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NHC-Catalyzed Cross-Coupling of Aldehydes for C(sp2)−O Bond Formation

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07 March 2024

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07 March 2024

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Abstract
In the past few decades, N-heterocyclic carbenes (NHCs) open the new field of organocatalysis in synthetic organic chemistry. This review highlights the dramatic progress in the NHC-catalyzed C−O bond formation based on the activation of aldehyde C(sp2)−H bonds. The oxidative and redox transformations for the synthesis of various molecules with structural diversity and complexity are summarized. Furthermore, new methods and strategies for NHC catalysis are emerging continuously; thus, cooperative catalysis with Brønsted acid, hydrogen-bonding catalyst, transition-metal catalyst, and photocatalyst is also described.
Keywords: 
Subject: Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

N-Heterocyclic carbenes (NHCs) have gained increasing attention as a powerful and versatile organocatalyst in organic synthesis, since the first isolation of stable carbene in 1991 [1]. The NHC catalysis leads to the novel approach for activating the aldehyde C(sp2)−H bonds via the formation of Breslow intermediates. Particularly, reversing the reactivity of aldehydes “umpolung of aldehydes” opens the new field of organocatalysis [2–7].
In recent years, the use of chiral NHCs has attracted substantial attention for the enantioselective synthesis of various molecules with structural diversity and complexity [8–13]. Furthermore, new methods and strategies for NHC catalysis are emerging continuously, leading to the remarkable progress on the cooperative catalysis with Lewis acid, Brønsted acid, hydrogen-bonding organocatalyst, and transition-metal catalyst [14–17]. More recently, the NHC catalysis has been expanded by the combination with photocatalysis as well as radical catalysis [18–23]. In this review article, we overview the progress on NHC-catalyzed C−O bond formation of aldehydes by showing the representative reactions.

2. Oxidative Esterification of Aldehydes

2.1. Esterification of Aldehydes under Oxidation Conditions

The NHC-catalyzed esterification of aldehydes was widely investigated under the oxidation conditions as an important approach to achieve the dehydrogenative cross-coupling of aldehydes with alcohols [24–33]. The oxidative NHC-catalysis was achieved by using MnO2 or azobenzene as an oxidant (Scheme 1) [24,25]. In the presence of NHC generated from triazolium-based NHC precursor A1 (10 mol%) and DBU (1.1 equiv), the dehydrogenative cross-coupling of aldehyde 1 with alcohols was performed in CH2Cl2 at room temperature under the oxidative conditions using MnO2 [24]. The corresponding esters 2 were obtained in good yields. The oxidative esterification of benzaldehyde 3 using precursor A2 and azobenzene as a stoichiometric oxidant gave the esters 4 [25]. These transformations are initiated by the formation of Breslow intermediate, which is oxidized to acyl azolium by an oxidant. Finally, the reaction of acyl azolium with ROH results in the release of free NHC catalyst and the formation of ester. Furthermore, 3,3,5,5-t-butyldiphenoqinone (DQ), phenazine, CCl3CN, phenazine, and tert-butyl hydroperoxide (TBHP) are used as an oxidant for the esterification of aldehydes [26–34]. The aerobic or electrochemical oxidations were also used in conjunction with NHC-catalyzed esterification of aldehydes [35–40].
Chiral NHCs have gained increasing attention as an organocatalyst for the enantioselective synthesis. The enantioselective synthesis of β-hydroxyl esters from enals was achieved under the oxidation conditions using chiral NHC catalysts (Scheme 2) [41,42]. Employing 4-nitropyridine N-oxide as an oxidant with chiral NHC generated from precursor A3 (10 mol%) and NaOAc, the β-hydroxylation of cinnamaldehyde 5 took place to generate β-hydroxyl ester 6 in 45% yield with 92% ee [41]. In this reaction, β-hydroxyl group is introduced by the oxygen transfer from nitro group of an oxidant through the radical pathway. The enantioselective synthesis of α-fluoro esters from aldehydes was reported [43]. In the presence of precursor (5aS,10bR)-A4a, K2CO3 and N-fluorobenzenesulfonimide (NFSI), the oxidative functionalization of aliphatic aldehyde 7 proceeded to give α-fluoro ester 8 with good enantioselectivity. In this reaction, NFSI serves not only as the electrophilic fluorination reagent but also an oxidant. Chiral NHC catalyst was used for the atroposelective synthesis of axially chiral styrenes [43]. When precursor (5aS,10bR)-A5 having a bulkier N-tricyclohexylphenyl substituent was employed under the oxidation conditions using DQ as an oxidant, the reaction of ynal 9 with sulfinic acid and 2-methoxyphenol afforded the styrene 10 bearing a chiral axis in 91% yield with > 99:1 er and > 20:1 E/Z selectivity. This transformation proceeds through the 1,4-addition of sulfinic anion to acetylenic acyl azolium intermediate followed by E-selective protonation to set up the chiral axis. Furthermore, the chiral NHC-catalyzed oxidative coupling of enals with carboxylic acids was developed by employing hypervalent iodine-(III) reagent [45]. Additionally, chiral NHCs were used for the regioselective functionalization of carbohydrates [46,47]. The oxidative esterification of carbohydrates proceeded with excellent regioselectivities when 2,6-dichloro-benzaldehyde or 2-fluoro-6-iodo-benzaldehyde was employed as an acylation precursor [46].

2.2. Kinetic Resolution

Chiral NHC-catalyzed oxidative esterification has been used for achieving the kinetic resolution [48–57]. The kinetic resolution of racemic 3-hydroxy oxindole rac-11 was examined by using chiral NHC generated from (5aS,10bR)-A6b (Scheme 3) [48]. In the presence of Mg(OTf)2 and NaBF4, the use of MnO2 as an external oxidant effectively induced the reaction between rac-11 and cinnamaldehyde 5 to give the ester 12 in 52% yield and 87% ee, accompanied with the recovered 11 in 45% yield and 98% ee. The dynamic kinetic resolution of racemic 3-hydroxyphthalide 13 was achieved by the NHC-catalyzed acylation [52]. In the presence of chiral NHC generated from (5aS,10bR)-A4a (20 mol%) and i-Pr2NEt (1 equiv), the acylation of 13 with aldehyde 14 was performed in EtOAc at room temperature under the oxidative conditions using DQ (1.2 equiv) as an oxidant. The corresponding ester 15 was obtained in 96% yield with 98:2 er.
The NHC-catalyzed dynamic kinetic resolution was applied to the synthesis of axially chiral compounds (Scheme 4) [55,56]. Atroposelective dynamic kinetic resolution of racemic biaryl aldehyde 16 was developed by using the oxidative NHC catalysis [55]. In the presence of NHC, generated from precursor (5aR,10bS)-A7b, and DQ oxidant, the esterification of aldehyde 16 with benzyl alcohol gave chiral biaryl amino ester 17 in 90% yield with 96.5:3.5 er. The one-pot synthesis of the axially chiral binaphthyl compound 21 from racemic ketone 18 was also developed [56]. Initially, the NHC-catalyzed atroposelective acylation of ketone oxygen atom on 18 with aldehyde 19 gave the enol ester intermediate 20 via dynamic kinetic resolution. The subsequent one-pot oxidation of 20 by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidant led to the chiral binaphthyl compound 21.

2.3. Desymmetrization

The desymmetrization of diols based on chiral NHC-catalyzed oxidative esterification of aldehydes was studied [58–60]. The desymmetrization reaction of triarylmethane-bisphenol 22 with benzaldehyde 3 was performed under the conditions using precursor (5aR,10bS)-A4b, 1,4-diazobicyclo(2.2.2)octane (DABCO), and DQ as an oxidant in 1,2-dimethoxyethane at 0 °C (Scheme 5) [59]. The desymmetrization product 23 was obtained in 98% yield with 97.2:2.8 er.
The chiral NHC-catalyzed oxidative esterification of dialdehydes was studied [61–64]. The NHC-catalyzed atroposelective esterification of biaryl dialdehyde 24 was reported (Scheme 6) [61]. In the presence of precursor (5aS,10bR)-A4b, Cs2CO3 and DQ, the selective esterification of 24 proceeded to give the axially chiral ester 25 in 81% yield with 96% ee. The mechanistic studies indicate that the highly enantioselective transformation is achieved through the NHC-catalyzed desymmetrization of dialdehyde 24 and the further kinetic resolution by the second esterification of undesired enantiomer of ester 25. The atroposelective esterification of dialdehyde 26 was also studied [63,64]. The NHC-catalyzed desymmetrization of prochiral dialdehyde 26 gave the axially chiral diaryl ether 27 with the excellent enantioselectivity. The enantioselectivity of 27 is also improved by the kinetic resolution leading to diether.

3. Oxidative Cyclization and Annulation

3.1. Cyclization

Several examples of the oxidative cyclization were reported [65–68]. The NHC-catalyzed aerobic oxidation of ynamide-tethered benzaldehyde 28 was studied (Scheme 7) [67]. The regioselective synthesis of (Z)-3-aminomethylenephthalide 29 was achieved by using NEt3 as a base, whereas the use of i-Pr2NEt led to the 6-end cyclization giving 3-aminoisocoumarin 30. Initially, the carboxylic acid intermediate is generated through the aerobic oxidation of Breslow intermediate. Next, the base-promoted regioselective cyclization of carboxylic acid toward the ynamide moiety affords 29 or 30. Furthermore, chiral NHC-catalyzed macrocyclization was developed for the atroposelective synthesis of planar-chiral indoles [68].
3.2.[3 + 3] Annulation
In the NHC catalysis, the α,β-unsaturated acyl azoliums are Michael acceptors acting as a C3 synthon for the [3 + 3] annulation [69–77]. The oxidative reaction of β-cyano-substituted α,β-unsaturated aldehyde 31 and ethyl acetoacetate 32 was studied (Scheme 8) [70]. Under the optimized conditions using the precursor (5aR,10bS)-A4a (20 mol%), DMAP (20 mol%), LiCl (1 equiv) and DQ (1.5 equiv) as an oxidant, dihydropyran-4-carbonitrile 33 bearing a quaternary carbon center was obtained in 90% yield with 97:3 er. In this reaction, both the reaction efficiency and stereoselectivity were improved by the use of LiCl as an additive. This annulation is initiated by the generation of Breslow intermediate, which is oxidated into the α,β-unsaturated acyl azolium. Next, the Michael addition of 32 to acyl azolium intermediate and the subsequent lactonization provide the annulation product 33, accompanied by the liberation of NHC catalyst. Asymmetric synthesis of axially chiral molecules was achieved by oxidative [3 + 3] annulation [76] Chiral NHC-catalyzed oxidative annulation of cinnamaldehyde 5 and indole-1-pyruvate ester 34 gave the N-arylindole 35 with a C−N chiral axis.
The NHC-catalyzed oxidative esterification of α,β-unsaturated aldehydes with 2-naphthols was applied to the enantioselective [3 + 3] annulation reaction by merging with Claisen rearrangement (Scheme 9) [78]. The chiral NHC-catalyzed annulation reaction of α,β-unsaturated aldehyde 36 and 3-phenyl 2-naphthol 37 gave the enantioenriched product 38 via the route involving the oxidative esterification and the subsequent Claisen rearrangement.
3.3.[3 + 2] Annulation
Oxidative [3 + 2] annulation between cinnamaldehyde 5 and 4-hydroxy oxindole 39 was reported by Biju’s and Ye’s groups, respectively (Scheme 10) [79–81]. In the presence of precursor (5aR,10bS)-A4a (10 mol%), DBU (20 mol%), LiCl (50 mol%) and DQ (1 equiv) as an oxidant, the reaction of aldehyde 5 with oxindole 39 was carried out in DME, affording spirooxindole-γ-lactone 40 in 78% yield with 90:10 er [79]. In this reaction, the α,β-unsaturated acyl azolium is Michael acceptor acting as a C3 synthon for [3 + 2] annulation; thus, the enolate, generated from 39 under basic conditions, adds to α,β-unsaturated acyl azolium in a 1,4 fashion. When aldehyde 5 and oxindole 39 were treated with precursor (5aS,10bR)-A4b (20 mol%), DBU (20 mol%), DABCO (1 equiv) and nitrobenzene (NB, 2 equiv) as a single electron oxidant in toluene, the annulation product ent-40 was obtained in 78% yield with 95% ee [80]. Since both radicals from enolate and homoenolate were observed by EPR spectra. a radical/radical cross-coupling pathway is proposed as a possible reaction mechanism. The reaction of homoenolate radical generated from 5 with the radical generated from 39 leads to the cross-coupling intermediate, which is further converted to the final product ent-40 via tautomerization and lactonization.
Oxidative [3 + 2] annulation reactions involving the activation of the nitrogen atoms of the aromatic π-rings were investigated [82,83]. In the presence of chiral NHC generated from precursor (5aR,10bS)-A12a and DQ, the annulation between indole aldehyde 41 and isatin 42 proceeded smoothly to give the cyclic product 43 (Scheme 11) [82]. In this catalytic cycle, a key step is the formation of aza-fulvene intermediate from acyl azolium under the basic conditions. The nucleophilic addition of nitrogen atom on aza-fulvene to isatin 42 followed by the intramolecular ester formation would lead the annulation product 43.
3.4.[4 + 2] Annulation
The NHC-linked vinyl enolates (dienolates) act as a C4 synthon for the [4 + 2] annulation (Scheme 12) [84–88]. The oxidative γ-functionalization of α,β-unsaturated aldehydes with trifluoroacetophenone 45 was studied under the NHC catalysis [84]. The high enantioselectivities were achieved by the NHC and Sc/Mg-based Lewis acid cooperative catalysis. In the presence of precursor (5aR,10bS)-A4b, Sc(OTf)3, Mg(OTf)2, K2CO3 and DQ as an oxidant, α,β-unsaturated aldehyde 44 reacted with ketone 45 to give δ-lactone 46 in 81% yield with 94% ee. In this reaction, a key step is the activation of γ-carbon of α,β-unsaturated acyl azolium. The γ-CH deprotonation of α,β-unsaturated acyl azolium leads to the NHC-linked vinyl enolate bearing a nucleophilic γ-carbon, which adds to ketone 45 by coordinating of scandium Lewis acid with the reaction partners. Similarly, treatment of aldehyde 44 with ketoester 47 in the presence of precursor (5aR,10bS)-A13b, Sc(OTf)3, CsOAc and DQ led to the formation of δ-lactone 48 in 75% yield with 94% ee [85]. As the relative examples, the [4 + 2] annulation reactions via NHC-linked ortho-quinine methide intermediate or the formal [10+2] cycloaddition reaction via NHC-linked 12π species were reported [89,90]. Additionally, the [4 + 2] annulation using azolium enolate as a C2 synthon was also developed [91,92].
3.5.[4 + 3] Annulation
The NHC-Lewis acid cooperatively catalyzed formal [4 + 3] annulation was developed (Scheme 13) [93]. In the presence of precursor (5aR,10bS)-A12ba, Bi(OTf)3, Cs2CO3 and DQ, the reaction of indole-2-carboxaldehyde 49 with 2-hydroxy phenyl p-quinone methide 50 was carried out in toluene, affording tetracyclic ɛ-lactone 50 in 72% yield with 95:5 er. Initially, Lewis acidic Bi(OTf)3 promotes the addition of indole-2-carboxaldehyde 49 to p-quinone methide 50, generating in situ the Friedel–Crafts adduct as a racemic intermediate. Subsequently, chiral NHC and Bi(OTf)3 catalyzed the oxidative lactonization of racemic Friedel–Crafts adduct with good enantioselectivity via the dynamic kinetic resolution process.

3.6. Cascade Annulation

Cascade annulation reactions using chiral NHC catalyst have been studied [94–99]. Enantioselective cascade reaction of cinnamaldehyde 5 with malonates or β-diketone 52 was developed (Scheme 14) [94]. Under the optimized conditions using the precursor (5aR,10bS)-A4a (5 mol%), LiCl (50 mol%). DQ (1 equiv) and DBU (1.2 equiv), the lactones 53 were obtained with excellent diastereo- and enantioselectivities. In the NHC catalysis, Michael addition of anions, generated from 52, to α,β-unsaturated acyl azolium leads to intermediate enolates. The lactones 53 were formed from enolates via the concerted, asynchronous formal [2 + 2] aldol lactonization process or the two-step sequence involving an intramolecular aldol reaction and subsequent intramolecular lactonization.
Employing the precursor (5aS,10bR)-A12b, LiCl, DQ and DBU for the reaction of cinnamaldehyde 5 with malonate 54, the bicyclic product 55 was obtained in 86% yield with 99% ee (Scheme 15) [97]. This cascade annulation is also initiated by the oxidation of Breslow intermediate to α,β-unsaturated acyl azolium. The bicyclic product 55 is formed by Michael addition of malonate 54 to α,β-unsaturated acyl azolium, the subsequent intermolecular aldol reaction and the final lactonization.

4. Redox Esterification of Aldehydes

4.1. Esterification of Aldehydes under Redox Conditions

The redox esterification can be achieved by the incorporation of a reducible functionality into aldehyde substrates. In the absence of oxidants, the redox esterification of α,β-epoxy aldehydes, or α-haloaldehydes takes place due to the simultaneous reduction of epoxy moiety or halogen substituent on substrate [100–106].
The NHC-catalyzed redox esterification of α,β-epoxy aldehyde 56 led to the formation of β-hydroxy esters 57 in good yields (Scheme 16) [100]. This transformation proceeds via the formation of Breslow intermediate followed by the epoxide-opening step leading to acyl azolium. The subsequent reaction with alcohols provides esters 57, accompanied by the regeneration of NHC catalyst.
The enantioselective redox esterification of α,α-dichloroaldehydes was studied using chiral NHC catalyst (Scheme 17) [102]. Employing chiral NHC precursor (5aS,10bR)-A6b, the redox reaction of α,α-dichloroaldehyde 58 with phenol gave α-chloroester 59 in 79% yield with 93% ee. Initially, aldehyde 58 reacts with NHC catalyst to give Breslow intermediate. The subsequent dehalogenation and the stereoselective α-protonation of chiral α-chloroenolate led to chiral α-chloroester 59. The redox esterification of α-bromoenals proceeds, because α-bromoenals react with NHC catalyst to afford α,β-unsaturated acyl azoliums in the absence of oxidant via debromination [105,106]. The NHC-catalyzed three-component tandem β-sulfonylation/esterification of α-bromoenals was developed [105]. Under the optimized conditions using precursor A10, three-component reaction of α-bromoenal 60 with sodium sulfinate and alcohols gave sulfone esters 61. The addition of NHC to α-bromoenal 60 leads to the formation of Breslow intermediate, which is transformed into α,β-unsaturated acyl azolium through tautomerization and debromination. The proposed reaction mechanism involves the 1,4-addition of sodium sulfinate to α,β-unsaturated acyl azolium. Additionally, the redox esterification was also achieved by using the aldehydes having cyclopropyl moiety or leaving group as a reducible functionality [107–109].
The α,β-unsaturated aldehydes are widely used as reducible substrates for the redox esterification [110–115]. In the absence of oxidant, the NHC-catalysis of α,β-unsaturated aldehydes leads to the redox esterification accompanying with the reduction of C=C bond to C−C bond or C≡C bond to C=C bond.
Interestingly, the combined use of 2-phenyl-indol-3-one 62 as a reducible substrate with simple aldehydes led to the redox esterification (Scheme 18) [116]. In the presence of precursor A15 and Cs2CO3, the hydroacylation of 62 with benzaldehyde 3 proceeded effectively to give 1H-indol-3-yl ester 63 in 80%. The proposed reaction mechanism involves a reductive hydride transfer from NHC-linked tetrahedral intermediate to the carbonyl of 62.

4.2. Cascade Redox Esterification of Aldehydes

The cascade redox esterification of enals was achieved via the pathway involving the reaction of NHC-linked homoenolate intermediates with electrophiles [117–124]. In the presence of chiral NHC generated from precursor A3, the reaction of cinnamaldehyde 5 with (E)-1-nitrobut-1-ene 64 was performed in EtOH at 23 °C to generate δ-nitroester 65 in 70% yield with 93% ee (Scheme 19) [118]. This transformation is initiated by the formation of the NHC-linked homoenolate from cinnamaldehyde 5. Next, the 1,4-addition of homoenolate to nitroalkene 64 generates the acyl azolium. Finally, δ-nitroester 65 is obtained by the esterification of acyl azolium with EtOH. Ender’s group developed the cascade reaction using isatin-derived ketimines as an electrophile toward NHC-linked homoenolate intermediates [119]. Chiral NHC-catalyzed reaction of cinnamaldehyde 5 with isatin ketimine 66 gave the highly functionalized oxindole-γ-amino ester 67 in 86% yield with 95% ee. Recently, the NHC-catalyzed reactions involving radical intermediates were developed [125,126]. The asymmetric β-pyridylation of cinnamaldehyde 5 with pyridinium salt 68 was reported [126]. In the presence of chiral precursor (5aS,10bR)-A16, β-pyridylation of 5 proceeded effectively under the irradiation of visible light using blue LED to give the adduct 68 in 67% yield with 96:4 er. In this reaction, the use of hexafluorobenzene as a solvent is the key to achieve the excellent enantioselectivity. The proposed mechanism involves the formation of homoenolate radical from NHC-linked homoenolate by the single-electron-transfer (SET). The final product 69 will be obtained via the addition of homoenolate radical to the C4 position of pyridinium salt 68.
Furthermore, cascade redox esterification reactions were developed using NHC-linked dienolates (vinylogous NHC-linked enolates) [127], NHC-linked enolate [128], and NHC-linked p-quinodimethane [129].

4.3. Kinetic Resolution

The kinetic resolution has been studied by chiral NHC-catalyzed redox esterification [130–135]. The kinetic resolution of racemic anilide rac-70 was achieved by the redox esterification using alkynal 71 as a reducible substrate (Scheme 20) [130]. In the presence of (5aR,10bS)-A17b and NaOAc, the enantioselective acylation of rac-70 gave the ester 72 in 52% yield with 85% ee, accompanied with the enantioenriched (S)-70 in 46% yield with 93% ee. Chiral NHC-catalyzed redox esterification was used for achieving the dynamic kinetic resolution of racemic pyranones [131]. The acylation of 73 with cinnamaldehyde 5 was performed in toluene at 0 °C under the optimized conditions using (5aS,10bR)-A18b (10 mol%) and PhCO2Na (40 mol%). The corresponding ester 74 was obtained in 90% yield with 95:5 er.

4.4. Desymmetrization

Chiral NHC-catalyzed desymmetrization of the cyclohexadienone-tethered enals was studied (Scheme 21) [136,137]. The redox cyclization of enal-tethered cyclohexadienone 75 was achieved via the esterification of formyl group [136]. Treatment of 75 with precursor (5aR,10bS)-A12b (10 mol%) and NaOAc (1 equiv) in t-butyl methyl ether:MeOH (10:1, v/v) at 0 °C led to the cyclized product 76 in 83% yield with 96% ee. This transformation involves the desymmetric Michael addition of NHC-linked homoenolate intermediate to the prochiral cyclohexadienone moiety. Similarly, asymmetric desymmetrization of the cyclohexadienone-tethered enal 77 was also achieved [137].

4.5. Dearomatization

The chiral NHC-catalyzed dearomatization of prochiral aromatic compounds is the powerful strategy for preparing the chiral compounds. The dearomatizing annulation of isoquinolinium bromide 79 with cinnamaldehyde 5 was developed (Scheme 22) [138]. Employment of precursor (5aR,10bS)-A19b, KOAc and EtOH in CH2Cl2 allowed for the asymmetric dearomatization of 79 to give the substituted tropane derivative 80 having four contiguous stereocenters in 67% yield with 93% ee. The reaction is initiated by the catalytical generation of NHC-linked homoenolate from Breslow intermediate. Subsequent double Mannich addition of homoenolate to 79 leads to the formation of tropane derivative 80.
Asymmetric induction into the prochiral alkyl pyridinium 82 was achieved by chiral NHC-catalyzed dearomatization based on the addition of NHC-linked homoenolate (Scheme 23) [139]. Under the optimized conditions using precursor A20, the dearomatization of pyridinium 82 with enal 81 gave 1,4-dihydropyridine 83 with 85% ee as a major product, accompanied with 1,4-dihydropyridine 84 as a regioisomer.

5. Redox Cyclization and Annulation

5.1. Cyclization

Several redox cyclization reactions were reported [136–138,140]. In the presence of precursor A21, Cs2CO3 and H2O, treatment of 85 with tosyl chloride in toluene at 45 °C gave the cyclized product 86 in 90% yield with 98% ee (Scheme 24) [140]. As a proposed reaction mechanism, this transformation involves the oxidation of Breslow intermediate by tosyl chloride leading to the formation of tosylated intermediate. Next, the tosylated intermediate is converted into acyl azolium and tosyl anion. Finally, the enantioselective 1,4-addition of tosyl anion followed by lactonization affords the product 86. Since the overall reaction is a redox-neutral process, we classified this reaction as redox cyclization. However, tosyl chloride behaves not only nucleophile but also oxidant; thus, this reaction may also be considered one of the oxidative cyclization.
5.2.[3 + 3] Annulation
In the NHC-catalyzed redox [3 + 3] annulation, the α,β-unsaturated acyl azoliums are Michael acceptors acting as a C3 synthon [141–144]. In the absence of oxidant, the [3 + 3] annulation of ynals proceeds via the formation of α,β-unsaturated acyl azolium intermediates (Scheme 25) [141]. The ynal 71 is used as a reducible substrate for the redox transformation. Under the optimized conditions using precursor (5aR,10bS)-A4a, the redox reaction of ynal 71 with ethyl pyruvate 87 gave the annulation product 88. As a possible mechanism, the pathway involving Claisen rearrangement was proposed. This catalysis is initiated by the formation of α,β-unsaturated acyl azolium from ynal 71 and NHC. Next, pyruvic ester 87 isomerizes to enol, which undergoes the 1,2-addition to α,β-unsaturated acyl azolium. The [3 + 3] product 88 is formed through Claisen rearrangement, tautomerization, and lactamization.
Furthermore, the redox [3 + 3] annulation using α-bromoenals was developed, because α-bromoenals react with NHC catalyst to afford α,β-unsaturated acyl azoliums in the absence of oxidant via debromination [142−144].
5.3.[3 + 2] Annulation
For the redox [3 + 2] annulation, the reducible aldehydes are employed [145–155]. The NHC-linked homoenolate derivatives act as a C3 synthon for [3 + 2] annulation [145–153]. The NHC-linked homoenolate, generated from α,β-unsaturated aldehyde 44 and NHC catalyst, reacts as a C3 synthon (Scheme 26) [145]. Employing the precursor A22 (10 mol%), K3PO4 (50 mol%) and o-fluorobenzoic acid (1 equiv) as Brønsted acid, the [3 + 2] annulation of aldehyde 44 with N-methyl isatin 89 led to the formation of spirooxindole 90 in 83% yield with 92:8 er. The reactivity and diastereo- and enantioselectivity were dependent on the acid cocatalyst; thus, Brønsted acid would promote the addition of homoenolate to isatin 89 by hydrogen bonds. The [3 + 2] annulation reaction between alkynal 91 and isatin 89 was developed [154]. In the presence of precursor (5aS,10bR)-A12b (20 mol%) and K3PO4 (50 mol%), the reaction of alkynal 91 with isatin 89 was performed in MeOH at 0 °C, leading to the allene product 92. The allene product 92 could be converted to spirooxindole 93 by treatment of the reaction mixture with K3PO4 (2 equiv) as additional base at 60 °C. This transformation is initiated by the formation of azolium cumulenolate intermediate form alkynal 91. The subsequent addition of the α-carbon on cumulenolate to isatin 89 affords the allene product 92. Additionally, the NHC-linked enolate was used as a C2 synthon for [3 + 2] annulation [155].
5.4.[4 + 2] Annulation
The NHC-linked enolates act as a C2 synthon for the [4 + 2] annulation [156–168]. In the presence of precursor (5aR,10bS)-A4a (10 mol%) and Et3N (1.6 equiv), the [4 + 2] annulation reaction of α-chloroaldehyde 94 with N-phenyl-N′-benzoyl-diazene 95 proceeded effectively to give 1,3,4-oxadiazin-6-one 96 in 75% yield with 98% ee via the generation of the NHC-linked enolate from α-chloroaldehyde 94 (Scheme 27) [156]. The [4 + 2] annulation of with cinnamaldehyde 5 with nitroalkene 97 was studied [157]. Under the optimized reaction conditions using precursor (5aR,10bS)-A13b, the desired dihydrocoumarin 98 was obtained in 90% yield with 99% ee. The reaction is initiated by the formation of homoenolate, which is converted to azolium enolate by proton transfer. This NHC-linked enolate reacts as a C2 synthon with nitroalkene 97 to give the annulation product 98.
The redox [4 + 2] annulation using the NHC-linked dienolate (vinyl enolate) as a C4 synthon was developed (Scheme 28) [169]. In the presence of chiral NHC catalyst generated from precursor (5aS,10bR)-A6b, 2-bromo-2-enal 99 reacted with N-methylisatin 89 to give the [4 + 2] annulation product 100. Initially, Breslow intermediate is formed by the addition of NHC to enal 99. Breslow intermediate is transformed to α,β-unsaturated acyl azolium via debromination. The subsequent deprotonation at γ-H on α,β-unsaturated acyl azolium leads to the NHC-linked dienolate (vinyl enolate), which undergoes nucleophilic addition to N-methylisatin 89. Similarly, the [4 + 2] annulation between 2-(chloromethyl)furan-3-carbaldehyde 101 and N-benzylisatin 42 gave the cycloadduct 102 via the formation of the NHC-linked dienolate by the dearomative 1,4-elimination of HCl [170].
The annulation using the NHC-linked aza-dienolate as a C4 synthon was reported (Scheme 29) [171,172]. In the presence of precursor A23 and Cs2CO3, treatment of 2H-azirine-2-carbaldehyde 103 with ketone 45 in THF gave the cyclized product 104 in 81% yield [171]. This transformation involves the formation of NHC-linked aza-dienolate form Breslow intermediate of aldehyde 103.
5.5.[4 + 3] Annulation
The NHC-linked homoenolate intermediates are used as a C3 synthon for [4 + 3] annulation [173–179]. The enantioselective reaction of isatin-derived enal 105 with o-hydroxyphenyl-substituted p-quinone methide 50 was reported (Scheme 30) [177]. In the presence of precursor A23 (20 mol%) and Et3N (1.5 equiv), treatment of enal 105 with p-quinone methide 50 in CHCl3 at 0 °C gave the oxindole-ε-lactone 106 in 84% yield with 94:6 er. This annulation proceeds via the 1,6-addition of NHC-linked homoenolate, generated form enal 105, to the hydroxy donor−1,6-Michael acceptor 50 followed by the lactonization leading to ε-lactone 106.
5.6.[2 + 2] Annulation
The NHC-linked enolate is used as a C2 synthon for [2 + 2] annulation (Scheme 31) [180]. The chiral NHC-catalyzed formal [2 + 2] cycloaddition between α-aroyloxyaldehyde 107 and ketone 45 afforded the unstable β-lactone product 108. Thus, β-trifluoromethyl-β-hydroxyamide 109 was isolated as a stable product after ring opening with allylamine. The elimination of para-nitrobenzoate form Breslow intermediate leads to azolium enol. Subsequent deprotonation gives enolate, which undergoes the formal [2 + 2] cycloaddition with ketone 45. Additionally, the similar oxidative [2 + 2] annulation was also reported [181].

5.7. Cascade Annulation

The NHC-catalyzed cascade reactions were widely investigated under the redox conditions [182–192]. The α,β-unsaturated acyl azoliums are Michael acceptors acting as a C2 synthon for the cascade annulation reactions [182–187]. Under the optimized conditions using precursor (5aR,10bS)-A4a (7.5 mol%) and DABCO (1.65 equiv), the cascade reaction of α-bromocinnamaldehyde 60 with 2-aminophenylenone110 gave the cyclized product 111 in 98% yield with 97.2% ee (Scheme 32) [183]. In this reactions, α,β-unsaturated acyl azolium is initially formed from Breslow intermediate via bromide elimination. The subsequent aza-Michael addition of 110 to α,β-unsaturated acyl azolium provides enolate, which undergoes the intramolecular Michael addition. Finally, the cyclized product 111 is obtained by the lactonization. The cascade reaction between α-bromocinnamaldehyde 60 and imine 112 having the benzylic carbon of 4-nitrobenyl group was achieved [184]. The tetrahydrochromeno[4,3-b]pyrrole derivative 113 was obtained in 82% yield with 98:2 er under the redox catalysis using precursor (5aR,10bS)-A4b and DABCO. The cyclized product 113 is obtained through Michael addition of anion of imine 112 to α,β-unsaturated acyl azolium.
The atropo-enantioselective synthesis of bridged biaryls was achieved by the NHC-catalyzed cascade reaction (Scheme 33) [188]. Employing the precursor (5aS,10bR)-A4b and i-Pr2NEt, the cascade reaction of α,β-unsaturated aldehyde 114 with triol 115 led to the formation of bridged biaryl 116 having an eight-membered lactone in 85% yield with 99% ee. This NHC-catalyzed transformation proceeds through the propargylic substitution of propargylic alcohol 115 with NHC-linked enolate. Furthermore, the redox cascade reactions using NHC-linked homoenolates was also developed [189–191].

6. Cooperative Catalysis with Brønsted Acid and Hydrogen-Bonding Catalyst

6.1. Cooperative Catalysis Using Brønsted Acid

Since the Rovis’s group reported the cooperative NHC catalysis using Brønsted acid [193], the use of Brønsted acid has widely been demonstrated in the NHC-catalyzed activation of aldehyde C(sp2)−H bonds for C−O bond formation [194–200].
In the presence of NHC precursor (5aR,10bS)-A12b (15 mol%), Cs2CO3 (1.0 equiv) and DQ (1.4 equiv), the oxidative [3 + 2] annulation of cinnamaldehyde 5 with N-Ts amino ketone 117 gave the cyclized product 118 having β-lactone moiety in 74% yield with 96:4 er (Scheme 34) [197]. Enantioselectivity of this transformation was improved by employing sulfonyl amide (10 mol%) as an additive. In this reaction, α,β-unsaturated acyl azolium is a Michael acceptor acting as C3 synthon.
The combined use of chiral Brønsted acid in NHC catalysis has gained increasing attention as a novel method to improve the enantioselectivity. The NHC-catalyzed enantioselective synthesis of medium-ring lactones was developed [198]. The desymmetrization of prochiral 1,3-diol 119 was studied under the oxidative conditions using DQ (1.2 equiv) as an oxidant (Scheme 35). In the presence of precursor (5aR,10bS)-A24b (20 mol%), 2,6-lutidine (20 mol%) and chiral phosphoric acid (20 mol%), the reaction of 119 was carried out to give the nine-membered-ring lactone 120 in 75% yield with 98:2 er. In this reaction, chiral spiro-phosphoric acid was employed as a cocatalyst to enhance the enantioselectivity and catalytic performance. This NHC-catalyzed macrolactonization proceeds via the oxidation of Breslow intermediate to acyl azolium.
Glorius’s group developed [4 + 2] annulation of ketone 45 with 2-(bromomethyl)-benzaldehyde 121 as a substrate having a leaving group at the ortho-benzylic position (Scheme 36) [199]. However, the use of chiral NHC led to only moderate enantioselectivity for product 122. Later, the Rovis’s group achieved the highly enantioselective [4 + 2] annulation of identical starting materials by using chiral phosphoric acid and chiral NHC [197]. In the presence of precursor (5aR,10bS)-A6b (20 mol%), KOAc (2.0 equiv) and chiral phosphoric acid (10 mol%), the reaction of 121 with 45 gave the product 122 in 68% yield with 95% ee. In this reaction, the extrusion of the bromide within Breslow intermediate leads to dienolate, which undergoes [4 + 2] annulation with ketone 45.

6.2. Cooperative Catalysis Using Hydrogen-Bonding Catalyst

The dual catalysis using NHC and hydrogen-bonding catalyst has been developed [201]. The cooperative catalysis using cinchonine as chiral bifunctional organocatalyst with achiral NHC catalyst was reported [202]. In the presence of achiral NHC precursor A25 (20 mol%) and cinchonine (40 mol%), the domino oxidation/oxa-Michael addition reaction of aldehydes 123 proceeded without an additional base to give the phthalides 124 with good enantioselectivities (Scheme 37). This reaction is initiated by the NHC-catalyzed oxidation reaction of aldehydes 123 leading to carboxylic acids as a key intermediate. Next, the intramolecular oxa-Michael addition reaction of carboxylic acids was promoted by cinchonine to give the products 124 in an enantioselective manner. In this process, the hydrogen bond donor (OH) and tertiary amine (quinuclidine) of cinchonine would activate and orient nucleophile and electrophile, respectively.
The cooperative catalysis using chiral NHC catalyst and H-bond doner catalyst (HBD) was reported to achieving the enantioselective β-protonation in the redox esterification of α,β-unsaturated aldehydes (Scheme 38) [203]. In the presence of precursor A26 (10 mol%), H-bond doner catalyst (HBD, 30 mol%), DMAP (5 mol%) and i-Pr2NEt (0.4 equiv), the reaction of β-ethyl ester 125 with ethanol was performed at 0 °C. The saturated bis-ester 126 was obtained in 85% yield with 94:6 er. The coordination of HBD to β-ethyl ester group would enhance the enantioselectivity by the steric interactions near the β-position of 125.
Thiourea catalysts have been used in the NHC catalysis for the C−O bond formation of aldehydes [204–207]. The NHC-catalyzed annulation of enals and α-ketoesters was studied (Scheme 39) [204]. In this reaction, the combined use of Ca(OMe)2 as Lewis acid and thiourea B1 as a H-bond doner catalyst enhanced the enantioselectivity and yield of products. Under the optimized conditions using chiral precursor A27, the annulation between cinnamaldehyde 5 and α-ketoester 127 proceeded with the modest diastereoselectivity (2:1 dr) to give the major diastereomer 128 with 92% ee. This reaction promoted by the addition of homoenolate, generated from 5 and NHC, to α-ketoester 127.
Sequential three-component reaction of nitroalkenes 129, 3-phenylpropanal 1 and cinnamaldehyde 5 was achieved by one-pot procedure (Scheme 40) [205]. The use of two different NHC catalysts, generated from achiral precursor A10 and chiral precursor (5aR,10bS)-A4a led to the enantioselective formation of dihydropyranones 130. In the presence of presence of A10, thiourea B2 and K2CO3, the reaction of nitroalkenes 129 and aldehyde 1 leads to the in situ generation of enone intermediates via the nitro-Stetter/elimination sequence [206]. Next, chiral presence (5aR,10bS)-A4a and cinnamaldehyde 5 (2+1 equiv) were employed with K2CO3, acetic acid and 4 Å molecular sieves for annulation. The dihydropyranone 130 are obtained via Michael addition of chiral NHC-linked enol to β-unsubstituted enones followed by lactonization.

7. Cooperative Catalysis with Transition-Metal Catalyst

7.1. Cooperative Catalysis Using Palladium Catalyst

Scheidt’s group reported the cooperative catalysis involving the simultaneous activation of substrates using NHC catalyst and palladium catalyst (Scheme 41) [208]. In the presence of NHC precursor A15 and palladium catalyst, generated from Pd2(dba)3 and dppf ligand, the carbonate 131 was converted to the allylated dihydrocoumarin 133. To improve the chemical yield, allyl carbonate 132 was used as an additive for increasing the concentration of π-allyl palladium intermediate. The substrate 131 reacts with NHC catalyst and palladium catalyst to give Breslow intermediate and π-allyl palladium. This cooperative transformation is based on the addition of enol, generated from Breslow intermediate, into π-allyl palladium intermediate.
The palladium-catalyzed allylic substitution is applied to the enantioselective cooperative catalysis by using chiral NHC catalyst [209–215]. Glorius’s group reported the enantioselective catalysis using the combination of chiral NHC, generated from precursor (5aS,10bR)-A13b, and chiral palladium catalyst, generated from Pd2(dba)3 and ligand L1 (Scheme 42) [211]. Under the optimized conditions, the [5 + 2] annulation reaction between phenyl vinylethylene carbonate 134 and cinnamaldehyde 5 gave the annulation product 135 with an excellent enantioselectivity. NHCs are known to act as a ligand for transition-metals; thus, the use of a bidentate phosphine ligand L1 is crucial to prevent the coordination of NHC to the active Pd catalyst. The proposed catalytic cycle involves the NHC-catalyzed activation of cinnamaldehyde 5 followed by the Pd-catalyzed allylic substitution. Initially, the palladium-catalyzed decarboxylation of 134 gives the π-allyl palladium(II) complex, which reacts with enol generated from 5 and NHC. The subsequent cyclization provides the cyclized product 135 accompanied by the regeneration of NHC catalyst.
Recently, [3 + 2] annulation reaction for the synthesis of enantioenriched α,β-disubstituted γ-butyrolactones was reported by using chiral NHC and chiral iridium catalysts [212,213]. Furthermore, the umpolung allylic and propargylic substitution reactions of enals were also achieved by using chiral NHC and nickel catalysts [214,215].
The umpolung 1,4-addition of aryl iodides or vinyl bromides to enals was developed under the cooperative NHC/palladium reaction conditions [216,217]. The 1,4-addition of iodobenzene to cinnamaldehyde 5 was promoted by the combination of NHC, generated from precursor A28, and palladium catalyst, generated from Pd2(dba)3 and ligand L2 to give methyl β,β-diphenyl propanoate 136 in 71% yield (Scheme 43) [216]. Initially, the homoenolate equivalent is generated from cinnamaldehyde 5 and NHC. Next, the nucleophilic homoenolate reacts with the activated PhPdI(Ln), which is generated by the oxidative addition of palladium catalyst to iodobenzene. The subsequent reductive elimination provides the NHC-bonding intermediate, which reacts with MeOH to afford methyl β,β-diphenyl propanoate 136. Additionally, 1,4-addition of vinyl bromides to enals was also studied under the similar reaction conditions [217].

7.2. Cooperative Catalysis Using Copper Catalyst

The copper catalysts are used for the cooperative NHC catalysis [218,219]. In the presence of precursor A29 (10 mol%), Cu(CH3CN)4PF6 (5 mol%) and Et3N (1.0 equiv), [3 + 3] annulation between the isatin-derived enal 105 and ethynylethylene carbonate 137 led to the formation of spirooxindole δ-lactones 138 with >95:5 dr and 99% ee (Scheme 44) [219]. Initially, copper acetylide is generated from 137 under the basic conditions. The decarboxylation of copper acetylide leads to copper allenylidene. Subsequently, enals 105 react with NHC to form homoenolates, which undergo the formal [3 + 3] cycloaddtion with copper allenylidene to afford δ-lactones 138. Since NHC serves as a ligand of copper, chiral Cu(I)-NHC complex would participate in the control of stereochemistry, together with chiral NHC catalyst.

7.3. Cooperative Catalysis Using Rhodium Catalyst

The one-pot reactions involving NHC catalysis and rhodium(III) catalysis were reported, although these sequential reactions cannot be strictly classified to the cooperative catalysis (Scheme 45) [220]. Initially, the aerobic oxidation of benzaldehyde 3 proceeded smoothly under the conditions using NHC generated from precursor A15 and DBU to give benzoic acid intermediate. Subsequent addition of ethyl acrylate, [Cp*RhCl2]2 and AgOAc to the reaction mixture induced the rhodium(III)-catalyzed oxidative coupling/annulation of benzoic acid with ethyl acrylate. The phthalide 139 was obtained in 60% yield. When 1,2-diphenylethyne was used for the second step, the isocoumarin 140 was obtained in 74% yield. In this case, Cu(OAc)2·H2O performed better than AgOAc as an oxidant in rhodium(III) catalysis. More recently, the NHC/Rh cooperative catalysis for desymmetric [3 + 3] annulation of oxabicyclic alkenes with enals was developed [221].

7.4. Cooperative Catalysis Using Ruthenium Catalyst

The combination of NHC catalysis and ruthenium redox catalysis was investigated [222–224]. The oxidative esterification of aldehydes was achieved by using NHC precursor A30b and Ru(bpz)3(PF6)2 (bpz=2,2’-bipyrazine) as a ruthenium(II) redox catalyst, under the mild aerobic conditions (Scheme 46) [222]. The catalytic ruthenium cycle involves the oxidation of Ru(I) complex to Ru(II) complex by molecular oxygen to give the superoxide radical anion. Initially, the Ru(I)-catalyzed oxidation of Breslow intermediate generated from aldehyde 141 leads to the radical cation, which will be further oxidized to the acyl azolium via tertiary radical.
The cooperative NHC/ruthenium redox catalysis was used for oxidative [3 + 3] annulation (Scheme 47) [223] The oxidation of Breslow intermediate leads to the formation of α,β-unsaturated acyl azolium acting as a C3 synthon. In the presence of chiral NHC generated from precursor (5aR,10bS)-A4b, RuCl3, and O2, the oxidative reaction of cinnamaldehyde 5 with 2,4-pentanedione 143 was performed in 1,4-dioxane, affording lactone 144 in 98% yield with 93% ee. The proposed reaction mechanism involves the oxidation of Breslow intermediate, generated from NHC and enal 5, by SET from RuCl3. A second oxidation of radical cation intermediate by RuCl3 gives α,β-unsaturated acyl azolium, which undergoes [3 + 3] annulation with 2,4-pentanedione 143. In this catalysis, Ru(III) is regenerated through the oxidation of Ru(II) by molecular oxygen.

7.5. Cooperative Catalysis Using Gold Catalyst

The enantioselective gold and NHC relay catalysis was reported (Scheme 48) [225]. The cascade annulation between α-amino-ynone 145 and cinnamaldehyde 5 was performed under the oxidative conditions using DQ as an oxidant. Initially, pyrrolin-4-one intermediate was obtained by gold catalysis. The anion of pyrrolin-4-one adds to α,β-unsaturated acyl azolium to produce pyrrole-fused lactone 146 with excellent enantioselectivity.

8. Cooperative Catalysis with Photocatalysts

In 2012, DiRocco and Rovis reported the first reaction involving NHC catalysis and photoredox Ru-catalysis [226]. In recent years, the cooperative NHC catalysis with photocatalyst has gained increasing attention as a novel redox catalysis [18–21].
The combined use of NHC and photocatalyst was applied to the oxidative transformation of aldehydes to the corresponding esters [227–234]. The oxidative esterification of aldehydes through the oxidation of Breslow intermediates was achieved by the dual organocatalysis based on the cooperation between NHC and an organophotocatalyst such as rhodamine 6G or eosin Y·Na (Scheme 49) [227,228]. In the presence of triazolium precursor A30c (5 mol%) and rhodamine 6G (5 mol%), the use of BrCCl3 (3 equiv) as a co-oxidant promoted the reaction of cinnamaldehyde 5 to give ester 147 in 79% yield [227]. Initially, it was assumed that electron-rich Breslow intermediate is photocatalytically oxidized to acyl azolium via the radical intermediate, whereas co-oxidant BrCCl3 would act as a quencher toward the activated photocatalyst species having the reduction property to turn the catalytic photoredox cycle. After the detailed research [228], it was shown that BrCCl3 promotes the second oxidation as a brominating reagent toward radical intermediate to give the β-brominated intermediate. The acyl azolium is formed via the elimination of HBr from β-brominated intermediate. The use of C2Cl6 as a co-oxidant was the effective method for the oxidative esterification, because the oxidation steps are promoted by two pathways associated with the activated photocatalyst and C2Cl6 [228]. In the presence of precursor A30c (5 mol%) and eosin Y·Na (5 mol%), the reaction of 3,3-diphenylacrylaldehyde 148 was studied. Although BrCCl3 was less effective for the oxidative esterification of 148, the use of C2Cl6 (3 equiv) led to the formation of ester 149 in 94% yield.
The alkylation and esterification reaction of enal derivatives was achieved via a route involving the radical addition to dienolate derivatives generated from Breslow intermediates (Scheme 50) [229–232]. When racemic precursor racemic A4b was used in the presence of Ru(bpy)3(PF6)2 as a photocatalyst, the reaction of γ-oxidized enal 150 with iodoacetonitrile and MeOH gave γ-alkylated ester 151 in 86% yield with exclusive γ-regioselectivity [229]. In these reactions, iodoacetonitrile acts as not only oxidant for Ru-photocatalysis but also radical source giving cyanomethyl radical. Cyanomethyl radical adds to the dienolate intermediate to afford the homoenolate radical. The following photocatalytic oxidation of this radical leads to acyl azolium. This reaction was expand to ε-functionalization by using the enal 152 bearing a vinyl substituent at γ-position. Under the similar reaction conditions, the reaction of enal 152 gave the γ-cyanomethylated ester 153 in 56% yield with the exclusive ε-selectivity. The alkylation and esterification reaction also proceeds by using the dienolate generated from cyclopropane enal 154 via NHC-catalyzed ring opening [230]. In the presence of several alcohols, photo/NHC catalysis of 154 and diethyl 2-bromo-2-methylmalonate afford the corresponding γ-alkylated esters 155.
The esterification of aldehydes based on oxidative Smiles rearrangement was developed (Scheme 51) [233]. The oxidative Smiles rearrangement of O-aryl salicylaldehyde 156 was performed under the cooperative catalysis conditions using NHC and 9-mesityl-10-methyl-acridin-10-ium as an organophotocatalyst. In the presence of NaI (10 mol%) as an additive to facilitate the electron transfer, the reaction of 156 proceeded effectively to give the aryl salicylate 157 in 79% yield. The continuous oxidation of Breslow intermediate by activated photocatalyst and hydroperoxide radical, in situ generated from molecular oxygen, leads to acyl azolium. The acid intermediate is generated by hydrolysis of acyl azolium. Subsequently, the photocatalytic oxidation of acid intermediate promotes Smiles rearrangement to give phenoxy radical via the spirocyclic intermediate. Finally, the reduction of this radical by photocatalysis gives the aryl salicylate 157. In the absence of a photocatalyst, the combined use of NHC catalysis and photoredox reaction has gained increasing attention as a novel catalysis [234]. Under the similar reaction conditions, the intramolecular reaction of tetrahydroisoquinoline-derived benzaldehyde 158 was investigated. The oxidative cyclization of aldehyde 158 proceeded effectively even in the absence of a photocatalyst under blue LED irradiation to give the cyclized product 159 in 77% yield. In this reaction, a photo-excited Breslow intermediate is proposed for explaining the photooxidation process.

9. Conclusions and Outlook

N-Heterocyclic carbenes are the highly reactive organocatalysts that induce the synthetically valuable chemical transformations. Furthermore, the enantioselective NHC catalysis has attracted substantial attention, since the highly functionalized compounds with multiple stereo-centers can be synthesized. Additionally, the oxidative reaction of aldehyde C(sp2)−H bonds with alcohol O−H bonds is has been recognized as a straightforward and atom-economical cross dehydrogenative coupling reaction [235,236]. As summarized above, the various synthetic strategies and methodologies have been developed as a cooperative catalysis. The recent dramatic progress in NHC-induced catalysis offer opportunities for the further exploration with intriguing possibilities in organocatalysis for the synthetic organic chemistry.

Author Contributions

Y.Y.; writing—original draft preparation and editing, H.Y.; writing— original draft preparation and editing. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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Preprints 100783 sch001
Scheme 1. Dehydrogenative cross-coupling of aldehydes with alcohols.
Scheme 1. Dehydrogenative cross-coupling of aldehydes with alcohols.
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Scheme 2. Enantioselective functionalization of aldehydes.
Scheme 2. Enantioselective functionalization of aldehydes.
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Scheme 3. Kinetic resolution by oxidative esterification.
Scheme 3. Kinetic resolution by oxidative esterification.
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Scheme 4. Atroposelective dynamic kinetic resolution.
Scheme 4. Atroposelective dynamic kinetic resolution.
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Scheme 5. Desymmetrization of diols by oxidative esterification.
Scheme 5. Desymmetrization of diols by oxidative esterification.
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Scheme 6. Desymmetrization of dialdehydes.
Scheme 6. Desymmetrization of dialdehydes.
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Scheme 7. Regioselective oxidative cyclization.
Scheme 7. Regioselective oxidative cyclization.
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Scheme 8. Oxidative [3 + 3] annulation.
Scheme 8. Oxidative [3 + 3] annulation.
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Scheme 9. NHC-catalyzed annulation via Claisen rearrangement.
Scheme 9. NHC-catalyzed annulation via Claisen rearrangement.
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Scheme 10. Oxidative [3 + 2] annulation.
Scheme 10. Oxidative [3 + 2] annulation.
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Scheme 11. Oxidative [3 + 2] annulation using acyl azolium.
Scheme 11. Oxidative [3 + 2] annulation using acyl azolium.
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Scheme 12. Oxidative [4 + 2] annulation using NHC-linked vinyl enolates.
Scheme 12. Oxidative [4 + 2] annulation using NHC-linked vinyl enolates.
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Scheme 13. NHC-Lewis acid cooperative catalyzed [4 + 3] annulation.
Scheme 13. NHC-Lewis acid cooperative catalyzed [4 + 3] annulation.
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Scheme 14. Cascade annulation through oxidative NHC catalysis.
Scheme 14. Cascade annulation through oxidative NHC catalysis.
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Scheme 15. Oxidative cascade annulation.
Scheme 15. Oxidative cascade annulation.
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Scheme 16. Redox esterification of α,β-epoxy aldehyde.
Scheme 16. Redox esterification of α,β-epoxy aldehyde.
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Scheme 17. Redox esterification of α-haloaldehydes.
Scheme 17. Redox esterification of α-haloaldehydes.
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Scheme 18. Redox esterification involving hydride transfer process.
Scheme 18. Redox esterification involving hydride transfer process.
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Scheme 19. Cascade redox esterification via NHC-linked homoenolate intermediates.
Scheme 19. Cascade redox esterification via NHC-linked homoenolate intermediates.
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Scheme 20. Kinetic resolution by redox esterification.
Scheme 20. Kinetic resolution by redox esterification.
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Scheme 21. Desymmetrization using redox esterification.
Scheme 21. Desymmetrization using redox esterification.
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Scheme 22. NHC-catalyzed dearomatizing annulation reaction.
Scheme 22. NHC-catalyzed dearomatizing annulation reaction.
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Scheme 23. Dearomatizing reaction of prochiral aromatic nitrogen-heterocycle.
Scheme 23. Dearomatizing reaction of prochiral aromatic nitrogen-heterocycle.
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Scheme 24. Redox cyclization of enal-tethered cyclohexadienone.
Scheme 24. Redox cyclization of enal-tethered cyclohexadienone.
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Scheme 25. NHC-catalyzed redox [3 + 3] annulation.
Scheme 25. NHC-catalyzed redox [3 + 3] annulation.
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Scheme 26. NHC-catalyzed redox [3 + 2] annulation reactions.
Scheme 26. NHC-catalyzed redox [3 + 2] annulation reactions.
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Scheme 27. Redox [4 + 2] annulation reactions using NHC-linked enolate.
Scheme 27. Redox [4 + 2] annulation reactions using NHC-linked enolate.
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Scheme 28. Redox [4 + 2] annulation using NHC-linked dienolate.
Scheme 28. Redox [4 + 2] annulation using NHC-linked dienolate.
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Scheme 29. Annulation using NHC-linked aza-dienolate.
Scheme 29. Annulation using NHC-linked aza-dienolate.
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Scheme 30. Redox [4 + 3] annulation using NHC-linked homoenolate.
Scheme 30. Redox [4 + 3] annulation using NHC-linked homoenolate.
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Scheme 31. Formal [2 + 2] cycloaddition using NHC-linked enolate.
Scheme 31. Formal [2 + 2] cycloaddition using NHC-linked enolate.
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Scheme 32. Cascade reactions using α,β-unsaturated acyl azoliums as a Michael acceptor.
Scheme 32. Cascade reactions using α,β-unsaturated acyl azoliums as a Michael acceptor.
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Scheme 33. Cascade reaction using NHC-linked enolate.
Scheme 33. Cascade reaction using NHC-linked enolate.
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Scheme 34. Oxidative [3 + 2] annulation using acyl azoliums.
Scheme 34. Oxidative [3 + 2] annulation using acyl azoliums.
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Scheme 35. Medium-ring lactone synthesis by desymmetrization of 1,3-diol.
Scheme 35. Medium-ring lactone synthesis by desymmetrization of 1,3-diol.
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Scheme 36. [4 + 2] Annulation using chiral phosphoric acid.
Scheme 36. [4 + 2] Annulation using chiral phosphoric acid.
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Scheme 37. Use of cinchonine as chiral hydrogen-bonding catalyst.
Scheme 37. Use of cinchonine as chiral hydrogen-bonding catalyst.
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Scheme 38. Reaction catalysis using chiral NHC catalyst and H-bond doner catalyst.
Scheme 38. Reaction catalysis using chiral NHC catalyst and H-bond doner catalyst.
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Scheme 39. Reactions using thiourea catalyst and Lewis acid.
Scheme 39. Reactions using thiourea catalyst and Lewis acid.
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Scheme 40. Sequential NHC-catalyzed reaction.
Scheme 40. Sequential NHC-catalyzed reaction.
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Scheme 41. Cooperation between NHC and palladium catalyst.
Scheme 41. Cooperation between NHC and palladium catalyst.
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Scheme 42. Enantioselective cooperative catalysis.
Scheme 42. Enantioselective cooperative catalysis.
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Scheme 43. Cooperative catalysis for umpolung 1,4-addition to cinnamaldehyde.
Scheme 43. Cooperative catalysis for umpolung 1,4-addition to cinnamaldehyde.
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Scheme 44. Cooperative catalysis with copper catalyst.
Scheme 44. Cooperative catalysis with copper catalyst.
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Scheme 45. Sequential reactions via NHC catalysis and rhodium(III) catalysis
Scheme 45. Sequential reactions via NHC catalysis and rhodium(III) catalysis
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Scheme 46. Cooperative catalysis with ruthenium catalyst.
Scheme 46. Cooperative catalysis with ruthenium catalyst.
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Scheme 47. Oxidative [3 + 3] annulation using ruthenium catalyst.
Scheme 47. Oxidative [3 + 3] annulation using ruthenium catalyst.
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Scheme 48. Relay catalysis with gold catalyst.
Scheme 48. Relay catalysis with gold catalyst.
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Scheme 49. Cooperation between NHC and organophotocatalyst.
Scheme 49. Cooperation between NHC and organophotocatalyst.
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Scheme 50. Alkylation and esterification reaction.
Scheme 50. Alkylation and esterification reaction.
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Scheme 51. Oxidative Smiles rearrangement.
Scheme 51. Oxidative Smiles rearrangement.
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Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
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