Novel Methodologies for Chemical Activation in Organic Synthesis Under Solvent-Free Reaction Conditions

Review Novel Methodologies for Chemical Activation in Organic Synthesis under Solvent-Free Reaction Conditions

Claudia Gabriela Avila-Ortiz 1,* and Eusebio Juaristi 1,2,*

1 Departamento de Química, Centro de Investigación y de Estudios Avanzados, Av. IPN 2508, 07360 Ciudad de México, Mexico 2 El Colegio Nacional, Donceles 104, Centro Histórico, 06020 Ciudad de México, Mexico * Correspondence: [email protected] (C.G.A.-O.); [email protected] (E.J.); Tel.: +52-55-5747-3722 (E.J.)

Academic Editor: Vadim A. Soloshonok Received: 15 July 2020; Accepted: 3 August 2020; Published: 6 August 2020

Abstract: One central challenge for XXI century chemists is the development of sustainable processes that do not represent a risk either to humanity or to the environment. In this regard, the search for more eﬃcient and clean alternatives to achieve the chemical activation of molecules involved in chemical transformations has played a prominent role in recent years. The use of microwave or UV-Vis light irradiation, and mechanochemical activation is already widespread in many laboratories. Nevertheless, an additional condition to achieve “green” processes comes from the point of view of so-called atom economy. The removal of solvents from chemical reactions generally leads to cleaner, more eﬃcient and more economical processes. This review presents several illustrative applications of the use of sustainable protocols in the synthesis of organic compounds under solvent-free reaction conditions.

Keywords: solvent-free; mechanochemistry; biocatalysis; microwave activation; photocatalysis; green chemistry; sustainable synthesis

1. Introduction Classic chemical activation strategies are often associated with highly energy-demanding processes, as well as with the use of solvents that often times are not friendly with the environment and are commonly associated with costly and time-consuming procedures for the preparation and isolation of the desired product. In recent decades, the search for more environmentally friendly processes constitutes one central theme of research and development in both academic and industrial chemistry. In the 1990s, Anastas and Warner coined the concept of “Green Chemistry” in terms of the design of products and processes that imply the reduction or elimination of substances that are harmful to life or the environment. This philosophy is based on the 12 principles advanced by Anastas and Warner [1]. Following the postulation of the twelve Green Chemistry principles, a signiﬁcant number of chemists in both academic and industrial settings have focused their eﬀorts on the development of processes that meet those criteria. Conceptually, one obvious approach to achieve more sustainable processes is by avoiding the use of solvents, since this strategy minimizes the use of chemical auxiliaries while simultaneously decreasing the generation of waste [2]. Indeed, already in 2005, Sheldon argued that “the best solvent is no solvent”[3]. Occasionally, this strategy takes advantage of the fact that some of the reactants are actually liquids at ambient temperature, which helps to achieve a homogeneous reaction mixture. Occasionally, a slight excess of one liquid reagent may be used and the process can still be considered

Molecules 2020, 25, 3579; doi:10.3390/molecules25163579 www.mdpi.com/journal/molecules Molecules 2020, 25, 3579x FOR PEER REVIEW 2 of 25 solvent-free. In this context, the use of liquid adjuvants or activators acting as reaction medium can solvent-free. In this context, the use of liquid adjuvants or activators acting as reaction medium can be be particularly convenient—salient examples are ionic liquids and deep eutectic solvents. particularly convenient—salient examples are ionic liquids and deep eutectic solvents. Another aspect that is essential for the eventual fulfillment of the principles of Green Chemistry Another aspect that is essential for the eventual fulfillment of the principles of Green Chemistry refers to the chemical activation associated to the reaction of interest. According to conventional refers to the chemical activation associated to the reaction of interest. According to conventional methodologies, chemical reactions involving high activation energy require heating for long periods methodologies, chemical reactions involving high activation energy require heating for long periods of of time that result in high inherent cost and the concomitant risk of decomposition of reagents and/or time that result in high inherent cost and the concomitant risk of decomposition of reagents and/or products. In the last two or three decades, organocatalysis, mechanochemical activation, microwave products. In the last two or three decades, organocatalysis, mechanochemical activation, microwave irradiation, and photocatalysis are among the most effective alternatives for efficient activation under irradiation, and photocatalysis are among the most effective alternatives for efficient activation under sustainable conditions. sustainable conditions. As a topic of great current relevance, Green Chemistry has recently generated a significant As a topic of great current relevance, Green Chemistry has recently generated a significant number number of review articles and monographs describing successful approaches to achieve the of review articles and monographs describing successful approaches to achieve the activation of activation of chemical transformations in sustainable processes [4–15]. The present review focuses on chemical transformations in sustainable processes [4–15]. The present review focuses on the discussion the discussion of several recent applications of non-conventional chemical activation strategies in of several recent applications of non-conventional chemical activation strategies in organic synthesis in organic synthesis in the absence of solvents. the absence of solvents. 2. Mechanochemistry 2. Mechanochemistry Mechanochemistry is defined as the use of mechanical energy to conduct chemical Mechanochemistry is defined as the use of mechanical energy to conduct chemical transformations. transformations. The simplest equipment employed to carry out a mechanochemical reaction is the The simplest equipment employed to carry out a mechanochemical reaction is the mortar with its mortar with its pestle, a methodology that can be dated back to the Stone Age. Nevertheless, the first pestle, a methodology that can be dated back to the Stone Age. Nevertheless, the first documented documented mechanochemical reaction is attributed to Theophrastus of Eresus, who was a student mechanochemical reaction is attributed to Theophrastus of Eresus, who was a student of Aristotle. of Aristotle. He observed that during the milling process of some cinnabar fragments (HgS) using a He observed that during the milling process of some cinnabar fragments (HgS) using a copper mortar, copper mortar, drops of a liquid metal (mercury) were produced [16]. drops of a liquid metal (mercury) were produced [16]. Currently, there exists various grinding equipment that are already automated for their Currently, there exists various grinding equipment that are already automated for their convenient convenient and reliable use in laboratory (small scale) or industrial (large scale) processes. The most and reliable use in laboratory (small scale) or industrial (large scale) processes. The most widely used widely used are high speed ball mills (HSBMs), planetary mills and screw mills (Figure 1). are high speed ball mills (HSBMs), planetary mills and screw mills (Figure1).

Figure 1.1. CommonCommon grinding grinding and and milling milling apparatus. apparatus. (a) Mortar (a) Mortar and pestle. and pestle. (b) Automatic (b) Automatic mortar (Retsch).mortar ((Retsch).c) Vertical (c vibrational) Vertical vibrational mini-mill (Fritsch).mini-mill ( d(Fritsch).) Vibratory (d) micro-mill Vibratory (Fritsch).micro-mill (e )(Fritsch). Vibrational (e) ball-millingVibrational f g (Retsch).ball-milling ( ) Vibrational(Retsch). ( ball-millingf) Vibrational with ball-milling temperature with control temperature (Retsch, Cryomill). control ((Retsch,) Planetary Cryomill). ball-milling (g) (Retsch). (h) Multi-sample milling (Automaxion). (i) Twin-screw used for continuous mechanochemical Planetary ball-milling (Retsch). (h) Multi-sample milling (Automaxion). (i) Twin-screw used for processes. Reproduced with permission of the American Chemical Society from [17]. continuous mechanochemical processes. Reproduced with permission of the American Chemical TheSociety stress from generated [17]. by the friction and the knocking of the spheres in the mill reactor give rise to high-temperature microsites in the reaction mixture, promoting the breaking of bonds in the substrate The stress generated by the friction and the knocking of the spheres in the mill reactor give rise and the formation of new bonds to aﬀord the corresponding products [18]. to high-temperature microsites in the reaction mixture, promoting the breaking of bonds in the Among the advantages oﬀered by mechanochemistry, most important is the complete elimination substrate and the formation of new bonds to afford the corresponding products [18]. of solvent, or alternatively the use of very small quantities of it as a grinding assistant (i.e., liquid Among the advantages offered by mechanochemistry, most important is the complete elimination of solvent, or alternatively the use of very small quantities of it as a grinding assistant

Molecules 2020, 25, x FOR PEER REVIEW 3 of 25 Molecules 2020, 25, 3579 3 of 25 (i.e., liquid assisted grinding, LAG) [19]. From the above, it is evident that mechanochemistry offers assisteda sustainable grinding, alternative LAG) [19 for]. From the design the above, of clean it is and evident efficient that mechanochemistryprocesses in the absence oﬀers of a sustainablebulk solvent alternative[20–30]. for the design of clean and eﬃcient processes in the absence of bulk solvent [20–30].

2.1.2.1. Catalyzed Catalyzed Reactions Reactions under under Solvent-Free Solvent-Free Ball-Milling Ball-Milling Conditions Conditions InIn the the year year 2000, 2000, the the essentially essentially simultaneous simultaneous publication publication of of the the articles articles by by List, List, Lerner Lerner and and BarbasBarbas [31 [31],], on on the the one one hand, hand, and and MacMillan MacMillan and and coworkers coworkers [32 [32],], on on the the other other hand, hand, gave gave rise rise to to the the developmentdevelopment of of a newa new area area of of rather rather fruitful fruitful research research in in organic organic chemistry: chemistry: organocatalysis organocatalysis [33 [33–35].–35]. ParticularlyParticularly attractive attractive in in this this novel novel field field is is the the demonstration demonstration that that small small organic organic molecules molecules can can catalyzecatalyze the the same same chemical chemical reactions reactions that that otherwise otherwise require require large large organic organic biomolecules biomolecules (enzymes), (enzymes), usuallyusually through through similar similar mechanistic mechanistic pathways. pathways. On On the the other other hand, hand, MacMillan’s MacMillan’ works work conceptualized conceptualized organocatalysisorganocatalysis in in an an important important way way by by showing showing its it economic,s economic, environmental environmental and and scientific scientific benefits, benefits, whilewhile simultaneously simultaneously describing describing general general activation activation strategies strategies that that could could then then be be applied applied to to a widea wide rangerange of of reactions. reactions. Presently,Presently, organocatalysis organocatalysis continues continues to to be be a rapidlya rapidly developing developing research research area, area, as as shown shown by by the the largelarge number number of publications of publications that have that appeared have appeared since 2000 since [36]. 2000 Some [36]. recent Some examples recent are examples highlighted are inhighlighted references [ 37in– references56]. [37–56]. InIn a particularlya particularly interesting interesting development, development, the the combination combination of of mechanochemical mechanochemical activation activation and and organocatalysisorganocatalysis has has provided provided a powerful a powerful synergistic synergistic tool in organictool in synthesisorganic sincesynthesis it aff ordssince unusually it affords effiunusuallycient processes efficient presenting processes high yieldspresenting and remarkable high yields chemo-, and regio- remarkable and stereoselectivities. chemo-, regio- Below, and somestereoselectivities. illustrative examples Below, are some highlighted. illustrative examples are highlighted. OneOne of of the the most most thoroughly thoroughly studied studied organocatalytic organocatalytic reactions reactions is is the the aldol aldol reaction, reaction, since since it it constitutesconstitutes one one of theof mostthe most useful useful strategies strategies for the fo formationr the formation of C-Cbonds. of C-C In bonds. a seminal In worka seminal reported work inreported 2006, Bolm in 2006, et al. Bolm carried et outal. carried asymmetric out asymmetric aldol reactions aldol by reactions means ofby chiral means organocatalysts of chiral organocatalysts in a ball millin witha ball excellent mill with results excellent [57, 58results]. Indeed, [57,58]. these Ind experimentseed, these experiments demonstrated demonstrated the advantages the ofadvantages the use ofof mechanochemistry the use of mechanochemistry in enantioselective in enantioselective organocatalyzed organocatalyzed aldol reactions, aldol since reactions, not only since the solventnot only wasthe removed solvent was but theremoved results but clearly the results showed clearly that reactionshowed that times reaction were considerably times were considerably shorter, relative shorter, to thoserelative in solution to those (Scheme in solution1). (Scheme 1).

N CO2H 1 H O OH (10% mol) 5.5 h Yield: 99% HSBM dr 89:11 Solvent-free ee: 94% NO2

O H O vs

NO2 N CO2H 1 H O OH (10% mol) 96 h Yield: 98% stirring dr 87:13 Solvent-free ee: 94% NO2 Scheme 1. Asymmetric aldol reaction organocatalyzed by (S)-proline, 1. Comparison between Scheme 1. Asymmetric aldol reaction organocatalyzed by (S)-proline, 1. Comparison between conventional stirring in solution and high-speed ball-milling (HSBM) conditions. dr, diastereomeric conventional stirring in solution and high-speed ball-milling (HSBM) conditions. dr, diastereomeric ratio; ee, enantiomeric excess. ratio; ee, enantiomeric excess. Soon thereafter, Hernández and Juaristi found that even higher enantioselectivities were obtained Soon thereafter, Hernández and Juaristi found that even higher enantioselectivities were when the reaction depicted in Scheme1 was catalyzed with dipeptides derived from ( S)-proline in a obtained when the reaction depicted in Scheme 1 was catalyzed with dipeptides derived from (S)- HSBM (Figure2). [ 59,60]. This observation can be attributed to the fact that dipeptides can be better proline in a HSBM (Figure 2). [59,60]. This observation can be attributed to the fact that dipeptides

Molecules 2020, 25, x FOR PEER REVIEW 4 of 25 Molecules 2020, 25, 3579 4 of 25 Molecules 2020, 25, x FOR PEER REVIEW 4 of 25 can be better incorporated into the reaction mixture because they are less polar compounds. Thus, dipeptideincorporatedcan be better 2 showed intoincorporated the a reactioncatalytic into mixtureactivitythe reaction becausesuperi mixtor theyureto that because are exhibited less they polar areby compounds. prolineless polar 1 requiringcompounds. Thus, dipeptide only Thus, 7%2 catalystshoweddipeptide charge a catalytic2 showed [59]. activity In a subsequentcatalytic superior activity studies to that superi exhibited[60], ordipeptides to by that proline exhibited 3 and1 requiring 4 were by proline compared only 7% 1 catalystrequiring with 2 charge, showing only [597%]. thatIncatalyst subsequent 4 was charge a better studies[59]. catalyst. In [subsequent60], dipeptides Furthermore, studies3 and [60],the4 addition weredipeptides compared of 31.1 and equivalents with 4 were2, showing compared of water that with increased4 was 2, showing a better the catalyticcatalyst.that 4 was activity Furthermore, a better of this catalyst. thedipeptide addition Furthermore, 4 ofallowing 1.1 equivalents the us addition to reduce ofwater of the 1.1 increasedrequired equivalents amount the catalyticof water of it activitydownincreased to of 3%. thisthe Thesedipeptidecatalytic results activity4 allowing were of explained this us todipeptide reduce in terms the 4 requiredallowingof a π-π amount stackingus to reduce of between it down the requiredthe to 3%. aromatic These amount groups results of it werepresent down explained into the3%. catalystinThese terms results and of athe πwere- πaldehydestacking explained as between illustrated in terms the ofin aromatic aFigure π-π stacking 3 groups [60]. between present inthe the aromatic catalyst groups and the present aldehyde in the as illustratedcatalystThe andexchange in the Figure aldehyde of3[ 60the]. ascarbonyl illustrated oxygen in Figure atom 3 in[60]. dipeptides 2, 3 and 4 for one sulfur in the thiocarbonylThe exchangeexchange present of of thein the peptides carbonyl carbonyl oxygen5, 6oxygen and atom 7, atomrespectively, in dipeptides in dipeptides 2led, 3 andto an24, for 3improvement and one sulfur4 for inone in the sulfurthe thiocarbonyl catalytic in the activitypresentthiocarbonyl of in the peptides thiopeptidepresent5 ,in6 andpeptides analogs.7, respectively, This5, 6 anddifference 7, led respectively, toin anefficiency improvement led is toexplained an inimprovement the in catalytic terms of in activitythe the increased catalytic of the aciditythiopeptideactivity of of the the analogs. N-Hthiopeptide hydrogen This dianalogs.ﬀ erenceatom Thisin in the e differenceﬃ ciencythioamide is in explained efficiencysegment, in iswhich terms explained facilitates of the in increased terms the offormation aciditythe increased ofof the a strongerN-Hacidity hydrogen ofhydrogen the N-H atom bond hydrogen in the and thioamide therefore atom in segment, a the more thioamide robust which transition facilitatessegment, state thewhich formation for facilitates the reaction of a the stronger (Figure formation hydrogen 3) [61]. of a bondstronger and hydrogen therefore bond a more and robust therefore transition a more state robust for the transition reaction state (Figure for 3the)[61 reaction]. (Figure 3) [61].

Figure 2. (S)-Proline-containing dipeptides 2–7 used as organocatalysts for the asymmetric aldol Figure 2. (S)-Proline-containing dipeptides 2–7 used as organocatalysts for the asymmetric aldol reaction carried out under solvent-free HSBM conditions. reactionFigure 2. carried (S)-Proline-containing out under solvent-free dipeptides HSBM 2 conditions.–7 used as organocatalysts for the asymmetric aldol reaction carried out under solvent-free HSBM conditions. AsAs can can be be observed observed in in Figure Figure 2,2, the best dipeptidic dipeptidic organocatalysts turn out to be 44 andand 55, ,whose whose catalyticcatalyticAs canactivity activity be observed and and efficiency eﬃ inciency Figure could could 2, the be be bestimproved improved dipeptidic upon upon organocatalysts the the addition addition of ofturn one one out equivalent equivalent to be 4 and of of water5 water, whose to to thethecatalytic reaction reaction activity mixture, mixture, and together togetherefficiency with with could a a catalytic catalyticbe improved am amountount upon of of benzoicthe benzoic addition acid. acid. ofA Apparently, pparently,one equivalent these these of additives additives water to induceinducethe reaction the the formation formation mixture, of oftogether a a hydrophobic hydrophobic with a catalytic cavity cavity during during amount the the of transition transitionbenzoic acid.state state Athat thatpparently, is is further further these stabilized stabilized additives by by ππinduce--ππ stackingstacking the formation between between theof the a indole indolehydrophobic fragment fragment cavity of of tryptophan tryptophan during the and transition the aldehyde state that (Figure is further 33))[ [60,62].60 ,stabilized62]. by π-π stacking between the indole fragment of tryptophan and the aldehyde (Figure 3) [60,62].

Figure 3. Proposed transition state for the asymmetric aldol reaction between cyclohexanone and Figurep-nitro 3. benzaldehyde Proposed transition catalyzed state by for dipeptide the asymmetric4. aldol reaction between cyclohexanone and p- nitroFigure benzaldehyde 3. Proposed catalyzedtransition by state dipeptide for the 4asymmetric. aldol reaction between cyclohexanone and p- nitro benzaldehyde catalyzed by dipeptide 4.

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Subsequent studies showed, upon comparis comparisonon with with the the catalytic catalytic efficiency efficiency of of ( (SS)-proline)-proline 11 itself,itself, that thethe chiral chiral site site of theof secondthe second amino amino acid fragment acid fragment in dipeptide in dipeptide catalysts doescatalysts not play does a determiningnot play a determiningrole in the stereoselectivity role in the stereoselectivity of the reaction. of Itthe is, reac therefore,tion. It the is, prolinetherefore, segment the proline that is segment responsible that for is responsiblethe stereochemistry for the stereochemistry and selectivity of and the aldolselectivity product. of the Nevertheless, aldol product. the secondNevertheless, amino acidthe residuesecond aminodoes improve acid residue the catalytic does improve performance the catalytic of the performance dipeptide when of the an dipeptide aromatic when group an is aromatic present group in the isside present chain asin inthe compounds side chain 1as–6 ;in as compounds was previously 1–6; argued,as was thispreviously is probably argued, a consequence this is probably of a π -πa consequenceinteraction with of a the π-π aromatic interaction ring with of the the aldehyde aromatic [ 63ring]. of the aldehyde [63]. Recently, FrišˇcićandFriščić and collaborators collaborators reported reported the the use use of of ball-milling ball-milling mechanochemistry mechanochemistry to carry to carry out outthe couplingthe coupling reaction reaction of isatines, of isatines, benzamides, benzamides, imides imides and phthalimides and phthalimides to isocyanates to isocyanates [64]. This [64]. reaction This reactionleads to aleads variety to ofa variety amide derivativesof amide derivatives which are useful which in are the useful synthesis in the of peptides, synthesis polymers of peptides, and polymerspharmacological and pharmacological compounds [65 compounds]. In general, [65]. when In thesegeneral, types when of reactions these types are performedof reactions under are performedconventional under conditions, conventional they require conditions, long reaction they requ times,ire long high reaction temperatures times, and high expensive temperatures transition and expensivemetal catalysts. transition In Frišˇcić’swork, metal catalysts. di ffInerent Frišč copperić’s work, salts different and metallic copper copper salts and were metallic tested copper as potential were testedcatalysts, as potential revealing catalysts, that CuCl revealing afforded thethat best CuCl reaction afforded yields. theThese best reaction coupling yields. reactions These were coupling carried reactionsout in a ball were mill carried at room out temperature in a ball mill and underat room solvent-free temperature conditions and under (Scheme solvent-free2). The use conditions of small (Schemequantities 2). of The solvent use of turns small out quantities to be crucial of solvent for theturns reaction out to be to takecrucia place,l for the since reaction the mixture to take ofplace, the sincestarting the materials mixture of and the CuCl starting alone materials does not and give Cu anyCl alone product. does The not use give of any nitromethane product. The as ause LAG of nitromethaneliquid allowed as the a high-yieldLAG liquid preparation allowed the of thehigh-yield expected preparation products. Thisof the study expected highlights products. the power This studyof mechanochemistry highlights the power as a chemicalof mechanochemistry activation strategy as a chemical since, when activation trying strategy the same since, reactions when trying under theconventional same reactions conditions, under conventional temperatures conditions, above 100 ◦teCmperatures were required above to obtain100 °C were the desired required products to obtain in thepoor desired yields products [64]. in poor yields [64].

Scheme 2. Catalytic nitrogen-carbon coupling reaction using mechanochemistry [64]. Scheme 2. Catalytic nitrogen-carbon coupling reaction using mechanochemistry [64]. In this context, peptide synthesis is presently one of the most salient areas in organic synthesis becauseIn this of itscontext, central peptide relevance synthesis in chemistry is presently and biochemistry. one of the most Peptides salient have areas interesting in organic properties, synthesis becausenot just asof catalystsits central for relevance many metabolic in chemistry reactions and biochemistry. but also as pharmacological Peptides have interesting and biological properties, agents. notIt is just therefore as catalysts not surprising for many thatmetabolic a signiﬁcant reactions number but also of syntheticas pharmacological chemists are and working biological actively agents. to Itdevelop is therefore “greener” not surprising methodologies that a for significant the synthesis number of both of synthetic natural andchemists unnatural are working peptides actively [65–73]. to develop “greener” methodologies for the synthesis of both natural and unnatural peptides [65–73]. In a pioneering study, Cavani et al. determined the structure and catalytic activity of hydrotalcite Mg-Al minerals with the general formula [Mg2+1−xAl3+x(OH)2]x+(CO3n−x/n)·mH2O [74]. Among the useful

Molecules 2020, 25, 3579 6 of 25

Molecules 2020, 25, x FOR PEER REVIEW 6 of 25 MoleculesIn a2020 pioneering, 25, x FOR study,PEER REVIEW Cavani et al. determined the structure and catalytic activity of hydrotalcite6 of 25 properties of hydrotalcite materials, one can mention2+ their3+ basic xch+ aracter;n furthermore, following Mg-Al minerals with the general formula [Mg 1 xAl x(OH)2] (CO3 −x/n) mH2O[74]. Among properties of hydrotalcite materials, one can mention− their basic character; furthermore,· following heatthe useful treatment properties (420–470 of hydrotalcite°C) they form materials, mixed oxid onees can which mention are homogeneous. their basic character; On the furthermore,other hand, whenheat treatment rehydrated (420–470 by water °C) vapor, they theirform originalmixed oxid layeredes which structure are homogeneous.is restored. On the other hand, following heat treatment (420–470 ◦C) they form mixed oxides which are homogeneous. On the other when rehydrated by water vapor, their original layered structure is restored. hand,Taking when rehydratedadvantage of by the water properties vapor, their exhibited original by layered hydrotalcites, structure in is 2016 restored. Landeros and Juaristi Taking advantage of the properties exhibited by hydrotalcites, in 2016 Landeros and Juaristi reportedTaking a convenient advantage strategy of the propertiesfor peptide exhibitedsynthesis in by the hydrotalcites, absence of solvent in 2016 using Landeros mechanochemical and Juaristi reported a convenient strategy for peptide synthesis in the absence of solvent using mechanochemical activationreported a and convenient hydrotalcite strategy as a for catalyst peptide [75]. synthesis Hydrotalcite in the (HT-S), absence its of calcined solvent using derivative mechanochemical (HT-C), and activation and hydrotalcite as a catalyst [75]. Hydrotalcite (HT-S), its calcined derivative (HT-C), and aactivation reconstructed and hydrotalcite variant (HT-R) as a catalystwere analyzed [75]. Hydrotalcite as basic catalysts (HT-S), itsin calcinedamino acid derivative coupling (HT-C), reaction and to a a reconstructed variant (HT-R) were analyzed as basic catalysts in amino acid coupling reaction to providereconstructed a variety variant of peptides (HT-R) under were analyzedsolvent-free as basicconditions. catalysts Preliminary in amino results acid coupling suggested reaction that the to provide a variety of peptides under solvent-free conditions. Preliminary results suggested that the providebest basic a varietycatalyst of is peptides Mg-Al hydrotalcite under solvent-free (HT-S) conditions.(Table 1, Essay Preliminary 1). results suggested that the best best basic catalyst is Mg-Al hydrotalcite (HT-S) (Table 1, Essay 1). basic catalyst is Mg-Al hydrotalcite (HT-S) (Table1, Essay 1). Table 1. Effect of the catalyst (base) in the coupling reaction of amino acids activated by HSBM [75]. Table 1. Effect of the catalyst (base) in the coupling reaction of amino acids activated by HSBM [75]. Table 1. Eﬀect of the catalyst (base) in the coupling reaction of amino acids activated by HSBM [75].

. . EssayEssay Catalyst Catalyst (Base) (Base) [mg] [mg] Yield Yield [%] [%] Essay11 CatalystHT-S HT-S (Base) [mg]250 250 Yield89 [%] 89 212 HT-CHT-S HT-C 250 250 5589 55 323 HT-RHT-C HT-R 250 250 8955 89 4 NaHCO3 250 76 43 NaHCOHT-R 3 250 7689 5 Cs2CO3 250 67 54 NaHCOCs2CO3 3 250250 67 76 6 K2CO3 250 15 65 CsK22COCO33 250250 1567 6 K2CO3 250 15 Once the best reaction conditions had been established, several α- and β-amino acids were Once the best reaction conditions had been established, several α- and β-amino acids were employedOnce asthe substrates best reaction and the conditions dipeptides had of interestbeen established, were obtained several in good α- and yields β-amino as shown acids in Tablewere employed as substrates and the dipeptides of interest were obtained in good yields as shown in 2employed [75]. It is asimportant substrates to andmention the dipeptides that the catalyst of interest can werebe recovered obtained and in good reused yields with as minor shown loss in Tableof its Table2[ 75]. It is important to mention that the catalyst can be recovered and reused with minor loss of catalytic2 [75]. It activity.is important to mention that the catalyst can be recovered and reused with minor loss of its its catalytic activity. catalytic activity. Table 2. Scope of the coupling reaction of amino acids catalyzed by Mg-Al hydrotalcite [75]. Table 2. Scope of the coupling reaction of amino acids catalyzed by Mg-Al hydrotalcite [75]. Table 2. Scope of the coupling reaction of amino acids catalyzed by Mg-Al hydrotalcite [75].

Amino Acid Amino Acid Dipeptide Yield Essay AminoA Acid Amino BAcid DipeptideProduct Yield(%) Essay 1Amino Boc-LeuA Acid AminoB Ala Acid Dipeptide Boc-Leu-AlaProduct Yield(%) 89 Essay 1 2Boc-Leu Boc-A β-ala AlaB Phe Boc-Leu-Ala Boc-Productβ-Ala-Phe (%)89 89 3 Boc-β-ala Val Boc-β-Ala-Val 85 21 Boc-Boc-Leuβ-ala Phe Ala Boc- Boc-Leu-Alaβ-Ala-Phe 89 4 Boc-β-ala Ala Boc-β-Ala-Ala 79 2 Boc-β-ala Phe Boc-β-Ala-Phe 89 3 5Boc- Boc-β-alaβ-ala Val Leu Boc- Boc-ββ-Ala-Val-Ala-Leu 85 89 43 6Boc- Boc-β-alaβ-ala-ala AlaVal Ile Boc-Boc- Boc-βββ-Ala-Ala-Ala-Val-Ala-Ile 7985 82 54 7Boc- Boc-β-alaβ-ala-ala LeuAla Gly Boc-Boc- Boc-βββ-Ala-Leu-Ala-Ala-Ala-Gly 8979 78 65 8Boc- Boc-β-alaβ-ala-ala LeuIle His Boc-Boc- Boc-βββ-Ala-Leu-Ala-Ile-Ala-His 8289 70 9 Boc-β-ala β-Ala Boc-β-Ala-β-Ala 73 76 Boc-β-ala-ala GlyIle Boc-Boc-ββ-Ala-Gly-Ala-Ile 7882 10 Cbz-Phe Phe Cbz-Phe-Phe 83 8711 Boc- Cbz-Pheβ-ala-ala HisGly Ala Boc- Cbz-Phe-Alaβ-Ala-His-Ala-Gly 70 78 85 9812 Boc- Fmoc-Valβ-ala-ala βHis-Ala Phe Boc-Boc- Fmoc-Val-Pheββ-Ala--Ala-Hisβ-Ala 73 70 83 10913 Boc-Cbz-Phe Fmoc-Valβ-ala β Phe-Ala Ala Boc- Cbz-Phe-Phe Fmoc-Val-Alaβ-Ala-β-Ala 83 73 88 1110 Cbz-Phe AlaPhe Cbz-Phe-AlaCbz-Phe-Phe 8583 1211 Fmoc-ValCbz-Phe Phe Ala Fmoc-Val-Phe Cbz-Phe-Ala 8385 1312 Fmoc-Val AlaPhe Fmoc-Val-AlaFmoc-Val-Phe 8883 13 Fmoc-Val Ala Fmoc-Val-Ala 88

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In aa particularlyparticularly usefuluseful applicationapplication ofof mechanochemistry,mechanochemistry, MackMack etet al.al. recently reported a methodology for the the synthesis synthesis of of polyaromatic polyaromatic compounds compounds [76]. [76]. These These compounds compounds are are of ofinterest interest in insynthetic synthetic chemistry chemistry owing owing to to their their application application in in nanotechnology; nanotechnology; neverthe nevertheless,less, their preparationpreparation represents aa technical technical and and ecological ecological challenge challenge since polyaromaticsince polyaromatic derivatives derivatives are practically are practically insoluble ininsoluble most solvents. in most solvents. Mechanochemistry Mechanochemistry oﬀers then offers the then advantage the advantage that substrates that substrates can be usedcan be under used solvent-freeunder solvent-free reaction reaction conditions. conditions. Indeed, Indeed, several severa of thel of steps the steps in the in synthesis the synthesis advanced advanced by Mack by Mack and coworkersand coworkers were were carried carried out in out a ball in milla ball (HSBM) mill (HSBM) under solvent-freeunder solvent-free conditions, conditions, making thismaking strategy this anstrategy environmentally an environmentally friendly alternativefriendly alternative (Scheme 3(Scheme). 3).

Scheme 3. Synthesis of polyaromatic compounds under solvent-free HSBM [76]. Scheme 3. Synthesis of polyaromatic compounds under solvent-free HSBM [76]. In this context, compounds of the furaxane type are of interest in organic chemistry because In this context, compounds of the furaxane type are of interest in organic chemistry because they they are synthetic intermediates of molecules with pharmacological activity or with applications are synthetic intermediates of molecules with pharmacological activity or with applications in the in the field of agronomy. In 2019, Guo’s group reported the synthesis of diacyl furoxanes under field of agronomy. In 2019, Guo’s group reported the synthesis of diacyl furoxanes under solvent- solvent-free reaction conditions using a high-speed ball mill (Scheme4)[ 77]. This methodology uses free reaction conditions using a high-speed ball mill (Scheme 4) [77]. This methodology uses Fe(NO3)3 9H2O as a nitrating agent and phosphorous pentoxide as an oxidant. The authors tested Fe(NO3)3·9H· 2O as a nitrating agent and phosphorous pentoxide as an oxidant. The authors tested different nitrate salts but Fe(NO3)3 9H2O afforded the highest yields. The scope of these reactions different nitrate salts but Fe(NO3)3·9H· 2O afforded the highest yields. The scope of these reactions includes acetophenones which are substituted with either donor or electron withdrawing groups, includes acetophenones which are substituted with either donor or electron withdrawing groups, and the expected products were obtained in moderate to good yields as shown in Scheme4. and the expected products were obtained in moderate to good yields as shown in Scheme 4. A multicomponent reaction is one where three or more reagents combine to afford a new product. A multicomponent reaction is one where three or more reagents combine to afford a new This type of reaction is important from the sustainability point of view due to their high atom economy, product. This type of reaction is important from the sustainability point of view due to their high as well as the elimination of several reaction steps that would require isolation and purification atom economy, as well as the elimination of several reaction steps that would require isolation and protocols. Multicomponent reactions reflect also the state of the art in chemical control since generally purification protocols. Multicomponent reactions reflect also the state of the art in chemical control C-C and C-X (X = heteroatom) bonds are formed in one single step. For recent interesting applications since generally C-C and C-X (X = heteroatom) bonds are formed in one single step. For recent of mechanochemistry in multicomponent reactions see references [78–87]. interesting applications of mechanochemistry in multicomponent reactions see references [78–87]. In 2016, Polindara-García and Juaristi reported a methodology for the Ugi 4-CR and the Passerini In 2016, Polindara-García and Juaristi reported a methodology for the Ugi 4-CR and the Passerini 3-CR multicomponent reactions in the absence of solvent using a ball mill. [88]. In the case of the 3-CR multicomponent reactions in the absence of solvent using a ball mill. [88]. In the case of the Ugi Ugi 4-CR, the energy provided by the ball mill was sufficient to afford the products of interest. 4-CR, the energy provided by the ball mill was sufficient to afford the products of interest. When When comparing the results with those of reactions carried out in solution under normal heating or comparing the results with those of reactions carried out in solution under normal heating or even even microwave conditions, it is concluded that mechanochemistry is a better synthetic strategy since it microwave conditions, it is concluded that mechanochemistry is a better synthetic strategy since it shortened the reaction times and afforded better yields for a variety of substrates as shown in Scheme5. shortened the reaction times and afforded better yields for a variety of substrates as shown in Scheme Equally good results were obtained with the Passerini 3-CR reaction. It is important to note that 5. in the Passerini 3-CR reaction, the heat generated within the mill reactor was sufficient to promote the Equally good results were obtained with the Passerini 3-CR reaction. It is important to note that reaction without the need for additional energy input, and that the reaction times are shorter than in the Passerini 3-CR reaction, the heat generated within the mill reactor was sufficient to promote those required under conventional reflux conditions in solution, affording the desired products in the reaction without the need for additional energy input, and that the reaction times are shorter than moderate to excellent yields (Scheme6). those required under conventional reflux conditions in solution, affording the desired products in Very recently, Eldahy’s group reported a methodology for the Ugi 4-CR reaction in a twin-screw moderate to excellent yields (Scheme 6). grinding system without catalyst and without solvent [89]. The reaction proceeded with good yields at Very recently, Eldahy’s group reported a methodology for the Ugi 4-CR reaction in a twin-screw a temperature of 100 C (Scheme7). grinding system without◦ catalyst and without solvent [89]. The reaction proceeded with good yields at a temperature of 100 °C (Scheme 7).

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Scheme 4. Synthesis of diacylfuroxans under solvent-free HSBM [77]. Scheme 4. Synthesis of diacylfu diacylfuroxansroxans under solvent-free HSBM [[77].77].

Scheme 5. Ugi 4-CR Reaction under solvent-free and HSBM conditions [88]. Scheme 5. Ugi 4-CR Reaction under solvent-free and HSBM conditions [88]. In 2019, LambatScheme and 5. Banerjee Ugi 4-CR developed Reaction under a methodology solvent-free for and the HSBM synthesis conditions of 4-oxo-tetrahydroindoles [88]. usingIn a solvent-free,2019, Lambat multicomponent and Banerjee one-pot developed reaction ina amethodology high energy ball for mill the (HEBM) synthesis [90]. Sulphamicof 4-oxo- acidtetrahydroindoles wasIn 2019, used asLambat the using catalyst; anda solvent-free, itBanerjee was easily multicomponedeveloped isolated and a recoveredntmethodology one-pot from reaction thefor reaction inthe a highsynthesis mixture energy andof ball reused4-oxo- mill up(HEBM)tetrahydroindoles to five [90]. times Sulphamic with using the same aacid solvent-free, was efficiency used as (Schememulticompone the catalyst;8). ntit wasone-pot easily reaction isolated in and a high recovered energy fromball mill the reaction(HEBM) mixture[90]. Sulphamic and reused acid up was to usedfive ti asmes the with catalyst; the same it was efficiency easily isolated (Scheme and 8). recovered from the reaction mixture and reused up to five times with the same efficiency (Scheme 8).

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Scheme 6. Passerini 3-CR reaction under solvent-free HSBM conditions [88]. Scheme 6. Passerini 3-CR reaction under solvent-free HSBM conditions [88]. Scheme 6. Passerini 3-CR reaction under solvent-free HSBM conditions [88]. Scheme 6. Passerini 3-CR reaction under solvent-free HSBM conditions [88].

Scheme 7. Ugi reaction under solvent-free conditions using a twin-screw reactor [[89].89]. Scheme 7. Ugi reaction under solvent-free conditions using a twin-screw reactor [89]. Scheme 7. Ugi reaction under solvent-free conditions using a twin-screw reactor [89].

Scheme 8. Synthesis of 4-oxo-tetrahydroindo 4-oxo-tetrahydroindolesles with solvent-free HEBM [[90].90]. Scheme 8. Synthesis of 4-oxo-tetrahydroindoles with solvent-free HEBM [90]. Scheme 8. Synthesis of 4-oxo-tetrahydroindoles with solvent-free HEBM [90].

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2.2. Enzymatic Reactions under Solvent-Free Ball-Milling Conditions Enzymes are conveniently used as catalysts because they present a large number of advantages (see below), they operate at room temperature, are highly selective, and promote a wide variety of reactions [91–95]. Processes involving enzymes are considered green and sustainable because they comply with at least 10 of the 12 principles of Green Chemistry; that is:

- Waste generation is minimized; - Atom economy is maximized; - Formation of toxic products is avoided; - Functional and safe products are produced; - The use of auxiliary substances is minimized; - Energy consumption is reduced; - Renewable materials are employed; - The use of derivatives is eliminated or reduced; - Catalytic reagents are employed; - Biodegradable products are usually obtained.

Indeed, enzymes are naturally available molecules representing non-toxic reagents, and biodegradable molecules [96]. Due to their high efficiency and versatility, enzymes (in particular lipases) have been used both in small-scale settings (e.g., laboratories) and large-scale synthetic industrial pharmaceutical processes for the preparation of a wide variety of organic compounds. The necessary synthetic steps that may be assigned to enzymes can involve hydrolytic, enantioselective, condensation reactions, and even multicomponent reactions [97–100]. These processes can be carried out on scales of several grams in either batch or continuous flow reactors [101]. Although it may seem counterintuitive, enzymes present significant resistance in unconventional media such as ionic liquids [102], deep eutectic solvents [103] and ball-milling apparatus (cf. mechanoenzymatic methodologies) [104]. Below, we will present some examples of the combined use of enzymes and mechanochemistry in organic synthesis. The first report disclosing the use of enzymes in mechanochemistry was the one revealed by Hernández et al. who described the mechanoenzymatic resolution of secondary alcohols [105]. When carrying out the enantioselective resolution of racemic carbinols with Candida antarctica Lipase B (CALB) enzyme in a ball mill (HSBM), Hernández and coworkers obtained excellent results. For instance, for the separation of 1-phenylethanol a conversion = 47% (out of a theoretical maximum of 50%), with enantiomeric excess (ee) higher than 99% for the acetate product, and ee = 90% for the recovered alcohol (Scheme9a). The wide scope of the method was verified by the good results obtained for a family of racemic secondary alcohols that could be resolved through this methodology. Not only that, the process could be carried out on a gram scale in a planetary mill, obtaining practically the same conversion and selectivity (Scheme9b). An additional bonus is that the enzyme could be recovered and reused up to three more cycles with some loss in the degree of conversion but maintaining an excellent enantioselectivity for the acetylated product. By contrast, when the resolution process was carried out with the immobilized enzyme lipase PS-IM, the products of interest were obtained with less efficiency in terms of conversion and enantiomeric excess in the recovered alcohol (Scheme9c). Soon thereafter, Pérez-Venegas et al. reported a methodology for the enzymatic resolution of N-benzylated-β3-amino esters using Candida antarctica lipase B in a ball mill (HSBM) [106,107]. The resolution process took place essentially in the absence of solvent with only a half equivalent of water added to the reaction mixture and 0.2 mL of 2-methyl-2-butanol (2M2B) as the liquid grinding assistant (LAG). The reaction proceeded at ambient temperature; that is, no additional heating was required. The yields achieved in this mechanoenzymatic approach were comparable to those obtained in solution [108] but conveniently with a significant reduction in reaction times. Furthermore, the process could be scaled up one order of magnitude and the enzyme catalyst could be recovered Molecules 2020, 25, x FOR PEER REVIEW 11 of 25 Molecules 2020, 25, 3579 11 of 25 a decreaseMolecules in 2020 yield, 25, xdue FOR PEERto partial REVIEW denaturation of the enzyme and partial destruction of the11 ofsupport 25 (Scheme 10). and reuseda decrease twice, in yield maintaining due to partial the enantiomericdenaturation of excess the enzyme of the and products, partial destruction although withof the a support decrease in yield(Scheme due to partial 10). denaturation of the enzyme and partial destruction of the support (Scheme 10).

Scheme 9. Mechanoenzymatic resolution of secondary alcohols with CALB. (a) Separation of racemic SchemeScheme 9. Mechanoenzymatic 9. Mechanoenzymatic resolution resolution of of se secondarycondary alcoholsalcohols with with CALB. CALB. (a) ( Separationa) Separation of racemic of racemic 1-phenylethanol. (b) Process carried out on a gram scale. (c) Process carried out with the immobilized 1-phenylethanol.1-phenylethanol. (b) Process(b) Process carried carried out out on on a a gram gram scale. ((cc)) Process Process carried carried out out with with the theimmobilized immobilized enzymeenzyme lipase lipase PS-IM PS-IM [[105].105 [105].]. Subsequently, Pérez-Venegas and Juaristi reported the mechanoenzymatic resolution of chiral Subsequently,Subsequently, Pérez-Venegas Pérez-Venegas and and Juaristi Juaristi reportedreported thethe mechanoenzymatic mechanoenzymatic resolution resolution of chiral of chiral amines [109], including the enantioselective synthesis of (R)-Rasagiline (a drug employed for the aminesamines [109], [109], including including the the enantioselective enantioselective synthesissynthesis ofof (R(R)-Rasagiline)-Rasagiline (a (adrug drug employed employed for thefor the treatmenttreatment of Parkinson’s of Parkinson’s disease) disease) and and its its ( S(S)) enantiomer. enantiomer. In In this this case, case, the the resolution resolution process process required required treatment of Parkinson’s disease) and its (S) enantiomer. In this case, the resolution process required dioxanedioxane as a grindingas a grinding adjuvant adjuvant (Scheme (Scheme 11 11a).a). FollowingFollowing the the initial initial enantioselective enantioselective acylation acylation reaction reaction dioxane as a grinding adjuvant (Scheme 11a). Following the initial enantioselective acylation reaction of theof (S the) enantiomer, (S) enantiomer, the addition the addition of propargyl of propargyl mesylate mesy tolate the to reaction the reaction mixture mixture aﬀorded afforded (S)-Rasagiline (S)- of the (S) enantiomer, the addition of propargyl mesylate to the reaction mixture afforded (S)- (SchemeRasagiline 11b). (Scheme On the other11b). On hand, the other (R)-Rasagiline hand, (R)-Rasagiline was prepared was prepared by acid by hydrolysis acid hydrolysis of the of acylated the Rasagiline (Scheme 11b). On the other hand, (R)-Rasagiline was prepared by acid hydrolysis of the productacylated followed product by followed treatment bywith treatm propargylent with propargyl mesylate mesylate in the ball in the mill ball (Scheme mill (Scheme 11b). 11b). Chiral Chiral amines acylatedamines product are important followed building by treatm blocksent withfor the propargyl synthesis mesylateof molecules in thewith ball pharmacological mill (Scheme activity.11b). Chiral are important building blocks for the synthesis of molecules with pharmacological activity. According aminesAccording are important to this mechanoenzymatic building blocks for procedure, the synt ithesis was ofpossible molecules to obtain with a familypharmacological of chiral amines activity. to this mechanoenzymatic procedure, it was possible to obtain a family of chiral amines with high Accordingwith high to this enantiomeric mechanoenzymatic purity under procedure, solvent-free itconditions. was possible to obtain a family of chiral amines enantiomeric purity under solvent-free conditions. with high enantiomeric purity under solvent-free conditions.

Scheme 10. Enzymatic resolution of N-benzylated-β3-amino esters under solvent-free HSBM conditions [106].

β3 Scheme 10.10. EnzymaticEnzymatic resolution resolution of of N-benzylated-β3-amino-amino esters esters under under solvent-free HSBM conditions [[106].106].

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Scheme 11. (a) Mechanoenzymatic resolution of chiral amines and (b) synthesis of both enantiomers Scheme 11. (a) Mechanoenzymatic resolution of chiral amines and (b) synthesis of both enantiomersenantiomers of Rasagiline [109]. of Rasagiline [[109].109]. As was mentioned above, peptide synthesis continues to be one of the areas of greatest interest As was mentioned above, peptide synthesis continuescontinues to be one of the areas of greatest interest in organic chemistry. This is due to the fact that peptides have many diverse applications, not only inin organicorganic chemistry.chemistry. This is duedue toto thethe factfact thatthat peptidespeptides havehave manymany diversediverse applications,applications, not only in the synthesis of organic compounds, but most importantly in the food and pharmaceutical inin thethe synthesissynthesis ofof organicorganic compounds,compounds, butbut mostmost importantlyimportantly inin thethe foodfood andand pharmaceuticalpharmaceutical industry [110–112]. In this regard, in recent years mechanochemistry has played an important role in industryindustry [[110–112].110–112]. In this regard, in recent years mechanochemistry has played an important role in the green synthesis of these compounds [103–118]. the greengreen synthesissynthesis ofof thesethese compoundscompounds [[103–118].103–118]. In 2017, Bolm’s group reported the mechanoenzymatic synthesis of dipeptides using the enzyme In 2017, Bolm’s group reported the mechanoenzym mechanoenzymaticatic synthesis of dipeptides using the enzyme Papain in a HSBM reactor [119]. The results obtained from this research proved the versatility of the Papain in a HSBM reactor [[119].119]. The results obtained from this research proved the versatility of the mechanoenzymatic method since it allowed the high yield preparation of a variety of dipeptides, mechanoenzymatic method since it allowed the high yield preparation of a variety of dipeptides, including those containing amino acids with steric impediment, which are generally difficult to includingincluding thosethose containing containing amino amino acids acids with with steric steric impediment, impediment, which which are generally are generally diﬃcult difficult to couple, to couple, such as valine and isoleucine. It was also possible toα prepareβ α,β-dipeptides containingβ the suchcouple, as valinesuch as and valine isoleucine. and isoleucine. It was also It was possible also topossible prepare to prepare, -dipeptides α,β-dipeptides containing containing the -alanine the β-alanine residue (Scheme 12). By contrast, it was observed that the enzyme is not capable of residueβ-alanine (Scheme residue 12 (Scheme). By contrast, 12). By it wascontrast, observed it was that observed the enzyme that isthe not enzyme capable is of not incorporating capable of dincorporating D-amino acids. The reproducibility of the process was verified in a planetary mill and incorporating-amino acids. D The-amino reproducibility acids. The reproducibility of the process was of the veriﬁed process in was a planetary verified mill in a and planetary in a twin-screw mill and in a twin-screw reactor [120]. reactorin a twin-screw [120]. reactor [120].

Scheme 12. Mechanoenzymatic synthesis of dipeptides with Papain [119]. Scheme 12. Mechanoenzymatic synthesis of dipeptides with Papain [119]. Scheme 12. Mechanoenzymatic synthesis of dipeptides with Papain [119].

Molecules 2020,, 25,, 3579x FOR PEER REVIEW 13 of 25 Molecules 2020, 25, x FOR PEER REVIEW 13 of 25 Furthermore, in 2017, Hernández et al. reported the Strecker reaction between aldehydes and ketonesFurthermore, with amines in in 2017,catalyzed 2017, Hernández Hern withández lignin et et al. al. underreported reported solvent-free the theStrecker Strecker conditions reaction reaction andbetween betweenHSBM aldehydes to aldehydesobtain and α- andaminonitrilesketones ketones with with amines[121]. amines The catalyzed reaction catalyzed with proceeds with lignin lignin underwell, under andsolvent-free solvent-freethe yields conditions are conditions good and to and HSBMexcellent HSBM to obtain towith obtain the α- αminimumaminonitriles-aminonitriles presence [121]. [121 of].The the The reaction imine reaction obtained proceeds proceeds as well, a well, by-p androduct and the the ofyields yields the reactionare are good good (Scheme to to excellent 13). The with study the minimumcompared peanut presence shell of thepowder, imineimine cellulose obtainedobtained and asas aalignin by-productby-p asroduct promoters ofof thethe of reactionreaction the Strecker (Scheme(Scheme reaction, 1313).). The the studylatter comparedshowing the peanut best catalytic shell powder, activity. cellulosecellulose and lignin as promoters of the Strecker reaction, the latter showing the best catalytic activity.activity.

Scheme 13. Strecker reaction promoted by Kraft lignin under solvent-free HSBM conditions [121]. Scheme 13. Strecker reaction promoted by Kraft ligninlignin under solvent-free HSBM conditions [[121].121]. Very recently, Juaristi and coworkers reported a dual mechanoenzymatic resolution of Ketorolac Very recently, Juaristi and coworkers reported a dual mechanoenzymatic resolution of Ketorolac with VeryCALB recently, enzyme Juaristi [122]. This and coworkersstrategy allows reported for th a edual isolation mechanoenzymatic of both enantiomers resolution of the of drug Ketorolac with with CALB enzyme [122]. This strategy allows for the isolation of both enantiomers of the drug with highwith CALBenantiomeric enzyme purity,[122]. This either strategy through allows enanti for thomerice isolation esterification of both enantiomers of the racemic of the drugKetorolac with high enantiomeric purity, either through enantiomeric esteriﬁcation of the racemic Ketorolac carboxylic carboxylichigh enantiomeric acid with purity, methanol, either or viathrough the enantioselective enantiomeric esterificationhydrolysis of ofits theracemic racemic n-propyl Ketorolac ester acid with methanol, or via the enantioselective hydrolysis of its racemic n-propyl ester (Scheme 14). (Schemecarboxylic 14). acid Both with Ketorolac methanol, enantiomers or via the are enantioselective valuable because hydrolysis of their pharmacologicalof its racemic n-propyl activity. ester (S)- S BothKetorolac(Scheme Ketorolac 14). is a Both powerful enantiomers Ketorolac pain are enantiomersreliever, valuable while becauseare its valuable enantiomer of their because pharmacological (R)-Ketorolac of their pharmacological is activity. used in( the)-Ketorolac treatmentactivity. ( isS of)- a R powerfulovarianKetorolac cancer. painis a powerful reliever, while pain itsreliever, enantiomer while (its)-Ketorolac enantiomer is ( usedR)-Ketorolac in the treatment is used in of the ovarian treatment cancer. of ovarian cancer. O MeOH Bz N Bz N CALB OH N OR O OH MeOH HSBM Bz N Bz N N LAGCALB (MTBE) O OH O OR O OH HSBM rac-Ketorolac LAG (MTBE) (S)-KetorolacO (R)-Ketorolac methylO ester O 42% conv. rac-Ketorolac (S)-Ketorolacee: 72% (R)-Ketorolac ee: >99% methyl ester 42% conv. ee: 72% ee: >99%

O H2O CALB Bz N Bz N O N OnPr OnPr OH HSBMH2O CALB Bz N Bz N N OnPr LAG (2M2B) O OnPr O OH O HSBM rac-Ketorolac LAG46% (2M2B) conv. (S)-KetorolacO (R)-KetorolacO n-propyl esterO n-propyl ester rac-Ketorolac 46% conv. (S)-Ketorolac (R)-Ketorolac n-propyl ester n-propylee: 85% ester ee: >99% Scheme 14. Dual mechanoenzymatic resolution of Ketorolacee: under 85% solvent-free HSBM ee: conditions >99% [122 ]. Scheme 14. Dual mechanoenzymatic resolution of Ketorolac under solvent-free HSBM conditions 3. Microwave[122].Scheme 14. Activation Dual mechanoenzymatic under Solvent-Free resolution Conditions of Ketorolac under solvent-free HSBM conditions Microwave[122]. irradiation has been revolutionizing organic chemistry for over a couple of decades.

Just as in home cooking, instant heating and optimization of reaction times are the main attractive

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3. Microwave Activation under Solvent-Free Conditions Molecules 2020, 25, 3579 14 of 25 Microwave irradiation has been revolutionizing organic chemistry for over a couple of decades. Just as in home cooking, instant heating and optimization of reaction times are the main attractive feature of this form of activationactivation [[123].123]. Among the advantages offe offeredred by the use of microwaves in organic synthesis, are better yields and higher puri purityty of the reaction reaction products, energy saving, uniform heating and good reproducibility [[123,124].123,124]. Due to the above, above, the use use of of microwave microwave activation is now quite widespread among groups working in the area of organic synthesis, ge generatingnerating a large number of publications [[125–131].125–131]. One ofof the the potential potential problems problems in the in employmentthe employme of microwavent of microwave reactors reactors is the occasional is the occasional explosion explosionof the reactor of the flasks reactor or tubes flasks owing or tubes to the owing pressure to th exertede pressure by exerted the reaction by the solvent reaction during solvent irradiation. during irradiation.For this reason, For this the reason, elimination the elimination of solvent of has so becomelvent has rather become important, rather important, which actually which leadsactually to leadsshorter to reaction shorter timesreaction and times better and yields better [124 yields]. Below [124]. there Below are somethere illustrativeare some illustrative examples ofexamples the use of themicrowaves use of microwaves in solvent-free in solvent-free reactions. reactions. In 2017, Monga et al.al. reported the synthesis of coumarins using microwaves in a solvent-free process [132[132].]. Coumarins Coumarins are are compounds compounds found found in a varietyin a variety of plants of and plants have interestingand have therapeuticinteresting properties.therapeutic Thisproperties. procedure This uses procedure oxalic acid inuses catalytic oxalic amounts acid in and catalytic allows theamounts preparation and allows of a variety the preparationof products thatof a demonstratevariety of products the scope that of demo the methodnstrate the (Scheme scope 15 of). the method (Scheme 15). In thisthis context,context, Fernandes’ Fernandes’ group group published published in 2019in 2019 a convenient a convenient synthesis synthesis of Julolidines of Julolidines by means by meansof a microwave-assisted of a microwave-assisted supported supported catalysis catalysis in the absence in the ofabsence solvent of[ 133solvent]. This [133]. strategy This involvesstrategy involvesa multicomponent a multicomponent reaction reaction as shown as inshown Scheme in Scheme 16. The 16. supported The supported catalyst catalyst is a Calix[4]arene is a Calix[4]arene that thatshowed showed synergistic synergistic catalytic catalytic activity activity when when acting acti togetherng together with with microwave microwave activation activation in a in metal-free a metal- process.free process. In addition, In addition, the the easy easy removal removal of of the the catalyst catalyst simplifies simplifies the the isolation isolation of of thethe productsproducts (both diastereomers of the Julolidines of interest) that were obtained in an approximate 1:1 ratio. Julolidines are aa familyfamily ofof compounds compounds of of relevance relevance owing owing to theirto their application application asantivirals, as antivirals, antidepressants, antidepressants, as well as wellas for as their for their useful useful properties properties in non-linear in non-linear optics optics [134, 135[134,135].].

Scheme 15. Solvent-freeSolvent-free synthesis of coumarins under microwave irradiation [[132].132].

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Scheme 16. Microwave assisted solvent-free synthesis of Julolidines [133]. Scheme 16. Microwave assisted solvent-free synthesis of Julolidines [133]. Scheme 16. Microwave assisted solvent-free synthesis of Julolidines [133]. An additionalScheme application 16. Microwave of microwave assisted activationsolvent-free under synthesis solvent-free of Julolidines conditions [133]. was described An additional application of microwave activation under solvent-free conditions was described in 2019An by additional Rao et al., application who reported of microwave the multicompo activationnent undermicrowave-assisted solvent-free conditions preparation was of described Biginelli in 2019An by additional Rao et al., application who reported of microwave the multicompo activationnent undermicrowave-assisted solvent-free conditions preparation was of described Biginelli inderivatives 2019 by Rao in the et al.,absence who reportedof solvent the [136]. multicomponent This reaction proceeds microwave-assisted in just a few preparation minutes with of yields Biginelli in derivativesin 2019 by Rao in the et al.,absence who ofreported solvent the [136]. multicompo This reactionnent proceeds microwave-assisted in just a few preparation minutes with of yieldsBiginelli in derivativesthe range of in 84–94% the absence as shown of solvent in Scheme [136]. 17. This reaction proceeds in just a few minutes with yields in thederivatives range of in 84–94% the absence as shown of solvent in Scheme [136]. 1717. This. reaction proceeds in just a few minutes with yields in the range of 84–94% as shown in Scheme 17.

Scheme 17. Solvent-free Biginelli reaction usingusing microwave irradiation [[136].136]. Scheme 17. Solvent-free Biginelli reaction using microwave irradiation [136]. In anotheranother interestingSchemeinteresting 17. Solvent-free example, example, in in Biginelli 2017 2017 Lomonaco Lomonaco reaction us et inget al. al. microwave reported reported the irradiation the synthesis synthesis [136]. of benzoxazinesof benzoxazines by In another interesting example, in 2017 Lomonaco et al. reported the synthesis of benzoxazines meansby means of an of environment-friendlyan environment-friendly microwave-assisted microwave-assisted methodology methodology in the in absence the absence of solvent of solvent [137]. by meansIn another of an interesting environment-friendly example, in 2017microwave- Lomonacoassisted et al. methodology reported the synthesisin the absence of benzoxazines of solvent Benzoxazines[137]. Benzoxazines are useful are intermediatesuseful intermediates in the manufacture in the manufacture of resins employedof resins inemployed the area ofpolymersin the area [137].by means Benzoxazines of an environment-friendly are useful intermediates microwave- in theassisted manufacture methodology of resins in theemployed absence in of the solvent area andofpolymers synthetic and materials. synthetic This material works. presents This work the synthesispresents the of a synthesis family of of compounds a family of obtained compounds with ofpolymers[137]. Benzoxazines and synthetic are useful material intermediatess. This work in presentsthe manufacture the synthesis of resins of a employedfamily of compoundsin the area shortobtained reaction with timesshort ofreaction 2–6 min times with of moderate 2–6 min with to good moderate yields asto showngood yields in Scheme as shown 18. in Scheme 18. obtainedofpolymers with and short synthetic reaction material times ofs. 2–6This min work with presents moderate the to synthesis good yields of aas family shown of in compoundsScheme 18. obtained with short reaction times of 2–6 min with moderate to good yields as shown in Scheme 18.

Scheme 18. Microwave synthesis of benzoxazines under solvent-free conditions [[137].137]. Scheme 18. Microwave synthesis of benzoxazines under solvent-free conditions [137]. 4. Photocatalysis under Solvent-Free Conditions 4. PhotocatalysisScheme under 18. Microwave Solvent-Free synthesis Conditions of benzoxazines under solvent-free conditions [137]. 4. Photocatalysis under Solvent-Free Conditions The use of light as an energy source for chemical activation has boomed in recent years. It is 4. PhotocatalysisThe use of light under as Solvent-Freean energy source Conditions for chemical activation has boomed in recent years. It is certainlyThe ause rapidly of light growing as an researchenergy source area that for has chemical largely activation been promoted has boomed by the availability in recent years. of eﬃcient It is certainly a rapidly growing research area that has largely been promoted by the availability of certainlylightThe sources, usea rapidly of which light growing areas an cheap, energy research with source precise area for that wavelengths,chemical has largely activation and been quite haspromoted powerfulboomed by in (e.g., the recent availability light years. emitting It ofis efficient light sources, which are cheap, with precise wavelengths, and quite powerful (e.g., light efficientdiodes,certainly LED) lighta rapidly [sources,138]. growing Photocatalysis which researchare cheap, with area with visible that prec lighthasise largely haswavelengths, multiple been promoted applicationsand quite by powerful inthe the availability synthesis (e.g., light of efficient light sources, which are cheap, with precise wavelengths, and quite powerful (e.g., light

Molecules 2020, 25, x FOR PEER REVIEW 16 of 25 Molecules 2020, 25, 3579 16 of 25 emitting diodes, LED) [138]. Photocatalysis with visible light has multiple applications in the organicsynthesis compounds of organic compounds via cross coupling via cross reactions, coupling cycloadditions, reactions, cycloadditions, ﬂuorination, fluorination, etc. When comparing etc. When thesecomparing procedures these withprocedures conventional with ones,conventional one ﬁnds thatones, photocatalysis one finds that frequently photocatalysis promotes frequently reactions underpromotes milder reactions reaction under conditions, milder suchreaction as at conditions, ambient temperature such as at [139 ambient]. Photocatalysis temperature generally [139]. dependsPhotocatalysis on the generally use of catalytic depends amounts on the use of metallicof catalytic complexes amounts (thatof metallic are toxic complexes and expensive) (that areor toxic on organicand expensive) pigments or that on may organic not be pigments recyclable that [140 ].ma Asy anot consequence, be recyclable researchers [140]. As in synthetica consequence, organic chemistryresearchers work in synthetic day by dayorganic in the chemistry development work ofday processes by day in that the are development friendly to theof processes environment thatand are thatfriendly may to be the achieved environment through and photo-organocatalytic that may be achieved processes; through photo-organoca that is, by the usetalytic of small processes; molecules that thatis, by interact the use with of light small promoting molecules chemical that interact reactions with [141 ].light Photocatalysis promoting is thereforechemical areactions topic of current [141]. interestPhotocatalysis and has is given therefore rise to a manytopic of publications current interest [142– 144and]. has However, given rise there to are many very publications few reports of[142– the use144]. of However, this technique there underare very solvent-free few reports conditions. of the use of this technique under solvent-free conditions. In the yearyear 2018,2018, SiddiquiSiddiqui andand collaboratorscollaborators described a photocatalyzedphotocatalyzed methodology for the synthesis of imidazole pyridines and imidazole thiazoles under solvent-free conditions and without the need for a catalyst, using only visible lightlight asas anan activatoractivator (Scheme(Scheme 1919))[ [145].145].

Scheme 19. Photocatalytic synthesis of imidazol pyridines and imidazol thiazoles under solvent-free Scheme 19. Photocatalytic synthesis of imidazol pyridines and imidazol thiazoles under solvent-free conditions. The yellow bulb-shaped sign indicates irradiation with visible light [145]. conditions. The yellow bulb-shaped sign indicates irradiation with visible light [145]. Imidazol pyridines and imidazol thiazoles are of interest as intermediaries in drug synthesis. Imidazol pyridines and imidazol thiazoles are of interest as intermediaries in drug synthesis. The methodology reported by the Siddiqui’s group is a simple and “green” alternative because it does The methodology reported by the Siddiqui’s group is a simple and “green” alternative because it not require catalysts or solvent. It is important to remember that photochemical reactions often require does not require catalysts or solvent. It is important to remember that photochemical reactions often metal complexes as catalysts. The reported yields for a variety of substrates range from 83 to 98%, require metal complexes as catalysts. The reported yields for a variety of substrates range from 83 to which demonstrates the usefulness of the method. 98%, which demonstrates the usefulness of the method.

Molecules 2020, 25, 3579 17 of 25

Molecules 2020, 25, x FOR PEER REVIEW 17 of 25 In this context, Lee’s group recently reported the photochemical solvent-free reaction of aldehydes In this context, Lee’s group recently reported the photochemical solvent-free reaction of with thiols in the synthesis of thioacetals. The reaction is catalyzed by Eosyn Y and activated by blue aldehydes with thiols in the synthesis of thioacetals. The reaction is catalyzed by Eosyn Y and LED light at ambient temperature with good yields (Scheme 20)[146]. This work was highlighted by activated by blue LED light at ambient temperature with good yields (Scheme 20) [146]. This work scaling of the process to obtain 49 g of the reaction product between benzaldehyde and dodecanothiol was highlighted by scaling of the process to obtain 49 g of the reaction product between benzaldehyde (Scheme 20b). and dodecanothiol (Scheme 20b).

Scheme 20. (a) Photocatalytic thioacetalization of aldehydes under solvent-free conditions. Scheme 20. (a) Photocatalytic thioacetalization of aldehydes under solvent-free conditions. (b) (b) Scaling-up of the process to obtain 49 g of the reaction product. The blue bulb-shaped sign Scaling-up of the process to obtain 49 g of the reaction product. The blue bulb-shaped sign indicates indicates irradiation with blue LED light [146]. irradiation with blue LED light [146]. Very recently, Siddiqui reported the photocatalytic synthesis of 1,3-thiazolidin-4-ones in the absenceVery of arecently, solvent [Siddiqui147]. This reported is another the multicomponent photocatalytic reactionsynthesis that of proceeds 1,3-thiazolidin-4-ones under photochemical in the activationabsence of without a solvent the need [147]. of a metalThis catalyst.is another The scopemulticomponent of this technique reaction afforded that excellent proceeds results under (all yieldsphotochemical exceeding activation 90%) for awi varietythout ofthe substrates need of a (Scheme metal catalyst. 21). The The protocol scope is of superior, this technique relative afforded to those previouslyexcellent results reported (all thatyields required exceeding the use90%) of for toxic a va andriety expensive of substrates metal catalysts,(Scheme 21). high The temperatures, protocol is andsuperior, the use relative of solvent. to those previously reported that required the use of toxic and expensive metal catalysts,In conclusion, high temperatures the search, and for processes the use of that solvent. comply with the principles of “Green Chemistry” has motivatedIn conclusion, researchers the in search organic for synthesis processes to that develop comp elyffi cientwith alternativesthe principles to carryof “Green out the Chemistry” chemical activationhas motivated of numerous researchers synthetic in organic processes. synthesis Among to thedevelop most profitableefficient alternatives alternatives to are carry solvent-free out the mechanochemistry,chemical activation microwaveof numerous activation, synthetic photocatalysis processes. Among and the the combination most profitable of enzymatic alternatives catalysis are withsolvent-free mechanochemical mechanochemistry, activation. Themicrowave reactions activation, carried out photocatalysis according to these and methodologies the combination usually of aenzymaticfford good catalysis yields, takewith placemechanochemical under mild reaction activation. conditions The reactions and o ffcarrieder the possibilityout according of scale-upto these processes.methodologies It is usually true that afford from good a strict yields, point take of view, place theunder isolation mild reaction of products conditions and the and subsequent offer the purificationpossibility of procedures scale-up processes. often require It is true column that fr chromatographyom a strict point orof atview, least the filtration isolation followed of products by recrystallization,and the subsequent involving purification necessarily procedures the use often of solvent. require Nevertheless, column chromatography non-traditional or activation at least strategiesfiltration followed such as mechanochemistry, by recrystallization, microwave involving activation necessarily and the photochemistry, use of solvent. whenNevertheless, carried out non- in thetraditional absence ofactivation solvent, certainly strategies result insuch more as effi cientmechanochemistry, synthetic procedures microwave and contribute activation significantly and tophotochemistry, the overall atom when economy, carried waste out in minimization the absence of and solvent, sustainability certainly ofresult the process.in more efficient synthetic procedures and contribute significantly to the overall atom economy, waste minimization and sustainability of the process.

Molecules 2020, 25, 3579 18 of 25 Molecules 2020, 25, x FOR PEER REVIEW 18 of 25

R2 CHO O H2N S 1 2 R HS R OH Solvent-free N Catalyst-free O R1

O2N Cl NO2 O2N

S S S S S N N N N N O O O O O Me 94% 94% 95% 96% 96%

O2N Cl Me

S S S S N S N N N N N O O O O O MeO Cl 95% MeO Me 95% 96% 94% 93%

Cl N S Cl

S S O N S S S 2 N N N N N O O O O Me O Me 94% 91% 93% 94% 94%

F MeO

S S S S N N N N O O O O Me Me Me 92% 95% 88% 90%

Me Me

S S N N O O Me Me 91% 91% Scheme 21.21.Photocatalytic Photocatalytic synthesis synthesis of 1,3-Thiazolidin-4-onesof 1,3-Thiazolidin-4-ones under under solvent-free solvent-free conditions. conditions. The yellow The bulb-shapedyellow bulb-shaped sign indicates sign indicates irradiation irradiation with visible with lightvisible [147 light]. [147].

Funding: This research was funded by Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) via grant Funding: This research was funded by Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) via grantA1-S-44097 A1-S-44097 and by and fund by fund Secretaría Secretar deía Educación de Educaci óPública-Centron Pública-Centro dede Inve Investigacistigaciónó ny yde de Estudios Estudios Avanzados Avanzados (SEP-CINVESTAV,(SEP-CINVESTAV, Mexico) Mexico) via via grant grant 126. 126. Acknowledgments: We are grateful to Consejo Nacional de Ciencia y TecnologTecnologíaía (CONACYT, Mexico) for financialfinancial supportsupport via via grant grant A1-S-44097 A1-S-44097 and fundingand funding from Secretar from íaSecretaría de Educaci deón PEducaciónública-Centro Pública-Centro de Investigaci óden y de Estudios Avanzados (SEP-CINVESTAV, Mexico) via grant 126. Investigación y de Estudios Avanzados (SEP-CINVESTAV, Mexico) via grant 126. Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study;Conflicts in theof collection,Interest: The analyses, authors or declare interpretation no conflict of data; of interest. in the writing The funders of the manuscript,had no role orin inthe the design decision of the to publishstudy; in the the results. collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. References References 1. Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, UK, 1998. 2.1. Tanaka,Anastas, K.; P.T.; Toda, Warner, F. Solvent-Free J.C. Green OrganicChemistry: Synthesis. Theory andChem. Practice Rev.; Oxford2000, 100 University, 1025–1074. Press: [CrossRef Oxford,][ UK,PubMed 1998.] 2. Tanaka, K.; Toda, F. Solvent-Free Organic Synthesis. Chem. Rev. 2000, 100, 1025–1074, doi:10.1021/cr940089p.

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