**2. 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 [11–13]. 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 [15–20]. The cooperative catalysis was achieved by using chiral NHC catalyst and palladium catalyst (**Figure 1**) [15–17]. In the presence of palladium catalyst [Pd(PPh3)4 (5 mol%)] and chiral NHC generated from NHC precursor **(5a***S***,10b***R***)-A1** (15 mol%) and Cs2CO3 (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

**Figure 1.** *Enantioselective catalysis using NHC and* π*-allyl palladium(II) complex.*

#### *Recent Advances in Cooperative N-Heterocyclic Carbene Catalysis DOI: http://dx.doi.org/10.5772/intechopen.101328*

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 **(5a***S***,10b***R***)-A2** and Pd(PPh3)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 **(5a***S***,10b***R***)-A2**, and a chiral palladium catalyst, generated from Pd2(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**) [21–26]. 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(PPh3)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(PPh3)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.

The cooperative NHC/palladium reaction for the umpolung 1,4-addition of aryl iodides or vinyl bromides to enals was developed [27, 28]. The combination of NHC, generated from precursor **A5**, and a palladium catalyst, generated from Pd2(dba)3 and ligand **L3**, promoted the 1,4-addition of iodobenzene **19** to cinnamaldehyde **2** to give methyl β,β-diphenyl propanoate **20** in 71% yield (**Figure 3**) [27]. This reaction is the palladium-catalyzed arylation of NHC-bound homoenolate equivalent generated from cinnamaldehyde **2** and NHC. The oxidative addition of palladium catalyst to iodobenzene **19** generates the activated PhPdI(Ln) as an electrophile, which reacts with nucleophilic homoenolate equivalent. The subsequent reductive elimination provides the NHC-bound intermediate, which reacts with MeOH to afford methyl β,β-diphenyl propanoate **20**. Additionally, 1,4-addition of vinyl bromides to enals was also studied under similar reaction conditions [28].

The cooperative catalysis using NHC and copper catalyst was investigated (**Figure 4**) [29, 30]. The catalytic reaction using alkyne **21**, tosyl azide **22,** and isatin-derived imine **23** was investigated by using NHC precursor **A6** and CuI [29]. The spiro-azetidine oxindole **24** was obtained in 83% yield with 85:15 er. Initially,

*Carbene*

**Figure 2.**

*Cooperative catalysis based on umpolung of aldehydes.*

**Figure 3.** *Cooperative catalysis for umpolung 1,4-addition to cinnamaldehyde.*

*Recent Advances in Cooperative N-Heterocyclic Carbene Catalysis DOI: http://dx.doi.org/10.5772/intechopen.101328*

**Figure 4.**

*Cooperative catalysis with copper catalyst.*

copper acetylide is generated from **21** and Cu(I) under the basic conditions. The proposed catalytic cycle involves the formation of ketenimine intermediate *via* triazole generated by [3+2] cycloadditions between copper acetylide and azide **22**. Subsequently, ketenimine reacts with NHC to form azolium enamide, which undergoes the formal [2+2] cycloaddtion with imine **23** to afford product **24**. In the presence of NHC precursor **A7** (10 mol%), Cu(OTf)2 (5 mol%) and Et3N (1 equiv), [4 + 3] annulation between ethynyl benzoxazinanone **25** and isatinderived enal **26** led to the formation of spirooxindole **27** in 98% yield with 96% ee [30]. In this catalysis, the decarboxylation of copper acetylide leads to copper allenylidene, which reacts with the NHC-linked homoenolate generated from enal **26**. 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.

The cooperative catalysis using NHC and gold catalyst was reported (**Figure 5**) [31]. When NHC precursor **A8** (20 mol%), PPh3AuCl/AgPF6 (10 mol%), and DABCO (25 mol%) were employed, the relay reaction of ynamide substrate **28** with enal **29** gave the bicyclic lactam **30** in 84% yield with 99% ee. In this catalysis, Au(I) promotes the cyclization of ynamide **28** to generate α,β-unsaturated imine as a key intermediate. The subsequent reaction of α,β-unsaturated imine with the NHC-linked enolate, generated from enal **29** and NHC, gives the bicyclic product **30**.

The combination of NHC catalysis and ruthenium redox catalysis was investigated [32–34]. The oxidation of the Breslow intermediate leads to the formation of

**Figure 5.** *Cooperative catalysis with gold catalyst.*

**Figure 6.**

α,β-unsaturated acyl azolium *via* radical cation (**Figure 6**) [34]. In the presence of chiral NHC generated from precursor **(5a***R***,10b***S***)-A1**, RuCl3, and O2, the oxidative reaction of cinnamaldehyde **2** with 2,4-pentanedione **31** were performed in 1,4-dioxane, affording lactone **32** in 98% yield with 93% ee. The proposed reaction mechanism involves the oxidation of Breslow intermediate, generated from NHC and enal **2**, by SET from RuCl3. The second oxidation of radical cation intermediate by RuCl3 gives α,β-unsaturated acyl azolium, which undergoes [3 + 3] annulation with 2,4-pentanedione **31**. In this catalysis, Ru(III) is regenerated through the oxidation of Ru(II) by molecular oxygen. Furthermore, cooperative catalysis using NHC and iridium catalyst was also developed [35, 36].
