catalysts

Review : A Brief Overview on Its Evolution and Applications

Vanessa da Gama Oliveira 1 , Mariana Filomena do Carmo Cardoso 2 and Luana da Silva Magalhães Forezi 2,*

1 Programa de Pós-Graduação em Ciências Aplicadas a Produtos para Saúde, Faculdade de Farmácia, Universidade Federal Fluminense, Niterói 24241-000, RJ, Brazil; [email protected] 2 Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal Fluminense, Niterói 24210-000, RJ, Brazil; [email protected] * Correspondence: [email protected]; Tel.: +55-21-2629-2345

 Received: 20 October 2018; Accepted: 23 November 2018; Published: 3 December 2018 

Abstract: The use of small organic molecules as catalysts has gained increasing importance recently. These substances, the so-called organocatalysts, present a lot of advantages, like being less toxic, less polluting, and more economically viable than the organometallic catalysts that dominate asymmetric synthesis. This work intends to briefly show some classic works and recent publications, explaining the advantages of organocatalysis and the different types of compounds used in this field, as well as their course of action.

Keywords: organocatalysis; organocatalyst; green ; chiral; asymmetric;

1. Introduction A catalyst is a substance that facilitates the course of a reaction without affecting its equilibrium position; it acts by decreasing the activation energy of the process, allowing it to happen under milder conditions [1]. Regarding their chemical composition, catalysts can be metallic, enzymatic, or organic, but for years this area has been dominated by metal catalysts. However, the use of metals or organometallic compounds present some related environmental concerns, mostly owing to their toxicity and the generation of polluting metal waste. In this context, organocatalysis is the use of small organic molecules to activate substrates, whether these substrates are electrophiles or [2,3]. This type of methodology has existed for a long time, and one of the earliest known organocatalyzed described reactions is the use of alkaloids for the HCN ( cyanide) addition to aldehydes, published in 1912 by Breding and Fiske. In this synthesis, they observed that enantioselectivity was observed if the reaction media underwent the addition of quinine (1) or quinidine (2) (Scheme1)[4,5]. In addition to the primary advantage of the use of catalysts, which is the reduction of the activation energy of the reaction, organocatalysis is also inserted in the context of , since the execution of reactions using is considered as one of the main points of this expanding area of chemistry [1].

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Scheme 1. 1 2 Scheme 1. CinchonaCinchonaCinchona alkaloids alkaloidsalkaloidsquinine quininequinine ( ((1)) or or quinidine quinidine ( (),2), used used by by Bredig Bredig and and Fiske Fiske in in the the addition addition of HCN to aldehydes [4,5]. of HCN to aldehydes [4,,5]. Organocatalysis can be greener than traditional catalysis because: Organocatalysis can be greener than traditional catalysis because: − -− TheThe use of catalysts is, itself, a green chemistry principle; − -− ItIt employs employs mild mild conditions, conditions, consequently saving energy; − -− ItIt uses, uses, in in general, general, oxygen-stable oxygen-stable reagents reagents and does not require anhydrous conditions,conditions, reducingreducing thethe cost cost of of the the synthesis synthesis [3]; [3]; − -− ItIt is compatible with several functional groups thatthat couldcould bebe sensitivesensitive toto otherother processes—thisprocesses—this reducesreduces the need for protection groups, loweringlowering thethe totaltotal numbernumber ofof reactionreaction steps;steps; − -− ItIt uses uses less less toxic toxic and and safer substances; − -− ItIt prevents prevents the formation of metallic waste and avoids traces ofof metalsmetals inin thethe products,products, whichwhich isis anan essential feature for applications in medicinal chemistry.

2.2. as Organocatalysts OneOne of theof the main main purposes purposes of of organocatalysis organocatalysis is is the the execution execution of of stereoselectivestereoselective reactionsreactions [6]. [6]. L AA classicclassic exampleexample isis thethe useuse ofof LL-proline-proline ((66),), anan aminoacid,aminoacid, donatingdonating aa protonproton andand functioningfunctioning asas aa BrønstedBrønsted acid.acid. Being Being a secondary a secondary , amine, this aminoacid this aminoacid can form can form withenamines carbonyl with compounds; carbonyl L bycompounds; having its by amine having group its amine inserted group into inserted a cyclic system,into a cyclicL-proline system, (6) hasL-proline rigidity (6) andhas canrigidity be used and incan sub-stoichiometric be used in sub-stoichiometric amounts to induce amountsamounts the toto formation induceinduce thethe of formationformation one ofof oneone overenantiomerenantiomer the other overover in the carbonylthe otherother additioninin carbonylcarbonyl reactions. additionaddition reactions.reactions. L TheThe first first reported reported use use of Lof-proline L-proline (6 )(6 as) as a catalysta catalyst was was in in the the process process developed developed by by HajosHajos andand Parrish,Parrish, whichwhich waswas patentedpatented inin 19711971 andand publishedpublished inin 1974.1974. This synthesis involves the useuse ofof organocatalysisorganocatalysis toto obtainobtain aa chiralchiral alcoholalcohol ((88)) (Scheme(Scheme2 2))[ [1,7–9].1,7–9]. TheThe use of different different chiralchiral aminoacidsaminoacids waswas alsoalso extensivelyextensively studiedstudied byby Eder,Eder, Sauer,Sauer, andand WiechertWiechert forfor thethe synthesissynthesis ofof chiralchiral fusedfused bicyclesbicycles fromfrom prochiralprochiral centerscenters [[10].10].

Scheme 2. Hajos and Parrish synthesis of fused bicyclic compounds using L-proline as a catalyst. SchemeScheme 2. 2.HajosHajos and and Parrish Parrish synthesis synthesis of of fused fused bicyclic bicyclic compounds compounds using using L-prolineL-proline as as a acatalyst. catalyst.

InIn thisthis reaction,reaction, prolineproline ((66)) initiallyinitially actsacts as a , addi addingng to the terminal carbonyl . group. TheThe formed enamine 1212 reactsreactsreacts withwith with oneone one ofof ofthethe the ringring ring carbonylscarbonyls carbonyls inin anan in aldolaldol an aldol condensationcondensation condensation reaction,reaction, reaction, withwith with100% 100% yield yield of the of cis the additionadditioncis addition productproduct product ((13). ( Thereafter,13). Thereafter, the catalyst the catalyst is regenerated, is regenerated, being being available available for fora new a new catalytic catalytic cycle cycle (Scheme (Scheme 3) [2,7–9].3)[2,7– 9].

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Scheme 3. Adapted mechanism for the L-proline-catalyzed aldol condensation reaction [2]. SchemeScheme 3. 3. Adapted mechanism for the L-proline-catalyzed aldol condensation reaction [2]. Scheme 3.Adapted Adapted mechanism mechanism forfor thethe L-proline-catalyzed aldol aldol cond condensationensation reaction reaction [2]. [2 ]. Recently, Xu et al. showed that aminoacids are not the only molecules capable of inducing Recently,Recently, XuXu etet al. al. showed showed that thataminoacids aminoacids are not are the notonly themolecules only moleculescapable of capableinducing of in organic reactions. Using a primary amine 17 as a chiral catalyst, the Hajos-Parrish-Eder- inducingchirality chiralityin organic in reactions. organic Using reactions. a primary Using amine a 17 primary as a chiral amine catalyst,17 asthe aHajos-Parrish-Eder- chiral catalyst, the Sauer-Wiechert reaction was made in a “one-pot” fashion with excellent enantiomeric excesses (ee) Hajos-Parrish-Eder-Sauer-WiechertSauer-Wiechert reaction was made in reaction a “one-pot was” fashion made with in a excellent “one-pot” enantiomeric fashion withexcesses excellent (ee) (Scheme 4) [11]. enantiomeric(Scheme 4) [11]. excesses (ee) (Scheme4)[11].

Scheme 4. A Hajos-Parrish-Eder-Sauer-Wiechert reaction catalyzed by amine 17. SchemeScheme 4. 4. A A Hajos-Parrish-Eder-Sauer-Wiechert Hajos-Parrish-Eder-Sauer-Wiechert reaction reactionreaction catalyzed catalyzedcatalyzed by byby amine amineamine 17 17.17 .. There are also reports of a proline-pyrrolidine-oxyimide organocatalyst (21) being used in the ThereThereThere areare are alsoalso also reportsreports reports ofof of a aa proline-pyrrolidine-oxyimide proline-pyrrolidine-oxyimideproline-pyrrolidine-oxyimide organocatalyst organocatalystorganocatalyst (21 (21) being)) beingbeing used usedused in inthein thethe asymmetric Michael addition of (22) to nitroolefins (23) (Scheme 5). This catalyst allowed the asymmetricasymmetricasymmetric MichaelMichael Michael additionaddition addition ofof of ketones ketonesketones ((2222)) tototo nitroolefinsnitroolefinsnitroolefins ( (23(2323)) )(Scheme (Scheme(Scheme 5).5 5).). This This This catalyst catalyst catalyst allowed allowed allowed the the the synthesis of the Michael adducts with good yields (91–97%) and high enantioselectivity (up to 96% synthesissynthesis of of the the Michael Michael adducts adducts with with good good yields yields (91–97%) (91–97%) and and high high enantioselectivity enantioselectivity (up(up toto 96%96% ee) synthesisee) when of performed the Michael in water adducts [12]. wi th good yields (91–97%) and high enantioselectivity (up to 96% whenee)ee when) when performed performed performed in water in in water water [12]. [12]. [12].

Scheme 5. Asymmetric Michael addition of ketones to nitroolefins. Scheme 5. Asymmetric Michael addition of ketones to nitroolefins. Scheme 5.5. Asymmetric Michael addition ofof ketonesketones toto nitroolefins.nitroolefins.

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Honarmad et al. have synthesized a nanoaliphatic ammonium salt ([(PDA)(MeSO3)]) (25) using only 1,3-diaminopropane (26) and methanesulfonic acid (27) in water at room temperature [13]. The catalyst 25 was applied to catalyze the reaction between benzaldehyde (28), malononitrile (29), and dimedone (30), affording the 2-amino-3-cyano-4H-pyran (31). The best result was obtained using 10 Catalystsmol% of2018 the, 8, 605catalyst at 60 °C, under solvent-free conditions (Scheme 6). When the reaction4 ofwas 29 conducted in the absence of the catalyst, a very slow rate was observed, with only 10% of the product being formed after 12 h. HonarmadThey also verified et al. have the synthesizedgenerality of a this nanoaliphatic organocatalytic ammonium protocol salt by ([(PDA)(MeSO reacting several3)]) aldehydes (25) using onlybearing 1,3-diaminopropane electron-releasing (and26) andwithdrawing methanesulfonic groups and acid several (27) in carbonyl water at roomcompounds. temperature They observed [13]. The catalystyields ranging25 was from applied 80% to to catalyze 98%. the reaction between benzaldehyde (28), malononitrile (29), and dimedoneThe [(PDA)(MeSO (30), affording3)] ( the25) 2-amino-3-cyano-4could be easily recoveredH-pyran by (dissolut31). Theion best in water result followed was obtained by filtration using ◦ 10of mol%the product of the and catalyst evaporation at 60 C, of under the water solvent-free and reus conditionsed for five (Scheme cycles 6without). When loss the in reaction its catalytic was conductedactivity. This in thereaction absence could of thealso catalyst, be scaled-up a very fr slowom a rate 1 mmol was observed,to a 20 mmol with scale only with 10% the of the same product yield beingand reaction formed time. after 12 h.

Scheme 6.6. SynthesisSynthesis ofof aa nanoaliphaticnanoaliphatic ammoniumammonium saltsalt ([(PDA)(MeSO([(PDA)(MeSO33)]) (25) and evaluationevaluation of itsits catalytic activityactivity inin thethe synthesissynthesis ofof 2-amino-3-cyano-42-amino-3-cyano-4HH-pyran.-pyran.

TheyJørgensen also verifiedet al. described the generality the use of organocatalysis this organocatalytic in the protocol asymmetric by reacting α-alkylation several of aldehydesaldehydes bearing(32) via electron-releasingthe 1,6-conjugated and addition withdrawing of enamines groups to andp-quinone several methides carbonyl ( compounds.33) [14]. They They used observed a chiral yieldssecondary ranging amine from catalyst 80% to ( 98%.34) to synthesize α-diarylmethine-substituted aldehydes (35) with two neighboringThe [(PDA)(MeSO stereocenters3)] ((Scheme25) could 7) be with easily good recovered diastereocontrol by dissolution and enantioselectivity. in water followed byIn this filtration case, ofthe the (diphenylmethyl)trimethylsiloxy product and evaporation of the group water andwas reusedproposed for fiveto shield cycles withoutone face loss of inthe its enamine, catalytic activity.providing This enantiocontrol, reaction could while also the be scaled-upother silyloxy from moiety a 1 mmol determines to a 20 mmol the approach scale with of the the same p-quinone yield andmethide reaction to the time. enamine. The use of a derivative as a Lewis acid additive (36) accelerated the reaction.Jørgensen et al. described the use of organocatalysis in the asymmetric α-alkylation of aldehydes (32) viaAnother the 1,6-conjugated approach for additionthe α-alkylation of enamines of aldehydes to p-quinone was described methides by (33 Guo)[14 et]. al., They in this used case a chiral with secondaryα-amino aldehydes amine catalyst (37) and (34 3-indolylmethanols) to synthesize α-diarylmethine-substituted (38) as alkylating agents (Scheme aldehydes 8). The (35 )amine with two(39) neighboringwas employed as catalyst (Scheme and the7) with chiral good products diastereocontrol 40 were and obtained enantioselectivity. in yields up In thisto case,99%, thediastereoselectivities (diphenylmethyl)trimethylsiloxy up to 88:12, and group enantiomeric was proposed excess to up shield to 96% one [15]. face of the enamine, providing enantiocontrol,Alexakis whileet al. thedescribed other silyloxy an moietyenantio determines and diastereoselective the approach of theorganocatalyticp-quinone methide domino to theMichael/Aldol enamine. The reaction use of asequence. thiourea derivativeThis approach as a Lewiswas applied acid additive in the ( 36preparation) accelerated of thebicyclo[3.2.1] reaction. octaneAnother (41) employing approach forbifunction the α-alkylational organocatalysts of aldehydes (42 was) (thiourea described and by Guotertiary et al., amine) in this case[16]. withThe αreaction-amino worked aldehydes very (37 we) andll for 3-indolylmethanols several substituted (β38,γ)-unsaturated as alkylating 1,2-ketoesters agents (Scheme (43)8 ).and The cyclic amine 1,3- (ketoesters39) was employed (44). It allows as catalyst for the formation and the chiral of the productscorrespondent40 were bicyclo[3.2.1]oc obtained intanes yields in good up to yields 99%, diastereoselectivities(53−98%) with enantioselectivities up to 88:12, and up enantiomericto 90% ee (Scheme excess 9). up to 96% [15]. Alexakis et al. described an enantio and diastereoselective organocatalytic domino Michael/ sequence. This approach was applied in the preparation of bicyclo[3.2.1] octane (41) employing bifunctional organocatalysts (42) (thiourea and tertiary amine) [16]. The reaction worked very well for several substituted β,γ-unsaturated 1,2-ketoesters (43) and cyclic 1,3-ketoesters (44). It allows for the formation of the correspondent bicyclo[3.2.1]octanes in good yields (53−98%) with enantioselectivities up to 90% ee (Scheme9).

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Scheme 7. Organocatalytic asymmetric α-alkylation of aldehydes with p-quinone methides. SchemeScheme 7.7. Organocatalytic asymmetricasymmetric αα-alkylation-alkylation ofofof aldehydesaldehydesaldehydes withwithwith p-quinonep-quinonep-quinone methides.methides.methides.

Scheme 8. α-Alkylation of α-amino aldehydes with 3-indolylmethanols. SchemeScheme 8.8. αα-Alkylation-Alkylation ofof αα-amino-amino aldehydesaldehydes withwithwith 3-indolylmethanols.3-indolylmethanols.3-indolylmethanols.

Scheme 9.9. DominoDomino Michael/aldolMichael/aldol reaction of methylcyclopentanone carboxylate to ββ,,γ-unsaturated-unsaturated Scheme 9. DominoDomino Michael/aldolMichael/aldol reactionreaction ofof methylcyclopentanonemethylcyclopentanone carboxylatecarboxylate toto β,,γ-unsaturated-unsaturated 1,2-ketoesters catalyzedcatalyzed byby aa chiralchiral thioureathiourea catalyst.catalyst. 1,2-ketoesters1,2-ketoesters catalyzedcatalyzed byby aa chiralchiral thioureathiourea catalyst.catalyst.

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Catalysts 2018, 8, x FOR PEER REVIEW 6 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 6 of 29 The interest in the asymmetric synthesis of compounds containing the trifluoromethyl group at The interest in the asymmetric synthesis of compounds containing the trifluoromethyl group at stereogenicThe interest centers in is crescent,the asymmetric but not synthesis many methods of compounds are available containing for thethe enantiomericallytrifluoromethyl group enriched at stereogenic centers is crescent, but not many methods are available for the enantiomerically enriched stereogenic centers is crescent, but not many methods are available for the enantiomerically enriched synthesissynthesis of thisof this type type of of compound compound [17 [17].]. A A possible possible solution solution to to this this challenge, challenge, as as showed showed in in Scheme Scheme 10 , synthesis of this type of compound [17]. A possible solution to this challenge, as showed in Scheme is the10, asymmetricis the asymmetric conjugate conjugate addition addition of nitromethane of nitromethane to sterically to sterically congested congestedβ,β β-disubstituted,β-disubstitutedβ -CFβ- 3 10, is the asymmetric conjugate addition of nitromethane to sterically congested β,β-disubstituted β- enonesCF3 enones (45) under (45) high-pressureunder high-pressure using ausing non-covalent a non-covalent catalyst. catalyst. In this In case, this thecase, use the of use a chiral of a chiral tertiary CF3 enones (45) under high-pressure using a non-covalent catalyst. In this case, the use of a chiral amine-thioureatertiary amine-thiourea catalyst (46 ) affordedcatalyst a( variety46) afforded of γ-nitroketones a variety containing of γ-nitroketones trifluoromethylated containing chiral tertiary amine-thiourea catalyst (46) afforded a variety of γ-nitroketones containing quaternarytrifluoromethylated in chiral the β -positionquaternary (47 carbons) (80−97%, in the 92 β−-position98% ee)[ (4718)]. (80−97%, 92−98% ee) [18]. trifluoromethylated chiral quaternary carbons in the β-position (47) (80−97%, 92−98% ee) [18].

SchemeScheme 10. 10.Synthesis Synthesis of of trifluoromethylated trifluoromethylated products modified modified in in the the ββ-position.-position. Scheme 10. Synthesis of trifluoromethylated products modified in the β-position. AnotherAnother important important synthetic synthetic challenge challenge isis thethe constructionconstruction of of non- non-aromaticaromatic polycyclic polycyclic skeletons skeletons Another important synthetic challenge is the construction of non-aromatic polycyclic skeletons duedue to to their their presence presence in in bioativebioative molecules. In In this this sense, sense, Greck Greck et al. et reported al. reported a one-pot a one-pot reaction reaction for due to their presence in bioative molecules. In this sense, Greck et al. reported a one-pot reaction for forthe the direct direct conversion conversion of ofhydroquinone hydroquinone derivatives derivatives (49) (into49) intoenantioenriched enantioenriched tricyclic tricyclic skeletons. skeletons. The the direct conversion of hydroquinone derivatives (49) into enantioenriched tricyclic skeletons. The Thereaction reaction takes takes place place through through an oxidative an oxidative dearomatization dearomatization and is andcatalyzed is catalyzed by amine by 50 amine in a Diels-50 in a reaction takes place through an oxidative dearomatization and is catalyzed by amine 50 in a Diels- Alder/Michael cascade process (Scheme 11) [19]. The endo product (51) is obtained under these Diels-Alder/MichaelAlder/Michael cascade cascade process process (Scheme (Scheme 11) 11[19].)[19 The]. The endoendo productproduct (51 ()51 is) isobtained obtained under under these these conditions with excellent control of regio and stereo-selectivity [20]. conditionsconditions with with excellent excellent control control of of regio regio and and stereo-selectivity stereo-selectivity [[20].20].

Scheme 11. Dearomatization and trienamine/enamine activation sequence for the synthesis of SchemeScheme 11. 11.Dearomatization Dearomatization andand trienamine/enaminetrienamine/enamine ac activationtivation sequence sequence for for the the synthesis synthesis of of enantioenriched tricyclic scaffolds. enantioenrichedenantioenriched tricyclic tricyclic scaffolds. scaffolds. The organocatalyzed asymmetric synthesis of a series of spirocyclobutyl oxindoles (56) was TheThe organocatalyzed organocatalyzed asymmetric asymmetric synthesissynthesis ofof a series of spirocyclobutyl oxindoles oxindoles (56 (56) was) was achieved based on H bond-directing dienamine activation using the amine 55 as a catalyst through a achievedachieved based based on on H H bond-directing bond-directing dienamine dienamine activationactivation using the the amine amine 5555 asas a acatalyst catalyst through through a a formal [2+2] cycloaddition reaction (Scheme 12). They were obtained in good yields (63–83%), formalformal [2+2] [2+2] cycloaddition cycloaddition reaction reaction (Scheme (Scheme 12). They12). They were were obtained obtained in good in yieldsgood (63–83%),yields (63–83%), excellent excellent β,γ-regioselectivity (> 19:1), and stereocontrol (up to > 19:1 dr and 97% ee) [21]. β,γexcellent-regioselectivity β,γ-regioselectivity (>19:1), and (> stereocontrol 19:1), and stereocontrol (up to >19:1 (updr toand > 19:1 97% dr eeand)[21 97%]. ee) [21].

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Scheme 12. Organocatalyzed [2+2] cycloaddition reaction of ethyleneindolinones to α,β-unsaturated SchemeScheme 12. 12. Organocatalyzed Organocatalyzed [2+2] [2+2] cycloadditioncycloaddition reactionreaction of of ethyleneindolinones ethyleneindolinones to toα, βα-unsaturated,β-unsaturated aldehydes. aldehydes.aldehydes. Ma et al. showed a series of electron-deficient 1-sulfonyl-1-azadienes (59) acting as regio and MaMa et et al. al. showed showed a a series series ofof electrelectron-deficient 1-sulfonyl-1-azadienes1-sulfonyl-1-azadienes (59 (59) acting) acting as asregio regio and and chemo-selective dienophiles with their 2π-participation in Normal-Electron-Demand Diels-Alder chemo-selectivechemo-selective dienophiles dienophiles withwith theirtheir 2π-participation inin Normal-Electron-DemandNormal-Electron-Demand Diels-Alder Diels-Alder (NEDDA) reactions with 2,4-dienal (60) via trienamine activation, leading to the formation of (NEDDA)(NEDDA) reactions reactions with with 2,4-dienal2,4-dienal ((6060) via trienaminetrienamine activation,activation, leading leading to to the the formation formation of of multifunctionalmultifunctionalmultifunctional cycloadducts cycloadducts ( (6161)) (Scheme (Scheme(Scheme 13).13). TheseThese These reactionsreactions reactions ocurred ocurred ocurred in in the in the thepresence presence presence of ofamine ofamine amine 62 62 62as asthe the catalyst catalyst catalyst [22,23]. [22,23]. [22,23 ].

SchemeScheme 13. 13.NEDDA NEDDA reactions reactions ofof 4-styryl-1,2,3-benzoxathiazine-2,2-dioxides.4-styryl-1,2,3-benzoxathiazine-2,2-dioxides. Scheme 13. NEDDA reactions of 4-styryl-1,2,3-benzoxathiazine-2,2-dioxides. 3. Chiral3. Chiral Amides Amides as as Organocatalysts Organocatalysts 3. Chiral Amides as Organocatalysts SeveralSeveral proline-based proline-based organocatalysts organocatalysts havehave been developed in in recent recent years years with with the the aim aim of of improvingimprovingSeveral the proline-basedthe enantio enantio and and organocatalysts diastereo-selectivity diastereo-selectivity have been ofof aldolaldol developed reactions.reactions. in recentAn An example example years withis isthe thethe use useaim of ofof prolinamidesimprovingprolinamides the to toenantio provide provide and double double diastereo-selectivity hydrogen-bondinghydrogen-bondi ngof withaldol the reactions. corresponding An example substrates; substrates; is the here, here,use a of a functionalizedprolinamidesfunctionalized too-phenylenediamine o-phenylenediamineprovide double hydrogen-bondi prolinamideprolinamide was ng applied applied with theas as an ancorresponding organocatalyst organocatalyst substrates;(63 (63) in) inthe the directhere, direct a asymmetricfunctionalizedasymmetric aldol aldol o-phenylenediamine reaction reaction between between prolinamide aromaticaromatic aldehydes was applied ( (6464)) and andas ancyclohexanone cyclohexanone organocatalyst (65 ( 65()63 (Scheme)) (Scheme in the 14).direct 14 ). StableasymmetricStable imidazolidinones imidazolidinones aldol reaction ( 67(67 between)) were were observed observed aromatic inin aldehydes organicorganic solvents, (64) and but but cyclohexanone their their unwanted unwanted ( 65formation formation) (Scheme was was14). significantlyStablesignificantly imidazolidinones suppressed suppressed aqueous( 67aqueous) were conditions. conditions.observed in Furthermore,Furthermore, organic solvents, the the catalytic catalytic but their activity activity unwanted of of the the prolinamides formation prolinamides was wassignificantlywas improved, improved, suppressed with with high high aqueous yieldsyields conditions. (up(up toto 99%),99%) Furthermore,, good diastereoselectivity diastereoselectivity the catalytic activity (up (up to of to> the >20:120:1 prolinamides drdr), ),and and enantioselectivitywasenantioselectivity improved, with (up (up tohigh to 95% 95% yieldsee ee)[) 24[24]. ].(up to 99%), good diastereoselectivity (up to > 20:1 dr), and L-prolinamides (68) were also employed in the asymmetric Michael addition of aldehydes (69) enantioselectivityL-prolinamides (up (68 to) were95% ee also) [24]. employed in the asymmetric Michael addition of aldehydes (69) to to nitroalkenes (70), affording the products (71) under mild conditions with good yields (up to 94%) nitroalkenesL-prolinamides (70), affording (68) were the productsalso employed (71) under in the mild asymmetr conditionsic Michael with good addition yields of (up aldehydes to 94%) with (69) with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1 dr) (Scheme 15) excellentto nitroalkenes enantioselectivities (70), affording (up the to products 99% ee) and (71) diastereoselectivities under mild conditions (up with to 99:1 gooddr) yields (Scheme (up 15 to)[ 94%)25]. with[25]. excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1 dr) (Scheme 15) [25].

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SchemeScheme 14.14. DirectDirect asymmetric aldol reaction of substitutedsubstituted benzaldehydesbenzaldehydes andand cyclohexanonecyclohexanone catalyzedcatalyzed byby prolinamidesprolinamides inin aqueusaqueus conditions.conditions.

O Ph N HN Ph O R2 H Ph 2 H Ph (R) NO O NO (68) Ph NO2 O NO2 (68) H (S) R R2 (S) R1 R2 benzoic acid R1 (69) (70) 1 (71) (69) (70) toluene, -20 ºC, 24 h (71) 74-94 %

O N Ph N N Ph H H Ph R R1 O R O R2 N Si O Possible transition state

SchemeScheme 15.15. Asymmetric Michael additions of aldehydesaldehydes to nitroalkenes catalyzedcatalyzed byby LL-prolinamides.-prolinamides.

γ 0 TheThe directdirect constructionconstruction ofof opticallyoptically purepure bispiro[bispiro[γ-butyrolactone-pyrrolidin4,4-butyrolactone-pyrrolidin4,4′-pyrazolone]-pyrazolone] skeletonsskeletons containingcontaining four four contiguous contiguous new new stereo-centers stereo-centers was was conducted conducted via a directvia a direct catalytic catalytic 1,3-dipolar 1,3- α cycloadditiondipolar cycloaddition between between an -arylidene an α-arylidene pyrazolonone, pyrazolonone, the 4-benzyl-idene-3-methyl-1-phenyl-1- the 4-benzyl-idene-3-methyl-1-phenyl-H α γ pyrazol-5(41-H pyrazol-5(4H)-oneH)-one (72), (72 and), and the the-imino α-imino-lactone γ-lactone (73 ()73 (Scheme) (Scheme 16 16).). The The organocatalyst organocatalyst usedused forfor thisthis purposepurpose waswas aa bifunctionalbifunctional squaramidesquaramide (75).). The productproduct ((74)) waswas obtainedobtained withwith anan 85%85% yieldyield andand withwith excellentexcellent diatereodiatereo (>20:1(>20:1 dr)) andand enantio-selectivityenantio-selectivity (94%(94% eeee)[) [26].26].

SchemeScheme 16. 16. SynthesisSynthesis of bispirocyclic of bispirocyclic scaffolds scaffolds in high in yields high yieldsand excellent and excellent diastereo diastereo and enantio- and enantio-selectivities.selectivities. 4. Iminium 4. Iminium Chan et al. reported the asymmetric epoxidation of dihydroquinolines (76) by using iminium salt Chan et al. reported the asymmetric epoxidation of dihydroquinolines (76) by using iminium organocatalysts (77, 78, and 79). The formation of various 3,4-epoxytetrahydroquinoline (80) products salt organocatalysts (77, 78, and 79). The formation of various 3,4-epoxytetrahydroquinoline (80) products via epoxidation with m-CPBA showed that the olefin double bond is reactive towards

Catalysts 2018, 8, 605 9 of 29

Catalysts 2018, 8, x FOR PEER REVIEW 9 of 29 m viaelectrophilic epoxidation oxygen with sources.-CPBA showedThe products that the were olefin obtained double in bondgood isyields reactive and towards with up electrophilicto 73% ee oxygen(Scheme sources. 17) [27]. The products were obtained in good yields and with up to 73% ee (Scheme 17)[27].

SchemeScheme 17. 17.Asymmetric Asymmetric epoxidationepoxidation of dihydroquinoline using using iminium iminium salts. salts.

MarcosMarcos et et al. al. described a a switchable switchable organocatalyst organocatalyst based based on a on rotaxane a rotaxane (81). The (81). use The of such use of suchcatalyst catalyst is important is important to control to control the degree the degree of the of Michael the Michael addition addition of an aliphatic of an aliphatic thiol to thioltrans- to transcinnamaldehyde-cinnamaldehyde [28]. [28 Structurally,]. Structurally, the thecatalyst catalyst consists consists of ofa adibenzo-24-crown-8 dibenzo-24-crown-8 macrocycle macrocycle containingcontaining a lockeda locked position, position, comprised comprised of of a a dibenzylamine/ammonium dibenzylamine/ammonium moiety, moiety, characterizing characterizing the the catalyticcatalytic unit, unit, and and a triazoliuma triazolium ring. ring. InIn this this work, work, they they chose chose an an amino-catalyst amino-catalyst ( 81(81)) to to explore explore itsits efficacyefficacy asas aa switchableswitchable catalyst catalyst in in a varietya variety of activation of activation modes modes [29 [29].]. Mechanistically, Mechanistically, the the catalyst catalyst (81) can activate activate carbonyl carbonyl compounds compounds throughthrough both both enamine enamine and and iminium iminium ion ion mechanisms,mechanisms, which makes makes this this catalyst catalyst ideal ideal for for reactions reactions wherewhere aldehydes aldehydes substituted substituted in in both both thethe αα andand ββ positions can can be be formed, formed, such such as as in in some some known known tandemtandem reactions. reactions. An example that demonstrates that this can be achieved with rotaxane (81) was reported, the An example that demonstrates that this can be achieved with rotaxane (81) was reported, the addition of thiol (82) to transcinnamaldehyde (83) catalyzed by 81 via iminium formation, followed addition of thiol (82) to transcinnamaldehyde (83) catalyzed by 81 via iminium formation, followed by the subsequent addition of vinyl bis-sulfone (84) via enamine catalysis to afford compound (85) by the subsequent addition of vinyl bis-sulfone (84) via enamine catalysis to afford compound (85) (Scheme 18). Two new bonds were formed, i.e., a C–S bond via iminium ion catalysis, and a C–C (Scheme 18). Two new bonds were formed, i.e., a C–S bond via iminium ion catalysis, and a C–C bond bond via enamine catalysis, with a 50% yield. via enamine catalysis, with a 50% yield.

Catalysts 2018, 8, 605 10 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 10 of 29

Scheme 18. Michael addition of aldehydes to a vinyl bis-sulfone promoted by catalyst (81). Scheme 18. Michael addition of aldehydes to a vinyl bis-sulfone promoted by catalyst (81). 5. Carbenes as Organocatalysts 5. Carbenes as Organocatalysts Carbenes are neutral substances with a atom containing only six electrons in the valence layer.Carbenes This carbon are isneutral divalent substances and has awith free a pair carbon of electrons atom containing [30]. only six electrons in the valence layer.Wilson This carbon and Chen is divalent have synthesized and has a somefree pair furoins of electrons (86, 87, 88 [30]., and e 89) through the cross-coupling betweenWilson furfural and (Chen90) and have 5-hydroxymethylfurfural synthesized some furoins (91 (),86 which, 87, 88, do and not e have89) throughα-, the cross-coupling preventing aldolbetween condensation. furfural (90) and To 5-hydroxymethylfurfural accomplish this transformation, (91), which they do not generated have α-hydrogens, the carbene preventing catalyst (92aldol) in condensation. situ from the To pre-catalyst accomplish 5-methoxy-1,3,4-triphenyl-4,5-dihydro-1this transformation, they generated the Hcarbene-1,2,4-triazoline catalyst (92) (93 in). Tositu catalyze from the the pre-catalyst reaction, the 5-methoxy-1,3,4-triphenyl-4,5-dihydro-1 carbene (92) initially adds to the furfural’sH-1,2,4-triazoline carbonyl group, (93 generating). To catalyze a tetrahedralthe reaction, intermediate the carbene ((9492)), whichinitially is adds converted to the tofurfural’s the Breslow carbonyl intermediate group, generating (95) after dehydration.a tetrahedral Thisintermediate intermediate (94), then which reacts is with converted 5-hydroxymethylfurfural, to the Breslow intermediate followed by the(95) elimination after dehydration. of the catalyst This (Schemeintermediate 19)[31 then]. reacts with 5-hydroxymethylfurfural, followed by the elimination of the catalyst (SchemeCarbenes 19) [31]. were also used in the highly enantioselective synthesis of functionalized cyclopentenes. Biju etCarbenes al. developed were the alsoN-heterocyclic used in the carbene-catalyzed highly enantioselective enantioselective synthesis synthesis of offunctionalized substituted five-memberedcyclopentenes. carbocyclesBiju et al. developed via chiral theα,β -unsaturatedN-heterocyclic acyl carbene-catalyze azolium intermediates,d enantioselective which takes synthesis place throughof substituted a Michael five-membered intramolecular carbocycles aldol/β-lactonization/decarboxylation via chiral α,β-unsaturated acyl sequence azolium [32intermediates,]. To prove thewhich efficiency takes place of the through protocol, a Michael a series ofintramolecular chiral cyclopentene aldol/β derivatives-lactonization/decarboxylation (100) were synthesized sequence from malonic[32]. To esterprove derivatives the efficiency (97) and of the 2-bromoenals protocol, a ( 98series) in theof presencechiral cyclopentene of triazolium derivatives salt (99) and (100 isolated) were insynthesized moderate tofrom good malonic yields with excellentderivativesee (99%)(97) and (Scheme 2-bromoenals 20)[33]. (98) in the presence of triazolium salt (99) and isolated in moderate to good yields with excellent ee (99%) (Scheme 20) [33].

Catalysts 2018, 8, 605 11 of 29 CatalystsCatalysts 2018 2018, ,8 8, ,x x FOR FOR PEER PEER REVIEW REVIEW 1111 ofof 2929

SchemeSchemeScheme 19. 19.19.N NN-heterocyclic-heterocyclic-heterocyclic carbene-catalyzed carbene-catalyzedcarbene-catalyzed coupling coupling reactionreaction reaction ofof of aldehydes.aldehydes. aldehydes.

SchemeSchemeScheme 20. 20.20.Synthesis SynthesisSynthesis and andand proposed proposedproposed mechanism mechanismmechanism ofof thethe NHNHC-catalyzedNHC-catalyzedC-catalyzed enantioselectiveenantioselective enantioselective synthesissynthesis synthesis ofof of substitutedsubstitutedsubstituted cyclopentenes. cyclopentenes.cyclopentenes.

CatalystsCatalysts2018 2018,,8 8,, 605 x FOR PEER REVIEW 12 ofof 2929

Diazepines and styryl pyrazoles are important heterocycles, since both are present in several naturalDiazepines products and and styryl bioactive pyrazoles compounds are important [34]. heterocycles,In this sense, since a bothsuccessful are present NHC-catalyzed in several naturalasymmetric products formal and [4+3] bioactive cycloaddtion compounds was [34 reported]. In this for sense, the asynthesis successful of NHC-catalyzed 1,2-diazepine heterocycles asymmetric formal(103) in [4+3] good cycloaddtion yields and excellent was reported enantioselectivities for the synthesis from of 1,2-diazepineenals (101) and heterocycles azoalkenes ( 103(102)) in formed good yieldsin situ. and As excellentshown in enantioselectivities Scheme 21, a change from in enalsthe NHC-catalyst (101) and azoalkenes led to a formal (102) formed [4+1] reaction in situ. As pathway, shown ingenerating Scheme 21syntheticall, a changey inuseful the NHC-catalystpyrazoles (104 led) [35]. to aIt formal is important [4+1] reaction to highlight pathway, that the generating modest syntheticallyenantioselectivity useful in pyrazoles this case (104is probably)[35]. It iscaused important by the to interaction highlight that of theboth modest cyclic enantioselectivityrings of the NHC incatalyst this case (105 is probablyand 106). caused by the interaction of both cyclic rings of the NHC catalyst (105 and 106).

SchemeScheme 21.21. NHC-catalyzedNHC-catalyzed synthesissynthesis ofof 1,2-diazepines1,2-diazepines andand pyrazoles.pyrazoles.

ChiChi etet al.al. reported reported a areductive reductive β,ββ,-carbonβ-carbon coupling coupling of ofα,βα-nitroalkenes,β-nitroalkenes catalyzed catalyzed by bya N a- Nheterocyclic-heterocyclic carbene. carbene. The The reactions reactions proceed proceed via via a a single-electron single-electron transfer (SET) processprocess mimickingmimicking nature’snature’s TPP-mediatedTPP-mediated oxidative oxidative decarboxylation decarboxylation of pyruvates, of pyruvates, but using but using an organic an organic substrate substrate instead ofinstead living of systems. living systems. The reaction The goesreaction through goes athro radicalugh a anion radical intermediate anion intermediate generated generated under a catalytic under a redoxcatalytic process redox [36 process]. [36]. AnAn aldehydealdehyde moleculemolecule ((107107)) waswas usedused toto reactreact withwith thethe NHCNHC catalystcatalyst (108(108),), generatinggenerating intermediateintermediate ( (II),), which which has has one oneelectron electron removed removed by the bynitroalkene the nitroalkene (109), forming (109), a nitroalkene- forming a nitroalkene-derivedderived anionic radical anionic intermediate radical intermediate (III). Simultaneously, (III). Simultaneously, the oxidation the oxidation of intermediate of intermediate (I) takes (placeI) takes giving place (II giving), which (II ),is whichsubsequently is subsequently oxidized oxidizedto form the to formNHC-bound the NHC-bound intermediate intermediate (IV). The (radicalIV). The intermediate radical intermediate (III) combines (III) with combines a molecule with aof molecule the nitroalkene of the ( nitroalkene109) to form ( the109 )β to,β-reductive form the βcoupling,β-reductive product coupling (110 product) after protonation. (110) after protonation. As a consequence, As a consequence, intermediate intermediate IV is attackedIV is attacked by a bymethanol a methanol molecule molecule to form to formthe ester the ( ester111) with (111) the with regeneration the regeneration of the ofNHC the catalyst NHC catalyst that can that initiate can initiateanother another reaction reaction cycle (Scheme cycle (Scheme 22). 22).

Catalysts 2018, 8, 605 13 of 29 CatalystsCatalysts 20182018,, 88,, xx FORFOR PEERPEER REVIEWREVIEW 1313 ofof 2929

RR2 2 NHCNHC O R2 RR1 O R2 1 NO OO NHCNHC (108), (108), DIEA DIEA NO22 N (108)(108) NO2 N FF R NO2 NO NN RR HH R11 NO22 RR OO N CHCH3OH,OH, 0 0 ºC, ºC, 24 24 h h RR1 N F 3 1 R BF F (107)(107) (109)(109) 54-92 % R22 BF44 54-92 % (110)(110) (111)(111) FF dldl + + meso meso FF FF

O HOHO R HO R OO RR O RR R SET HO R SET SETSET DeprotonationDeprotonation C F C6F5 N C F CC6FF5 N N C66F55 N NN C6F5 NN N C66F55 NN NN 6 5 N N N N N NN NN N N VI IV II IIII VI IV R R22 R SET NONO2 RR2 R22 R SET R R1 2 2 SETSET R22 R22 R1 RR1 RR1 1 NO 1 NO NO22 ++ NO22 NONO2 NONO2 2H2H RR1 2 RR1 2 NO NO 1 1 NO22 R NO22 RR1 R11 III 1 R R III R22 R22 V (110) radicalradical anion anion V (110) intermediate intermediate SchemeSchemeScheme 22. 22.22. NHC-catalyzed NHC-catalyzed reductivereductivereductive β ββ,,β,β-carbon-carbon couplingcoupling ofof αα,,ββ-nitroalkenes.-nitroalkenes.-nitroalkenes. 6. Supramolecular Organocatalysis 6.6. SupramolecularSupramolecular OrganocatalysisOrganocatalysis Supramolecular catalysis is a fast-growing field that has benefited from developments from SupramolecularSupramolecular catalysiscatalysis isis aa fast-growingfast-growing fieldfield thatthat hashas benefitedbenefited fromfrom developmentsdevelopments fromfrom bothboth both supramolecular chemistry and homogeneous catalysis. Supramolecular organocatalysts act supramolecularsupramolecular chemistrychemistry andand homogeneoushomogeneous catalycatalysis.sis. SupramolecularSupramolecular organocatalystsorganocatalysts actact viavia via hydrogen bonding and other supramolecular interactions [37]. For instance, compound (112), hydrogenhydrogen bondingbonding andand otherother supramolecularsupramolecular ininteractionsteractions [37].[37]. ForFor instance,instance, compoundcompound ((112112),), synthesized by Ashokkarar et al., was employed as a catalyst in the reaction between a variety synthesizedsynthesized byby AshokkararAshokkarar etet al.,al., waswas employedemployed asas aa catalystcatalyst inin thethe reactionreaction betweenbetween aa varietyvariety ofof of aldehydes such as 4-NO2-benzaldehyde (113) with different ketones, e.g., acetone (114), via an aldehydesaldehydes suchsuch asas 4-NO4-NO22-benzaldehyde-benzaldehyde ((113113)) withwith differentdifferent ketones,ketones, e.g.,e.g., acetoneacetone ((114114),), viavia anan asymmetric List–Lerner–Barbas aldol reaction, achieving yields up to 98% with a 99% enantiomeric asymmetricasymmetric List–Lerner–BarbasList–Lerner–Barbas aldolaldol reaction,reaction, achievingachieving yieldsyields upup toto 98%98% withwith aa 99%99% enantiomericenantiomeric excess (Scheme 23). Using acetic acid as a proton donor, this catalyst can form ionic interactions and excessexcess (Scheme(Scheme 23).23). UsingUsing aceticacetic acidacid asas aa protonproton dodonor,nor, thisthis catalystcatalyst cancan formform ionicionic interactionsinteractions andand hydrogen bonds with the substrates, forcing the acetone attack on the Si face of the aldehyde [38]. hydrogenhydrogen bondsbonds withwith thethe substrates,substrates, forcingforcing thethe acetoneacetone attackattack onon thethe SiSi faceface ofof thethe aldehydealdehyde [38].[38].

SchemeScheme 23.23. 23. SynthesisSynthesisSynthesis ofof aa supramolecular ofsupramolecular a supramolecular organocatalystorganocatalyst organocatalyst andand itsits useuse and inin itsthethe useasymmetricasymmetric in the List–Lerner–List–Lerner– asymmetric List–Lerner–BarbasBarbasBarbas aldolaldol reaction.reaction. aldol reaction.

AA straightforwardstraightforward routeroute employedemployed tunabletunatunableble bifunctionalbifunctional phosphoniumphosphonium salts salts ( (119119)) asas organocatalysts in the atom-efficient synthesis of cyclic carbonates (120) from (121) and organocatalystsorganocatalysts inin thethe atom-efficientatom-efficient synthesissynthesis ofof cycliccyclic carbonatescarbonates ((120120)) fromfrom epoxidesepoxides ((121121)) andand COCO22 CO((1221222))( 122(Scheme(Scheme) (Scheme 24).24). In24In ). additionaddition In addition toto thethe to activation theactivation activation provprov providedidedided byby the bythe the phosphoniumphosphonium phosphonium saltsalt salt moiety,moiety, moiety, therethere there isis is aa asynergicsynergic synergic effecteffect effect ofof the the hydrogenhydrogen bonding bondingbonding arising arisingarising from fromfrom the thethe terminal terminalterminal alcohol. alcohol.alcohol. The TheThe catalytic catalyticcatalytic activity activityactivity of this ofof thisthis saltsalt waswas evaluatedevaluated inin thethe synthesissynthesis ofof cycliccyclic carbonatescarbonates withwith excellentexcellent yieldsyields (93–99%).(93–99%). Furthermore,Furthermore, inin thisthis strategy,strategy, thethe catalystcatalyst couldcould bebe recoveredrecovered andand reusedreused upup toto fivefive timestimes [39].[39].

Catalysts 2018, 8, 605 14 of 29 salt was evaluated in the synthesis of cyclic carbonates with excellent yields (93–99%). Furthermore, in this strategy, the catalyst could be recovered and reused up to five times [39]. CatalystsCatalysts 20182018,, 88,, xx FORFOR PEERPEER REVIEWREVIEW 1414 ofof 2929

SchemeScheme 24.24. BifunctionalBifunctional organocatalystorganocatalyst forfor thethe synthesissynthesis ofof cycliccycliccyclic carbonates.carbonates.carbonates.

AA bifunctionalbifunctionalbifunctional squaramidesquaramidesquaramide catalystcatalyst ((123123))) derivedderivedderived fromfromfrom LLL---tertterttert-leucine-leucine-leucine promotedpromotedpromoted thethethe asymmetricasymmetricasymmetric tandemtandemtandem Michael/thiolysis Michael/thiolysis reactionreaction reaction sequensequen sequencecece betweenbetween between 9-methylindoline-2-thiones9-methylindoline-2-thiones 9-methylindoline-2-thiones ((124124 (124)) andand) and NN-- Nalkenoylphthalimidesalkenoylphthalimides-alkenoylphthalimides ((125125 (125)) toto) to furnishfurnish furnish 3,4-dihydro-9-methylthiopyrano[2¨C-b]indol-2(93,4-dihydro-9-methylthiopyrano[2¨C-b]indol-2(9 3,4-dihydro-9-methylthiopyrano[2¨C-b]indol-2(9HH)-ones)-ones ( (126126)) ininin goodgoodgood yieldsyieldsyields andandand withwithwith highhighhigh levelslevelslevels ofofof enantioselectivity enantioselectivityenantioselectivity (up (up(up to toto 98% 98%98% ee eeee))) (Scheme (Scheme(Scheme 25 25)25))[ [40].40[40].].

SchemeSchemeScheme 25. 25.25. Squaramide-catalyzed Squaramide-catalyzedSquaramide-catalyzed tandem tandemtandem Michael MichMichaelael addition/thiolysis addition/thiolysisaddition/thiolysis reaction. reaction.

CatalystsCatalysts bearing bearingbearing multiple multiplemultiple H-bond H-bondH-bond donors donorsdonors have havehave shown shownshown great greatgreat potential potentialpotential to toto generate generategenerate better betterbetter levels levelslevels of enantio-selectivityofof enantio-selectivityenantio-selectivity in the inin reactionsthethe reactionsreactions [41]. Taking[41].[41]. TaTa thesekingking factorsthesethese factorsfactors into account, intointo account,account, Wang et WangWang al. have etet exploredal.al. havehave aexploredexplored series of aa bifunctionalseriesseries ofof bifunctionalbifunctional asymmetric asymmetricasymmetric phase-transfer phphase-transferase-transfer catalysts catalystscatalysts bearing multiplebearingbearing multiplemultiple hydrogen-bonding hydrogen-hydrogen- sites.bondingbonding Two sites.sites. quaternary TwoTwo quaternaquaterna ammoniumryry ammoniumammonium compounds compoundscompounds (127 and (128(127127), andand derived 128128),), from derivedderived cinchona fromfrom alkaloids,cinchonacinchona werealkaloids,alkaloids, synthesized werewere synthesizedsynthesized and used as andand highly usedused efficient asas highlyhighly catalysts efficientefficient for catalystscatalysts asymmetric forfor nitro-Mannichasymmetricasymmetric nitro-Mannichnitro-Mannich reactions of amidosulfonesreactionsreactions ofof amidosulfonesamidosulfones (Scheme 26). (Scheme(Scheme When compared 26).26). WhenWhen to comparedcompared previous toto reports, previousprevious a very reports,reports, broad aa veryvery substrate broadbroad generality substratesubstrate wasgeneralitygenerality observed, waswas with observed,observed, both withwith bothboth enantiomersenantiomers being achieved bebeinging with achievedachieved high enantio- withwith high andhigh diastereo-selectivity enantio-enantio- andand diastereo-diastereo- [42]. selectivityselectivityAn asymmetric [42].[42]. organocatalytic tandem process comprising a cyclization reaction followed by aAnAn transfer asymmetricasymmetric hydrogenation organocatalyticorganocatalytic has beentandemtandem established, processprocess comprisingcomprising leading a toa cyclizationcyclization the step-economical reactionreaction followedfollowed synthesis byby aa oftransfertransfer enantio-enriched hydrogenationhydrogenation dihydroquinoxalinones hashas beenbeen established,established, leadlead frominging readily toto thethe step-economicalstep-economical accessible materials synthesissynthesis with ofof excellent enantio-enantio- enantio-selectivityenrichedenriched dihydroquinoxalinonesdihydroquinoxalinones (up to 99% ee). fromfrom This readilyreadily strategy accessibleaccessible provided materialsmaterials an easy with accesswith excellentexcellent to biologically enantio-selectivityenantio-selectivity significant chiral(up(up totoN 99%99%-heterocycles eeee).). ThisThis strategystrategy [43,44]. providedprovided anan easyeasy accessaccess toto biologicallybiologically significantsignificant chiralchiral NN-heterocycles-heterocycles [43,44].[43,44].

Catalysts 2018, 8, 605 15 of 29 Catalysts 2018,, 8,, xx FORFOR PEERPEER REVIEWREVIEW 15 of 29

Scheme 26. Nitro- using two quaternary ammonium catalysts.catalysts. As indicated in Scheme 27, the reaction sequence consists initially in the cyclization of As indicated in Scheme 27, the reaction sequence consists initially in the cyclization of 1,2- 1,2-phenylenediamine (133) with ethyl 2-oxo-2-phenylacetate (134), giving intermediate product I, phenylenediamine (133) with ethyl 2-oxo-2-phenylacetate (134), giving intermediate product I, which which next undergoes a enantio-selective step using the Hantzsch ester (135) next undergoes a enantio-selective transfer hydrogenation step using the Hantzsch ester (135) as a as a hydride source in the presence of a chiral phosphoric acid (136), finally giving the desired hydride source in the presence of a chiral phosphoric acid (136), finally giving the desired enantio- enantio-enriched product (137) in a step-economical overall process. enriched product (137) in a step-economical overall process.

Scheme 27. Synthesis of 3,4-dihydroquinoxalinones usingusing chiral phosphoric acidsacids asas catalysts.catalysts. Using computer models to identify the best catalyst candidates, a series of organocatalysts was Using computer models to identify the best catalyst candidates, a series of organocatalysts was synthesized and applied in the cyclo-addition between propylene oxide (138) and carbon dioxide synthesized and applied in the cyclo-addition between propylene oxide (138) and carbon dioxide (139), giving propylene carbonate (140) (Scheme 28). This protocol represents one more tool in the (139), giving propylene carbonate (140) (Scheme 28). This protocol represents one more tool in the fight against global warming, since it contributes to the fixation of the atmospheric carbon dioxide. fight against global warming, since it contributes to the fixation of the atmospheric carbon dioxide. Among the tested catalysts, compounds (141) and (142) were the best ones, with catalyst (141) giving propylene carbonate (140) in 85% yield at 10 bar, 69% at five bar, and 42% at one bar. Unlike most

Catalysts 2018, 8, x FOR PEER REVIEW 16 of 29

Catalystsapproaches2018, 8, 605used for this transformation, these organocatalysts could promote the cyclo-addition16 of 29 under solvent-free conditions at room temperature, with only a 2 mol% catalyst loading and at a low CO2 pressure [45]. AmongThe the high tested activity catalysts, of the compounds catalyst arises (141 from) and its ( 142ability) were of acting the best as hydrogen ones, with bond catalyst donor (141 through) giving propyleneits hydroxyl carbonate groups (140 and) inthe 85% fact yield that atit 10carries bar, 69%the nucleophile at five bar, andthat 42%promotes at one the bar. Unlike ring most approachesopening, usedthe iodide for this anion. transformation, It is also noteworthy these organocatalysts to mention could that promotethe catalyst the has cyclo-addition shown a good under solvent-freerecyclability, conditions being recovered at room by temperature, precipitation with and only reused a 2 for mol% five catalysttimes with loading no significant and at a lowloss COin 2 pressureefficiency. [45]. This protocol showed a broad substrate scope, being applicable to several epoxides.

O O (141) or (142) (2 mol %) O CO2 O (138) (139) rt, 24 h (140)

I I N N

N N

OH HO OH HO (141) (142)

SchemeScheme 28. 28.Synthesis Synthesis of of cycliccyclic carbonatescarbonates using multifunctional multifunctional catalysts. catalysts.

7. TheImmobilized high activity Organocatalysts of the catalyst arises from its ability of acting as hydrogen bond donor through its hydroxyl groups and the fact that it carries the nucleophile that promotes the epoxide ring opening, the iodideAn anion.important It is alsoaspect noteworthy about organocatalysis to mention that is the the challenge catalyst has in the shown separation a good recyclability,and recycling being of the catalysts. Unlike some organometallic catalysts, most organocatalysts cannot be used in their solid recovered by precipitation and reused for five times with no significant loss in efficiency. This protocol state. In this sense, the development of heterogeneous organocatalytic processes has become a showed a broad substrate scope, being applicable to several epoxides. tendency, but for this kind of system to work, the immobilization of the catalyst molecules over a 7. Immobilizedsolid support is Organocatalysts required. This immobilization may be accomplished by the covalent attachment of the catalyst to the carrier or via other interactions such as adsorption impregnation, i.e., through electrostaticAn important interactions aspect and about London organocatalysis forces. In regards is the challengeto materials in for the the separation support, the and possibilities recycling of theare catalysts. diverse, including Unlike some magnetic organometallic particles, silica, catalysts, polystyrene, most organocatalysts and dendrimers [46]. cannot be used in their solid state.For instance, In this sense, Luo theet al. development functionalized of heterogeneousmagnetic nanoparticles organocatalytic with the processes chiral amine has become 1,2- a tendency,diaminocyclohexane but for this (143 kind), and of systemthe immobilized to work, thecatalyst immobilization (145) was used of thein aldol catalyst reactions molecules between over a solidan aromatic support aldehyde is required. (146) Thisand cyclohexanone immobilization (147 may) in water be accomplished at room temperature. by the covalent The reaction attachment yield of thewas catalystup to 98% to thewith carrier 98% ee or (Scheme via other 29). interactions In addition such to the as exce adsorptionllent stereo-selectivity, impregnation, the i.e., catalyst through electrostaticcould be recycled interactions for seven and times London without forces. the In loss regards of catalytic to materials activity for [47]. the support, the possibilities are diverse,Nogrun including et al. have magnetic used particles,thiamine hy silica,drochloride, polystyrene, also andknown dendrimers as vitamin [46 B].1, to functionalize FeFor2O3@SiO instance,2 nanoparticles Luo et (149 al.). Vitamin functionalized B1 can catalyze magnetic organic nanoparticles transformations, with and the in chiral this case amine it 1,2-diaminocyclohexanewas used to catalyze the (143 three-component), and the immobilized condensation catalyst between (145) wasdifferent used aryl in aldol aldehydes reactions (150 between), 1,3- ancyclohexanediones aromatic aldehyde ( (151a146) andor 151b cyclohexanone) or 4-hydroxy-coumarin (147) in water (152 at room), and temperature. malononitrile The (153 reaction) or ethyl yield cyanoacetate (154) (Scheme 30). The challenge here was that vitamin B1 is too water soluble, which was up to 98% with 98% ee (Scheme 29). In addition to the excellent stereo-selectivity, the catalyst compromises its reusability, which was solved by its immobilization onto magnetic nanoparticles, could be recycled for seven times without the loss of catalytic activity [47]. facilitating the work-up and the catalyst recovery by using an external magnet. They also used Nogrun et al. have used thiamine hydrochloride, also known as vitamin B , to functionalize ultrasound irradiation to increase the rate of the reaction and observed that it could1 be conducted in Fe O @SiO nanoparticles (149). Vitamin B can catalyze organic transformations, and in this case 2fifteen3 minutes,2 while six hours were required1 when using conventional heating [48,49]. it was used to catalyze the three-component condensation between different aryl aldehydes (150), 1,3-cyclohexanediones (151a or 151b) or 4-hydroxy-coumarin (152), and malononitrile (153) or ethyl cyanoacetate (154) (Scheme 30). The challenge here was that vitamin B1 is too water soluble, which compromises its reusability, which was solved by its immobilization onto magnetic nanoparticles, facilitating the work-up and the catalyst recovery by using an external magnet. They also used ultrasound irradiation to increase the rate of the reaction and observed that it could be conducted in fifteen minutes, while six hours were required when using conventional heating [48,49]. Catalysts 2018, 8, 605 17 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 17 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 17 of 29

Scheme 29. Preparation of a MNP-supported chiral primary amine catalyst and its use in the SchemeScheme 29.29. Preparation of a MNP-supported chiral primaryprimary amine catalyst and itsits useuse inin thethe asymmetric direct aldol reaction between cyclohexanone and aromatic aldehydes. asymmetricasymmetric directdirect aldolaldol reactionreaction betweenbetween cyclohexanonecyclohexanone and and aromatic aromatic aldehydes. aldehydes.

Scheme 30.30. Preparation of benzo[b]pyransbenzo[b]pyrans usingusing FeFe2OO3@SiO2@VB@VB1 NPsNPs ( (149149)) as as catalyst underunder Scheme 30. Preparation of benzo[b]pyrans using Fe22O33@SiO2@VB11 NPs (149) as catalyst under ultrasonic condition. ultrasonicultrasonic condition.condition. Miraki et al. linked guanidine acetic acid (GAA), a metabolite of glycine, to magnetic nanoparticles MirakiMiraki etet al.al. linkedlinked guanidineguanidine aceticacetic acidacid (GAA),(GAA), aa metabolitemetabolite ofof glycine,glycine, toto magneticmagnetic throughnanoparticles the COOH through group. the COOH They gr haveoup. applied They have the Feapplied3O4-GAA the Fe nanoparticles3O4-GAA nanoparticles (160) to perform (160) to a nanoparticles through the COOH group. They have applied the Fe3O4-GAA nanoparticles (160) to transamidation reaction between acetamide (161) and aniline (162) under solvent-free conditions. performperform aa transamidationtransamidation reactionreaction betweenbetween acetamideacetamide ((161161)) andand anilineaniline ((162162)) underunder solvent-freesolvent-free The guanidines can catalyze transamidation reactions via H-bonding (Scheme 31). The Fe O -GAA conditions.conditions. TheThe guanidinesguanidines cancan catalyzecatalyze transamidationtransamidation reactionsreactions viavia H-bondingH-bonding (Scheme(Scheme3 31).31).4 TheThe nanoparticlesFe3O4-GAA nanoparticles were the most were effective the most catalyst effective when comparedcatalyst when to other compared catalysts to like other proline, catalysts chitosan, like Fe3O4-GAA nanoparticles were the most effective catalyst when compared to other catalysts like iron,proline, ionic chitosan, liquids, iron, and ionic the bare liquids, Fe3O and4 nanoparticles. the bare Fe3O4 Regarding nanoparticles. the reactionRegarding scope, the reaction in addition scope, to proline, chitosan, iron, ionic liquids, and the bare Fe3O4 nanoparticles. Regarding the reaction scope, acetamide, non-primary amides such as , thiourea and phtalimide, and various amines including inin additionaddition toto acetamide,acetamide, non-primarynon-primary amidesamides suchsuch asas urea,urea, thioureathiourea andand phtalimide,phtalimide, andand variousvarious electron-donating and withdrawing substituted amines were used with good-to-excellent yields. aminesamines includingincluding electron-donatingelectron-donating andand withdrawinwithdrawingg substitutedsubstituted aminesamines wewerere usedused withwith good-to-good-to- The catalyst could be reused at least six times without treatment with no loss in catalytic activity [50]. excellentexcellent yields.yields. TheThe catalystcatalyst couldcould bebe reusedreused atat leastleast sixsix timestimes withoutwithout treatmenttreatment withwith nono lossloss inin catalyticcatalytic activityactivity [50].[50].

Catalysts 2018, 8, 605 18 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 18 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 18 of 29

SchemeScheme 31. 31.Fe Fe3O3O4-GAA4-GAA nanoparticlesnanoparticles as a catalyst catalyst in in transamidation transamidation reactions. reactions. Scheme 31. Fe3O4-GAA nanoparticles as a catalyst in transamidation reactions. ChoCho et et al. al. have have prepared prepared hollow hollow microporous microporous organicorganic polymers and and functionalized functionalized them them with with pyrrolidinespyrrolidinesCho et (H-MOP-P)al. (H-MOP-P) have prepared (162 (162) ) usinghollow using post-synthetic post-syntheticmicroporous organic modificationmodification polymers methods. methods. and functionalized Hollow Hollow polymers polymers them withwere were chosenpyrrolidineschosen because because (H-MOP-P) they they can can undergo ( 162undergo) using post-synthetic post-synthetic post-synthetic modifications modifications modification easier easiermethods. than than the Hollow the solid solid microporouspolymers microporous were ones. Furthermore,chosenones. Furthermore, because the hollowthey the can microporoushollow undergo microporous post-synthetic catalyst catalyst has modifications a betterhas a solventbetter easier solvent dispersibily than dispersibily the thansolid thethanmicroporous non-hollow the non- counterpartones.hollow Furthermore, counterpart and shorter theand diffusionhollow shorter mi diffusion pathwayscroporous pathways [ 51catalyst]. [51]. has a better solvent dispersibily than the non- hollowToTo obtain counterpart obtain the the functionalized functionalizedand shorter diffusion polimers, polimers, pathways silicasilica spheressphe [51].res were prepared prepared by by the the Stöber Stöber method method [52] [52 ] andand functionalized Tofunctionalized obtain the withfunctionalized with the the tetrakis(4-ethynylphenyl) tetrakis(4-ethynylphenyl) polimers, silica spheres adamantane were prepared (165 (165 ),by), followed followedthe Stöber by by methodthe the reaction reaction [52] andwith functionalized 1,4-bis(trimethylsylethy with the tetrakis(4-ethynylphenyl)nyl)-2,5-dibromo-benzene adamantane (166) via (a165 Sonogashira), followed bycoupling. the reaction The with 1,4-bis(trimethylsylethynyl)-2,5-dibromo-benzene (166) via a Sonogashira coupling. The terminal withterminal 1,4-bis(trimethylsylethy alkyne groups (167)nyl)-2,5-dibromo-benzene were then functionalized ( 166with) via(S)- Na-Boc-2-azidomethylpyrrolidine Sonogashira coupling. The alkyne groups (167) were then functionalized with (S)-N-Boc-2-azidomethylpyrrolidine (168) via a terminal(168) via alkyne a click groups reaction. (167 Finally,) were thenthe desprotectionfunctionalized ofwith the ( SBoc)-N-Boc-2-azidomethylpyrrolidine group was conducted using click reaction. Finally, the desprotection of the Boc group was conducted using trifluoracetic acid, (trifluoracetic168) via a click acid, reaction.giving catalyst Finally, 169 the (Scheme desprotection 32) [51]. of the Boc group was conducted using giving catalyst 169 (Scheme 32)[51]. trifluoraceticThey catalytic acid, giving activity catalyst of 169H-MOP-P (Scheme was 32) [51].evaluated in the malonate (170) addition to 170 cinnamaldehydeTheyThey catalytic catalytic (171 activityactivity). After of72of hours, H-MOP-PH-MOP-P when was using evaluated a 10 mol %in in loadingthe the malonate malonate of H-MOP-P (170 ( ) (1,28)addition addition mmol toof to cinnamaldehydecinnamaldehydepyrrolidine per ( g),171(171 a). ).93% AfterAfter yield 72 72 hours,was hours, observed. when when using usingThe anon-hollow 10 a 10mol mol % loading %polymer loading of catalyst H-MOP-P of H-MOP-P gave (1,28 only (1,28mmol 30% mmol ofof ofpyrrolidine conversion inper per the g), g), same a a 93% 93% reaction yield yield wastime was observed.[51 observed.Error! BookmarkThe The non-hollow non-hollow not defined. polymer polymer]. catalyst catalyst gave gave only only 30% 30% of of conversionconversion in in the the same same reaction reaction time time [[5151].Error! Bookmark not defined.].

Scheme 32. Synthesis of hollow and microporous organic polymers functionalized with pyrrolidine SchemeSchemeand their 32. 32. useSynthesis Synthesis in the addition of of hollow hollow of and malonateand microporousmicroporous to cinnamaldehyde. organi organicc polymers polymers functionalized functionalized with with pyrrolidine pyrrolidine andand their their use use in in the the addition addition of of malonate malonate toto cinnamaldehyde.cinnamaldehyde.

Catalysts 2018, 8, 605 19 of 29

AnotherCatalysts 2018, successful8, x FOR PEER REVIEW example was the inclusion complexes synthesized19 by of 29 Li et al. with β-cyclodextrin (β-CD) (173) as a host compound and the organic bases Another successful example was the inclusion complexes synthesized by Li et al. with β- 1,8-diazobicyclo-[5.4.0]undec-7-ene (DBU)-based phenolates (174) as guest compound. β-CD cyclodextrin (β-CD) (173) as a host compound and the organic bases 1,8-diazobicyclo-[5.4.0]undec-7- α is a highlyene (DBU)-based thermally phenolates stable cyclic (174 oligosaccharide) as guest compound. connected β-CD by is a-1,4 highly linkages; thermally it has stable the shapecyclic of a cone,oligosaccharide with the primary connected hydroxy by groupsα-1,4 linkages; of glucose it has units the shape located of ona cone, the narrowerwith the primary rim of thehydroxy cone, and the secondarygroups of glucose hydroxy units groups located on on the the large narrower one. ri Them ofβ the-CD’s cone, external and the surfacesecondary is hydroxy hydrophilic, groups which makeson it the soluble large one. in water, The β while-CD’s itsexternal hydrophobic surface is cavity hydrophilic, can host which a variety makes of it organicsoluble in molecules water, while through supramolecularits hydrophobic interactions cavity can [ 53host]. a variety of organic molecules through supramolecular interactions To[53]. synthesize the salts, the phenols were neutralized (175) with DBU (176). Next, the salts were includedTo synthesize in a β the-CD’s salts, aqueous the phenols solution, were neutralized and the formed(175) with complex DBU (176 had). Next, its the thermal salts were stability included in a β-CD’s aqueous solution, and the formed complex had its thermal stability analyzed. analyzed. Decomposition events were not observed when the temperature was up to 200 ◦C[53]. Decomposition events were not observed when the temperature was up to 200 °C [53]. The The cycloaddition reaction between propylene oxide (177) and CO2 (178) to form propylene carbonate cycloaddition reaction between propylene oxide (177) and CO2 (178) to form propylene carbonate (179)( was179) was used used as a as model a model reaction reaction to to evaluate evaluate thethe catalyticcatalytic performance performance (Scheme (Scheme 33). 33 ).

SchemeScheme 33. Synthesis33. Synthesis of inclusionof inclusion complexes complexes andand their application application as ascatalysts catalysts in the in thecycloaddition cycloaddition

reactionreaction between between propylene propylene oxide oxide and and CO CO22..

TheThe use use of immobilizedof immobilized metal-free metal-free catalystscatalysts offers promising promising features features for forthe thedevelopment development sustainablesustainable processes processes under under flow flow conditions. conditions. Porta et Porta al. have et synthesized al. have chiral synthesized amines through chiral the amines stereo-selective reduction of with trichlorosilane (HSiCl3). In this case, a polystyrene- through the stereo-selective reduction of imines with trichlorosilane (HSiCl3). In this case, a immobilized imidazolidinone-based picolinamide, a chiral Lewis base, was used as catalyst under polystyrene-immobilized imidazolidinone-based picolinamide, a chiral Lewis base, was used as continuous flow conditions, with no significant decrease in the catalytic efficiency when compared catalystto batch under conditions continuous [54]. flow conditions, with no significant decrease in the catalytic efficiency when comparedFor to the batch preparation conditions of the [54 supported]. picolinamide (180), the styrene-containing imidazolidinone For(181) the [55] preparation reacted with of picolinic the supported acid and picolinamideethyl chloroformate (180), to the give styrene-containing picolinamide (182), imidazolidinone which was (181)[polymerized55] reacted via with an picolinicAIBN-promoted acid and radical ethyl copolymerization chloroformate with to give divinylbenzene picolinamide as (co-monomer182), which was polymerized(Scheme 34). via The an AIBN-promoted efficiency of the supported radical copolymerization catalyst was evaluated with in divinylbenzene the reduction of asthe co-monomer N-PMP (Scheme(p-methoxyphenyl) 34). The efficiency protected of the supported (183). The catalyst desired amine was evaluated (184) was obtained in the reduction with an (R of) absolute the N-PMP (p-methoxyphenyl)configuration (the protected same of when imine the (183 homogeneous). The desired catalyst amine was (184 used),) was with obtained a 94% yield with and an 97% (R) absoluteee. Additionally, by employing microreactors, Munirathinam et al. have immobilized three configuration (the same of when the homogeneous catalyst was used), with a 94% yield and 97% ee. different chiral organocatalysts—cinchonidine, proline, and quinidine derivatives—through a Additionally, by employing microreactors, Munirathinam et al. have immobilized three covalent connection. They have used silica-containing glycidyl methacrylate polymer brushes different(PGMA) chiral as organocatalysts—cinchonidine,the anchoring layer. To prepare the proline, polymeric and catalysts, quinidine they derivatives—through initially proceeded with a covalent a connection.ring opening They in the have PGMA used epoxide silica-containing (185) with NaN glycidyl3 (Scheme methacrylate 35), followed by polymer a reaction brushes of the azide (PGMA) as themoiety anchoring (186) with layer. three To different prepare propargyl the polymeric derivatives: catalysts, O-propargylcinchonidine they initially proceeded (187), O-propargyl with a ring openingproline in the(188), PGMA and the epoxide quinidine (185 derivative) with ( NaN189). 3A(Scheme Diels-Alder 35 ),reaction followed between by a anthrone reaction (192 of) the and azide moietyN-methylmaleimide (186) with three different(193) giving propargyl (194) was derivatives: employed toO study-propargylcinchonidine the catalytic activity of (187 the), alkaloidsO-propargyl prolinecinchonidine (188), and (190 the) quinidineand quinidine derivative (191), while (189 an). Aaldol Diels-Alder reaction between reaction cyclohexanone between anthrone (196) and (192 4-) and N-methylmaleimidenitrobenzaldehyde (193 (197)) giving giving ( 198194)) and was (199 employed) was used to to study study the the catalyticcatalytic activity activity of of the the proline alkaloids derivative (195) [56]. cinchonidine (190) and quinidine (191), while an aldol reaction between cyclohexanone (196) and

Catalysts 2018, 8, 605 20 of 29

4-nitrobenzaldehydeCatalysts 2018, 8, x FOR PEER (197 )REVIEW giving (198) and (199) was used to study the catalytic activity of the20 prolineof 29 derivativeCatalysts (195 2018)[, 8,56 x FOR]. PEER REVIEW 20 of 29

SchemeSchemeScheme 34. 34. Synthesis34. Synthesis Synthesis and and and catalyticcatalytic catalytic evaluation evaluation ofof a a polymer-supported polymer-supported picolinamide. picolinamide. picolinamide.

(187),DMF (187),DMF OO CuBrCuBr BrBr O nn O SiOSiO22 O Si OO OO BrBr Me6TRENMe6TREN n n O SiO2SiOO2 SiO Si O O O O OO OO O O (190)(190) O NN H H O NN (185)(185) HOHO NN NaN NaN3 3 N N DMF N N DMF O O O (188),DMF O Br (188),DMF O Br O Br n CuBr Br SiO2 O Si O n O CuBr n SiO2 O Si O O SiO2 O Si O n O O SiO2 O Si O O O O Me6TREN O (186) O Me6TREN O O (186) O O N3 N O N3 OH N N OH (195) HO N (195) HO N N HN HN COOH COOH 1) (189),DMF, O H O 1) (189)CuBr,DMF, O H O N O COOH CuBrMe6TREN O Br n Br N N COOH Me6TREN SiO2 O Si O O (187) n N FMoc 2) Piperazine SiO2 O SiO O O O 4 O H N N (187) FMoc 2) PiperazineDMF O (188) O O N 4 DMF O H N H O (188) (191) N O O HO 4 N H O N N (191) NN N O H N HO 4 N N N N N N N N H N N N N O N O N H N O O N HN (189) O NO (189) O N O Diels-Alder reaction N CH3 Diels-AlderO reaction O (190) or (191) O N CH3 O O O (190)CH2orCl(191)2, rt s s N CH3 O N Flow O CHMicroreactor2Cl2, rt s s (192) NO CH3 Flow52 min OH (193) (192) O Microreactor17-54 % (194) 52 min OH Aldol reaction (193) 17-54 % (194) O O O OH O OH Aldol reaction (195) H O, rt H 2 O O OH O Flow O OH NO NO(195)2 MicroreactorH O, rt NO2 2 2 (198) (199) (196)H (197) 52 min Flow 23 % NO NO2 Microreactor NO2 2 (198) (199) (196) (197) 52 min Scheme 35. Synthesis and23 % application of polymer-supported organocatalysts. SchemeScheme 35. 35.Synthesis Synthesis andand applicationapplication of polymer-supported organocatalysts. organocatalysts.

Catalysts 2018, 8, 605 21 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 21 of 29

Based on the isomerization of E-retinal, which occurs in the eyes of mammals catalyzed by Based on the isomerization of E-retinal, which occurs in the eyes of mammals catalyzed by (−)- (−)-riboflavin (200), Metternich et al. developed a silica-supported (−)-riboflavin organocatalyst (201) riboflavin (200), Metternich et al. developed a silica-supported (−)-riboflavin organocatalyst (201) that that was able to photocatalyze the E→Z isomerization of cinnamonitrile (202) and compound (203) was able to photocatalyze the E→Z isomerization of cinnamonitrile (202) and compound (203) (Scheme 36)[57]. The nanoparticle was prepared using a methodology, stabilized by Ravoo and Du (Scheme 36) [57]. The nanoparticle was prepared using a methodology, stabilized by Ravoo and Du Prez [58,59], and the isomerization occurred with a quantitative yield, with a Z/E ratio of 88:12 [57]. Prez [58,59], and the isomerization occurred with a quantitative yield, with a Z/E ratio of 88:12 [57].

Scheme 36. E→ZZ isomerization isomerization of compounds using a silica-supported ((−−)-riboflavin)-riboflavin organocatalyst. organocatalyst.

There areare also also reported reported examples examples of immobilized of immobilized squaramide squaramide catalysts, catalysts, such as chiral such squaramide as chiral squaramidecatalyst (204 ),catalyst which ( is204 obtained), which fromis obtained a natural from aminoacid-derived a natural aminoacid-derived chiral diamine, chiral an diamine, aminoalkyl an polystyrene,aminoalkyl polystyrene, and diethyl and squarate. diethyl Compound squarate. Compound204 was used 204 as was a catalyst used as in a the catalyst addition in the of differentaddition ofdicarbonyl different compoundsdicarbonyl compounds as pentanedione as pentanedione and ethyl 2-oxocyclopentane-1-carboxylate,and ethyl 2-oxocyclopentane-1-carboxylate, for example, for example,to trans-β to-nitrostyrene trans-β-nitrostyrene (205) (Scheme (205) 37 (Scheme)[60]. 37) [60].

Scheme 37. AdditionAddition of of different different acyclic and cyclic nucleophiles to trans-β-nitrostyrene using a supported squaramide catalyst.

Osorio-Planes etet al. al. developed developed a resin-supporteda resin-supported catalyst catalyst (210 )( that210) wasthat able was to able catalyze to catalyze a Michael a Michaeladdition addition reaction betweenreaction lawsonebetween ( 208lawsone) and different(208) and (E different)-2-nitro-3-arylallyl (E)-2-nitro-3-arylallyl acetates with acetates over 96% withee. Theover Michael 96% ee addition. The Michael products addition were cyclized products under were basic cy conditionsclized under to form basic pyranonaphthoquinones, conditions to form pyranonaphthoquinones,and the reactions were conducted and the reactions in a continuous were cond flowucted reactor. in a Whencontinuous the (E flow)-2-nitro-3-phenylallyl reactor. When the (acetateE)-2-nitro-3-phenylallyl (209) was used as acetate nitroalkene, (209) thewas product used as (nitroalkene,212) was obtained the product in 4 h ( with212) awas 97% obtained conversion in 4 inh withthe first a 97% step, conversion 100% conversion in the first in thestep, second 100% step,conversion 98% ee, inand the 87:13seconddr step,(87% 98% yield) ee, (Scheme and 87:13 38 dr)[ 61(87%]. yield) (Scheme 38) [61].

Catalysts 2018, 8, x FOR PEER REVIEW 22 of 29 Catalysts 2018, 8, 605 22 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 22 of 29 O O O OH O OH OAc NaHCO (sat) O 210 (0.23 mmol) O 3 O OH 0.45 mL/min OH OAc NaHCO (sat) O 210 (0.23 mmol) 3 CH2Cl2/THF (9:1) NO2 0.45 mL/min NO2 O (208) 0.2 mL/min O O CH2Cl2/THF (9:1) NO2 NO2 + O (208) 0.2 mL/min NO2 O (212O ) + (211) NO2 (211) (212) OAc (209) OAc O (209) 210 = O O O O 210 = O O O O N H HN O N H HN N N

Scheme 38. Enantioselective continuous flow synthesis of the pyranonaphthoquinone using a Schemesupported 38.38. squaramide EnantioselectiveEnantioselective catalyst. continuous continuous flow flow synthesis synthesis of of the pyranonaphthoquinone using a supported squaramide catalyst. 8. Ionic Liquids 8. Ionic Liquids 8. IonicIonic Liquids liquids are organic salts having melting points under 100 °C. They have low or insignificant ◦ vaporIonic pressure liquids and are are organic chemically salts having and thermally melting pointsstable under[62]. 100 °C.C. They have low or insignificant insignificant vaporYadav pressure and andand Singh are chemicallyhavechemically reported andand the thermallythermally synthesis stablestable of an [[62].62 ].imidazolium-based ionic liquid from the bromoesterYadav andof trans-4-hydroxy-( Singh have reportedL)-prolinamide the synthesis and of anN-methylimidazole imidazolium-basedimidazolium-based with ionic excellent liquid fromcatalytic the bromoesteractivity in the ofof trans-4-hydroxy-(direct trans-4-hydroxy-( asymmetricL )-prolinamidealLdol)-prolinamide reaction. and First, andN-methylimidazole trans-4-hydroxy-( N-methylimidazole withS)-proline excellentwith (excellent213 catalytic) was protectedcatalytic activity activityinwith the a direct Nin-boc the asymmetric directprotecting asymmetric aldolgroup reaction. andaldol then reaction. First, reacted trans-4-hydroxy-( First, with trans-4-hydroxy-( (S)-1-phenyl-ethylamine,S)-)-proline (213) was (resulting213 protected) was protectedin N with-boc- a withNprolinamide-boc a protectingN-boc (protecting215 group). The and Ngroup-boc-prolinamide then and reacted then with reacted ((S215)-1-phenyl-ethylamine, )with was (Sesterified)-1-phenyl-ethylamine, with resulting 5-bromovaleric in resultingN-boc-prolinamide acid, in Nwhich-boc- (prolinamidereacted215). The withN -boc-prolinamide(N215-methyl). The imidazoliumN-boc-prolinamide (215) wasleading esterified ( 215to the) was intermediate with esterified 5-bromovaleric 217.with Next, 5-bromovaleric acid, the whichbromide reactedacid, anion which with was reactedNexchanged-methyl with imidazolium by N -methylKPF6 and imidazolium leading the N- toboc the groupleading intermediate removed to the 217.intermediate [63].Next, The the organocatalyst 217. bromide Next, anion the 218 bromide was had exchanged its anion catalytic was by KPF and the N-boc group removed [63]. The organocatalyst 218 had its catalytic activity evaluated in exchangedactivity6 evaluated by KPF in6 and the aldolthe N- reactionboc group between removed 4-nitrobenzaldeyde [63]. The organocatalyst (219) and 218cyclohexanone had its catalytic (220) activitythe(Scheme aldol evaluated 39). reaction between in the aldol 4-nitrobenzaldeyde reaction between (219 4-nitrobenzaldeyde) and cyclohexanone (219 (220) and) (Scheme cyclohexanone 39). (220) (Scheme 39).

SchemeScheme 39.39. SynthesisSynthesis of aa ionicionic liquidliquid catalystcatalyst andand itsits applicationapplication inin thethe asymmetricasymmetric aldolaldol reactionreaction Schemebetweenbetween 39.cyclohexanonecyclohexanone Synthesis of and ana dionic 4-nitrobenzaldehyde.4-nitrobenzaldehyde. liquid catalyst and its application in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde.

Catalysts 2018, 8, 605 23 of 29 Catalysts 2018, 8, x FOR PEER REVIEW 23 of 29

Tukhvatshin etet al.al. have developed a novel approachapproach for the synthesis of tertiary amine-derived supported squaramide catalysts based on thethe useuse ofof cyclohexane-1,2-diaminecyclohexane-1,2-diamine derivativesderivatives bearingbearing linear oror cycliccyclic hydroxyalkylhydroxyalkyl groupsgroups asas keykey precursorsprecursors [[64].64]. Starting from cyclohexane-1,2-diamine ( 222), the compound ( 224)224) was produced by reductivereductive amination from dialdehyde (223)) followed by de-protection with hydrochlorichydrochloric acid. Then, compound 224 waswas convertedconverted to to an an ionic ionic liquid-supported liquid-supported catalyst catalyst (230 ()230 via) condensationvia condensation with squaramidewith squaramide (225), followed(225), followed by a DCC/DMAP-promoted by a DCC/DMAP-promoted esterification esterificati ofon the of hydroxyl the hydroxyl group group with with 5-bromovaleric 5-bromovaleric acid. Catalystacid. Catalyst (230) was(230 synthesized) was synthesized via the Nvia-alkylation the N-alkylation of 1-methylimidazole of 1-methylimidazole (229) with ((228229)) followed with (228) by − anfollowed anion exchangeby an anion with exchange the PF6 withanion the [PF64].6− anion The scope [64Error! of the Bookmark developed not protocol defined. using]. The supported scope of catalystthe developed (230) was protocol examined using in supported the asymmetric catalyst conjugate (230) was addition examined of acetylacetone in the asymmetric (231) toconjugate several βaddition-nitrostyrenes of acetylacetone (232) bearing (231 electron-releasing) to several β or-nitrostyrenes withdrawing (232 groups) bearing in the aromaticelectron-releasing ring at room or temperature,withdrawing givinggroups product in the aromatic (233) (Scheme ring at 40 room). temperature, giving product (233) (Scheme 40).

Scheme 40. Synthesis of catalyst ( 230) and its application in the asymmetric addition of acetylacetone to β-nitrostyrenes.

Javle and Kinage havehave synthesizedsynthesized a chiralchiral aminoacidaminoacid amide-basedamide-based ionic liquid (237), obtainedobtained from alanine ((234).). To obtain the ionic liquid (237), the amidation of alanine ( 234) with with 4-chloroaniline 4-chloroaniline ((235)) waswas performed,performed, followed by the protonation of product (236) with perchloric acid in dichloromethane (Scheme 4141).). The organocatalyst ( 237) could be reused at least three times withoutwithout significantsignificant losses inin yieldyield oror stereoselectivitystereoselectivity [[65].65]. The ionic liquid liquid 237237 stoodstood out out as as an an organocatalyst, organocatalyst, replacing replacing chiral chiral transition-metal transition-metal catalysts catalysts in inthe the asymmetric asymmetric transfer transfer hydrogenation hydrogenation of of acetophenone acetophenone (238 (238) )using using 2-propanol 2-propanol ( (239239)) as hydrogen source to obtain thethe enantioenrichedenantioenriched ((SS)-alcohol)-alcohol ((240240)[) [65].65].

Catalysts 2018, 8, 605x FOR PEER REVIEW 2424 of of 29 Catalysts 2018, 8, x FOR PEER REVIEW 24 of 29

NH2 Cl Cl O NH2 dichlorodimethyl O Cl O Cl O O (S) dichlorodimethylsilane (S) O perchloric acid (S) O OH O ClO O (S) silane (S) N perchloric acid (S) N OH Py, rt HN CHCl2,rt O Cl O HN NH2 NH2 O NH3 Py, rt H CHCl2,rt H NH2 60-65 % NH 98-99 % O NH (234) Cl 2 (236) (237)3 60-65 % 98-99 % (234) (235)Cl (236) (237) (235) O OH O OH OH O (237) (S) OH O (237) (S) sodium (238) (239) t-butoxidesodium (240) (241) (239) t-butoxidert (240) (241) (238) 96-97 % ee rt 86-88 % 96-97 % ee 86-88 % Scheme 41. Synthesis and application of chiral aminoaci aminoacidd amide-based ionic liquids in the transfer Scheme 41. Synthesis and application of chiral aminoacid amide-based ionic liquids in the transfer hydrogenation of acetophenone. hydrogenation of acetophenone. 9. Photoorganocatalysis 9. Photoorganocatalysis Organocatalysts have have also also showed showed to to be be useful useful in in the the photochemistry photochemistry field. field. For For example, example, p- anisaldehydep-anisaldehydeOrganocatalysts (244 (244), ),a asimplehave simple also molecule, molecule, showed efficiently efficientlyto be useful catalyzed catalyzed in the the thephotochemistry intermolecular intermolecular field. atom-transfer atom-transfer For example, radical radical p- additionanisaldehyde (ATRA) (244 of), a varietysimple molecule, of haloalkanes efficiently (242) tocatalyzed olefinsolefins (the243 )intermolecular (Scheme 4242).). The atom-transfer reaction could radical be carriedaddition out (ATRA) under ofmild a variety conditions—at of haloalkanes ambient (242 temperature ) to olefins (and 243) under (Scheme illumination 42). The reaction of a fluorescent fluorescent could be lightcarried bulb out (irradiation (irradiation under mild from from conditions—at a a household household ambient 23 23 W W compac compact temperaturet fluorescente fluorescente and under light light illumination(CFL)). (CFL)). Initial Initial of investigations investigations a fluorescent supportlight bulb a mechanism (irradiation fromwhereby a household the aldehyde 23 W catalystcompac tphotochemically fluorescente light generates (CFL)). Initial the reactive investigations radical speciessupport by a mechanismsensitization whereby of the organic the aldehyde halides catalyst via an energy-transfer photochemically pathwaypathway generates [[66].66 ].the reactive radical species by sensitization of the organic halides via an energy-transfer pathway [66].

SchemeScheme 42. PhotochemicalPhotochemical organocatalytic organocatalytic ATRA of olefins.olefins. Scheme 42. Photochemical organocatalytic ATRA of olefins. 3 Aiming the direct and controlled C–HC−H functionalization of Csp 3-H-H bonds, bonds, MacMillan MacMillan et et al. al. 3 describedAiming the thephotoredox-mediated direct and controlled coupling coupling C−H functionalizationof of benzylic benzylic ethers ethers of ( (249249Csp)) with-H with bonds, Schiff Schiff MacMillanbases bases ( (248248) )[ et[67].67 al.]. Theydescribed activated the photoredox-mediatedthe benzylic C−H bond coupling with a combinationof benzylic ethersof a thiol (249 organocatalyst) with Schiff bases and an (248 iridium) [67]. They activated the benzylic C−H bond with a combination of a thiol organocatalyst and an iridium

Catalysts 2018, 8, 605 25 of 29

Catalysts 2018, 8, x FOR PEER REVIEW 25 of 29 They activated the benzylic C–H bond with a combination of a thiol organocatalyst and an iridium Catalysts 2018, 8, x FOR PEER REVIEW 25 of 29 photo-catalyst.photo-catalyst. ByBy usingusing thisthis methodology,methodology,a a radicalradical−−radical coupling with secondary aldimines waswas achievedachievedphoto-catalyst. and a varietyvariety By using ofof th ββis-amino-amino methodology, ether products a radical − (250radical) werewere coupling obtainedobtained with in insecondary goodgood toto aldimines excellentexcellent was yieldsyields (Scheme(Schemeachieved 4343) )[and [68].68 ].a variety of β-amino ether products (250) were obtained in good to excellent yields (Scheme 43) [68].

Scheme 43. Photoredox-mediated coupling of benzylicbenzylic ethersethers withwith SchiffSchiff bases.bases. Scheme 43. Photoredox-mediated coupling of benzylic ethers with Schiff bases. AA novelnovel methodmethod forfor thethe synthesissynthesis ofof αα,,ββ-unsaturated-unsaturated ketones and aldehydes (252) fromfrom theirtheir A novel method for the synthesis of α,β-unsaturated ketones and aldehydes (252) from their correspondingcorresponding silyl enol ethers (251) waswas developeddeveloped using Eosin Y, aa inexpensiveinexpensive organicorganic dye,dye, asas aa corresponding silyl enol ethers (251) was developed using Eosin Y, a inexpensive organic dye, as a photosensitizer involving a visible-light organocatalytic reaction and an aerobic oxidation [69]. Eosins photosensitizerphotosensitizer involving involving aa visible-lightvisible-light organocatalytic reactionreaction and and an an aerobic aerobic oxidation oxidation [69]. [69]. are known to excite molecular oxygen from its triplet to its singlet state under light irradiation [70–73]. EosinsEosins are are known known to to excite excite molecular molecular oxygenoxygen from itsits triplettriplet to to its its singlet singlet state state under under light light irradiation irradiation In this protocol, an ene reaction takes place between the singlet oxygen and the silyl enol ether through [70–73].[70–73]. In In this this protocol, protocol, an an ene ene reactionreaction takestakes place betweenbetween the the singlet singlet oxygen oxygen and and the the silyl silyl enol enol intermediate A (Scheme 44) to generate a hydroperoxy silyl hemiacetal B. This intermediate B might etherether through through intermediate intermediate AA (Scheme(Scheme 44)44) to generategenerate aa hydroperoxyhydroperoxy silyl silyl hemiacetal hemiacetal B . BThis. This undergointermediateintermediate an intramolecular B Bmight might undergo undergo silyl an transferan intramolecularintramolecular to release thesilylsilyl desired trantransfersfer product to to release release along the the withdesired desired hydroperoxysilane, product product along along which would decompose to form O and silanol [69]. This methodology, unlike the existing procedures withwith hydroperoxysilane, hydroperoxysilane, which which wouldwould2 decomposedecompose toto formform OO2 2and and silanol silanol [69]. [69]. This This methodology, methodology, forunlikeunlike this the synthesis, the existing existing isprocedures procedures metal-free, forfor operates thisthis synthesis,synthesis, under aerobic isis metal-free,metal-free, conditions, operates operates uses under under ethanol aerobic aerobic as a conditions, low conditions, toxicity solventusesuses ethanol ethanol and operates as as a alow low effectivelytoxicity toxicity solvent solvent at ambient andand op temperature.erates effectivelyeffectively at at ambient ambient temperature. temperature.

SchemeScheme 44. 44.Synthesis Synthesis of ofα α,β,β-unsaturated-unsaturated ketones and and aldehydes aldehydes using using Eosin Eosin Y Yas as a photosensitizer. a photosensitizer. Scheme 44. Synthesis of α,β-unsaturated ketones and aldehydes using Eosin Y as a photosensitizer.

Catalysts 2018, 8, 605 26 of 29

Author Contributions: V.d.G.O. and L.d.S.M.F. have been engaged in writing the initial and final manuscript versions and have made the adequate literature search, while M.F.d.C.C. have been involved in formatting of the review and contributing with suggestions to the final version of the manuscript. Funding: This research received no external funding. Acknowledgments: The authors wish to thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ). Conflicts of Interest: The authors declare no conflict of interest.

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