Cl O O MW, 100°C 15% mol [othyaz]BF4 X SchemeX 44. MW‐assisted thiazolium salts‐catalyzed intramolecular Stetter 20 reaction min [116]. Scheme 44. MW-assisted thiazolium0.15 equiv. Et salts-catalyzedN intramolecular Stetter reaction [116]. 3 O O Blank experiments demonstrated that thyazoliumisolated saltsyield, 82-97% are real catalysts, since no reaction Blank experimentsX = Me, demonstrated OMe, Cl that thyazolium salts are real catalysts, since no reaction occurs occurs without them; the base was necessary as well, while the IL solvent was of help, but the results without them; the base was necessary as well, while the IL solvent was of help, but the results were were satisfactoryScheme 44.also MW under‐assisted no‐solvent thiazolium conditions. salts‐catalyzed intramolecular Stetter reaction [116]. satisfactory also under no-solvent conditions. Blank experiments demonstrated that thyazolium salts are real catalysts, since no reaction 3.4. Cyclization Reactions to Carbocycles with C–CBond Formation occurs without them; the base was necessary as well, while the IL solvent was of help, but the results were Cyclotrimerizationsatisfactory also under of of alkynes alkynes no‐solvent to to benzenes benzenes conditions. was was brilliantly brilliantly achieved achieved using using Pd Pd catalyst catalyst supported supported on Auon Au nanoparticles nanoparticles stabilized stabilized with with thiolates thiolates [117]. [117]. With aWith loading a loading of 4 mol of % 4 Au-boundmol % Au Pd(II)‐bound catalyst, Pd(II) 3.4.mostcatalyst, Cyclization of tested most ofReactions alkynes tested reacted alkynesto Carbocycles completely reacted with completely C–CBond in 1 h. The in Formation 1 method h. The becamemethod appealingbecame appealing when MW when heating MW was used in IL solvent. Under such conditions, 1–5 min were sufﬁcient to obtain quantitative alkyne Cyclotrimerization of alkynes to benzenes was brilliantly achieved using Pd catalyst supported onconversion Au nanoparticles and good selectivitystabilized with (Scheme thiolates 45). [117]. With a loading of 4 mol % Au‐bound Pd(II) catalyst, most of tested alkynes reacted completely in 1 h. The method became appealing when MW

Catalysts 2017, 7, 261 32 of 56

Catalystsheating2017 was, 7 ,used 261 in IL solvent. Under such conditions, 1–5 min were sufficient to obtain quantitative32 of 57 alkyne conversion and good selectivity (Scheme 45).

3 3

MW, 62°C 0.4% mol AuNP-Pd 0.4% mol AuNP-Pd MW, 62°C 1.5 min [bmim]PF 2 min [bmim]PF6 6

conv. > 99% conv. > 99%

0.4% mol AuNP-Pd 3 + +

[bmim]PF6

conv. > 99% MW, 62°C 2 min ratio: 22 : 75 : 3 Scheme 45. MW‐promoted AuNP‐Pd catalyzed cyclotrimerization of alkynes in IL [117]. Scheme 45. MW-promoted AuNP-Pd catalyzed cyclotrimerization of alkynes in IL [117].

Diels‐Alder reaction—ILs were used as solvents also in this reaction and with time new ILs were synthesizedDiels-Alder on reactionpurpose.—ILs For were example, used as a solventsnumber alsoof inammonium this reaction salts and were with prepared time new from ILs were2‐dimethylaminoethanol synthesized on purpose. and used For as example, the medium a number of the of uncatalyzed ammonium and salts catalyzed were prepared Diels‐Alder from 2-dimethylaminoethanolreaction [118]. Cyclopentadiene and used was as chosen the medium as the probe of the diene uncatalyzed and was and reacted catalyzed with a Diels-Alder number of reactiondienophiles, [118 ].with Cyclopentadiene and without Lewis was chosenacids (triflates as the probeof Y, Sc, diene Yb, Al, and Cu, was Zn, reacted Mg, Li). with a number of dienophiles,One of withthe first and withoutstudies aimed Lewis acidsat investigating (triflates of Y,ILs Sc, combined Yb, Al, Cu, with Zn, Mg,microwave Li). heating was appliedOne to of Diels the first‐Alder studies reaction aimed [119]. at investigating Actually, the ILs combinedauthors were with interested microwave in heating heating was non applied polar tosolvents Diels-Alder above reaction their boiling [119]. point Actually, in sealed the authorsvessels adding were interested a small amount in heating of an non ionic polar liquid, solvents thus aboverendering their the boiling medium point more in sealed polar vesselsand thereby adding usable a small for amount microwave of an‐assisted ionic liquid, chemistry. thus rendering They also thechecked medium eventual more contamination polar and thereby by IL usable decomposition for microwave-assisted after MW irradiation chemistry. and found They alsoalmost checked none, eventualeven after contamination prolonged times by IL decomposition(30 min at 300 after °C). MW As irradiation the probe and reaction, found almostthey tested none, eventhe after[4+2] ◦ prolongedcycloaddition times between (30 min 2,3 at 300‐dimethylbutadieneC). As the probe and reaction, methyl they acrylate, tested the that [4+2] takes cycloaddition 18–24 h in between boiling 2,3-dimethylbutadienetoluene or xylene to and occur. methyl Adding acrylate, a thatsmall takes amount 18–24 hof in boiling1‐isopropyl toluene‐2‐methylimidazolium or xylene to occur. Addinghexafluorophosphate, a small amount [ipmim]PF6, of 1-isopropyl-2-methylimidazolium to toluene and irradiating hexafluorophosphate, with MW, 80% Diels [ipmim]PF6,‐Alder adduct to tolueneformed andin 5 irradiating min. Noticeably, with MW, MW 80% irradiation Diels-Alder of toluene adduct without formed in IL 5 required min. Noticeably, 5 h to give MW 73% irradiation adduct. of tolueneSuccessively, without ILother required studies 5 h combined to give 73% MW adduct. heating and ILs in Diels‐Alder reaction, often in conjunctionSuccessively, with Lewis other acid studies catalysts. combined MW heating and ILs in Diels-Alder reaction, often in conjunctionA tungsten with Lewis Lewis acid acid catalyst catalysts. was prepared and used in Diels‐Alder cycloaddition of a variety A tungsten Lewis acid catalyst was prepared and used in Diels-Alder cycloaddition of a variety of of dienes and dienophiles [120]. Water or [bmim]PF6 were the solvents and MW irradiation dienesaccelerated and dienophiles the reaction [120 in ].both Water solvents, or [bmim]PF decreasing6 were them the solvents from hours and MW to seconds. irradiation However, accelerated the the reaction in both solvents, decreasing them from hours to seconds. However, the selectivity reaction selectivity reaction and the catalyst recycling were more favorable in the IL than in H2O. Selected andexamples the catalyst are shown recycling in Scheme were more 46. The favorable procedure in the was IL than tested in H with2O. Selectedseveral combinations examples are shownof dienes in Schemeand dienophiles, 46. The procedure all with good was yields tested (71–96%) with several and combinations reaction times of from dienes 25 andto 60 dienophiles, s. all with good yields (71–96%) and reaction times from 25 to 60 s. Unusual dienes derived from oxazolidinone underwent Diels-Alder cycloaddition under different conditions, among which MW heating and IL solvents [121] (Scheme 47). In this case there is not a clear advantage in using the combination MW/IL with respect to the other conditions, shorter reaction time notwithstanding. In fact, yields and selectivity were much better in dichloromethane at −78 ◦C.

Catalysts 2017,, 7,, 261 33 of 56

MW, 50°C O MW, 50°C O 30 s 30 s 3% mol catalyst O 3% mol catalyst O + [bmim]PF6 [bmim]PF6 O O O O O O Catalysts 2017, 7, 261 isolated yield, 81% P 33 of 57 isolated yield, 81% P Catalysts 2017, 7, 261 (BF ) 33 of 56 O O N NN (BF4 )2 O O N NN 4 2 W 3% mol catalyst ON W 3% mol catalyst ON NO + O MW, 50°C OC NO OC + [bmim]PF 30 s [bmim]PF6 Lewis acid catalyst 3% mol catalyst6 O Lewis acid catalyst O + O O O [bmim]PF 6 isolated yield, 91% isolated yield, 91% O O O Scheme 46. Selected examples of W‐catalyzed MW‐assisted Diels‐alder reaction in [bmim]PF6 IL Scheme 46. Selected examples of W‐catalyzed MWisolated‐assisted yield, 81% Diels‐alder reactionP in [bmim]PF6 IL [120]. (BF ) [120]. O O N NN 4 2 W ON 3% mol catalyst NO Unusual dienes+ derived from oxazolidinone underwent DielsOC‐Alder cycloaddition under Unusual dienes derived from[bmim]PF oxazolidinone underwent Diels‐Alder cycloaddition under different conditions, among which MW heating6 and IL solvents [121] (SchemeLewis acid catalyst 47). In this case there different conditions, among which MW heating and ILO solvents [121] (Scheme 47). In this case there is not a clear advantageO in using the combination MW/IL with respect to the other conditions, is not a clear advantage in using the combinationisolated MW/IL yield, 91% with respect to the other conditions, shorter reaction timetime notwithstanding. In fact, yields and selectivity were much better inin Scheme 46. Selected examples of W‐catalyzed MW‐assisted Diels‐alder reaction in [bmim]PF6 IL dichloromethaneScheme 46. Selected at − −78 examples °C. of W-catalyzed MW-assisted Diels-alder reaction in [bmim]PF6 IL [120]. [120].

MW, 60°C O MW, 60°C O Unusual dienes derived from oxazolidinone 1.7 h underwent ODiels‐Alder cycloaddition under 1.7 h O O O O O O O O O different conditions, among which MW heatingm-xylene/IL and IL solventsO [121] (Scheme+ O 47). In this case there m-xylene/IL O + N N O + O N is not a clear advantageN O in using+ the combination MW/ILN with respect to the other conditions, Cl N shorter reactionCl time notwithstanding. In fact, yields and selectivity were much better in

Cl dichloromethane at −78 °C. Cl Cl Cl with IL = [mpeim]Br yield, 78% 88 : 12 with IL = [mpeim]Br yield, 78% 88 : 12 with IL = [pepy]Br yield, 76% 87 : 13 with IL = [pepy]BrMW, 60°C yield, 76% 87 : 13 O 1.7 h O O Scheme 47. ExampleO of Diels‐‐AlderO cycloaddition of 2‐‐oxazolidinone dienes, MW‐‐heated and Scheme 47. Example of Diels-Alder cycloadditionm-xylene/IL ofO 2-oxazolidinone+ dienes,O MW-heated and ILsILs‐‐catalyzed [121].[121]. + O N ILs-catalyzed [121N]. O N Cl Other procedures used heterogeneous catalysts, such as montmorillonite (a mineral of hydrated Other procedures used heterogeneous catalysts, such as montmorillonite (aCl mineral of hydrated aluminum silicate thatthat isis neutralized by exchangeable cationsCl and interactsinteracts with organic molecules viaaluminum electrostatic silicate interaction, that is neutralized amongwith alia), IL by = [mpeim]Br exchangeable embedded yield, 78% in cations bmim ‐ type and 88 interacts ILs : (changing 12 with organicthe anion molecules did not via electrostatic interaction, amongwith alia), IL = [pepy]Br embedded yield, 76% in bmim ‐ type 87 ILs : (changing 13 the anion did not via electrostatic interaction, among alia), embedded in bmim-type ILs (changing the anion did not make any substantial difference) [122]; thisthis protocol gave better yields thanthan thethe reaction inin ILs makeScheme any substantial 47. Example difference) of Diels [122‐Alder]; this cycloaddition protocol gave of better2‐oxazolidinone yields than dienes, the reaction MW‐heated in ILs and without without montmorillonite and was accelerated by MW irradiation.irradiation. montmorilloniteILs‐catalyzed and[121]. was accelerated by MW irradiation. A screening of different Lewis acids, different ILs, and different activation modes (high pressure,A screening ultrasound, of different and MW Lewis heating) acids, was different performed ILs, and on different Diels‐Alder activation reaction modes of cyclopentadiene (high pressure, pressure,Other ultrasound, procedures andused MW heterogeneous heating) was catalysts, performed such on as Dielsmontmorillonite‐Alder reaction (a mineral of cyclopentadiene of hydrated withultrasound, some dienophiles and MW heating) [123] ( was performed on Diels-Alder reaction of cyclopentadiene with some aluminumwith some silicatedienophiles that is[123] neutralized ( by exchangeable cations and interacts with organic molecules dienophilesScheme [ 12348).] (Scheme 48). via electrostaticScheme 48). interaction, among alia), embedded in bmim‐type ILs (changing the anion did not make any substantial difference) [122];O this protocol gave better yields than the reaction in ILs O without montmorillonite and was acceleratedIL by MW irradiation.+ + IL + + 10% mol Lewis acid A screening of different Lewis acids,10% mol Lewis different acid ILs, and differentO activation modes (high endo O exo O pressure, ultrasound, and MW heating) was performedendo on ODielsexo‐Alder reaction of cyclopentadiene reaction conditions 100 MPa, 5°C, 4 h or , 60°C, 24 min or sonication, 25°C, 8 h reaction conditions 100 MPa, 5°C, 4 h or , 60°C, 24 min or sonication, 25°C, 8 h with some dienophiles [123] ( MW, 50°C or MW, 50°C or 30 s Scheme 48). 30 s

O O dienophiles: O O dienophiles:O CN CN O IL O + + 10% mol Lewis acid O endo O exo Lewis acids: ZnCl2, AlCl3, InCl3, Sc(OTf)3 Lewis acids: ZnCl2, AlCl3, InCl3, Sc(OTf)3 reaction conditions 100 MPa, 5°C, 4 h or , 60°C, 24 min or sonication, 25°C, 8 h IL: [bmim]NTf2, [bdmim]NTF2, [hmim]NTf2, [emim]NTf2, [EtMe2NCH2CH2OH]NTf2, IL: [bmim]NTf2, [bdmim]NTFMW,2, [hmim]NTf 50°C 2, [emim]NTf2, [EtMe2NCH2CH2OH]NTf2, [EtMe NCH CH CHorOH]NTf , [bmpyr]NTf , [bupy]NTf , [bnpy]NTf , [3-Mebupy]NTf [EtMe2 NCH2 CH2 CH2 OH]NTf 302 , s[bmpyr]NTf2 , [bupy]NTf2 , [bnpy]NTf2 , [3-Mebupy]NTf2 2 2 2 2 2 2 2 2 2

Scheme 48. Summary of Lewis acids-catalyzedO Diels-AlderO reaction in ILs, under different activation dienophiles: CN modes [123]. O

From the hugeLewis amount acids: ZnCl of2, collectedAlCl3, InCl3, Sc(OTf) data,3 the authors concluded that: (i) the relatively high concentration ofIL:Lewis [bmim]NTf acid2, [bdmim]NTF catalysts2, [hmim]NTf improved2, [emim]NTf selectivity2, [EtMe2NCH and2CH2OH]NTf the yields;2, (ii) high pressure [EtMe NCH CH CH OH]NTf , [bmpyr]NTf , [bupy]NTf , [bnpy]NTf , [3-Mebupy]NTf 2 2 2 2 2 2 2 2 2

Catalysts 2017, 7, 261 34 of 56

Scheme 48. Summary of Lewis acids‐catalyzed Diels‐Alder reaction in ILs, under different activation modes [123].

From the huge amount of collected data, the authors concluded that: (i) the relatively high Catalysts 2017, 7, 261 34 of 57 concentration of Lewis acid catalysts improved selectivity and the yields; (ii) high pressure accelerated the catalysed reaction, with only minor improvements in the selectivity; (iii) microwave acceleratedirradiation accelerated the catalysed the reaction, reaction with considerably; only minor (iv) improvements ultrasound irradiation in the selectivity; led to increased (iii) microwave yields irradiationand selectivities. accelerated the reaction considerably; (iv) ultrasound irradiation led to increased yields and selectivities.A noticeable synergistic effect of the combination of microwave irradiation and protic ILs was evidencedA noticeable in the synergisticDiels‐Alder effect reactions of the between combination methylbutadiene of microwave and irradiation heterocycles and as protic dienophiles ILs was evidenced[124]. The instudy the Diels-Alder was accompanied reactions by between DFT calculations, methylbutadiene aimed and at elucidating heterocycles the as dienophilesrole of IL. It [ 124was]. Thesuggested study wasthat accompanied the protic IL by protonates DFT calculations, the pyrrole aimed nitro at elucidating group, thus the favoring role of IL. an It wasasynchronous suggested thattransition the protic state. IL protonates the pyrrole nitro group, thus favoring an asynchronous transition state. Further examples of MW-activatedMW‐activated Diels-AlderDiels‐Alder reaction in ILs were provided by the study in imidazolium-baseimidazolium‐base tetrachloroaluminatestetrachloroaluminates [[125,126].125,126]. Lithium bis(triﬂuorometansulfonyl)amidebis(trifluorometansulfonyl)amide waswas used as LewisLewis acid,acid, butbut resultedresulted notnot muchmuch determinantdeterminant inin thethe outputoutput ofof thethe reaction.reaction. Instead,Instead, onceonce again, MW irradiation accelerated the reaction, bringing it to completion in few minutes from hours (6–12)(6–12) ofof conventionalconventional heating.heating.

3.5. Cyclization Reactions to Heterocycles with C–CC–C BondBond FormationFormation The importance of heteroaromatic compounds, especially in pharmaceutical chemistry, is wellwell known. Thus, Thus, it it is is not not surprising surprising that that the the synthesis synthesis of of key rings has been explored in terms of sustainability, as wellwell illustratedillustrated inin 20142014 reviewsreviews discussingdiscussing alternativealternative reactionreaction methods for thethe synthesis of quinoline quinoline [127] [127] and and benzothiazole benzothiazole [128] [128 derivatives,] derivatives, including including syntheses syntheses promoted promoted by bymicrowave microwave or orultrasound, ultrasound, recyclable recyclable and and reusable reusable catalysts, catalysts, non non-volatile‐volatile solvents solvents as as ILs, or solvent-freesolvent‐free conditions.conditions. Other heteroaromatic compounds were prepared taking advantage of the MW-ILMW‐IL synergisticsynergistic efficiency.efficiency. The The synthesis synthesis of of benzofuran benzofuran derivatives derivatives was was promoted promoted by [meim]Br by [meim]Br and basicand basic alumina alumina [129]. Salicylaldehyde[129]. Salicylaldehyde cyclocondensed cyclocondensed with α-chloro with α‐ ketoneschloro and ketones esters. and MW esters. irradiation MW was irradiation compared was to conventionalcompared to heatingconventional and resulted heating more and efficientresulted as more to reaction efficient time, as to but reaction almost thetime, same but yields almost were the obtainedsame yields with were the obtained two methods. with the two methods. Twenty-fiveTwenty‐five aromatic aromatic and heteroaromaticand heteroaromatic haloaldehydes haloaldehydes and haloketones and were haloketones cyclocondensated were withcyclocondensated ethyl isocyanoacetate with ethyl to isocyanoacetate give 2-ethoxycarbonylindoles to give 2‐ethoxycarbonylindoles in a reaction catalyzed in a reaction by catalyzed CuI and [bmim]OH,by CuI and [bmim]OH, under MW irradiationunder MW [ 130irradiation] (Scheme [130] 49). (Scheme 49).

MW, 50°C 10 min

O yield, 91%

Br 24% mol CuI O or + CN O [bmim]OH O N O O H yield, 74% Cl

24% mol CuI O O + CN O [bmim]OH O N O Br H yield, 95%

N 24% mol CuI N O O + CN O [bmim]OH O N O Br H yield, 90%

Scheme 49. Examples of MW MW-assisted‐assisted cyclocondensation reaction toto indoleindole derivativesderivatives inin ILIL [[130].130].

Tetrahydrocarbazole was prepared in a Fischer-type cyclocondensation catalyzed by pyridinium-based ILs and MW irradiated [131]. Different temperatures and different pyridinium ILs—with and without Lewis acid (ZnCl2)—were tested; optimized conditions are shown in Scheme 50. Catalysts 2017, 7, 261 35 of 56 Catalysts 2017, 7, 261 35 of 56 Tetrahydrocarbazole was prepared in a Fischer‐type cyclocondensation catalyzed by pyridiniumTetrahydrocarbazole‐based ILs and wasMW irradiatedprepared [131].in a DifferentFischer‐ typetemperatures cyclocondensation and different catalyzed pyridinium by ILs—withpyridinium and‐based without ILs andLewis MW acid irradiated (ZnCl2)—were [131]. tested;Different optimized temperatures conditions and aredifferent shown pyridinium in Scheme Catalysts 2017, 7, 261 35 of 57 ILs—with50. and without Lewis acid (ZnCl2)—were tested; optimized conditions are shown in Scheme 50.

O MW, 110°C H O MW, 3 min 110°C N [mbupy]Br H NH 3 min N 2 + [mbupy]Br NH ZnCl 2 2 N + N ZnCl2 H N yield, 90% + H mbupyN yield, 90% + mbupy

Scheme 50. MWMW-assisted‐assisted and ILs ILs-catalyzed‐catalyzed Fischer synthesis of tetrahydrocarbazole [[131].131]. Scheme 50. MW‐assisted and ILs‐catalyzed Fischer synthesis of tetrahydrocarbazole [131]. An original approach to substituted pyranes was the functionalization of ionic liquid, in order An original approach to substituted pyranes was the functionalization of ionic liquid, in order to to obtainAn original a soluble approach support to for substituted one reactant pyranes and the was successive the functionalization cyclization, followed of ionic liquid,by detachment in order obtain a soluble support for one reactant and the successive cyclization, followed by detachment of the ofto theobtain formed a soluble pyrane support [132] (Schemefor one reactant 51). and the successive cyclization, followed by detachment offormed the formed pyrane pyrane [132] (Scheme [132] (Scheme 51). 51). OH OH MW OH 2MW min OH N N 2 min N NaBF4 Cl +N BF - N + +N Cl- NaBF 4 OH 80°C, 244 h N+ - N Cl N - BF4 + OH + Cl N N N 80°C, 24 h

OH MW O OH 10 min N N O O MW + O + O O 10 min N - O O +N BF - N+ BF4 4 O - O O N+ - + N BF4 BF4 O N O NH2 MW, O NH2 CN 15-20 MW, min O O CN N 15-20 min N O CN + O + + N - O CN N - O O CN py, MeCN N BF4 N+ BF4 + + - X CN reflux BF - O N BF O O py, MeCN N 4 4 X reflux X X O NH2 MeONa, MeOH X = H, 4-OH, 4-OMe, 4-Cl, 4-Me, O NH2 MeONa, r.t., 6 h MeOH X = 3-NOH, 4-OH,2, 3-Br, 4-OMe, 4-OH-3-OMe 4-Cl, 4-Me, O CN r.t., 6 h 3-NO2, 3-Br, 4-OH-3-OMe O O CN O isolated yields, 84-91% isolated yields, 84-91% X X Scheme 51. MW‐irradiated synthesis of pyranes using functional ILs as soluble support [132]. Scheme 51. MWMW-irradiated‐irradiated synthesis of pyranes using functional ILs as soluble support [[132].132]. 3.6. Multi‐Component Reactions (MCRs) with C–CBond Formation 3.6. Multi Multi-Component‐Component Reactions (MCRs) with C–CBond Formation Among the examples of carbon‐carbon bond forming reactions, the protocols of multiAmong‐components thethe examples reactionsexamples of carbon-carbon wereof carbonrevised,‐ bondcarbon looking forming bond for reactions,eco forming‐friendly the reactions, protocolsconditions. of the multi-componentsFor protocolsexample, theof multiMannichreactions‐components werereaction, revised, reactionsi.e., lookingthe formationwere for revised, eco-friendly of β‐ lookingamino conditions. forcarbonyl eco‐ Forfriendly compounds example, conditions. the from Mannich Fora non example, reaction,‐enolizable i.e.,the Mannichaldehydethe formation withreaction, of anβ enolizable-amino i.e., the carbonyl formationcarbonyl compounds compound of β‐amino from and carbonyl a an non-enolizable amine compounds (either aldehyde primary from or with a secondary), non an‐ enolizable was aldehydethoroughlycarbonyl compoundwith examined, an enolizable and also an amine carbonylin view (either compoundof the primary opportunity and or secondary), an amine to be (either wasinvolved thoroughly primary in tandem or examined, secondary), or cascade also was in viewthoroughlyprocesses, of the with opportunityexamined, consequent also to behigh in involved viewatom economy,of in the tandem opportunity as or discussed cascade to processes,in be recent involved reviews with in consequent [133–135].tandem or high cascade atom processes,economy,The features as with discussed consequent that make in recent high MCRs reviews atom appealing economy, [133– 135are as]. the discussed possibility in recentof one reviews‐pot formation [133–135]. of two bonds and, Theeven features more thatinteresting, make MCRs is the appealing easy access are the of possibility libraries ofof one-potonecompounds,‐pot formation simply of two changing bonds and,substituents eveneven more more in interesting,any interesting, of the iscomponent. the is easythe accesseasy Ionic access of liquids libraries of and libraries of compounds,MW techniqueof compounds, simply found changing applicationsimply substituents changing in the substituentsMCRs,in any ofat first the in component. separately any of the [135–137], Ioniccomponent. liquids but quite andIonic MW soonliquids technique the andtwo MWwere found techniqueused application together. found in application the MCRs, atin ﬁrstthe MCRs,separatelyA atstrategy first [135 separately– 137to ],use but [135–137],task quite‐specific soon but the ionic quite two were liquidssoon used the was two together. developedwere used together.and applied to the one‐pot threeA‐component strategy tosynthesis use task-speciﬁctask ‐ofspecific heterocyclic ionic liquidscompounds, was developed together withand applied MW irradiation to the one-potone [138].‐pot three three-component‐component synthesis of heterocyclic compounds, together together with with MW MW irradiation irradiation [138]. [138]. Imidazolium-based ILs were linked to poly(ethyleneglycol) (PEG), giving matrices to be used for the so called Ionic Liquid Phase Organic Synthesis (IoLiPOS). This method offers the advantage of Catalysts 2017, 7, 261 36 of 56 Catalysts 2017, 7, 261 36 of 56 Catalysts 2017, 7, 261 36 of 57 Imidazolium‐based ILs were linked to poly(ethyleneglycol) (PEG), giving matrices to be used for the Imidazoliumso called Ionic‐based Liquid ILs werePhase linked Organic to poly(ethyleneglycol) Synthesis (IoLiPOS). (PEG), This givingmethod matrices offers tothe be advantage used for the of so called Ionic Liquid Phase Organic Synthesis (IoLiPOS). This method offers the advantage of solid-statesolid‐state synthesis, since side products can be easily removed by simple washing IL-PEGIL‐PEG system. solid‐state synthesis, since side products can be easily removed by simple washing IL‐PEG system. Moreover,Moreover, thethe combinationcombination ofof IL-PEG/microwaveIL‐PEG/microwave decreases the viscosity of the reactionreaction mediummedium Moreover, the combination of IL‐PEG/microwave decreases the viscosity of the reaction medium withwith consequentconsequent raterate enhancement.enhancement. Thiazolidinone formation was achieved in 1–2 h inin goodgood yieldsyields with consequent rate enhancement. Thiazolidinone formation was achieved in 1–2 h in good yields byby microwavemicrowave irradiationirradiation withwith IL-phaseIL‐phase boundbound arylidenearylidene imineimine derivativesderivatives (Scheme(Scheme 5252).). Primary oror by microwave irradiation with IL‐phase bound arylidene imine derivatives (Scheme 52). Primary or secondarysecondary aminesamines performedperformed easyeasy cleavagecleavage ofof thethe ILP-boundILP‐bound thiazolidinones.thiazolidinones. secondary amines performed easy cleavage of the ILP‐bound thiazolidinones.

OH O OH NH MW, 100°C Br HS 2 + OH + OH + NH MW, 100°C O HS O 2 HO + Br O + + O HO O PEG1mim

PEGor 1mim orPEG pim O 1 N OH PEG pim + O 1 N OH N+ O PEG mim N 1 O O O PEG mim N O 1 + O O O N O N OH N S + O + N OH N S +N N PEG pim N 1 N O PEG1pim N H O N H O O O N O N S S N N O O Scheme 52. Example of thiazolidinone formation via Ionic Liquid PhasePhase OrganicOrganic SynthesisSynthesis [[138].138]. Scheme 52. Example of thiazolidinone formation via Ionic Liquid Phase Organic Synthesis [138]. By the same procedure, 2‐thioxotetrahydropyrimidin‐4‐(1H)‐ones were prepared in good yields By the same procedure, 2-thioxotetrahydropyrimidin-4-(1H)-ones were prepared in good yields in 15By themin same [139] procedure, (Scheme 2‐53).thioxotetrahydropyrimidin In the latter case, however,‐4‐(1H)‐ones MWs were were prepared used in onlygood inyields the in 15 min [139] (Scheme 53). In the latter case, however, MWs were used only in the transesteriﬁcation intransesterification 15 min [139] reaction(Scheme to 53). link Inthe theIL and latter the β‐case,ketoester. however, MWs were used only in the transesterificationreaction to link the reaction IL and theto linkβ-ketoester. the IL and the β‐ketoester. Cl O Cl O O a. O H MW, 120°C N OH O N O N + O a. O H MW,15-45 120°C min N OH O +N O N N R 15-45 min + b. RNH . N+ 2 R N N R' b. RNH2. R' NCS NCS R

O S Et2NH RN S Et NH O O S H 2 N S R = Ph-CH2, iPr-CH2, Pr N O N N N + O H R' RR' = = Ph-CH Me, Bu2, iPr-CH2, Pr N O N N N N R R' R' = Me, Bu + O R' N R R' O isolated yield, 94-98% isolated yield, 94-98% Scheme 53. Synthesis of 2‐thioxotetrahydropyrimidin‐4‐(1H)‐ones via Ionic Liquid Phase Organic Scheme 53. Synthesis of 2‐thioxotetrahydropyrimidin‐4‐(1H)‐ones via Ionic Liquid Phase Organic SchemeSynthesis 53. [139].Synthesis of 2-thioxotetrahydropyrimidin-4-(1H)-ones via Ionic Liquid Phase Organic SynthesisSynthesis [139]. [139]. The same research group applied the same strategy for the synthesis of dihydropyrimidinones The same research group applied the same strategy for the synthesis of dihydropyrimidinones [140]The (Scheme same research54). group applied the same strategy for the synthesis of dihydropyrimidinones [140] [140] (Scheme 54). (Scheme 54). Polyhydroquinolines were prepared by a three-component reaction using ionic liquid-phase bound β-oxo esters that were synthesized by a solventless transesteriﬁcation without catalyst, under microwave irradiation [141] (Scheme 55). MW heating was not used in the multi-component synthesis.

Catalysts 2017, 7, 261 37 of 56

O O O N OH O + N O HO + Catalysts N2017, 7,PEG 261 mim O O 37 of 57 1 N Catalysts 2017, 7, 261 O or IL 37 of 56 or O O DCC, DMAP O O O O N OH N O + O O + N PEG py OH O O + 1 N O HO + N PEG mim O O 1 N O IL or or MW,O 120°C O 10 min DCC, DMAP O O O O O O O O N O IL O O IL N OH O +O + + R + R' PEG py R' N NH O 1 O 2 O H

R = H, Me MeONa, N N MeOH MW, R120°C 10 min refluxO O O O O O O O IL IL O + + R O R' O R' N NH O 2 O O O H HO R' R = H, Me MeONa, N N MeOH R reflux N ON isolated yield, 80-88% R O O O O Scheme 54. Synthesis of dihydropyrimidinones via MW‐assistedHO Ionic Liquid PhaseR' Organic Synthesis [140]. N N isolated yield, 80-88% R Polyhydroquinolines were prepared by a three‐component reaction usingO ionic liquid‐phase bound β‐oxo esters that were synthesized by a solventless transesterification without catalyst, under microwaveScheme irradiation 54.54. SynthesisSynthesis [141] of of dihydropyrimidinones dihydropyrimidinones(Scheme 55). MW heatingvia via MW MW-assisted was‐assisted not Ionic used Liquid in the Phasemulti Organic‐component Synthesis [140]. synthesis.Synthesis [140].

Polyhydroquinolines were preparedHO by a three‐componentO reaction using ionic liquid‐phase N bound β‐oxo esters that were synthesized by a solventless+ transesterification without catalyst, under OH OH OH N O O N K Emim microwave irradiation+ [141] (Scheme 55). MW heatingMe was not used in the multi‐component MW, 100°C synthesis. N HOC mim O 2 HO N + HO N O O OH OH N O + KEtEmim OH OH OH N O O N K Emim + Me H MW, 100°C H N N N O HOC2mim KMeHEmimO O N O N + or N Ar O + NH4OAc + + + or N O O OH OHN O Ar O N O Ar O O O KEtEmim KEtEmim

base H H Ar = Cl N N O H H N N KMeEmim O O O HO N or N Ar O + NH4OAc + + + O or HO or HO N O Ar O N O Ar O O O KEtEmim O O Ar O O Ar O O base O Ar = Cl O H H N N SchemeO 55. ExampleHO of polyhydroquinoline formation via Ionic Liquid Phase Organic Synthesis Scheme 55. Example of polyhydroquinolineO formationHO via Ionic Liquid Phaseor HO Organic Synthesis [141]. [141]. O O Ar O O Ar O O A complex system of condensedO heterocycles was developed by two steps, three-components A complex system of condensed heterocycles was developed by two steps, three‐components cascade reactions performed with ionic liquid supported 2-cyanomethylbenzimidazoles, coupled cascade reactions performed with ionic liquid supported 2‐cyanomethylbenzimidazoles, coupled with 2-formylbenzoate and isocyanides under microwave irradiation [142]. All the combinations of with Scheme2‐formylbenzoate 55. Example and of polyhydroquinolineisocyanides under formationmicrowave via irradiation Ionic Liquid [142]. Phase All Organic the combinations Synthesis of N-substitutes[141]. benzimidazoles and different isocyanides gave the desired polycyclic isoquinolines, with N‐substitutes benzimidazoles and different isocyanides gave the desired polycyclic isoquinolines, good overall isolated yields, after detachment from IL (Scheme 56). with good overall isolated yields, after detachment from IL (Scheme 56). A complex system of condensed heterocycles was developed by two steps, three‐components cascade reactions performed with ionic liquid supported 2‐cyanomethylbenzimidazoles, coupled with 2‐formylbenzoate and isocyanides under microwave irradiation [142]. All the combinations of N‐substitutes benzimidazoles and different isocyanides gave the desired polycyclic isoquinolines, with good overall isolated yields, after detachment from IL (Scheme 56).

CatalystsCatalysts 20172017,,7 7,, 261 261 3838 ofof 5756 CatalystsCatalysts 2017 2017, ,7 7, ,261 261 3838 of of 56 56 O O O O O OO N CN O N CN O O O O CN O O N N CN NN CN H O N CN OO O O N N NN + HH N R OO r.t N NNR N N ++ R r.t R O N+ R r.t NN+ R N N O O + N ++ O + N O NN O N O O OO O MW, 150°C R' N OO O 15 min O R' R' O N CN MW, 150°C R' N N O MW, 150°C N O R' 15 min O KCN R' N NN CNCN 15 min O N N OO + - O O N + R' NC N KCN O N + - O N CN KCNMeOH O N R + - MeCN O N N N N ++ R'R' NCNC r.t, 12 h O N CN CNCN MeOHMeOH O R O MeCNMeCN N R N N+ R N N r.t, 12 h CNCN N r.t, 12 h N R N OO O R N ++ NN+ R N O N isolated overallR Ryields, 46-89% N O ++ N N isolatedisolated overall overall yields, yields, 46-89% 46-89%

R = -CH CH CH OCH , Bu, iso-Pr, iso-Bu,-CH CH CH Ph, -CH CH , , 2 2 2 3 2 2 2 2 2 -CH -CH , 2 S 2 O R = -CH2CH2CH2OCH3, Bu, iso-Pr, iso-Bu,-CH2CH2CH2Ph, -CH2CH2 , , R = -CH2CH2CH2OCH3, Bu, iso-Pr, iso-Bu,-CH2CH2CH2Ph, -CH2CH2 -CH , -CH2 -CH-CH2 2 SS 2 OO + - NC R' NC = NC NC NC + - NCNC R' NC+ - = NC NC R' NC = NC NCNC NC

Scheme 56. Three‐components cascade synthesis of benzimidazo[1′,2′:1,5]pyrrolo[2,3‐c]isoquinolines 0 0 SchemeSchemewith 2‐cyanomethylbenzimidazoles 56.56. Three ThreeThree-components‐‐componentscomponents cascade cascade supported synthesis synthesis on of of ILbenzimidazo[1 benzimidazo[1 and MW irradiation′,2′,2,2′:1,5]pyrrolo[2,3′:1,5]pyrrolo[2,3:1,5]pyrrolo[2,3-c]isoquinolines [142]. ‐‐c]isoquinolinesc]isoquinolines withwith 2 2-cyanomethylbenzimidazoles2‐‐cyanomethylbenzimidazolescyanomethylbenzimidazoles supported supported on on IL IL and andand MW MWMW irradiation irradiation [142]. [[142].142]. A functional ionic liquid, 1‐(2‐aminoethyl)‐3‐methylimidazolium hexafluophosphate, catalyzed A functional ionic liquid, 1‐(2‐aminoethyl)‐3‐methylimidazolium hexafluophosphate, catalyzed the synthesisA functional of pyransionic liquid, with 1 1-(2-aminoethyl)-3-methylimidazoliumMW‐(2‐aminoethyl) heating [143]‐3‐methylimidazolium (Scheme 57). Water hexafluophosphate, hexafluophosphate, was the co‐solvent catalyzed and the the synthesis of pyrans with MW heating [143] (Scheme 57). Water was the co‐solvent and the theaqueous synthesissynthesis IL was of of pyrans reused,pyrans with afterwith MW filteringMW heating heating off [143 the [143]] insoluble (Scheme (Scheme 57 reaction). Water57). product,Water was the was co-solventin sixthe more co‐solvent and runs, the retaining aqueousand the aqueous IL was reused, after filtering off the insoluble reaction product, in six more runs, retaining aqueousILits was efficiency. reused, IL was after reused, filtering after off filtering the insoluble off the reaction insoluble product, reaction in product, six more runs,in six retaining more runs, its efficiency.retaining itsits efficiency.efficiency. MW, 100°C 1-4 min MW,MW, 100°C 100°C O X 1-4 1-4 min min O O [H NC mim]PF O 2 2 6 OO XX CN + OO OO + NC CN [H[H2NCNC2mim]PFmim]PF6 O NH O 2 2H O 6 CNCN 2 O O + NC CN 2 O ++ + NC CN O NHNH2 X O H2O O NH 2 O H2O 2 N X X OO NHNH2 + isolated yields, 81-93%2 NN X = H, 4-Cl, 4-CN, 4-OH, 4-OMe, 3-NO , 2,4-Cl , 3,4(-OCH O-) 2 2 2 ++N H NC mim isolatedisolated yields, yields, 81-93% 81-93% 2 2 XX = = H, H, 4-Cl, 4-Cl, 4-CN, 4-CN, 4-OH, 4-OH, 4-OMe, 4-OMe, 3-NO 3-NO2, ,2,4-Cl 2,4-Cl2, ,3,4(-OCH 3,4(-OCH2O-)O-) N 2 2 2 N H2NC2mim H2NC2mim

Scheme 57.57. MW-assisted,MW‐assisted, functionalfunctional IL-catalyzedIL‐catalyzed multimulti componentcomponent synthesissynthesis ofof pyranspyrans [[143].143]. SchemeScheme 57.57. MWMW‐‐assisted,assisted, functionalfunctional ILIL‐‐catalyzedcatalyzed multimulti componentcomponent synthesissynthesis ofof pyranspyrans [143].[143]. Imidazolium salts with different alkyl chains were used as catalysts in a MW‐irradiated MCR Imidazolium salts with different alkyl chains were used as catalysts in a MW-irradiated leadingImidazoliumImidazolium to tri saltssalts‐substituted withwith differentdifferent imidazoles alkylalkyl chainschains [144]. werewere usedusedThe as as catalystscatalystsmost efficientinin aa MWMW ‐‐irradiatedirradiatedcatalyst MCRMCRwas MCR leading to tri-substituted imidazoles [144]. The most efﬁcient catalyst was 1-heptyl-3- leadingleading1‐heptyl ‐3to‐tomethylimidazolium tritri‐‐substitutedsubstituted tetrafluoroborateimidazolesimidazoles [144].[144]. that was TheThe also easymostmost to recoverefficientefficient and recycle.catalystcatalyst Different waswas methylimidazolium tetraﬂuoroborate that was also easy to recover and recycle. Different aryl 11aryl‐‐heptylheptyl aldehydes‐‐33‐‐methylimidazoliummethylimidazolium reacted within tetrafluoroborate tetrafluoroboratefew minutes with thatthat excellent waswas alsoalso yields, easyeasy toto as recoverrecover shown andand in recycle.recycle.Scheme Different Different58. With aldehydes reacted within few minutes with excellent yields, as shown in Scheme 58. With conventional arylarylconventional aldehydesaldehydes heating, reactedreacted in withinwithin the same fewfew IL, minutesminutes the reaction withwith took excellentexcellent more yields,yields,than 2 hasas to shownshown complete; inin Scheme Schemehowever, 58.58. it WithisWith not heating, in the same IL, the reaction took more than 2 h to complete; however, it is not clear whether IL conventionalconventionalclear whether heating,heating, IL is really inin thethe a catalyst, samesame IL,IL, because thethe reactionreaction no blank tooktook experiment moremore thanthan 2was2 hh toto reported. complete;complete; however,however, itit isis notnot clearclearis really whetherwhether a catalyst, ILIL isis really becausereally aa catalyst,catalyst, no blank becausebecause experiment nono blankblank was reported. experimentexperiment waswas reported.reported. MW, 2-6 min MW, MW, 2-6 min O 2-6 min [C7mim]BF4 N O OO + NH4OAc [C7mim]BF4 N + [C7mim]BF4 N N OO N + NH4OAc + O + NH4OAc H +N X + N N O HN X +N X O H + C7mim X isolated yields, 74-96% N X = H, 4-F, 4-Cl, 4-Br, 4-Me, 4-OH, 4-OMe, 3-NO2, 2-Cl, 3,4(-OCH2O-) X N X CC7mimmim isolated yields, 74-96% 7 XX = = H, H, 4-F, 4-F, 4-Cl, 4-Cl, 4-Br, 4-Br, 4-Me, 4-Me, 4-OH, 4-OH, 4-OMe, 4-OMe, 3-NO 3-NO2, ,2-Cl, 2-Cl, 3,4(-OCH 3,4(-OCH2O-)O-) isolated yields, 74-96% 2 2 Scheme 58. Tri‐substituted imidazoles via MW‐heated, IL‐catalyzed MCR [144]. SchemeScheme 58.58. TriTri‐‐substitutedsubstituted imidazolesimidazoles viavia MWMW‐‐heated,heated, ILIL‐‐catalyzedcatalyzed MCRMCR [144].[144]. Scheme 58. Tri-substituted imidazoles via MW-heated, IL-catalyzed MCR [144]. Molten tetrabutylammonium bromide, Bu4NBr, resulted an efficient and recyclable catalyst for the MCRMoltenMolten of β‐ tetrabutylammoniumtetrabutylammoniumnaphthol and aromatic bromide,bromide, aldehydes BuBu44NBr,NBr, that resulted resultedproduced anan dibenzoxanthenes efficientefficient andand recyclablerecyclable [145] (Scheme catalystcatalyst for59).for the MCR of β‐naphthol and aromatic aldehydes that produced dibenzoxanthenes [145] (Scheme 59). theCompared MCR of β‐to naphtholother catalysts and aromatic (Brønsted aldehydes or Lewis thatacids), produced Bu4NBr dibenzoxanthenes was one of the most [145] efficient, (Scheme giving 59). ComparedCompared toto otherother catalystscatalysts (Brønsted(Brønsted oror LewisLewis acids),acids), BuBu44NBrNBr waswas oneone ofof thethe mostmost efficient,efficient, givinggiving

Catalysts 2017, 7, 261 39 of 57

Molten tetrabutylammonium bromide, Bu4NBr, resulted an efﬁcient and recyclable catalyst for β Catalyststhe MCR 2017 of, 7, 261-naphthol and aromatic aldehydes that produced dibenzoxanthenes [145] (Scheme39 of 59 56). Compared to other catalysts (Brønsted or Lewis acids), Bu4NBr was one of the most efﬁcient, giving theCatalysts samesame yield2017yield, 7 than, 261than those those reported reported for forp-toluenesulfonic p‐toluenesulfonic or sulfamicor sulfamic acids acids (90–94%). (90–94%). On the On other the39 otherof hand, 56 hand,other conditionsother conditions being the being same, the reaction same, reaction times dropped times dropped from 60–90 from min 60–90 with min conventional with conventional heating to heating4–6the min same to with 4–6 yield MW min than irradiation.with those MW reported irradiation. for p‐toluenesulfonic or sulfamic acids (90–94%). On the other hand, other conditions being the same, reaction times dropped from 60–90 min with conventional heating to 4–6 min with MW irradiation. OH O Ar = Me 2 + Ar H OH O

Ar O= HOMe 2 + Ar H Cl Cl [Bu N]Br MW, 130°C O HO 4 Cl 4-6 min Cl Cl [Bu4N]Br MW, 130°C F Cl 4-6 min F Br Ar F O N Ar Cl F Br2 yield 90-95% Cl O N O Cl 2 O N 2 yield 90-95% O Cl O2N Scheme 59. MW‐assisted and Bu4Br‐catalyzed multicomponent synthesis of xanthenes [145]. Scheme 59. MW-assisted and Bu4Br-catalyzed multicomponent synthesis of xanthenes [145]. Scheme 59. MW‐assisted and Bu4Br‐catalyzed multicomponent synthesis of xanthenes [145]. Xanthenones were synthesized in a solvent‐free one‐pot MCR catalyzed by task‐specific IL and assistedXanthenonesXanthenones by MW [146] were were (Scheme synthesized synthesized 60). 2 in ‐inNaphthol, a a solvent-free solvent aryl‐free and one-potone ‐alkylpot MCR aldehydes, catalyzed catalyzed and by by cyclictask task-speciﬁc‐specific 1,3‐dicarbonyl IL IL and and compoundsassistedassisted by by MW condensed MW [146 [146]] (Scheme in(Scheme the presence 60 60).). 2-Naphthol, 2‐ Naphthol,of a Brønsted arylaryl acid andand IL. alkylalkyl Optimization aldehydes, andof and the cyclic cyclic reaction 1,3 1,3-dicarbonyl‐dicarbonyl conditions showedcompoundscompounds that condensed5 condensedmol % functional in in the the presence presence IL was the of of a abest Brønsted Brønsted catalyst acidacid load IL. andOptimization the reaction of of thescope the reaction reaction was investigated conditions conditions withshowedshowed different that that 5 mol5substrates. mol % % functional functional The reaction IL IL was was the the worked best best catalystcatalyst well with load and all the the reaction reactiontypes of scope scope aldehydes, was was investigated investigated aromatic, aliphaticwithwith different different and even substrates. substrates. acid‐sensitive The The reaction ones,reaction worked but worked 2‐naphthol well well with was allwith the all typesonly the possible oftypes aldehydes, of phenolic aldehydes, aromatic, reagent, aromatic, aliphatic while neitherandaliphatic even 1‐naphthol acid-sensitive and even nor acid phenol ones,‐sensitive butreacted 2-naphtholones, at but all. 2 ‐naphthol was the onlywas the possible only possible phenolic phenolic reagent, reagent, while neitherwhile 1-naphtholneither 1‐ nornaphthol phenol nor reacted phenol at reacted all. at all. MW, 10-15 MW, min 10-15 min O O O OH O O 5% mol [bSO3Hmim]Ts O+ OH O O 5% mol [b mim]Ts + SO3H O + + X O X

X = H, 4-Me, 4-OMe, 4-OH, 4-F, 4-Cl, 4-Br, 4-NO2, X X = H, 4-Me, 4-OMe, 4-OH, 4-F, 4-Cl, 4-Br, 4-NO , X 3-NO2, 3,4-(O-CH2-O) 2 isolated yield, 80-89% 3-NO2, 3,4-(O-CH2-O) isolated yield, 80-89% MW, 10 MW, min 10 min O O

OH O O OH O O 5% mol [bSO3Hmim]Ts 5% mol [bSO3Hmim]Ts R O ++ R O R O ++ R O

isolatedisolated yield, yield, 72-75% 72-75% R =R Et, = Et, i-Pr i-Pr SO3H SO3H

NN ++ b mim bSOSO3H3Hmim NN

SchemeScheme 60. 60. MW MW‐irradiated,‐irradiated, acidic acidic IL IL‐catalyzed‐catalyzed oneone‐‐pot synthesis ofof xanthenonesxanthenones [146]. [146]. Scheme 60. MW-irradiated, acidic IL-catalyzed one-pot synthesis of xanthenones [146].

SubstitutedSubstituted quinolines quinolines could could be be prepared prepared inin ILIL solventsolvent by a MCR withwith aa LewisLewis acid acid catalyst, catalyst, withwith MW MW heating heating [147]. [147]. Different Different ILs ILs and and different different metalmetal triflatestriflates were usedused toto optimize optimize the the reaction reaction conditionsconditions that that were were successively successively used used forfor thethe reactionreaction with different substrates.substrates. TheThe results results are are summarizedsummarized in inScheme Scheme 61. 61.

Catalysts 2017, 7, 261 40 of 57

Substituted quinolines could be prepared in IL solvent by a MCR with a Lewis acid catalyst, with MW heating [147]. Different ILs and different metal triﬂates were used to optimize the reaction conditions that were successively used for the reaction with different substrates. The results are summarizedCatalysts 2017 in, 7, Scheme261 61. 40 of 56

MW, 80°C R 3 min NH2 10% mol Yb(OTf) O 3 + + R [bmim]BF4 N X R' R' X Synthesized quinolines, with isolated yields

F O O N N N N

yield, 90% O O yield, 77% yield, 76% yield, 88% O

N N N O O yield, 69% yield, 82% yield, 83% S

Br Br

N N N N

NO O yield, 89% 2 yield, 92% yield, 96% yield, 91%

Br Cl O2N I

Cl N N N N yield, 86% yield, 90% yield, 87% yield, 89% CN

NO2

Br Br Br

O O N N N N

CN O O CN yield, 88% yield, 91% O yield, 93% O yield, 90%

Scheme 61. Multi‐Component Reaction (MCR) to quinolines in IL and Yb(OTf)3 under MW heating Scheme 61. Multi-Component Reaction (MCR) to quinolines in IL and Yb(OTf)3 under MW heating[147]. [ 147].

In other cases, the three‐component reaction worked better in VOCs than in ILs. For example theIn best other conditions cases, the to three-componentprepare 3‐amino‐substituted reaction worked imidazo[1,2 better‐a]pyridines in VOCs thanfrom in2‐aminopyridines, ILs. For example thealdehydes best conditions and isocyanides to prepare were 3-amino-substituted montmorillonite as imidazo[1,2- the catalysta ]pyridinesand toluene from as the 2-aminopyridines, solvent, under MW conditions. On the other hand, in bmim ILs, lower yields and decomposition were observed [148]. Biginelli reaction—As reported in the 2014 chapter on carbonyl compounds as electrophilic reagents in multicomponent reactions [149], the so called Biginelli reaction is one of the most investigated one, with more than 1000 papers and almost 100 reviews at the time [150]. Since 2014,

Catalysts 2017, 7, 261 41 of 57 aldehydes and isocyanides were montmorillonite as the catalyst and toluene as the solvent, under MW conditions. On the other hand, in bmim ILs, lower yields and decomposition were observed [148]. Biginelli reaction—As reported in the 2014 chapter on carbonyl compounds as electrophilic reagents in multicomponent reactions [149], the so called Biginelli reaction is one of the most investigated one, Catalysts 2017, 7, 261 41 of 56 withCatalysts more 2017, than 7, 261 1000 papers and almost 100 reviews at the time [150]. Since 2014, more than41 of 300 56 othermore publicationsthan 300 other appeared, publications 17 of whichappeared, are reviews.17 of which The are interest reviews. is mainly The interest due to the is mainly importance due ofto multicomponentthemore importance than 300 otherof reactions multicomponent publications for drug appeared, reactions synthesis. for17 ofdrug which synthesis. are reviews. The interest is mainly due to the importanceClassical conditions of multicomponent involve heating reactions in an for organic drug synthesis. solvent, in the presence of acid catalyst, of an aromaticClassical aldehyde conditions with a involve 1,3-dicarbonyl1,3‐dicarbonyl heating compoundin an organic and solvent, urea or in thiourea, the presence as in of Scheme acid catalyst, 6262,, although of an thearomatic role of aldehyde thethe catalyst with has a 1,3 been‐dicarbonyl questioned compound [[151].151]. and urea or thiourea, as in Scheme 62, although the role of the catalyst has been questioned [151]. O O R O R' O R H2N NH2 O NH R' H2N NH2 O NH Bronsted or Ar N O R O Lewis acid H Ar O + R' Bronsted or S Ar N O R O Lewis acid O RH Ar O + R' solvent S O O heat H N NH R' O R solvent 2 2 O NH O O heat H N NH R' 2 2 O NH Ar N S H Ar N S H Scheme 62. Classical three three-component‐component Biginelli reaction. Scheme 62. Classical three‐component Biginelli reaction. A sustainable breakthrough was the Biginelli reaction catalyzed by ionic liquids in solvent‐free A sustainable breakthrough was the Biginelli reaction catalyzed by ionic liquids in solvent-free conditionsA sustainable [152], while breakthrough MWs were was introduced the Biginelli later. reaction We catalyzedwant to discussby ionic hereliquids examples in solvent of‐ freethe conditions [152], while MWs were introduced later. We want to discuss here examples of the reaction reactionconditions that [152], took advantagewhile MWs of werethe combined introduced use later.of MW We heating want andto discuss ILs. The here interested examples reader of canthe that took advantage of the combined use of MW heating and ILs. The interested reader can find the findreaction the otherthat took details advantage in [150] andof the references combined therein. use of MW heating and ILs. The interested reader can otherfind the details other in details [150] and in [150] references and references therein. therein. The ad hoc prepared [bmim]HSO4 IL in 10 mol % catalyzed a solvent‐free Biginelli The ad hoc prepared [bmim]HSO IL in 10 mol % catalyzed a solvent-free Biginelli condensation condensationThe ad tohoc dihydropyrimidinones prepared [bmim]HSO4 and4 ILdihydropyrimidinethiones, in 10 mol % catalyzed with a solventhigh yields‐free obtainedBiginelli to dihydropyrimidinones and dihydropyrimidinethiones, with high yields obtained after few minutes, aftercondensation few minutes, to dihydropyrimidinones under MW irradiation and at 140 dihydropyrimidinethiones, °C (Scheme 63) [153]. The with procedure high yields resulted obtained in an under MW irradiation at 140 ◦C (Scheme 63)[153]. The procedure resulted in an improvement of improvementafter few minutes, of reaction under outputMW irradiation as well as at of 140 sustainability. °C (Scheme 63) [153]. The procedure resulted in an reactionimprovement output of as reaction well as output of sustainability. as well as of sustainability. O Ar O + O Ar O + O O O O Ar = Ar = N Br [bmim]HSO4 MW, 140°C N Br [bmim]HSO4-8 min 4 MW, 140°C Br Cl O 4-8 min S Br Cl O S H N NH H N NH F O N O 2 2 2 2 2 H N NH H N NH F O N O 2 2 2 2 2O O Ar O Ar HO O O Ar O Ar HO O HO O NH O NH O HO O O NH O NH O N O N S H yield 72-85% N O H yield 72-85% N S H H Scheme 63. MW‐assisted, acidic IL‐catalyzed Biginelli synthesis of dihydropyrimidinones and Schemethiones [153]. 63.63. MWMW-assisted,‐assisted, acidic acidic IL IL-catalyzed‐catalyzed Biginelli synthesis of dihydropyrimidinonesdihydropyrimidinones andand thionesthiones [[153].153]. The heterocyclic products are of potential medical interest, the procedure is sustainable, yields The heterocyclic products are of potential medical interest, the procedure is sustainable, yields are fromThe heterocyclicmoderate to productshigh (75–90% are of using potential MW, medical 67–80% interest, using sonication), the procedure and isMW sustainable, irradiation yields was are from moderate to high (75–90% using MW, 67–80% using sonication), and MW irradiation was aredefinitely from moderate superior in to reducing high (75–90% reaction using times MW, (5–10 67–80% min, using vs. 40–55 sonication), min with and ultrasounds). MW irradiation However, was definitely superior in reducing reaction times (5–10 min, vs. 40–55 min with ultrasounds). However, definitelyit must also superior be considered in reducing that reactionthe reactions times with (5–10 sonication min, vs. 40–55 were min performed with ultrasounds). at 50 °C, a temperature However, it it must also be considered that the reactions with sonication were performed at 50 °C, a temperature lower than that of MW irradiation. [bSO3Hpy]HSO4− resulted the most efficient catalyst◦ and could be must also be considered that the reactions with sonication− were performed at 50 C, a temperature recycledlower than at thatleast of fourMW timesirradiation. with [bnoSO3H significantpy]HSO4 resultedloss− of activity.the most The efficient reaction catalyst performed and could with be lower than that of MW irradiation. [bSO3Hpy]HSO4 resulted the most efficient catalyst and could conventionalrecycled at least heating four at times70 °C withoutwith no solvents significant also gaveloss ofhigh activity. yields inThe 15 minreaction [154]. performed with conventionalLater, the heating multi at‐component 70 °C without condensation solvents also of gave β‐ naphtholhigh yields with in 15 aromaticmin [154]. aldehydes and acetamideLater, orthe urea multi was‐component performed incondensation [bmim]Br withof β‐ MWnaphthol irradiation with [155] aromatic (Scheme aldehydes 64). When and a comparisonacetamide or is urea possible, was performedyields are betterin [bmim]Br than those with previously MW irradiation described [155] and (Scheme reaction 64). times When are a amongcomparison the shortest is possible, reported. yields Moreover, are better the than IL thosecould previouslybe reused otherdescribed three and times, reaction with negligibletimes are differenceamong the in shortest results. reported.Thus the procedureMoreover, can the be IL considered could be reused a sustainable other three alternative times, for with the negligible family of 1difference‐amidoalkyl in results.‐2‐naphthols, Thus theprecursors procedure of biologicallycan be considered active a1,3 sustainable‐oxazines. alternative for the family of 1‐amidoalkyl‐2‐naphthols, precursors of biologically active 1,3‐oxazines.

Catalysts 2017, 7, 261 42 of 57 be recycled at least four times with no signiﬁcant loss of activity. The reaction performed with conventional heating at 70 ◦C without solvents also gave high yields in 15 min [154]. Later, the multi-component condensation of β-naphthol with aromatic aldehydes and acetamide or urea was performed in [bmim]Br with MW irradiation [155] (Scheme 64). When a comparison is possible, yields are better than those previously described and reaction times are among the shortest reported. Moreover, the IL could be reused other three times, with negligible difference in results. Thus theCatalysts procedure 2017, 7, 261 can be considered a sustainable alternative for the family of 1-amidoalkyl-2-naphthols,42 of 56 Catalystsprecursors 2017, of7, 261 biologically active 1,3-oxazines. 42 of 56 OH O Ar = Br + OH Ar O H MW, 130°C + Ar = BrO2N H MW, 130°C [bmim]Br 25-40Ar min O2N O2N O [bmim]Br 25-40 min O O N Cl 2 yield 78-94% Me O NH H N O NH Cl Cl 2 2 2 yield 78-94% Me NH H N NH Cl Cl 2 2 2 O Me O NH2 Cl Cl F Ar O NHMe Ar O NHNH2 Cl F Me Ar NH OH Ar NH OH Me Me OH OH Me Scheme 64. “Three‐component synthesis” of 1‐amidoalkyl‐2‐naphthols, in IL and MW irradiation Scheme[155]. 64. “Three‐component synthesis” of 1‐amidoalkyl‐2‐naphthols, in IL and MW irradiation Scheme 64. “Three-component synthesis” of 1-amidoalkyl-2-naphthols, in IL and MW irradiation [155]. [155]. A model Biginelli reaction (benzenecarbaldehyde, ethyl 3‐oxobutanoate and urea) was performedAA modelmodel testing Biginelli Biginelli different reaction reaction (benzenecarbaldehyde,ILs (benzenecarbaldehyde, as catalyst [156]. ethyl [Hmim]CF 3-oxobutanoateethyl 3‐oxobutanoate3CO2 andperformed urea) and was betterurea) performed wasthan testing different ILs as catalyst [156]. [Hmim]CF CO performed better than [Hmim]HSO and much performed[Hmim]HSO testing4 and muchdifferent better ILsthan asnon catalyst Brønsted3 [156]. acid2 ILs[Hmim]CF ([bmim]PF3CO6 and2 performed [bmim]BF 4).better 4Under than MW better than non Brønsted acid ILs ([bmim]PF and [bmim]BF ). Under MW irradiation the reaction was [Hmim]HSOirradiation the4 and reaction much betterwas completethan non Brønstedin6 2 min acid (99% ILs yield), 4([bmim]PF an improvement6 and [bmim]BF with4). Under respect MW to irradiationcompleteconventional in the 2 minheating reaction (99% that yield), was required complete an improvement 2 h inat 2100 min with°C. (99%Thirty respect yield), dihydropyrimidin to conventional an improvement heating‐2(1H )with that‐ones required respector thiones 2to h ◦ conventionalatwere 100 obtainedC. Thirty heating in dihydropyrimidin-2(1 high that yields required (Scheme 2 h65).H at)-ones 100 or°C. thiones Thirty weredihydropyrimidin obtained in high‐2(1 yieldsH)‐ones (Scheme or thiones 65). were obtained in high yields (Scheme 65). MW X 2 min MW X 2 min O 10 % mol [Hmim]CF CO O O O 3 2 O + + H N O NH 10 % mol [Hmim]CF CO O O NH O O 2 2 3 2 O O X + + H2N NH2 O N NH O O H X X = H, 4-OMe, 4-Cl, 4-NO , 3-NO 2 2 isolated yields,N 90-94%O H X = H, 4-OMe, 4-Cl, 4-NO , 3-NO 2 2 isolated yields, 90-94% MW X 2 min MW X 2 min S O O O 10 % mol [Hmim]CF3CO2 O + + H N S NH 10 % mol [Hmim]CF CO O O NH O O O 2 2 3 2 O X + + H2N NH2 O N NH S O H X X = 2-Me, 3-Me, 4-Me, 2-OMe, 2-NO , 2-F, 3-F, 2-OEt 2 isolated yields,N 84-93%S H X = 2-Me, 3-Me, 4-Me, 2-OMe, 2-NO2, 2-F, 3-F, 2-OEt Scheme 65. Examples of MW‐heated and IL‐catalyzed formationisolated of dihydropyrimidinyields, 84-93% ‐2(1H)‐ones Scheme 65. Examples of MW-heated and IL-catalyzed formation of dihydropyrimidin-2(1H)-ones and Schemeand thiones 65. Examples[156]. of MW‐heated and IL‐catalyzed formation of dihydropyrimidin‐2(1H)‐ones thiones [156]. and thiones [156]. An example where the synergy between IL catalyst and MW energy source is evident, is the formationAnAn example example of 3,4where where‐dihydropyrimidin the the synergy synergy between‐2 between‐(1H)‐ onesIL catalyst IL (Scheme catalyst and andMW66) MWenergy[157]. energy sourceUsing source is evident,the issame evident, is theIL formationis(1‐ thecarboxymethyl formation of 3,4‐ of3‐dihydropyrimidin‐methylimidazolium 3,4-dihydropyrimidin-2-(1‐2‐ (1tetrafluoroborate),H)‐onesH )-ones(Scheme (Scheme yields66) 66[157].are)[ 157better ].Using Usingand thereaction the same same times IL IL (1(1-carboxymethyl-3-methylimidazoliumsensibly‐carboxymethyl lower with‐3‐methylimidazolium MW irradiation than tetraﬂuoroborate), tetrafluoroborate), with conventional yields yields heating. are betterare The better and IL—probably reaction and reaction times acting sensibly times as a sensiblyBrønsted lower acid withcatalyst—could MW irradiation be easily than recoveredwith conventional and reused heating. for six The consecutive IL—probably runs, acting showing as a Brønstedalmost no acid loss catalyst—couldof activity. be easily recovered and reused for six consecutive runs, showing almostA nomodification loss of activity. of bmim side chain introduced the nitrite group. The prepared [ONObmim]Cl was Aused modification to catalyze of the bmim formation side chain of dihydropyrimidin introduced the nitrite‐2(H)‐ onesgroup. and The thiones, prepared with [ONObmim]Cl MW heating at was80 °C. used Within to catalyze 3–4 min, the products formation formed of dihydropyrimidin in 87–91% isolated‐2(H )yield.‐ones and[ONObmim]Cl thiones, with could MW be heating recycled at 80and °C. reused Within with 3–4 the min, same products performance formed for in 87–91%at least fiveisolated runs yield.[158]. [ONObmim]Cl could be recycled and reused with the same performance for at least five runs [158].

Catalysts 2017, 7, 261 43 of 57 lower with MW irradiation than with conventional heating. The IL—probably acting as a Brønsted acid catalyst—could be easily recovered and reused for six consecutive runs, showing almost no loss of activity. Catalysts 2017, 7, 261 43 of 56

O Ar O + Ar = Me O O O2N NO2 Catalysts 2017, 7, 261 43 of 56

O2N [HO2CC1mim]BF4 MW, 80°C O Cl Cl Ar 1-3O min+ Ar = Me O S Cl O O O2N NO2

Br Br H2N NH2 H2N NH2 O2N [HO2CC1mim]BF4 MW, 80°C Br O Ar O Ar Cl Cl 1-3 min OO NH O S NH Cl F HO N O Br H N NH H N N NHS OH Br 2 2 H yield 89-97% 2 H 2 O Ar BrHO O O Ar O O O O NH O NH F HO N O OH N O + N S OH yield 89-97% H N H O O HO O HO2CC1mim N O O O O S N OH O + Scheme 66. Synthesis of 3,4‐dihydropyrimidin‐2‐(1H)‐ones via microwaveN promoted Biginelli Scheme 66. SynthesisO O of 3,4-dihydropyrimidin-2-(1H)-ones via microwave promoted Biginelli reaction [157]. reaction [157]. HO2CC1mim N O S An amino acid ionic liquid, glycine nitrate, was used as catalyst for the multicomponent synthesisSchemeA modification of 3,466.‐ dihydropyrimidinSynthesis of bmim of side3,4‐dihydropyrimidin chain‐2(1H) introduced‐ones and‐2 ‐thiones(1 theH)‐ nitriteones with via group. MW microwave heating The prepared promoted[159]. An [ONObmim]Cl Biginelliample range wasof substituents usedreaction to catalyze[157]. on aryl the aldehydes formation confirmed of dihydropyrimidin-2( the generalityH of)-ones the reaction. and thiones, MW with irradiation MW heating ensured at ◦ 80fast C.reactions Within 3–4(10 min, min products with urea, formed 20 min in 87–91% with thiourea). isolated yield. Comparing [ONObmim]Cl their results could to be recycledthose of andpreviously reusedAn amino withreported acid the same protocols,ionic performance liquid, the glycineauthors for at nitrate,state least that five was their runs used catalyst [158 as]. catalyst is biodegradable for the multicomponent and recyclable synthesisand Ancould amino of be 3,4 reused‐dihydropyrimidin acid ionicfor more liquid, than‐2(1 glycine tenH) ‐cyclesones nitrate, and without thiones was significant used with as MW catalyst loss heating of foractivity. [159]. the multicomponentAnMoreover, ample rangegram ofsynthesisscale substituents synthesis of 3,4-dihydropyrimidin-2(1 onwas aryl performed, aldehydes formingconfirmedH)-ones the the biologically and generality thiones withactiveof the MW reaction.Monastrol, heating MW [a159 mitoticirradiation]. An amplekinesin ensured range Eg5 fastofinhibitor substituents reactions (Scheme (10 on 67). arylmin aldehydeswith urea, confirmed 20 min with the generality thiourea). of Comparing the reaction. their MW results irradiation to those ensured of previouslyfast reactions reported (10 min protocols, with urea, the 20 minauthors with state thiourea). that their Comparing catalyst their is biodegradable results to those and of previouslyrecyclable andreported could protocols, be reused the for authors more than state ten that cycles their catalystwithout is significant biodegradable lossMW, of and activity. recyclable Moreover, and could gram be scalereused synthesis for more was than performed, ten cycles without forming significant the biologically loss of activity. active Moreover,Monastrol,10 min gram a mitotic scale synthesis kinesinOH wasEg5 performed,inhibitor (Scheme forming 67). the biologically active Monastrol, a mitotic kinesin Eg5 inhibitor (Scheme 67). O O O S O 0.4 equiv. GlyNO3 + + O H N NH EtOH MW, O NH 2 2 OH OH 10 min N S 1 g H O O O S O 0.4 equiv. GlyNO3 Monastrol + + O EtOH O isolated yield, 72% H2N NH2 NH OH Scheme 67. Gram scale preparation of Monastrol via Biginelli reaction catalyzed by glycineN S nitrate 1 g H (GlyNO3) IL and promoted by MW irradiation [159]. Monastrol isolated yield, 72% Another IL, [bSO3Hpy]3PW12O403−, was used more recently as catalyst, under MW irradiation (120 °C), Schemeyielding 67. inGram 5–10 scale min preparation several of polysubstituted Monastrol via Biginelli dihydropyrimidinones reaction catalyzed by and glycine thiones nitrate [160]. (GlyNO3) IL and promoted by MW irradiation [159]. However,(GlyNO the3) ILpolyanion and promoted seems by not MW to irradiation be really [important,159]. while the acidic functionality of the cation plays a major role in catalyzing the reaction. AnotherThe “three IL,‐ [bcomponentSO3Hpy]3PW synthesis”12O403−, was of used amino more‐substituted1,3 recently as catalyst,‐diaza heteroaromaticunder MW irradiation derivatives (120 °C),was investigatedyielding in using5–10 amin variety several of ILs, polysubstituted i.e., [bmim] with dihydropyrimidinones different counterions (Cland−, Brthiones−, AcO −,[160]. BF4−, However,HSO4−), [b theSO3H polyanionmim] with seems HSO4 −not or toTfO be− anions,really important, [bSO3Hpy]HSO while4, andthe acidic [bSO3H mfunctionality2cyu](HSO4 )of2 (Figurethe cation 1), playsthat acted a major as catalystsrole in catalyzing with MW the irradiation reaction. and as both catalysts and solvents when an ultrasound irradiationThe “three was ‐usedcomponent [161] (Scheme synthesis” 68). of amino‐substituted1,3‐diaza heteroaromatic derivatives was investigated using a variety of ILs, i.e., [bmim] with different counterions (Cl−, Br−, AcO−, BF4−, HSO4−), [bSO3Hmim] with HSO4− or TfO− anions, [bSO3Hpy]HSO4, and [bSO3Hm2cyu](HSO4)2 (Figure 1), that acted as catalysts with MW irradiation and as both catalysts and solvents when an ultrasound irradiation was used [161] (Scheme 68).

Catalysts 2017, 7, 261 44 of 57

3− Another IL, [bSO3Hpy]3PW12O40 , was used more recently as catalyst, under MW irradiation (120 ◦C), yielding in 5–10 min several polysubstituted dihydropyrimidinones and thiones [160]. However, the polyanion seems not to be really important, while the acidic functionality of the cation plays a major role in catalyzing the reaction. The “three-component synthesis” of amino-substituted 1,3-diaza heteroaromatic derivatives was investigated using a variety of ILs, i.e., [bmim] with different counterions (Cl−, Br−, AcO−, − − − − BF4 , HSO4 ), [bSO3Hmim] with HSO4 or TfO anions, [bSO3Hpy]HSO4, and [bSO3Hm2cyu](HSO4)2 (Figure1), that acted as catalysts with MW irradiation and as both catalysts and solvents when an ultrasoundCatalysts 2017, irradiation 7, 261 was used [161] (Scheme 68). 44 of 56 Catalysts 2017, 7, 261 44 of 56

Ar = F Cl Ar = F Cl MW, 120°C +NH Br Me O O 2 MW, 120°C +NH 2- Br Me O O + 2 CO3 H2N NH2 2- Ar H + CO2 3 O O H N NH Ar H 2 2 2 O O O O O O O O

NH2 NH NH2 2 N N NH 2 N N N N NH NH 2 Ar N N 2 NH NH 2 Ar Ar 2 N N N N Ar Ar N N Ar N N Ar Ar Ar Ar Ar Ar

SchemeScheme 68.68.“Three-component “Three‐component synthesis” synthesis” of amino-substituted of amino‐substituted 1,3-diaza heteroaromatic1,3‐diaza heteroaromatic compounds, Scheme 68. “Three‐component synthesis” of amino‐substituted 1,3‐diaza heteroaromatic withcompounds, IL catalysts with and IL catalysts MW irradiation and MW [161 irradiation]. [161]. compounds, with IL catalysts and MW irradiation [161].

TheThe versatility of the the MW MW assisted assisted and and IL IL-catalyzed‐catalyzed Biginelli Biginelli reaction reaction prompted prompted the the extension extension of the methodThe versatility to the of synthesis the MW assistedof other and pharmaceutically IL‐catalyzed Biginelli relevant reaction heterocyclic prompted compounds. the extension Thus, of theof the method method to tothe the synthesis synthesis of of other other pharmaceutically pharmaceutically relevant relevant heterocyclic heterocyclic compounds. Thus, Thus, potentiallypotentially non-classical non‐classical malarial malarial antifolates antifolates made made of pyrazole-linked of pyrazole‐linked triazolo-pyrimidine triazolo‐pyrimidine hybrids hybrids were potentiallywere prepared non ‐classicalby Biginelli malarial‐type reaction,antifolates using made the of inexpensivepyrazole‐linked triethylammonium triazolo‐pyrimidine acetate hybrids as IL prepared by Biginelli-type reaction, using the inexpensive triethylammonium acetate as IL catalyst werecatalyst prepared and MW by Biginelliheating ‐type[162]. reaction, A library using of the30 compoundsinexpensive wastriethylammonium prepared, simply acetate changing as IL and MW heating [162]. A library of 30 compounds was prepared, simply changing substituents in the catalystsubstituents and inMW the heteroaromaticheating [162]. aldehydeA library andof in30 thecompounds β‐dicarbonyl was compound prepared, (Scheme simply 69).changing The IL heteroaromatic aldehyde and in the β-dicarbonyl compound (Scheme 69). The IL could be reused at substituentscould be reused in the at heteroaromatic least five times, aldehyde with some and lossin the in β‐ yielddicarbonyl only after compound the third (Scheme run. MW 69). heatingThe IL least ﬁve times, with some loss in yield only after the third run. MW heating lowered reaction times to couldlowered be reactionreused at times least to five 2–3 times,min from with 2.5 some to 3.5 loss h with in yield conventional only after heating. the third run. MW heating lowered2–3 min fromreaction 2.5 times to 3.5 hto with 2–3 min conventional from 2.5 to heating. 3.5 h with conventional heating. O H O HN R'' HNN + N R'' + N HNN + N O O + NH N N R' N 2 R N O O NH2 N R' N R

[Et3NH]OAc MW, 120°C [Et3NH]OAc MW, 10 120°C min 10 min

N N R' N N R' N O N O R N N N R N NH N isolated yield, 81-88% H R'' N N isolated yield, 81-88% R'' N N Scheme 69. MW assisted and IL‐catalyzed Biginelli reaction pyrazole derivatives [162]. SchemeScheme 69. 69. MWMW assisted assisted and and IL IL-catalyzed‐catalyzed Biginelli Biginelli reaction reaction pyrazole pyrazole derivatives [162]. [162]. Solid‐supported IL was prepared from 1‐methyl‐3‐(3‐trimethoxysilylpropyl)imidazolium Solid‐supported IL was prepared from 1‐methyl‐3‐(3‐trimethoxysilylpropyl)imidazolium hydrogen sulfate, [pSimim]HSO4, and Fe3O4 nanoparticles. The magnetic nanoparticles were used in hydrogenMW‐assisted sulfate, solvent [pSimim]HSO‐free Biginelli4, and reaction Fe3O4 nanoparticles. [163]. According The to magnetic the authors, nanoparticles this is an were eco‐ friendlyused in MWmethod‐assisted that solventrepresents‐free Biginellian improvement reaction [163].in terms According of reduced to the authors,reaction thistimes, is anhigh eco ‐turnoverfriendly methodfrequency, that high represents yields of products,an improvement absence ofin solvent terms andof reducedrecyclability. reaction times, high turnover frequency, high yields of products, absence of solvent and recyclability. 4. Carbon Dioxide Transformation 4. Carbon Dioxide Transformation The environmental impact of carbon dioxide excessive emission is well known and worldwide researchThe environmentalis currently aimed impact at addressing of carbon anddioxide possibly excessive solving emission the problem is well [164]. known Although and worldwide catalytic researchtechnologies is currently were developedaimed at addressing by chemical and industrypossibly solvingto transform the problem carbon [164]. dioxide Although into catalyticvaluable technologiesbuilding blocks, were not developed to speak of by polycarbonates chemical industry or polycarbamates, to transform muchcarbon more dioxide should into be donevaluable and buildingachieved blocks, by targeted not to research. speak of polycarbonates or polycarbamates, much more should be done and achieved by targeted research.

Catalysts 2017, 7, 261 45 of 57

Solid-supported IL was prepared from 1-methyl-3-(3-trimethoxysilylpropyl)imidazolium hydrogen sulfate, [pSimim]HSO4, and Fe3O4 nanoparticles. The magnetic nanoparticles were used in MW-assisted solvent-free Biginelli reaction [163]. According to the authors, this is an eco-friendly method that represents an improvement in terms of reduced reaction times, high turnover frequency, high yields of products, absence of solvent and recyclability.

4. Carbon Dioxide Transformation The environmental impact of carbon dioxide excessive emission is well known and worldwide research is currently aimed at addressing and possibly solving the problem [164]. Although catalytic technologies were developed by chemical industry to transform carbon dioxide into valuable building Catalysts 2017, 7, 261 45 of 56 blocks, not to speak of polycarbonates or polycarbamates, much more should be done and achieved by targetedCarbon research. dioxide is thermodynamically stable and kinetically inert, so that activation by catalysts is necessaryCarbon dioxide and the is MW/IL thermodynamically combination stablemight and play kinetically a major role. inert, In so the that field activation of carbon by catalysts dioxide isactivation, necessary one and of the the MW/IL processes combination most investigated might play is the a formation major role. of Inorganic the ﬁeld carbonates, of carbon in dioxide view of activation,their increasing one of importance the processes as sustainable most investigated and environmentally is the formation‐friendly of organic alkylating carbonates, agents in [165]. view of their increasingILs with importancetetrahaloindate as sustainable as the andanion environmentally-friendly were used to catalyze alkylating the transformation agents [165]. of oxacyclopropanesILs with tetrahaloindate into cyclic as carbonates, the anion were but MW used irradiation to catalyze thewas transformation used only to synthesize of oxacyclopropanes them [166] into(Scheme cyclic 70). carbonates, but MW irradiation was used only to synthesize them [166] (Scheme 70).

R N N + N+ P + Cl- - - + N Cl Cl Cl-

MW InCl InCl InCl InCl 3 3 3 3 15 s

R N + N+ P N + + InCl - N - InCl - - 4 InCl4 4 InCl4

0.5% mol IL O O O + CO2 R 120°C, 100 psi, 1 h R

R = Me, CH2Cl, Bn, Ph, OPh isolated yields, 62-98% selectivity 99-100%

Scheme 70. MW‐assisted synthesis of tetrachloroindate ILs and their use in CO2 reaction with Scheme 70. MW-assisted synthesis of tetrachloroindate ILs and their use in CO2 reaction with oxacyclopropanes [166]. oxacyclopropanes [166].

A mechanistic reaction scheme was proposed, where the superior performance of imidazolium tetrachloroindateA mechanistic was reaction attributed scheme to hydrogen was proposed, bonding where formation the superior between performance Cl of the anion of imidazolium and the H tetrachloroindatein position 2 of imidazolium was attributed cation to hydrogen that increases bonding the formation Lewis acidity between of In(III). Cl of the anion and the H in position 2 of imidazolium cation that increases the Lewis acidity of In(III). Only years later MW irradiation was used together ILs to form cyclic carbonates from CO2 and Only years later MW irradiation was used together ILs to form cyclic carbonates from CO2 and epoxides. The solvent‐free coupling reaction of CO2 with methyloxacyclopropane to produce cyclic epoxides.carbonate The under solvent-free microwave coupling irradiation reaction was performed of CO2 with in methyloxacyclopropane the presence of catalytic toamounts produce of cyclicZn(II) carbonatesalts and underILs [167], microwave with different irradiation combinations was performed of the in thetwo. presence An 11.2–278% of catalytic TOF amounts increment of Zn(II) was saltsobserved and ILs (depending [167], with on different the different combinations combination of the two.of zinc An salt 11.2–278% and ionic TOF liquid) increment with was MW observed heating (depending on the different combination of zinc salt and ionic liquid) with MW heating with respect with respect to oil bath. With the five different ILs tested, the activity order observed is Bu4NBr > to oil bath. With the ﬁve different ILs tested, the activity order observed is Bu NBr > [Hmim]Br > [Hmim]Br > [bmim]Br > [emim]Br > Bu4I. Under the optimized conditions, other4 oxacyclopropanes [bmim]Brwere reacted, > [emim]Br with good > Bu results4I. Under (Scheme the optimized 71). conditions, other oxacyclopropanes were reacted, with good results (Scheme 71).

O MW, 100°C 15 min O 0.04% Zn salt + CO OO 2 2% mol Bu NBr 3 MPa 4 yield, 75.9% TOF, 6989 h-1

cyclic carbonates prepared: O MW, 120°C 15 min O O OO OO OO

yield, 91.5% yield, 70.9% yield, 62.5% TOF, 8451 h-1 TOF, 6645 h-1 TOF, 5762 h-1

Scheme 71. MW‐heated formation of cyclic carbonates with Zn(II) salts and Bu4NBr catalysts [167].

Catalysts 2017, 7, 261 45 of 56

Carbon dioxide is thermodynamically stable and kinetically inert, so that activation by catalysts is necessary and the MW/IL combination might play a major role. In the field of carbon dioxide activation, one of the processes most investigated is the formation of organic carbonates, in view of their increasing importance as sustainable and environmentally‐friendly alkylating agents [165]. ILs with tetrahaloindate as the anion were used to catalyze the transformation of oxacyclopropanes into cyclic carbonates, but MW irradiation was used only to synthesize them [166] (Scheme 70).

R N N + N+ P + Cl- - - + N Cl Cl Cl-

MW InCl InCl InCl InCl 3 3 3 3 15 s

R N + N+ P N + + InCl - N - InCl - - 4 InCl4 4 InCl4

0.5% mol IL O O O + CO2 R 120°C, 100 psi, 1 h R

R = Me, CH2Cl, Bn, Ph, OPh isolated yields, 62-98% selectivity 99-100%

Scheme 70. MW‐assisted synthesis of tetrachloroindate ILs and their use in CO2 reaction with oxacyclopropanes [166].

A mechanistic reaction scheme was proposed, where the superior performance of imidazolium tetrachloroindate was attributed to hydrogen bonding formation between Cl of the anion and the H in position 2 of imidazolium cation that increases the Lewis acidity of In(III). Only years later MW irradiation was used together ILs to form cyclic carbonates from CO2 and epoxides. The solvent‐free coupling reaction of CO2 with methyloxacyclopropane to produce cyclic carbonate under microwave irradiation was performed in the presence of catalytic amounts of Zn(II) salts and ILs [167], with different combinations of the two. An 11.2–278% TOF increment was observed (depending on the different combination of zinc salt and ionic liquid) with MW heating with respect to oil bath. With the five different ILs tested, the activity order observed is Bu4NBr >

Catalysts[Hmim]Br2017 ,>7 ,[bmim]Br 261 > [emim]Br > Bu4I. Under the optimized conditions, other oxacyclopropanes46 of 57 were reacted, with good results (Scheme 71).

O MW, 100°C 15 min O 0.04% Zn salt + CO OO 2 2% mol Bu NBr 3 MPa 4 yield, 75.9% TOF, 6989 h-1

cyclic carbonates prepared: O MW, 120°C 15 min O O OO OO OO

yield, 91.5% yield, 70.9% yield, 62.5% TOF, 8451 h-1 TOF, 6645 h-1 TOF, 5762 h-1

CatalystsScheme 2017, 7, 26171. MW‐heated formation of cyclic carbonates with Zn(II) salts and Bu4NBr catalysts [167].46 of 56 Scheme 71. MW-heated formation of cyclic carbonates with Zn(II) salts and Bu NBr catalysts [167]. 4 A large number of papers dealing with formation of cyclic carbonates is due to the group of Dae‐WonA large Park. number They used of papers MW activation dealing with without formation ILs [168–170], of cyclic or carbonates ionic liquids is without due to the microwave group of activationDae-Won Park.[171–176], They as used well MW as activationthe combination without of ILs the [168 two–170 that], or will ionic be liquids discussed without here. microwave ILs with differentactivation cations [171– 176(ammonium,], as well asimidazolium) the combination and different of the two anions that (chloride, will be discussed bromide, here. iodide) ILs were with different cations (ammonium, imidazolium) and different anions (chloride, bromide, iodide) were tested as catalysts in MW‐assisted reaction of 2‐(phenoxymethyl)oxacyclopropane with CO2 [177]. Thetested study as catalysts indicated in MW-assistedan inverse dependence reaction of 2-(phenoxymethyl)oxacyclopropaneof reactivity on the ion dimension, withwith CO chloride2 [177]. and The study indicated an inverse dependence of reactivity on the ion dimension, with chloride and emim emim giving the best combination. [bmim]Cl and [bmim]Br were chosen to be grafted on SiO2, in ordergiving to the investigate best combination. the heterogeneous [bmim]Cl andcatalysis. [bmim]Br The werereaction chosen slowed to be (from grafted 5 to on 30 SiO min2, in with order the to sameinvestigate IL) but the selectivity heterogeneous improved catalysis. and The the reaction catalyst slowed was easily (from 5recovered to 30 min and with reused. the same Finally, IL) but differentselectivity epoxides improved were and reacted, the catalyst confirming was easily the recoveredapplicability and of reused. the procedure. Finally, different Significant epoxides results were are inreacted, Scheme conﬁrming 72. the applicability of the procedure. Signiﬁcant results are in Scheme 72.

2.5% mol Bu4NCl conv. 90.7%; yield, 82.6%, selectivity, 91.1% O O O + CO MW 2 O O 30 min

O SiO2-[bmim]Br conv. 90.8%; yield, 90.8%, selectivity, 100%

cyclic carbonates prepared: O O O O O O O O O O O O

with Bu4NCl yield 91.4% 83.3% 97.9% 41.0% with SiO2-[bmim]Br yield 87.9% 78.8% 74.1% 32.4%

MW 20 min montmorillonite-Oc4N

1.34 MPa O yield, 70.1% O

O + CO2 O O

5% mol bupyBr O

0.96 MPa MW 2 s conv. 95%; selectivity, 95% TOF, 2129 h-1

Scheme 72. MW‐assisted CO2 reaction with oxacyclopropanes catalyzed by homogeneous and Scheme 72. MW-assisted CO2 reaction with oxacyclopropanes catalyzed by homogeneous and heterogeneousheterogeneous ILs ILs [177–180]. [177–180].

The effects of variations in the morphology of silica support was investigated and published separately [178]. The same research group tested a different solid support, montmorillonite clay [179]. Tetraoctlylammonium chloride was immobilized on K+‐montmorillonite by ion exchange and was suggested to act both as an activator of the reaction mixture and as a catalyst. The substrate was 2‐(allyloxymethyl)oxacyclopropane, that was converted in the corresponding cyclic carbonate without solvent in good yield. The catalyst was reused three times, with yields decreasing slowly from 70.1% in the first run to 66.7% in the fourth one. The same epoxide was subjected to carbon dioxide reaction in a solvent‐free treatment with pyridinium‐based ILs, under WM heating [180]. Considering conversion, selectivity (vs. polymerization) and TOF, the best catalyst was bupyBr, but what makes the system especially appealing is the reaction time, 20 s, instead of 20–30 min of previous protocols (Scheme 72). Finally, metal‐organic framework (MOF) ligands carboxyl spacers were used to synthesize cyclic carbonates from oxacyclopropane and CO2 [181]. The carboxyl functional molecular ribbon catalyst (containing bipyridyl, benzenedicarboxylic acid, and Cu or Zn cations) was synthesized with the help of MW irradiation and the formation of the cyclic carbonate benefited of IL co‐catalyst, but the MW/IL has not yet tested with this MOF. Much less investigated was the CO2 transformation into non‐cyclic carbonates. Carbon dioxide was reacted with methanol to yield dimethyl carbonate with K2CO3/CH3I catalyst, with MW heating,

Catalysts 2017, 7, 261 47 of 57

The effects of variations in the morphology of silica support was investigated and published separately [178]. The same research group tested a different solid support, montmorillonite clay [179]. Tetraoctlylammonium chloride was immobilized on K+-montmorillonite by ion exchange and was suggested to act both as an activator of the reaction mixture and as a catalyst. The substrate was 2-(allyloxymethyl)oxacyclopropane, that was converted in the corresponding cyclic carbonate without solvent in good yield. The catalyst was reused three times, with yields decreasing slowly from 70.1% in the ﬁrst run to 66.7% in the fourth one. The same epoxide was subjected to carbon dioxide reaction in a solvent-free treatment with pyridinium-based ILs, under WM heating [180]. Considering conversion, selectivity (vs. polymerization) and TOF, the best catalyst was bupyBr, but what makes the system especially appealing is the reaction time, 20 s, instead of 20–30 min of previous protocols (Scheme 72). Finally, metal-organic framework (MOF) ligands carboxyl spacers were used to synthesize cyclic carbonates from oxacyclopropane and CO2 [181]. The carboxyl functional molecular ribbon catalyst (containing bipyridyl, benzenedicarboxylic acid, and Cu or Zn cations) was synthesized with the help of MW irradiation and the formation of the cyclic carbonate beneﬁted of IL co-catalyst, but the MW/IL has not yet tested with this MOF. Much less investigated was the CO2 transformation into non-cyclic carbonates. Carbon dioxide was reacted with methanol to yield dimethyl carbonate with K2CO3/CH3I catalyst, with MW heating, in a process that required lower temperature and shorter reaction time when performed in [bmim]Cl [182]. According to the authors, the IL not only accelerates the reaction because it facilitates MW heating, but also, on the basis of density functional theory calculations, it interacts with CO2, activating it.

5. Outlook The picture that emerges from survey of the recent literature points at an increasing importance of microwaves as energy source, especially with modern instruments, with infrared temperature control and possibility to regulate pressure, very far from pioneering “domestic” oven of early papers. In addition, the use of ionic liquids evolved over several years, from solvents with peculiar properties to recyclable ones, to catalysts, homogeneous or supported on liquid phase heterogeneous or supported on solid phase. After testing a huge number of cation/anion combinations and after the idea of task-specific ILs, the trend now seems to be to use small amounts of robust ILs, in solvent-free reactions, under MW heating. This makes work-up particularly easy, with less waste and little need for other solvents for product extraction. The large majority of papers were interested only in the reactions outcome, with wide screening of reaction conditions, experiments performed with systematic change of type and amount of catalyst and eventual additive, temperature, heating modes, accurate choice of IL and even synthesis of task-specific IL, investigation of substituent effects and of reproducibility, recycling of the IL/catalyst system. Unfortunately, scarce, if any, attention was paid to the role played by ILs in combination with MW irradiation. The only paper reporting an investigation aimed at investigating the combination IL/MW was interested in studying their effect on organic solvents, that could be heated in sealed vials, well above their boiling point [119], thus being usable in MW promoted reactions. Therefore, it is difficult to understand the real role of ILs in MW heated reactions. Generally, they may increase the MW heating efficiency rendering the reaction medium more polar. This resulted mainly in increased yields, lower temperatures and reduced reaction times. However, in some reactions they seemed to act as real catalysts. It always dangerous to foresee the future, but our feeling is that, with melioration of MW instruments technology, the range of reactions performed preferably by MW irradiation with the aid of ILs will increase and, eventually, MW heating will substitute, at least at lab level, oil bath heating, in the same way that this substituted the free flame Bunsen burner. Finally, it must be stressed that, although beyond the scope of the present review, there are other fields where a development may be found in the near future for the MW/IL combination, such as, for Catalysts 2017, 7, 261 48 of 57 example, the shape memory polymer composites (SMPC), combining the advantages of microwaves and polyIL [183] or microwave therapy [184,185].

Acknowledgments: University of Rome Tor Vergata “Ricerca Scientifica d’Ateneo 2015-SMART project” is acknowledged for financial support. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

Ac acetyl, CH3CO acac anion of 2,4-pentanedione(acetylacetone) Cp cyclopentadienyl anion dba dibenzylideneacetone DABCO 1,4-diazabicyclo[2.2.2]octane DMSO dimethylsulfoxide ECODS extractive catalytic oxidative desulfurization GO graphene oxide IL ionic liquid MCR multi-component reaction NP nanoparticle NTf2 bis(trifluorometanesulfonyl) amide PEG poly(ethyleneglycol) ODS oxidative desulfurization py pyridine SILLP supported ionic liquid-like phases TBHP tert-butylhydroperoxide − TfO triflate CF3SO3- (IUPAC trifluoromethanesulfonate) TOF turnover frequency tpm hydrotris-(pyrazol-1-yl)methane Ts tosylate (p-toluenesulfonate) VOC volatile organic compound

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