Recent Advances in Cooperative N -Heterocyclic Carbene Catalysis

The N -heterocyclic carbenes (NHCs) open the new field of organocatalysis, leading to the dramatic progress on the cooperative NHC catalysis with transition-metal catalysts or photocatalysts.


Introduction
In the past few decades, N-heterocyclic carbenes (NHCs) open the new field of organocatalysis in synthetic organic chemistry [1]. Particularly, chiral NHCs have gained increasing attention as a powerful and versatile organocatalyst for the enantioselective synthesis of various molecules with structural diversity and complexity [2][3][4][5][6][7]. Although a wide variety of chiral NHC precursors were developed, chiral thiazolium-derived carbenes are the most widely used catalysts for asymmetric synthesis. Based on the characteristic structures, chiral thiazolium precursors can be classified as aminoindanol-based thiazoliums, morpholine-based thiazoliums, pyrrolidine-based thiazoliums, and acyclic thiazoliums [6]. Furthermore, new methods and strategies for NHC catalysis are emerging continuously, leading to remarkable progress on cooperative catalysis using NHC/Lewis acid, NHC/Brønsted acid, and NHC/hydrogen-bonding organocatalyst [8,9]. In recent years, cooperative catalysis has been expanded by the combination of NHCs with transition-metal catalysts or photocatalysts [10]. This chapter highlights the recent dramatic progress in the cooperative NHC catalysis with transition-metal catalysts or photocatalysts.

Cooperative NHC catalysis with transition-metal catalysts
In recent years, the use of transition-metal catalysts in the NHC catalysis has become a widespread strategy for cooperative catalysis, although NHCs are known to act as a ligand for transition metals.
The palladium-catalyzed allylic substitutions are wildly used for achieving cooperative NHC catalysis. Initially, the successful combination of NHC catalysis with transition-metal catalysis was reported in the cascade reactions involving the addition of NHC-catalyzed product to π-allyl palladium intermediate [11][12][13]. In 2014, cooperative catalysis was achieved by the simultaneous activation of substrates using NHC catalyst and palladium catalyst [14]. This cooperative transformation proceeded via the addition of the Breslow intermediate, generated from the NHC catalyst, into the π-allyl palladium intermediate. The palladium-catalyzed allylic substitutions are applied to the enantioselective NHC catalysis [15][16][17][18][19][20]. The cooperative catalysis was achieved by using chiral NHC catalyst and palladium catalyst (Figure 1) [15][16][17]. In the presence of palladium catalyst [Pd(PPh 3 ) 4 (5 mol%)] and chiral NHC generated from NHC precursor (5aS,10bR)-A1 (15 mol%) and Cs 2 CO 3 (1 equiv), the enantioselective [4 + 3] annulation reaction between vinyl benzoxazinanone 1 and cinnamaldehyde 2 were performed in THF at room temperature. The benzazepine derivative 3 was obtained in 86% yield with 99% ee [15]. The proposed catalytic cycle involves the NHC-catalyzed activation of enal 2 followed by the Pd(0)-catalyzed allylic alkylation. Initially, the palladiumcatalyzed decarboxylation of vinyl benzoxazinanone 1 gives the π-allyl palladium(II) complex, which reacts with the azolium homoenolate generated from cinnamaldehyde 2 and NHC. The subsequent cyclization provides benzazepine 3 accompanied by the regeneration of the NHC catalyst. In this communication, the stereochemical outcome was explained by the proposed transition state, in which the formation of hydrogen-bonding interaction promotes allylic substitution. Later, a comprehensive investigation of the mechanism was conducted to understand the features of this reaction [16]. A detailed study shows that NHC not only serves as an organocatalyst to activate enal 2 but also a ligand of palladium. Furthermore, the cooperative catalysis was applied to the enantioselective [4 + 1] annulation between benzoxazinanone 1 and sulfur ylide 4. When NHC precursor (5aS,10bR)-A2 and Pd(PPh 3 ) 4 were employed, the desired annulation product 5 was obtained in 80% yield with 88% ee [16]. The combination of chiral NHC, generated from precursor (5aS,10bR)-A2, and a chiral palladium catalyst, generated from Pd 2 (dba) 3 and ligand L1, promoted the highly enantioselective [5 + 2] annulation reaction between phenyl vinylethylene carbonate 6 and cinnamaldehyde 2 [17]. In this reaction, the use of a bidentate phosphine ligand L1 is crucial to prevent the coordination of NHC to the active Pd catalyst.
NHCs can invert the reactivity of aldehyde from electrophilic to nucleophilic by the formation of Breslow intermediate as an acyl anion equivalent from NHC catalyst and aldehyde. The cooperative NHC/palladium reactions through the nucleophilic addition of Breslow intermediate to the π-allyl palladium(II) complex were investigated (Figure 2) [21][22][23][24][25][26]. The 2:1 coupling reaction of pyridine-2-carboxaldehyde 8 and allyl acetate 9 has been developed [21]. Under the optimized reaction conditions using Pd(PPh 3 ) 4 and NHC generated from precursor A3 and triethylamine, 2-methyl-1,4-di(pyridin-2-yl)butane-1,4-dione 10 was obtained in 83% yield as a 2:1 coupling product. The proposed catalytic cycle involves the formation of Breslow intermediate as an acyl anion equivalent from NHC catalyst and aldehyde 8 through the addition of NHC to the formyl group of 8 followed by the proton transfer. Next, the addition of Breslow intermediate to the π-allyl palladium(II) complex, generated from allyl acetate 9 and Pd(PPh 3 ) 4 , leads to the formation of unsaturated ketone 11 via the liberation of NHC. In this transformation, the N atom of the pyridine ring acts as a coordination site toward the palladium of the π-allyl complex. Finally, ketone 11 is converted to product 10 through condensation with another Breslow intermediate. This cooperative catalysis was extended to C-glycosylation using aldehyde 8 and glucal 12 [22].
The propargylation reaction of pyridine-2-carboxaldehyde 8 was also developed [23]. The propargylic ketone product 15 was obtained in 74% when propargylic carbonate 14 was used under the cooperative NHC/palladium catalysis conditions. Furthermore, the reaction of widely available aldehydes with diarylmethyl carbonates was studied [24]. When aliphatic aldehyde 16 and diarylmethyl carbonates 17 were employed under the cooperative conditions using NHC precursor A4, α-arylated ketone 18 was obtained in 78% yield.

Cooperative NHC catalysis with photocatalysts
The combined use of NHC and photocatalyst has gained increasing attention as novel redox catalysis. The compatibility of NHC with ruthenium photocatalyst was demonstrated (Figure 7) [37]. Acylation of N-phenyltetrahydroisoquinoline 34 with butanal 33 was promoted by using chiral NHC, generated from precursor (5aS,10bR)-A9 and photocatalyst Ru(bpy) 3 Cl 2 in the presence of m-dinitrobenzene  as an oxidant. This transformation proceeds via the generation of Breslow intermediate, which undergoes the addition to iminium intermediate generated by the photocatalytic oxidation of 34. Finally, the release of free NHC catalyst results in the formation of acylated product 35. The decarboxylative carbonylation reaction also proceeded via a similar mechanism [38].
The cooperative catalysis was applied to the oxidative transformation of aldehydes (Figure 8) [39][40][41][42]. The oxidative esterification of cinnamaldehyde 2 was achieved by the dual organocatalysis based on the cooperation between NHC and rhodamine 6G as an organophotocatalyst [39]. In this reaction, Breslow intermediate is photocatalytically oxidized to acyl azolium via the radical intermediate. The subsequent reaction of acyl azolium with MeOH gives ester 36. Furthermore, the alkylation and esterification reaction of γ-oxidized enal 37 was developed [40]. When racemic precursor A1 and photocatalyst Ru(bpy) 3 (PF 6 ) 2 were employed, the reaction of γ-oxidized enal 37 with iodoacetonitrile 38 and MeOH gave γ-alkylated ester 39 in 86% yield. In this Ru-photocatalysis, iodoacetonitrile 38 acts as not only a radical source but also an oxidant. The oxidative Smiles rearrangement was also reported [42]. Under the cooperative catalysis conditions using NHC and 9-mesityl-10-methyl-acridin-10-ium as an organophotocatalyst, the oxidative Smiles rearrangement of O-aryl salicylaldehyde 40 proceeded effectively to give the aryl salicylate 41 in 79% yield. Initially, the photocatalytic oxidation of Breslow intermediate, generated from salicylaldehyde 40 to acyl azolium leads to the generation of the acid intermediate via the subsequent reaction of acyl azolium with H 2 O. The subsequent oxidation of acid intermediate by photocatalysis promotes Smiles rearrangement to give another radical via the spirocyclic intermediate. Finally, the photocatalytic reduction of this radical gives the aryl salicylate 41.
The cooperative catalysis for preparing ketones from carboxylic acid derivatives was studied (Figure 9) [43,44]. The synthesis of ketone 44 was achieved by the combined NHC and Ir-photoredox catalysis of acyl imidazole 42 with benzyl Hantzsch ester 43 as a benzyl radical source [43]. In the presence of precursor A12 (15 mol%), photocatalyst [Ir(dFCF 3 ppy) 2 (dtbpy)]PF 6 (1 mol%), and Cs 2 CO 3 , the reaction between imidazole 42 and Hantzsch ester 43 led to the formation of ketone 44 in 79% yield under the LED irradiation. In this catalysis, the iridiumphotocatalyzed one-electron reduction of acyl azolium, generated from NHC and acyl imidazole 42, affords a radical intermediate. This radical undergoes the subsequent radical-radical coupling with a benzyl radical generated by the iridiumphotocatalyzed one-electron oxidation of benzyl Hantzsch ester 43. The cooperative triple catalysis using NHC catalyst, Ru-photocatalyst, and sulfinate catalyst was developed [44]. When precursor A13 (15 mol%), Ru(bpy) 3 (PF6) 2 (1.5 mol%), and 4-Cl-PhSO 2 Na (25 mol%) were employed, the acylation of 4-methylstyrene 46 with benzoyl fluoride 45 was promoted under the CFL irradiation to give ketone 47 in 78% yield. This triple catalysis involves photocatalysis, NHC catalysis, and sulfinate catalysis. The NHC catalysis gives a ketyl radical via the photocatalytic reduction of acyl azolium, generated from benzoyl fluoride 45 and NHC. In the sulfinate catalysis, the photocatalytic oxidation of 4-Cl-PhSO 2 Na affords sulfonyl radical, which adds to 4-methylstyrene 46 leading to the adduct radical. Finally, radical/ radical cross-coupling between these two radicals leads to the acylated product 47. In addition to the cooperative NHC catalysis with photocatalysts, the combined use of NHC catalysis and photoredox reaction in the absence of a photocatalyst has gained increasing attention as novel catalysis [45][46][47].

Conclusions
The N-heterocyclic carbenes (NHCs) are powerful and versatile organocatalysts that induce synthetically valuable chemical transformations. In addition to the cooperative catalysis using NHC/Lewis acid, NHC/Brønsted acid, and NHC/ hydrogen-bonding organocatalyst, the cooperative NHC catalysis combined with transition-metal catalysts are emerging continuously. In the last few years, the combined use of NHC and photocatalyst has gained increasing attention as dual redox catalysis. The recent dramatic progress in NHC-induced cooperative catalysis disclosed a broader aspect of the utility of NHC-organocatalysis for synthetic organic chemistry. This chapter will inspire creative new contributions to organic chemists.