N-Heterocyclic Carbene Catalysis Under Oxidizing Conditions

catalysts

Review N-Heterocyclic Carbene Catalysis under Oxidizing Conditions

Krzysztof Dzieszkowski and Zbigniew Rafi ński* Faculty of Chemistry, Nicolaus Copernicus University in Toruń,Gagarin Street 7, 87-100 Toruń,Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-56-611-4530

Received: 17 October 2018; Accepted: 14 November 2018; Published: 16 November 2018

Abstract: N-heterocyclic carbene organocatalysis under oxidizing conditions provides a vast range of various synthetic procedures via diverse mechanisms. The available catalysts, bases, oxidants, and oxidizing methods afford numerous opportunities for developing this branch of organocatalysis. Furthermore, implementation of tandem reactions and cooperative catalysis in the described methodology signiﬁcantly expands the possibilities of modern organic chemistry. This approach allows the synthesis of different structurally complex and often enantiomerically enriched substances, which can be interesting in terms of biological activity and natural product synthesis. Many esters, amides, thioesters, lactams, lactones, and other cyclic compounds obtained in oxidative or oxygenative reactions promoted by N-heterocyclic carbenes can be interesting precursors in advanced organic synthesis. Sophistication and broad applicability prove that the described synthetic approaches are exceptionally worthy of further development.

Keywords: N-heterocyclic carbenes; oxidations; Breslow intermediate; acylazolium; catalysis

1. Introduction N-heterocyclic carbene (NHCs) catalysis is constantly developing as a diverse strategy for the synthesis of complex organic molecules. NHC-catalyzed reactions enable the formation of many carbon-carbon and carbon-heteroatom bonds, including heterocyclic rings [1–8]. N-heterocyclic carbenes were originally applied in umpolung benzoin condensation [9], which is still the most examined NHC-catalyzed reaction model [10]. In this type of reaction, a Breslow intermediate is generated after the nucleophilic attack of carbene on a carbonyl carbon atom. Moreover, this intermediate exhibits nucleophilic properties, in contrast to carbonyl compounds which are typically electrophilic agents (Figure1)[11]. Unique α,β-unsaturated acylazoliums can also be generated by the reaction of NHCs with α,β-unsaturated enol esters or ethers [12–14], acyl ﬂuorides [15,16], ynals [17–20], or 2-bromoenals [21–24]. In contrast to the nucleophilic Breslow intermediate, the aforementioned acylazoliums exhibit electrophilic properties. Furthermore, the Breslow intermediate can be oxidized to acylazolium, which is a very useful acylium cation synthon. Consequently, among other protocols, oxidative NHC catalysis is a unique method for the synthesis of amides and esters [25–29]. This review contains examples of a broad range of oxygenative or oxidative NHC-catalyzed reactions, which are crucial for modern organic synthesis. The article is focused on the application of NHC catalysis under oxidizing conditions, as an example of cooperative catalysis with the use of an external oxidant [30]. The aim of this work is also the nomenclature overview of this signiﬁcant and relevant synthetic approach, and a breakdown by oxidation path. Moreover, this review is aimed at updating the status of NHC-catalyzed reactions under oxidizing conditions in existing review papers [31,32].

Catalysts 2018, 8, 549; doi:10.3390/catal8110549 www.mdpi.com/journal/catalysts Catalysts 2018, 8, x FOR PEER REVIEW 2 of 15 Catalysts 2018, 8, 549 2 of 16 Catalysts 2018, 8, x FOR PEER REVIEW 2 of 15

Figure 1. Benzoin condensation mechanism. Figure 1. Benzoin condensation mechanism. 2. Mechanistic and Nomenclature Issues 2. Mechanistic and Nomenclature Issues 2. MechanisticOxidative NHCand Nomenclature catalysis, similarly Issues to the classical umpolung process, is initiated by the Breslow umpolung intermediate,Oxidative which NHC is catalysis, generated similarly from a toN -heterocyclic the classical umpolungcarbene and process, carbonyl is initiated compound—typically by the Breslow N intermediate,aldehyde.intermediate, An whichacylazolium isis generatedgenerated ion, which fromfrom is aa electrophilicN-heterocyclic-heterocyclic acylium carbenecarbene cation andand carbonylcarbonylsynthon, compound—typicallycompound—typicallyis formed via transfer aldehyde.of two electrons AnAn acylazoliumacylazolium from the ion,ion, mentioned whichwhich is is electrophilic intermediateelectrophilic acylium acyliumto the cationoxidant cation synthon, synthon, in theis reaction is formed formed viamixture. via transfer transfer The of twonucleophileof two electrons electrons added from from theas mentioneda thereactant mentioned undergoes intermediate intermediate nucleoph to the oxidant toilic thesubstitution inoxidant the reaction into thethe mixture. reactioncarbonyl The mixture.group nucleophile of Thethe addedacylazoliumnucleophile as a reactant addedion, with undergoesas subsequenta reactant nucleophilic undergoes elimination substitution nucleoph of the azoliumilic to substitution the cation carbonyl and to group regeneration the ofcarbonyl the acylazolium of group the catalyst of ion,the with(Figureacylazolium subsequent 2) [31]. ion, eliminationwith subsequent of the elimination azolium cation of the and azolium regeneration cation ofand the regeneration catalyst (Figure of the2)[ catalyst31]. (Figure 2) [31].

Figure 2. Mechanism of oxidative NHC-catalyzed esteriﬁcation.esterification. Figure 2. Mechanism of oxidative NHC-catalyzed esterification. On the other other hand, hand, the the Breslow Breslow intermediate intermediate can can be be oxidized oxidized via via oxygen oxygen atom atom transfer transfer from from an an oxidizing agent. After formation of a peroxide zwitterion, a second molecule of aldehyde is oxidizingOn the agent. other After hand, formation the Breslow of a intermediateperoxide zwitterion, can be oxidized a second via molecule oxygen of atom aldehyde transfer is oxidized from an oxidized by the peroxide species, then the azolium intermediate is eliminated and the carboxylate ion byoxidizing the peroxide agent. Afterspecies, formation then the of aazolium peroxide intermediate zwitterion, ais second eliminated molecule and ofthe aldehyde carboxylate is oxidized ion is is formed. Next, the obtained carboxylate participate in the reaction with an electrophile is added to formed.by the peroxide Next, the species,obtained then carboxylate the azolium participate intermediate in the reaction is eliminated with an andelectrophile the carboxylate is added ionto the is the reaction mixture. This path is called oxygenative NHC catalysis, in contrast to the oxidative path reactionformed. Next,mixture. the obtainedThis path carboxylate is called oxygenative participate inNHC the reactioncatalysis, with in contrast an electrophile to the oxidativeis added to path the (Figure3). In oxygenative carboxylations, molecular oxygen can be used as external oxidant. In the (Figurereaction 3). mixture. In oxygenative This path carboxylations, is called oxygenative molecular NHC oxygen catalysis, can be in used contrast as external to the oxidant.oxidative In path the (Figure 3). In oxygenative carboxylations, molecular oxygen can be used as external oxidant. In the

Catalysts 2018, 8, 549 3 of 16 Catalysts 2018, 8, x FOR PEER REVIEW 3 of 15 casecase of of spin-allowed spin-allowed oxygenation oxygenation with with O O22, ,the the reaction reaction occurs occurs via via the the single-electron-transfer single-electron-transfer (SET) (SET) processprocess [33]. [33]. Some Some mechanisms mechanisms assume assume that that intermediate intermediate dioxetane dioxetane species species can can be be involved involved [34]. [34].

FigureFigure 3. 3. DifferenceDifference between between oxidative oxidative and and oxygenative oxygenative NHC NHC catalysis catalysis using using oxygen oxygen as as an an oxidant. oxidant.

Moreover,Moreover, the the oxygenative oxygenative path path is is not not the the only only po possiblessible reaction reaction mechanism mechanism in in the the case case of of using using molecularmolecular oxygenoxygen as as an oxidant.an oxidant. An acylazoliumAn acylazolium ion can beion formed can be after formed elimination after of elimination a hydroperoxyl of aanion hydroperoxyl from the peroxide anion from zwitterion. the peroxide This path zwitterion. is also oxidative This path NHC is catalysis,also oxidative because NHC an acylazolium catalysis, becauseintermediate an acylazolium is generated intermediate [33]. is generated [33].

3.3. Oxygenative Oxygenative NHC NHC Catalysis Catalysis OxygenativeOxygenative NHC NHC catalysis catalysis was was first ﬁrst reported reported by by Deng’s Deng’s group group in in 2010 2010 (Figure (Figure 44a)a) [[35].35]. Benzyl Benzyl benzoatebenzoate derivatives derivatives were were obtained obtained with with good good yiel yieldsds in in the the reaction reaction of of benzaldehydes benzaldehydes with with benzyl benzyl bromidesbromides under under aerobic aerobic conditions, conditions, using using a thiazolium a thiazolium catalyst. catalyst. Similar Similar syntheses syntheses were were described described one yearone yearlater laterby Liu by Liuet al. et al.[36]. [36 They]. They involved involved reactions reactions between between cinnamaldehydes cinnamaldehydes and and cinnamyl cinnamyl bromidesbromides or or allyl allyl bromides bromides using using a a benzimidazolium benzimidazolium catalyst catalyst (Figure (Figure 44b).b). Moreover, the authors used asas an an oxidant oxidant not not only only molecular molecular oxygen, oxygen, but but also also manganese(IV) manganese(IV) oxide. oxide.

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Figure 4. Synthesis reported by Deng et al. (a) and synthesis reportedreported byby LiuLiu etet al.al. ((b).).

Hui and and co-workers co-workers developed developed a reaction a reaction of benzaldehyde of benzaldehyde with alkyl with bromides alkyl bromides and tosylates, and tosylates,with 1,3-dimesitylimidazolium with 1,3-dimesitylimidazolium chloride as a precatal chlorideyst, as in a which precatalyst, alkyl benzoates in which were alkyl obtained benzoates with wererelatively obtained good yields with relatively[37]. In all the good aforementioned yields [37]. procedures In all the DBU aforementioned (1,8-diazabicyclo[5.4.0]undec- procedures DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)7-ene) was used as a base. In turn, in was 2011 used Youn as a and base. co-workers In turn, in 2011reported Youn the and synthesis co-workers of phtalides reported theand synthesis isocoumarins of phtalides in oxygenative and isocoumarins NHC-catalytic in oxygenative intramolecular NHC-catalytic reactions of intramolecular o-alkynyl benzaldehydes reactions of o[37].-alkynyl It was benzaldehydes the first example [37 ].of It an was oxygenative the ﬁrst example NHC-catalyzed of an oxygenative cyclization NHC-catalyzed reaction. Regioselectivity cyclization reaction.of the examined Regioselectivity process depends of the examined strongly processon the R depends substituent strongly nature on and the varies R substituent between nature <99:1 and varies17:83 (Figure between 5). <99:1 and 17:83 (Figure5).

Figure 5. Synthesis reported by Youn andand co-workers.co-workers.

Aryl esters can be obtainedobtained also viavia thethe oxygenativeoxygenative NHC reaction ofof aldehydesaldehydes withwith boronicboronic acids. Anand et al. reported this aerobic approach to obtain aryl esters with moderate to excellentexcellent yields inin 20122012 (Figure(Figure6 6))[ 38[38].].

Figure 6. Synthesis reported by Anand and co-workers. Figure 6. Synthesis reported by Anand and co-workers. Synthesis of amides via NHC catalysis under aerobic conditions is also possible. Soeta, Ukaji et al. Synthesis of amides via NHC catalysis under aerobic conditions is also possible. Soeta, Ukaji reported the synthesis of N-acylureas from ureas and N,N0-disubstituted carbodiimides in 2013 [39]. et al. reported the synthesis of N-acylureas from ureas and N,N′-disubstituted carbodiimides in 2013 [39]. Imidazolinium salt was used as a precatalyst and potassium carbonate as a base. The expected products were obtained with excellent yields of up to 93%.

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ImidazoliniumCatalysts 2018, 8, x saltFOR wasPEER used REVIEW as a precatalyst and potassium carbonate as a base. The expected products5 of 15 wereCatalysts obtained 2018, 8, xwith FOR PEER excellent REVIEW yields of up to 93%. 5 of 15 4. Oxidative NHC Catalysis 4.4. Oxidative NHC Catalysis Synthesis of esters and carboxylic acids via oxidative NHC catalysis with the addition of alcohols or water,SynthesisSynthesis respectively, ofof estersesters andas nucleophiles carboxylic acidsacids is a via well-d oxidativeoxidatevelopedive NHC reaction catalysis model. withwith the It additionis especially of alcohols worth ornotingor water,water, the respectively, respectively, research published as as nucleophiles nucleophiles by, among is a is well-developed aothers, well-d Stevelopedruder, reaction Zeitler reaction model. or model.Scheidt It is especially It[40–49]. is especially worthInitially, notingworth the theoxidativenoting research the path research published was applied published by, among to the by, others, synthesis among Struder, others,of benzoi Zeitler Stcruder, acid or Scheidt esters Zeitler derivatives. [40 or–49 Scheidt]. Initially, Connon [40–49]. the oxidativeet Initially, al. reported path the wastheoxidative synthesis applied path to of was thesimilar synthesisapplied species to of thein benzoic the synthesis reaction acid of esters of benzoi benzaldehydes derivatives.c acid esters with Connon derivatives. primary et al. and reportedConnon secondary et the al. synthesis reportedalcohols ofinthe similar2008 synthesis (Figure species of similar7) in[50]. the species In reaction this in case, the of reaction benzaldehydesazobenzene of benzaldehydes was with used primary as withan oxidizer and primary secondary and and 3-benzylthiazolium secondary alcohols alcohols in 2008 (Figurebromidein 20087 )[(Figure as50 a ].precatalyst. In 7) this [50]. case, In azobenzenethis case, azobenzene was used aswas an used oxidizer as an and oxidizer 3-benzylthiazolium and 3-benzylthiazolium bromide as abromide precatalyst. as a precatalyst.

Figure 7. NHC-catalyzed ester oxidative synthesis by Connon et al. Figure 7.7. NHC-catalyzed ester oxidative synthesis byby ConnonConnon etet al.al. Maki and Scheidt developed the oxidative reaction of aliphatic aldehydes with alcohols catalyzedMakiMaki by andand carbene Scheidt Scheidt liberated developed developed from the 1,3-dimethylimidazolium oxidativethe oxidative reaction reaction of aliphatic of iodide aliphatic aldehydes [41]. Manganese(IV)aldehydes with alcohols with oxide catalyzedalcohols was byusedcatalyzed carbene as an by external liberated carbene oxidizer, from liberated 1,3-dimethylimidazolium and from the 1,3-dimethylimidazoliumexpected produc iodidets were [41 obtained]. iodide Manganese(IV) [41]. with Manganese(IV) very oxide high was yields usedoxide of up as was anto external99%.used as an oxidizer, external and oxidizer, the expected and the products expected were produc obtainedts were with obtained very high with yields very high of up yields to 99%. of up to 99%.ItIt isis alsoalso possiblepossible toto designdesign tandemtandem oxidationoxidation reactionsreactions inin whichwhich oneone stepstep isis thethe NHC-catalyzedNHC-catalyzed oxidationIt is also process.process. possible Rose to Rose design and and tandemZeitler Zeitler oxidationperforme performed reactionsd a adomino domino in which protocol protocol one step of ofis thethe NHC-catalyzed oxidation of 2-(hydroxyethoxy)benzyloxidation process. Rose alcohols and Zeitler to cyclic performe lactonesd in 2010a domino (Figure 8 protocol8))[ [45].45]. In of the ﬁrstfirstthe step,step,oxidation aa benzylbenzyl of hydroxyl2-(hydroxyethoxy)benzyl group was oxidizedoxidized alcohols toto aldehydealdehyde to cyclic lactones byby manganese(IV)manganese(IV) in 2010 (Figure oxideoxide 8) and,and,[45]. then,then,In the the thefirst intramolecularintramolecular step, a benzyl reactionhydroxyl ofof group oxidativeoxidative was NHC-catalyzedNHC-catalyzed oxidized to aldehyde esteriﬁcationesterification by ma occurred.occurred.nganese(IV) Azobenzene oxide and, waswas then, usedused the in intramolecular this case as an equimolarreaction of oxidizer.oxidative NHC-catalyzed esterification occurred. Azobenzene was used in this case as an equimolar oxidizer.

Figure 8. Domino oxidation by Rose and Zeitler. Figure 8. Domino oxidation by Rose and Zeitler. Kang and Jang published a similar reaction of esterificationesterification of allylallyl alcoholsalcohols resulting in allylallyl cinnamatesKang and formation Jang published in 2014 (Figurea similar9 9))[ reaction[51].51]. In thethofe esterification firstfirst step, allyl of alcoholallyl alcohols is oxidizedoxidized resulting byby TEMPOTEMPO in allyl ((2,2,6,6-Tetramethylpiperidin-1-yl)oxyl)((2,2,6,6-Tetramethylpiperidin-1-yl)oxyl)cinnamates formation in 2014 (Figure 9) to to[51]. aldehyde, aldehyde In the which ,first which step, reacts reacts allyl then then alcohol with with the is the carbeneoxidized carbene present by present TEMPO in the in reactionthe((2,2,6,6-Tetramethylpiperidin-1-yl)oxyl) reaction mixture. mixture. Oxidation Oxidation of the of Breslowthe Breslow to intermediate aldehyde intermediate, which is followed isreacts followed then by TEMPO bywith TEMPO the in carbene two in stepstwo present steps via SET, via in andSET,the reaction results and results in mixture. a radicalin a radical Oxidation cation cation formation of formationthe Breslow which which inte is finally rmediateis finally oxidized oxidizedis followed to an to acylazolium.anby acylazolium.TEMPO in High two High yieldssteps yields via of oxidativeofSET, oxidative and results esterification esterification in a radical are promotedare cation promoted formation by the by addition which the addition is of finally hexafluoroisopropyl of oxidized hexafluoroisopropyl to an alcoholacylazolium. (HFIP). alcohol High Moreover, (HFIP). yields theMoreover,of oxidative oxidizer the isesterification recyclableoxidizer is becauserecyclable are promoted it undergoes because by it the oxidationundergoes addition by oxidation oxygenof hexafluoroisopropyl fromby oxygen air. from air.alcohol (HFIP). Moreover, the oxidizer is recyclable because it undergoes oxidation by oxygen from air.

Figure 9. Synthesis reported by Kang and Jang. Figure 9. Synthesis reported by Kang and Jang.

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4. Oxidative NHC Catalysis Synthesis of esters and carboxylic acids via oxidative NHC catalysis with the addition of alcohols or water, respectively, as nucleophiles is a well-developed reaction model. It is especially worth noting the research published by, among others, Struder, Zeitler or Scheidt [40–49]. Initially, the oxidative path was applied to the synthesis of benzoic acid esters derivatives. Connon et al. reported the synthesis of similar species in the reaction of benzaldehydes with primary and secondary alcohols in 2008 (Figure 7) [50]. In this case, azobenzene was used as an oxidizer and 3-benzylthiazolium bromide as a precatalyst.

Figure 7. NHC-catalyzed ester oxidative synthesis by Connon et al.

Maki and Scheidt developed the oxidative reaction of aliphatic aldehydes with alcohols catalyzed by carbene liberated from 1,3-dimethylimidazolium iodide [41]. Manganese(IV) oxide was used as an external oxidizer, and the expected products were obtained with very high yields of up to 99%. It is also possible to design tandem oxidation reactions in which one step is the NHC-catalyzed oxidation process. Rose and Zeitler performed a domino protocol of the oxidation of 2-(hydroxyethoxy)benzyl alcohols to cyclic lactones in 2010 (Figure 8) [45]. In the first step, a benzyl hydroxyl group was oxidized to aldehyde by manganese(IV) oxide and, then, the intramolecular reaction of oxidative NHC-catalyzed esterification occurred. Azobenzene was used in this case as an equimolar oxidizer.

Figure 8. Domino oxidation by Rose and Zeitler.

Kang and Jang published a similar reaction of esterification of allyl alcohols resulting in allyl cinnamates formation in 2014 (Figure 9) [51]. In the first step, allyl alcohol is oxidized by TEMPO ((2,2,6,6-Tetramethylpiperidin-1-yl)oxyl) to aldehyde, which reacts then with the carbene present in the reaction mixture. Oxidation of the Breslow intermediate is followed by TEMPO in two steps via SET, and results in a radical cation formation which is finally oxidized to an acylazolium. High yields Catalystsof oxidative2018, 8, 549esterification are promoted by the addition of hexafluoroisopropyl alcohol (HFIP).6 of 16 Moreover, the oxidizer is recyclable because it undergoes oxidation by oxygen from air.

CatalystsCatalysts 20182018,, 88,, xx FORFOR PEERPEER REVIEWREVIEWFigureFigure 9.9. Synthesis reportedreported byby KangKang andand Jang.Jang. 66 ofof 1515

AsAsAs mentioned, mentioned, thethe the KangKang Kang andand and JangJang Jang methodmethod method cancan can bebe recognized berecognized recognized asas oneone as of oneof thethe of firstfirst the examplesexamples ﬁrst examples ofof thethe ofexceptionalexceptional the exceptional cooperativecooperative cooperative NHC-catalyzedNHC-catalyzed NHC-catalyzed oxidativeoxidative oxidative reactionreaction reaction whichwhich occursoccurs which withwith occurs thethe with useuse ofof the electron-electron- use of electron-transfertransfertransfer mediatorsmediators mediators (ETMs).(ETMs). (ETMs). Studer’sStuder’s Studer’s groupgroup group reportedreported reported anan anaerobicaerobic aerobic NHC-catalyzedNHC-catalyzed NHC-catalyzed oxidationoxidation oxidation ofofof aldehydesaldehydesaldehydes tototo estersestersesters ininin 201320132013 (Figure(Figure(Figure 10 10)10))[ [52].[52].52]. OxygenOxygen fromfromfrom airairair isisis notnotnot aaa directdirectdirect oxidizeroxidizeroxidizer butbutbut oxidizesoxidizesoxidizes thethethe ruthenium(I)ruthenium(I)ruthenium(I) complexcomplex generatedgenerated viavia reductionreduction ofof thethethe ruthenium(II)ruthenium(II)ruthenium(II) complexcomplexcomplex addedaddedadded tototo thethethe reactionreactionreaction mixture.mixture.mixture. TheThe ruthenium(II)ruthenium(II) complexcomplex participatesparticipates inin BreslowBreslow intermediateintermediate oxidationoxidation to to acylazolium.acylazolium. ThisThisThis approach, approach,approach, with withwith the thethe use useuse of ruthenium ofof rutheniumruthenium complexes compcomp aslexeslexes ETMs, asas preventsETMs,ETMs, preventsprevents aerobic oxidation aerobicaerobic ofoxidationoxidation aldehydes ofof toaldehydesaldehydes carboxylic toto acidscarboxyliccarboxylic and enables acidsacids andand the enables expectedenables thethe products expectexpecteded to products beproducts obtained toto withbebe obtaobta moderateinedined withwith to goodmoderatemoderate yields. toto Moreover,goodgood yields.yields. during Moreover,Moreover, cooperative duringduring oxidative cooperativecooperative NHC oxidativoxidativ catalysis,ee NHCNHC less than catalysis,catalysis, equimolar lessless thanthan amounts equimolarequimolar of direct amountsamounts oxidizers ofof aredirectdirect used. oxidizersoxidizers areare used.used.

FigureFigureFigure 10.10.10. Struder’sStruder’s protocolprotocol withwith useuse ofof rutheniumruthenium compoundscompounds asasas ETM.ETM.ETM.

SundSundénSundénén andandand co-workersco-workers reportedreported thethe aerobicaerobic NHC-catalyzedNHC-catalyzed synthesissynthesis ofof dihydropyranonesdihydropyranones viaviavia multistepmultistepmultistep electronelectron transfertransfer inin 201620162016 (Figure(Figure(Figure 1111)11))[ [53].[53].53]. TheThe assumptionassumptionassumption ofof thisthis workworkwork isisis thethethe oxidationoxidationoxidation ofofof ETMETMETM first, first,first, by byby oxygen oxygenoxygen from fromfrom air. air.air. The TheThe first firstfirst ETM ETMETM oxidizes, oxidoxidizes, thenizes, thethenthen second thethe secondsecond ETM, which ETETM,M, iswhichwhich the final isis the oxidizerthe finalfinal inoxidizeroxidizer the NHC-catalyzed inin thethe NHC-catalyzedNHC-catalyzed reaction. The reaction.reaction. expected TheThe dihydropyranones exexpectedpected dihydropyranonesdihydropyranones were obtained werewere with obtainedobtained moderate withwith to goodmoderatemoderate yields toto and goodgood excellent yieldsyields enantiomericandand excellentexcellent excesses. enantiomerenantiomer In theicic excesses.excesses. same year, InIn Sund thethe samesameén’sgroup year,year, reportedSundén’sSundén’ssimilar groupgroup oxidativereportedreported similar esterificationsimilar oxidativeoxidative of aldehydes esterificationesterification [54]. ofof Moreover, aldehydesaldehydes iron [54].[54]. [48 Moreover,Moreover,] and palladium ironiron [48][48] [55 and]and compounds palladiumpalladium were [55][55] alsocompoundscompounds recognized werewere as alsoalso ETMs recognizedrecognized in similar asas reactions. ETMsETMs inin similarsimilar reactions.reactions.

FigureFigure 11.11.11. MultistepMultistep electronelectron transfertransfer bybyby SundSundénSundénén and andand co-workers. co-workers.co-workers. Direct oxidation of the Breslow intermediate to acylazolium by oxygen from air is also possible. DirectDirect oxidationoxidation ofof thethe BreslowBreslow intermediateintermediate toto acylazoliumacylazolium byby oxygenoxygen fromfrom airair isis alsoalso possible.possible. Blechert et al. reported the NHC-catalyzed oxidation of aldehydes to carboxylic acids with the addition BlechertBlechert etet al.al. reportedreported thethe NHC-catalyzedNHC-catalyzed oxidationoxidation ofof aldehydesaldehydes toto carboxyliccarboxylic acidsacids withwith thethe of mesoporous graphitic carbon nitride (mpg-C3N4) as a photocatalyst in 2013 (Figure 12)[56]. Various additionaddition ofof mesoporousmesoporous graphiticgraphitic carboncarbon nitridenitride (mpg-C(mpg-C33NN44)) asas aa photocatalystphotocatalyst inin 20132013 (Figure(Figure 12)12) carboxylic acids were obtained with moderate to good yields. Furthermore, the authors considered [56].[56]. VariousVarious carboxyliccarboxylic acidsacids werewere obtainedobtained withwith moderatemoderate toto goodgood yields.yields. Furthermore,Furthermore, thethe authorsauthors that the possible oxygenative path of the investigated mechanism occurs in the minority of cases. consideredconsidered thatthat thethe possiblepossible oxygenativeoxygenative pathpath ofof thethe investigatedinvestigated mechanismmechanism occursoccurs inin thethe minorityminority ofof cases.cases.

FigureFigure 12.12. ProtocolProtocol reportedreported byby BlechertBlechert etet al.al.

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As mentioned, the Kang and Jang method can be recognized as one of the first examples of the exceptional cooperative NHC-catalyzed oxidative reaction which occurs with the use of electron- transfer mediators (ETMs). Studer’s group reported an aerobic NHC-catalyzed oxidation of aldehydes to esters in 2013 (Figure 10) [52]. Oxygen from air is not a direct oxidizer but oxidizes the ruthenium(I) complex generated via reduction of the ruthenium(II) complex added to the reaction mixture. The ruthenium(II) complex participates in Breslow intermediate oxidation to acylazolium. This approach, with the use of ruthenium complexes as ETMs, prevents aerobic oxidation of aldehydes to carboxylic acids and enables the expected products to be obtained with moderate to good yields. Moreover, during cooperative oxidative NHC catalysis, less than equimolar amounts of direct oxidizers are used.

Figure 10. Struder’s protocol with use of ruthenium compounds as ETM.

Sundén and co-workers reported the aerobic NHC-catalyzed synthesis of dihydropyranones via multistep electron transfer in 2016 (Figure 11) [53]. The assumption of this work is the oxidation of ETM first, by oxygen from air. The first ETM oxidizes, then the second ETM, which is the final oxidizer in the NHC-catalyzed reaction. The expected dihydropyranones were obtained with moderate to good yields and excellent enantiomeric excesses. In the same year, Sundén’s group reported similar oxidative esterification of aldehydes [54]. Moreover, iron [48] and palladium [55] compounds were also recognized as ETMs in similar reactions.

Figure 11. Multistep electron transfer by Sundén and co-workers.

Direct oxidation of the Breslow intermediate to acylazolium by oxygen from air is also possible. Blechert et al. reported the NHC-catalyzed oxidation of aldehydes to carboxylic acids with the addition of mesoporous graphitic carbon nitride (mpg-C3N4) as a photocatalyst in 2013 (Figure 12) [56]. Various carboxylic acids were obtained with moderate to good yields. Furthermore, the authors Catalystsconsidered2018, 8that, 549 the possible oxygenative path of the investigated mechanism occurs in the minority7 of 16 of cases.

Catalysts 2018, 8, x FOR PEER REVIEWFigure 12. Protocol reported by Blechert et al.al. 7 of 15

Sudalai et al. reported the NHC-catalyzed esterifi esteriﬁcationcation of aromatic aldehydes by alcohols under aerobic conditionsconditions in in 2013 2013 [57 [57].]. Various Various esters esters were we obtainedre obtained with moderate with moderate yields without yields without the addition the ofaddition ETMs orof otherETMs catalysts. or other Incatalysts. this case, In 1,3-dimesitylimidazolium this case, 1,3-dimesitylimidazolium chloride was chloride used as awas precatalyst used as anda precatalyst DBU as a and base. DBU The as reaction a base. wasThe reaction carried out was in carried THF with out thein THF addition with ofthe methanol addition asof amethanol reagent. Shortlyas a reagent. thereafter, Shortly Zeitler thereafter, and Connon Zeitler showed and Conno a similarn showed aerobic a similar oxidation aerobic of aromatic oxidation aldehydes, of aromatic but inaldehydes, general with but betterin general yields with [58]. better In their yields procedure, [58]. In triazolium their procedure, salt was usedtriazolium as a precatalyst, salt was used DBU as a base,precatalyst, and THF DBU as aas solvent. a base, Nonetheless,and THF as a a solvent. considerable Nonetheless, excess of a methanol considerable as a reactantexcess of was methanol added toas thea reactant reaction was mixture. added to the reaction mixture. InIn 2010,2010, Nair Nair and and co-workers co-workers reported reported the NHC-catalyzedthe NHC-catalyzed oxidation oxidation of benzaldehydes of benzaldehydes to benzoic to acidsbenzoic using acids carbon using dioxide carbon as dioxide an oxidant as an [59 oxidant]. According [59]. toAccording the authors, to the Breslowauthors, intermediatethe Breslow wasintermediate oxidized was by carbonoxidized dioxide by carbon with dioxide the liberation with the of liberation carbon monoxide. of carbon monoxide. The expected The aromaticexpected carboxylicaromatic carboxylic acids were acids obtained were with obtained moderate with to highmoderate yields. to One high year yields. earlier, One Gu year and Zhangearlier, presented Gu and aZhang catalyzed presented by NHC a catalyzed oxidation by NHC of aromatic oxidation aldehydes of aromatic (including aldehydes cinnamaldehydes) (including cinnamaldehydes) to carboxylic acidsto carboxylic [60]. As acids an oxidant, [60]. As carbon an oxidant, dioxide carbon was alsodioxide used, was but also the used, authors but providedthe authors the provided mechanism the 2 withmechanism the NHC-catalyzed with the NHC-catalyzed step of CO2 stepreduction. of CO2 Gureduction. and Zhang Gu and assumed Zhang that assumed aldehyde that molecules aldehyde weremolecules directly were oxidized directly by oxidized oxygen by from oxygen the carbon from the dioxide-NHC carbon dioxide-NHC complex. Incomplex. this case, In this products case, wereproducts obtained were withobtained differentiated with differentiated yields. Bode yields. and co-workersBode and co-workers published anpublished article developing an article earlierdeveloping research earlier into research the oxidizing into the properties oxidizing ofproperties carbon dioxide of carbon in NHCdioxide catalysis in NHC in catalysis 2011 [61 ].in Their 2011 2 experiments[61]. Their experiments proved that proved molecular that oxygen, molecular instead oxygen, of CO instead2, plays of the CO role2, plays of the the oxidizing role of the agent oxidizing in the mentionedagent in the reactions mentioned (Figure reactions 13). Nonetheless,(Figure 13). Noneth carboneless, dioxide carbon prevents dioxide formation prevents of formation side products of side via aldehydeproducts via dimerization aldehyde dimeri or oligomerization.zation or oligomerization.

Figure 13. Difference between Zhang’s and Bode’s conclusions.

As is well well known, known, reactions reactions promoted promoted by by ch chiraliral NHC-catalysts NHC-catalysts enable enable the the synthesis synthesis of ofenantiomerically enantiomerically enriched enriched products. products. Scheidt’ Scheidt’ss group group reported reported the the dessymetrization dessymetrization of cis-1,2-cyclohexanediol by cinnamiccinnamic aldehydealdehyde oxidativeoxidative esteriﬁcationesterification inin 20072007 [[62].62]. TheyThey obtainedobtained a monocinnamate esterester withwith 80%80% eeee andand 58%58% yieldyield (Figure(Figure 1414).).

Figure 14. Synthesis reported by Scheidt and co-workers.

In 2011, Iida and Yashima reported an analogous reaction of the dessymetrization of cis-1,2-cyclohexanediol via oxidative catalytic benzoylation using triazolium salt as the NHC precursor and riboflavin as the co-catalyst [49]. Yields and enantiomeric excesses were lower than results showed in Scheidt’s work. Notwithstanding, the developed procedure was an aerobic oxidation, which is a considerable advantage. You and co-workers developed the oxidative NHC-catalyzed Claisen rearrangement in 2015 [63]. Bicyclic dihydropyranone-fused naphtols were obtained with generally high yields and moderate to good enantiomeric excesses. As an oxidant, the sterically hindered quinone reported in 1957 by Kharasch was used (Figure 15) [64]. More importantly, in this reaction, not only carbon- heteroatom bonds were generated but also a novel carbon-carbon bond was formed (Figure 16).

Catalysts 2018, 8, 549 8 of 16

In 2011, Iida and Yashima reported an analogous reaction of the dessymetrization of cis-1,2-cyclohexanediol via oxidative catalytic benzoylation using triazolium salt as the NHC precursor and riboﬂavin as the co-catalyst [49]. Yields and enantiomeric excesses were lower than results showed in Scheidt’s work. Notwithstanding, the developed procedure was an aerobic oxidation, which is a considerable advantage. You and co-workers developed the oxidative NHC-catalyzed Claisen rearrangement in 2015 [63]. Bicyclic dihydropyranone-fused naphtols were obtained with generally high yields and moderate to good enantiomeric excesses. As an oxidant, the sterically hindered quinone reported in 1957 by Kharasch was used (Figure 15)[64]. More importantly, in this reaction, not only carbon-heteroatom bondsCatalysts were 2018, 8 generated, x FOR PEER but REVIEW also a novel carbon-carbon bond was formed (Figure 16). 8 of 15

Figure 15. Kharasch’s oxidant.

Figure 16. Claisen rearrangement by You andand co-workers.co-workers. In 2018, Chi et al. reported the enantioselective NHC-catalyzed oxidative coupling of enals In 2018, Chi et al. reported the enantioselective NHC-catalyzed oxidative coupling of enals and and di(hetero)arylmethanes (Figure 17)[65]. In one of the proposed mechanisms, there occurs a di(hetero)arylmethanes (Figure 17) [65]. In one of the proposed mechanisms, there occurs a Claisen Claisen rearrangement or 1,4-addition, between the generated acylazolium and di(hetero)arylmethane rearrangement or 1,4-addition, between the generated acylazolium and di(hetero)arylmethane derivative. Another mechanism assumes oxidation via SET. The authors obtained the expected derivative. Another mechanism assumes oxidation via SET. The authors obtained the expected products with high yields and excellent enantioselectivities. products with high yields and excellent enantioselectivities.

Figure 17. Synthesis reported by Chi and co-workers.

InIn 2018,2018, Yang,Yang, Chi Chi and and co-workers co-workers reported reported the the NHC-catalyzed NHC-catalyzed oxidative oxidative acylation acylation of 1,2-diolsof 1,2-diols by aldehydesby aldehydes with with high high site-selectivities site-selectivities (Figure (Figure 18 18))[66 [66].]. The The authors authors obtained obtained variousvarious hydroxyestershydroxyesters acylated at primary hydroxylhydroxyl groupsgroups withwith moderatemoderate yieldsyields andand enantiomericenantiomeric excesses.excesses.

Figure 18. Synthesis reported by Yang, Chi et al.

Synthesis of amides and thioesters via oxidative NHC-catalyzed reactions is also possible. In 2011, some examples of enantiomerically enriched benzoic acid amides and thioesters were synthesized from benzaldehydes and racemic amines and thiols by Iida and Yashima, with moderate yields and very low enantiomeric excesses below 9% [49]. In 2017, Ma et al. showed that direct N-acylation of amides by aldehydes in oxidative NHC-catalyzed reaction is also possible [67]. Various carboxylic or sulfonic acids amides were acylated by diverse aldehydes with good yields. Bode et al. reported an enentioselective oxidative approach for the synthesis of dihydropyridinones via an NHC-catalyzed aza-Claisen rearrangement

Catalysts 2018, 8, x FOR PEER REVIEW 8 of 15

Figure 15. Kharasch’s oxidant.

Figure 16. Claisen rearrangement by You and co-workers.

In 2018, Chi et al. reported the enantioselective NHC-catalyzed oxidative coupling of enals and di(hetero)arylmethanes (Figure 17) [65]. In one of the proposed mechanisms, there occurs a Claisen rearrangement or 1,4-addition, between the generated acylazolium and di(hetero)arylmethane derivative. Another mechanism assumes oxidation via SET. The authors obtained the expected products with high yields and excellent enantioselectivities.

Figure 17. Synthesis reported by Chi and co-workers.

In 2018, Yang, Chi and co-workers reported the NHC-catalyzed oxidative acylation of 1,2-diols Catalystsby aldehydes2018, 8, 549with high site-selectivities (Figure 18) [66]. The authors obtained various hydroxyesters9 of 16 acylated at primary hydroxyl groups with moderate yields and enantiomeric excesses.

FigureFigure 18.18. Synthesis reportedreported byby Yang,Yang, ChiChi etet al.al.

Synthesis of amides and thioesters via oxidative NHC-catalyzed reactions is also possible. In 2011, Synthesis of amides and thioesters via oxidative NHC-catalyzed reactions is also possible. In some examples of enantiomerically enriched benzoic acid amides and thioesters were synthesized 2011, some examples of enantiomerically enriched benzoic acid amides and thioesters were from benzaldehydes and racemic amines and thiols by Iida and Yashima, with moderate yields and synthesized from benzaldehydes and racemic amines and thiols by Iida and Yashima, with moderate very low enantiomeric excesses below 9% [49]. yields and very low enantiomeric excesses below 9% [49]. In 2017, Ma et al. showed that direct N-acylation of amides by aldehydes in oxidative In 2017, Ma et al. showed that direct N-acylation of amides by aldehydes in oxidative NHC-catalyzed reaction is also possible [67]. Various carboxylic or sulfonic acids amides were acylated NHC-catalyzed reaction is also possible [67]. Various carboxylic or sulfonic acids amides were byCatalysts diverse 2018 aldehydes, 8, x FOR PEER with REVIEW good yields. Bode et al. reported an enentioselective oxidative approach9 of 15 Catalystsacylated 2018 by, 8 ,diverse x FOR PEER aldehydes REVIEW with good yields. Bode et al. reported an enentioselective oxidative9 of 15 for the synthesis of dihydropyridinones via an NHC-catalyzed aza-Claisen rearrangement in 2011 approach for the synthesis of dihydropyridinones via an NHC-catalyzed aza-Claisen rearrangement in 2011 (Figure 19) [68]. Kharasch’s oxidizer was also used as an external oxidant. Various examples (Figurein 2011 (Figure19)[68]. 19) Kharasch’s [68]. Kharasch’s oxidizer oxidizer was also was usedalso used as an as external an external oxidant. oxidant. Various Various examples examples of of unprotected dihydropyridinones were obtained with high yields and good enantioselectivities. unprotectedof unprotected dihydropyridinones dihydropyridinones were were obtained obtained with with high high yields yields and and good good enantioselectivities. enantioselectivities.

Figure 19. Aza-Claisen rearrangement by Bode et al. Figure 19. Aza-Claisen rearrangement by Bode et al.

LessLess popularpopular than than the the two-electron two-electron oxidation oxidation of theof the Breslow Breslow intermediate intermediate is oxidation is oxidation via the via SET the Less popular than the two-electron oxidation of the Breslow intermediate is oxidation via the process,SET process, in which in which instead instead of an acylazolium of an acylazolium ion, a very ion, reactive a very radicalreactive cation radical species cation is generated.species is SET process, in which instead of an acylazolium ion, a very reactive radical cation species is Thesegenerated. intermediates These intermediates can undergo can reactions undergo with reaction others radicals with other present radicals in the present reaction in mixture.the reaction Li, generated. These intermediates can undergo reactions with other radicals present in the reaction Webstermixture. and Li, Chi Webster reported and the Chiβ,β -couplingreported oftheα ,β-unsaturated,β-coupling of nitroalkanes α,β-unsaturated in the presence nitroalkanes of aldehyde, in the mixture. Li, Webster and Chi reported the β,β-coupling of α,β-unsaturated nitroalkanes in the methanolpresence of and aldehyde, an NHC methanol catalyst in and 2014 an (Figure NHC 20catalyst)[69]. SETin 2014 oxidation (Figure was 20) guaranteed[69]. SET oxidation by pyruvate was presence of aldehyde, methanol and an NHC catalyst in 2014 (Figure 20) [69]. SET oxidation was ferredoxinguaranteed oxidoreductase by pyruvate (PFOR).ferredoxin Structurally oxidoreductase complex (PFOR). products Structurally were obtained complex with highproducts yields were and guaranteed by pyruvate ferredoxin oxidoreductase (PFOR). Structurally complex products were moderateobtained with diastereomeric high yields excesses. and moderate diastereomeric excesses. obtained with high yields and moderate diastereomeric excesses.

Figure 20. Figure 20. SynthesisSynthesis reportedreported byby Li,Li, Webster,Webster, and and Chi. Chi. Figure 20. Synthesis reported by Li, Webster, and Chi. Sun and Ye developed the oxidative [3 + 2] annulation of dioxindoles and enals in 2017 [70]. The Sun and Ye developed the oxidative [3 + 2] annulation of dioxindoles and enals in 2017 [70]. The expectedSun and products Ye developed were obtained the oxidative in the efﬁcient[3 + 2] annulation radical cross-coupling of dioxindoles of and homoenolate enals in 2017 or [70]. enolate. The expected products were obtained in the efficient radical cross-coupling of homoenolate or enolate. Nitrobenzeneexpected products was usedwere asobtained an oxidizing in the agentefficient and radical triazolium cross-coupling salts as precatalysts of homoenolate (Figure or 21enolate.). The Nitrobenzene was used as an oxidizing agent and triazolium salts as precatalysts (Figure 21). The developedNitrobenzene approach was used was as distinguished an oxidizing as agent a highly and diastereoselective triazolium salts andas precatalysts enantioselctive (Figure method. 21). OneThe developed approach was distinguished as a highly diastereoselective and enantioselctive method. yeardeveloped later, Ye approach et al. reported was distinguished a similar synthesis as a highly using βdiastereoselective,β-disubstituted enalsand enantioselctive [71]. method. One year later, Ye et al. reported a similar synthesis using β,β-disubstituted enals [71]. One year later, Ye et al. reported a similar synthesis using β,β-disubstituted enals [71].

Figure 21. Synthesis reported by Sun and Ye. Figure 21. Synthesis reported by Sun and Ye.

SET oxidations of the Breslow intermediate are convenient enantioselective syntheses of SET oxidations of the Breslow intermediate are convenient enantioselective syntheses of 2-hydroxyketones via β-hydroxylation of enals [72,73]. Moreover, homo- and cross-coupling of enals, 2-hydroxyketones via β-hydroxylation of enals [72,73]. Moreover, homo- and cross-coupling of enals, resulting in 3,4-diarylcyclopentanones, is also possible with moderate to good ee values [74]. resulting in 3,4-diarylcyclopentanones, is also possible with moderate to good ee values [74]. Applications of radical species generated in SET oxidation of the Breslow intermediate are very Applications of radical species generated in SET oxidation of the Breslow intermediate are very promising with this continuously developing synthetic approach [75]. promising with this continuously developing synthetic approach [75]. NHC catalysis under oxidizing conditions does not only occur via oxidation of the Breslow NHC catalysis under oxidizing conditions does not only occur via oxidation of the Breslow intermediate. Several examples of the oxidizing of other species during the NHC-catalyzed reaction intermediate. Several examples of the oxidizing of other species during the NHC-catalyzed reaction have been reported. In 2006, Ding’s group developed an N-tosylaziridines ring opening using have been reported. In 2006, Ding’s group developed an N-tosylaziridines ring opening using

Catalysts 2018, 8, x FOR PEER REVIEW 9 of 15 in 2011 (Figure 19) [68]. Kharasch’s oxidizer was also used as an external oxidant. Various examples of unprotected dihydropyridinones were obtained with high yields and good enantioselectivities.

Figure 19. Aza-Claisen rearrangement by Bode et al.

Less popular than the two-electron oxidation of the Breslow intermediate is oxidation via the SET process, in which instead of an acylazolium ion, a very reactive radical cation species is generated. These intermediates can undergo reactions with other radicals present in the reaction mixture. Li, Webster and Chi reported the β,β-coupling of α,β-unsaturated nitroalkanes in the presence of aldehyde, methanol and an NHC catalyst in 2014 (Figure 20) [69]. SET oxidation was guaranteed by pyruvate ferredoxin oxidoreductase (PFOR). Structurally complex products were obtained with high yields and moderate diastereomeric excesses.

Figure 20. Synthesis reported by Li, Webster, and Chi.

Sun and Ye developed the oxidative [3 + 2] annulation of dioxindoles and enals in 2017 [70]. The expected products were obtained in the efficient radical cross-coupling of homoenolate or enolate. Nitrobenzene was used as an oxidizing agent and triazolium salts as precatalysts (Figure 21). The Catalystsdeveloped2018 ,approach8, 549 was distinguished as a highly diastereoselective and enantioselctive method.10 of 16 One year later, Ye et al. reported a similar synthesis using β,β-disubstituted enals [71].

Figure 21. Synthesis reported by Sun and Ye. Figure 21. Synthesis reported by Sun and Ye. SET oxidations of the Breslow intermediate are convenient enantioselective syntheses of SET oxidations of the Breslow intermediate are convenient enantioselective syntheses of 2-hydroxyketones via β-hydroxylation of enals [72,73]. Moreover, homo- and cross-coupling of 2-hydroxyketones via β-hydroxylation of enals [72,73]. Moreover, homo- and cross-coupling of enals, enals, resulting in 3,4-diarylcyclopentanones, is also possible with moderate to good ee values [74]. resulting in 3,4-diarylcyclopentanones, is also possible with moderate to good ee values [74]. Applications of radical species generated in SET oxidation of the Breslow intermediate are very Applications of radical species generated in SET oxidation of the Breslow intermediate are very promising with this continuously developing synthetic approach [75]. promising with this continuously developing synthetic approach [75]. NHC catalysis under oxidizing conditions does not only occur via oxidation of the Breslow NHC catalysis under oxidizing conditions does not only occur via oxidation of the Breslow intermediate. Several examples of the oxidizing of other species during the NHC-catalyzed reaction intermediate.Catalysts 2018, 8, xSeveral FOR PEER examples REVIEW of the oxidizing of other species during the NHC-catalyzed reaction10 of 15 have been reported. In 2006, Ding’s group developed an N-tosylaziridines ring opening using have been reported. In 2006, Ding’s group developed an N-tosylaziridines ring opening using aldehydes underunder aerobicaerobic conditionsconditions (Figure(Figure 2222))[ [76].76]. The resulting esters of 2-aminoalcohols arose via oxidation of the intermediate which was generated after the aziridine ring opening with the Breslow intermediate.intermediate. The The final ﬁnal products were obtained with moderate to high yields and, in several cases, veryvery goodgood regioselectivities.regioselectivities.

Figure 22. N-tosylaziridines ring openingopening by Ding and co-workers. Recently Zeitler and Connon have reported oxidative esteriﬁcation of aldehydes occurring Recently Zeitler and Connon have reported oxidative esterification of aldehydes occurring via via oxidation of benzoin, generated by the condensation of two molecules of benzaldehydes [77]. oxidation of benzoin, generated by the condensation of two molecules of benzaldehydes [77]. Furthermore, the obtained benzidin reacts with carbene to give the Breslow intermediate, which Furthermore, the obtained benzidin reacts with carbene to give the Breslow intermediate, which subsequently reacts with the corresponding alcohol. After elimination, esters of benzoic acids are subsequently reacts with the corresponding alcohol. After elimination, esters of benzoic acids are obtained with good yields (Figure 23). obtained with good yields (Figure 23).

Figure 23. Synthesis of benzoic acid esters by Zeitler and Connon. Figure 23. Synthesis of benzoic acid esters by Zeitler and Connon. In 2015 Sudalai et al. reported the synthesis of α,β-epoxyketones via the oxidative NHC-catalyzed In 2015 Sudalai et al. reported the synthesis of α,β-epoxyketones via the oxidative NHC- coupling of alkenes with aldehydes [78]. Styrene derivative was ﬁrstly oxidized by NBS catalyzed coupling of alkenes with aldehydes [78]. Styrene derivative was firstly oxidized by NBS (N-bromosuccinimide) and DMSO to phenacyl bromide. The resulting acylazolium reacted then (N-bromosuccinimide) and DMSO to phenacyl bromide. The resulting acylazolium reacted then with with a second molecule of aldehyde and, after elimination, α,β-epoxyketones were obtained with a second molecule of aldehyde and, after elimination, α,β-epoxyketones were obtained with moderate to good yields (Figure 24). moderate to good yields (Figure 24).

Figure 24. Synthesis reported by Sudalai et al.

5. Oxidative NHC Catalysis via Electrolysis The Breslow intermediate can also be oxidized to an acylazolium ion by anodic electrochemical oxidation. Cyclic voltammograms of Breslow intermediates lead to low oxidation potentials— approximately 0.5 V for first and 0.9 V for second step of the oxidation [79]. In 2012, Boydstone and co-workers reported the synthesis of esters in an NHC-catalyzed reaction of aldehydes and alcohols in an undivided electrochemical cell (Figure 25) [80]. Essentially, the reaction procedure with oxidation of the Breslow intermediate via electrolysis does not differ from an approach with an external oxidizer. The fundamental difference is the necessity of an electrolyte addition. In Boystone’s work, tetrabutylammonium bromide (TBAB) was added as an electrolyte. The expected esters were obtained with excellent yields.

Catalysts 2018, 8, x FOR PEER REVIEW 10 of 15 aldehydes under aerobic conditions (Figure 22) [76]. The resulting esters of 2-aminoalcohols arose via oxidation of the intermediate which was generated after the aziridine ring opening with the Breslow intermediate. The final products were obtained with moderate to high yields and, in several cases, very good regioselectivities.

Figure 22. N-tosylaziridines ring opening by Ding and co-workers.

Recently Zeitler and Connon have reported oxidative esterification of aldehydes occurring via oxidation of benzoin, generated by the condensation of two molecules of benzaldehydes [77]. Furthermore, the obtained benzidin reacts with carbene to give the Breslow intermediate, which subsequently reacts with the corresponding alcohol. After elimination, esters of benzoic acids are obtained with good yields (Figure 23).

Figure 23. Synthesis of benzoic acid esters by Zeitler and Connon.

In 2015 Sudalai et al. reported the synthesis of α,β-epoxyketones via the oxidative NHC- catalyzed coupling of alkenes with aldehydes [78]. Styrene derivative was firstly oxidized by NBS (N-bromosuccinimide) and DMSO to phenacyl bromide. The resulting acylazolium reacted then with Catalystsa second2018 ,molecule8, 549 of aldehyde and, after elimination, α,β-epoxyketones were obtained11 with of 16 moderate to good yields (Figure 24).

FigureFigure 24.24. Synthesis reported byby SudalaiSudalai etet al.al. 5. Oxidative NHC Catalysis via Electrolysis 5. Oxidative NHC Catalysis via Electrolysis The Breslow intermediate can also be oxidized to an acylazolium ion by anodic electrochemicalThe Breslow oxidation. intermediate Cyclic can voltammograms also be oxidized ofto Breslowan acylazolium intermediates ion by anodic lead to electrochemical low oxidation potentials—approximatelyoxidation. Cyclic voltammograms 0.5 V for of ﬁrst Breslow and 0.9 in Vtermediates for second lead step to of thelow oxidationoxidation [ 79potentials—]. In 2012, Boydstoneapproximately and co-workers0.5 V for first reported and 0.9 the V synthesisfor second of st estersep of inthe an oxidation NHC-catalyzed [79]. In reaction2012, Boydstone of aldehydes and andco-workers alcohols reported in an undivided the synthesis electrochemical of esters in cellan NHC-catalyzed (Figure 25)[80]. reaction Essentially, of aldehydes the reaction and procedure alcohols within an oxidation undivided of theelectrochemical Breslow intermediate cell (Figure viaelectrolysis 25) [80]. Essentially, does not differ the fromreaction an approach procedure with with an externaloxidation oxidizer. of the TheBreslow fundamental intermediate difference via electrolys is the necessityis does of not an differ electrolyte from addition. an approach In Boystone’s with an external oxidizer. The fundamental difference is the necessity of an electrolyte addition. In Boystone’s work, tetrabutylammonium bromide (TBAB) was added as an electrolyte. The expected esters were Catalystswork, tetrabutylammonium 2018, 8, x FOR PEER REVIEW bromide (TBAB) was added as an electrolyte. The expected esters11 were of 15 obtainedCatalysts 2018 with, 8, x excellent FOR PEER yields.REVIEW 11 of 15 obtained with excellent yields.

Figure 25. Electrochemical NHC esterification reported by Boydstone et al. Figure 25. Electrochemical NHC esterificationesterification reported by Boydstone etet al.al. Brown et al. reported the analogous synthesis of esters [81] [81] and amides [82] [82] using a microflowmicroflow Brown et al. reported the analogous synthesis of esters [81] and amides [82] using a microflow electrochemical cellcell (Figure(Figure 26 26).). Although Although good good product product yields yields were were achieved, achieved, Brown’s Brown’s procedure procedure has electrochemical cell (Figure 26). Although good product yields were achieved, Brown’s procedure anhas enormous an enormous disadvantage—NHC disadvantage—NHC salt mustsalt must be added be added as an equimolaras an equimolar reagent. reagent. Boydstone’s Boydstone’s group has an enormous disadvantage—NHC salt must be added as an equimolar reagent. Boydstone’s showedgroup showed a similar a similar procedure procedure of thioesters of thioesters synthesis synthesis in an undivided in an undivided cell in 2014 cell [ 83in]. 2014 The [83]. reported The group showed a similar procedure of thioesters synthesis in an undivided cell in 2014 [83]. The approachreported approach enables productenables product synthesis synthesis with good-to-excellent with good-to-excellent yields, yields, but disulfide but disulfide byproducts byproducts were reported approach enables product synthesis with good-to-excellent yields, but disulfide byproducts observedwere observed in some in some cases. cases. were observed in some cases.

Figure 26. MicroflowMicroﬂow electrochemical cell used by Brown and co-workers. Figure 26. Microflow electrochemical cell used by Brown and co-workers. 6. Conclusions 6. Conclusions N-Heterocyclic carbene catalysis under oxidizing conditions enables several diverse synthetic approaches.N-Heterocyclic Various carbene oxidizing catalysis mechanisms, under oxidizing oxidizer s,conditions and exploitation enables severalof domino diverse reactions synthetic or cooperativeapproaches. catalysisVarious extendsoxidizing the mechanisms, capabilities oxidizerand applicationss, and exploitation of NHC catalysis of domino under reactions oxidizing or conditionscooperative in catalysis organic extendssynthesis. the This capabilities branch of and organocatalysis applications hasof NHC been catalysisextensively under developed oxidizing in recentconditions years, in giving organic hope synthesis. for the futureThis branch discovery of organocatalysis of novel elegant has synthetic been extensivelyprocedures. developed Significantly in largerecent amounts years, giving of complex hope for organic the future molecules discovery and important of novel elegant substrates synthetic in the procedures. total synthesis Significantly of natural productslarge amounts and ofpharmaceuticals complex organic canmolecules be obtained and important via procedures substrates inimplementing the total synthesis oxidative of natural and oxygenativeproducts and NHC pharmaceuticals catalysis. Many can esters, be obtained amides , viathioesters, procedures lactones, implementing and lactames—frequently oxidative and enantioenriched—synthesizedoxygenative NHC catalysis. Many by organocatalytic esters, amides approaches, thioesters, can lactones, be very and appropriable lactames—frequently reactants in sophisticatedenantioenriched—synthesized syntheses. The futureby organocatalytic development approaches of NHC catalysiscan be very under appropriable oxidizing reactantsconditions in probablysophisticated will syntheses.be premised The on future electroorganic development chemistry of NHC and catalysis photochemistry. under oxidizing Increasingly conditions ideal equipmentprobably will for be electrosynthesispremised on electroorganic and common chemistry applications and photochemistry. of photoinduced Increasingly reactions ideal in organocatalysisequipment for areelectrosynthesis leading to progress and in commonthis branch a pplicationsof organic chemistry. of photoinduced reactions in organocatalysis are leading to progress in this branch of organic chemistry. Author Contributions: K.D. and Z.R. wrote the paper. Author Contributions: K.D. and Z.R. wrote the paper. Funding: The project is co-financed by the National Science Center as part of the SONATA BIS program. (UMO-2016/22/E/ST5/00469).Funding: The project is co-financed by the National Science Center as part of the SONATA BIS program. (UMO-2016/22/E/ST5/00469).

Catalysts 2018, 8, 549 12 of 16

6. Conclusions N-Heterocyclic carbene catalysis under oxidizing conditions enables several diverse synthetic approaches. Various oxidizing mechanisms, oxidizers, and exploitation of domino reactions or cooperative catalysis extends the capabilities and applications of NHC catalysis under oxidizing conditions in organic synthesis. This branch of organocatalysis has been extensively developed in recent years, giving hope for the future discovery of novel elegant synthetic procedures. Signiﬁcantly large amounts of complex organic molecules and important substrates in the total synthesis of natural products and pharmaceuticals can be obtained via procedures implementing oxidative and oxygenative NHC catalysis. Many esters, amides, thioesters, lactones, and lactames—frequently enantioenriched—synthesized by organocatalytic approaches can be very appropriable reactants in sophisticated syntheses. The future development of NHC catalysis under oxidizing conditions probably will be premised on electroorganic chemistry and photochemistry. Increasingly ideal equipment for electrosynthesis and common applications of photoinduced reactions in organocatalysis are leading to progress in this branch of organic chemistry.

Author Contributions: K.D. and Z.R. wrote the paper. Funding: The project is co-financed by the National Science Center as part of the SONATA BIS program. (UMO-2016/22/E/ST5/00469). Conflicts of Interest: The authors declare no conflict of interest.

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