Efficient Heterogeneous Palladium Catalysts in Oxidative Cascade Reactions

Conspectus Palladium-catalyzed oxidations involving cascade processes provide a versatile platform for streamlined conversion of simple feedstocks into functional molecules with high atom and step economy. However, the achievement of high palladium efficiency and selectivity in Pd-catalyzed oxidative cascade reactions is still challenging in many cases, as a result of the aggregation of active palladium species to Pd black and the possible side reactions during each bond-forming step. The two current solutions for addressing these issues are either to utilize oxidant-stable ligands or to use electron transfer mediators (ETMs). The former solution, which includes the use of amines, pyridines, sulfoxides, and carbene derivatives, inhibits aggregation of Pd0 during the catalytic cycle, while the latter solution facilitates reoxidation of Pd0 to PdII to improve the activity and selectivity. Following our long-standing interest in Pd-catalyzed oxidations, very recently we developed heterogeneous catalysts to resolve the issues mentioned above in oxidative cascade reactions. The heterogeneous palladium catalysts (Pd-AmP-MCF or Pd-AmP-CNC) comprise palladium nanoclusters (1–2 nm) immobilized on amino-functionalized siliceous mesocellular foam (MCF) or on crystalline nanocellulose (CNC), exhibiting high activity, selectivity as well as excellent recycling ability. In this Account, we will discuss the synthesis and characterizations of the heterogeneous palladium catalysts, as well as their catalytic behaviors, and the mechanisms involved in their reactions. An important aspect of these catalysts in oxidation reactions is the generation of active Pd(II) species within the heterogeneous phase. Typical oxidative cascade reactions of our recent research on this topic include oxidative carbocyclization-carbonylation, oxidative carbocyclization-borylation, oxidative alkynylation-cyclization, oxidative carbonylation-cyclization, and oxidative carbocyclization-alkynylation. These reactions provide access to important compounds attractive in medicinal chemistry and functional materials, such as γ-lactone/γ-lactam-based poly rings, cyclobutenols, highly substituted furans, and oxaboroles. During these processes, the heterogeneous catalysts exhibited much higher turnover numbers (TONs) than their homogeneous counterparts (e.g., Pd(OAc)2) as well as unique selectivity that cannot be achieved by homogeneous palladium catalysts. The origin of the high efficiency and unique selectivity of the heterogeneous catalysts was also investigated. Asymmetric syntheses for the construction of optically pure compounds were realized based on the excellent selectivity in these heterogeneous processes. Kinetic studies revealed that the rate and yield of the reactions were essentially maintained during recycling, which demonstrates that Pd-AmP-MCF and Pd-AmP-CNC are robust and highly active in these oxidative cascade reactions. In addition, inductively coupled plasma optical emisson spectroscopy (ICP-OES) analysis and hot filtration test suggest that these processes most likely proceed via a heterogeneous pathway. Recent progress in our group has shown that the activity of Pd-AmP-MCF and Pd-AmP-CNC could be improved even further by the addition of Ag+ to generate cationic Pd(II). Furthermore, intriguing solvent effects were observed in a Pd-AmP-MCF-catalyzed oxidative cascade process, and solvent-controlled chemoselective transformations were developed based on this property of the catalyst. The heterogeneous strategy of this Account provides solutions to palladium deactivation and selectivity issues in Pd(II)-catalyzed oxidative cascade reactions and enables efficient catalyst recycling, which will open up new opportunities in oxidative cascade reactions.

was observed for the f irst time by using Pd-AmP-MCF as the heterogeneous palladium catalyst. Ed. 2020, 59, 10391−10395. 3 AgOTf is able to remove Clon the surface of Pd-AmP-MCF, creating cationic Pd, which is highly active in oxidative carbonylation cascade reactions. Angew. Chem., Int. Ed. 2021, 60, 670−674. 4 The amino linker/ligand on Pd-AmP-MCF protects Pd f rom aggregation and regulates catalytic selectivity, resulting in high eff iciency of the heterogeneous palladium catalyst in oxidative carbocyclization-alkynylation reactions.

INTRODUCTION
Palladium-catalyzed oxidations provide the basis for streamlined conversion of simple feedstocks into valuable products. 5−7 The interest in this research field originates from the middle of the 1950s by the discovery of the Wacker process, 8 which was responsible for an annual production of over one billion pounds of acetaldehyde from ethylene at one point. The developed methodologies of Pd-catalyzed oxidations not only contribute to solve the poor selectivity problem in oxidation reactions, but also stimulate the progress of synthetic organic chemistry. Up to now, a wide range of oxidations have been realized based on homogeneous palladium catalysts, and illustrative examples include alkene and diene functionalizations, 9,10 alcohol oxidations, 11 and C−H activations. 12,13 In particular, these oxidative processes with subsequent cascade reactions enable diverse functionalizations of organic molecules, which provide a versatile platform for the construction of bioactive compounds and other functional molecules. 14,15 In spite of the significant progress in Pd-catalyzed oxidative cascade reactions, the achievement of high palladium efficiency is still challenging in many cases. 16,17 One of the major reasons is the aggregation of active palladium species to Pd black under homogeneous conditions (Scheme 1a), which results in the deactivation of the palladium catalyst. Additionally, although the oxidative cascade reactions lead to target products with high atom and step economy, the control of selectivity during these processes is difficult, because of the diverse side pathway during each bondforming step. Effective catalyst systems that address the issues of palladium deactivation and selectivity control in oxidative cascade reactions is always in high demand. In this context, considerable efforts have been made by different groups, and two efficient solutions have been developed to improve the activity and selectivity of homogeneous palladium catalysts. One of them is the utilization of oxidant-stable ligands such as sulfoxides, carbenes, and amines, which were developed by the Yu, White, Stahl, and other research groups. 18 The use of oxidant-stable ligands or electron transfer mediators in homogeneous Pd-catalyzed oxidative cascade reactions has played an important role for improving the catalytic turnover and selectivity. Meanwhile, it has been noticed that, among some of these cases, the real active catalyst species were in situ generated palladium clusters. In 1995, the Hiemstra group reported that the Pd(OAc) 2 /DMSO catalytic system efficiently catalyzed the oxidative cyclization of N-hydroxymethylamine. 23 Based on transmission electron microscopy (TEM), it was shown that Pd clusters were generated during the reaction and they could be isolated and reused without loss of catalytic activity. Results from the Sheldon group demonstrated that Pd nanoclusters, formed in situ during the reaction, were catalytically active in the alcohol oxidation. 24 Stahl and co-workers found that in the oxidation of cyclohexanones and cyclohexenones to phenols with the Pd(TFA) 2 / 2-dimethylaminopyridine catalytic system, the initial Pd II catalyst evolved to Pd clusters immediately and catalyzed the formation of phenols. 25 Additionally, Pd clusters exhibited distinct selectivity compared to monomeric palladium catalysts. Control experiments showed that monomeric palladium catalysts, disfavoring the formation of Pd clusters, catalyzed oxidation of cyclohexanone to cyclohexenone without subsequent oxidation to phenol. It is noteworthy that the continual growth of Pd clusters to nanoparticles (>100 nm) leads to loss of activity in these oxidation reactions. These reports together suggest that Pd clusters with small size would overcome the mass-transfer issue, generally associated with heterogeneous catalysts, and provide high activity in oxidative cascade reactions. Moreover, these clusters can also alter the catalytic selectivity compared with the monomeric palladium catalysts. Additionally, the easy removal of Pd clusters from the reaction Accounts of Chemical Research pubs.acs.org/accounts Article mixture enables catalyst recycling, which is highly beneficial concerning practical applications in the fine chemical and pharmaceutical industry. However, unlike the wide application of Pd nanoparticles in Pd 0 -catalyzed cross-coupling reactions, 26,27 heterogeneous nanopalladium-catalyzed oxidative cascade processes are still quite limited. 28,29 A reasonable explanation might be that the relatively harsh oxidative reaction conditions cause problems to control the activity and selectivity. Also, the oxidative conditions may lead to Pd leaching problems, which make it difficult to identify the real active species and catalytic sites. Our group has a long-standing interest in Pd-catalyzed oxidations, 5,21a,30 and recently we have been involved in the oxidative cascade transformations of allenes. 31,32 In the majority of cases, relatively high palladium loading (≥5 mol %) was needed for satisfactory conversion, and the control of selectivity was also challenging in some cases. Meanwhile, we designed and prepared a palladium catalyst which comprises small palladium clusters immobilized in amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF). 33 This heterogeneous Pd catalyst has been applied in various organic transformations, such as selective hydrogenation, 34 cycloisomerization, 35 and water splitting. 36 Not only has Pd-AmP-MCF been shown to display high activity, it has also proven to be recyclable during these reactions. Particularly, the combination of Pd-AmP-MCF with an enzyme (Candida antarctica lipase B, CALB) has been demonstrated to be highly efficient in dynamic kinetic resolution of primary amines, 37 in which the nanopalladium promotes racemization of amines. Inspired by these results and the previous reports on Pd cluster-catalyzed oxidations, we envisioned that Pd-AmP-MCF would be catalytically efficient in oxidative cascade transformation of allenes for two reasons: (1) the palladium clusters with ultrasmall size would circumvent the mass-transfer issue; (2) the amino linker and porous support would hold the palladium clusters firmly, avoiding Pd aggregation or leaching. After about 3 years of work, we have successfully developed a series of the heterogeneous palladiumcatalyzed oxidative cascade reactions of allene compounds by using BQ as the terminal oxidant. [1][2][3][4]38 During these transformations, Pd-AmP-MCF and its analogue Pd-AmP-CNC 3 exhibited much higher turnover numbers (TONs) than their homogeneous counterparts (e.g., Pd(OAc) 2 ). In some cases, the heterogeneous catalysts showed unique selectivity for the construction of complex molecules that cannot be achieved by homogeneous palladium catalysts. In addition, Pd-AmP-MCF and Pd-AmP-CNC were robust under the oxidative reaction conditions and no Pd leaching or aggregation was observed. It was demonstrated that the rate and yield of the oxidative cascade reactions were essentially maintained during recycling. In this Account, we discuss our recent developments on the oxidative cascade methodology of allenes to important compounds attractive in medicinal chemistry and functional materials, with a focus on the efficient heterogeneous palladium catalysts. The high activity, unique selectivity, and solvent effects in these transformations are summarized, and finally an introspective outlook is presented concerning heterogeneous palladiumcatalyzed oxidations.

Synthesis of Pd-AmP-MCF and Pd-AmP-CNC
Siliceous mesocellular foam (MCF) was used as the solid support, which was functionalized by 3-aminopropyltrimethoxysilane to introduce an amino group. Aminopropyl-functionalized MCF (AmP-MCF) was then impregnated with Li 2 PdCl 4 to furnish the Pd II -AmP-MCF, which was reduced by NaBH 4 to give Pd 0 -AmP-MCF. Both Pd II -AmP-MCF and Pd 0 -AmP-MCF were used in the oxidative cascade reactions discussed in this Account, and they are collectively called Pd-AmP-MCF. The pore and window sizes of Pd II -AmP-MCF and Pd 0 -AmP-MCF were measured and found to be essentially the same as those in Accounts of Chemical Research pubs.acs.org/accounts Article dominated by Pd(0) and Pd(II), respectively. By using ecofriendly crystalline nanocellulose (CNC) in place of MCF as the support, we also synthesized Pd 0 -AmP-CNC and Pd II -AmP-CNC catalysts 3 with the same procedure as in Figure 1a.

The Initial Use of Pd-AmP-MCF in an Oxidative Cascade Reaction
One of the major concerns with the use of Pd-AmP-MCF as the catalyst for oxidative cascade reactions was whether the oxidant could interact with the surface of the palladium cluster to generate and maintain active Pd(II) for the catalytic cycle. With this question in mind, we treated Pd 0 -AmP-MCF with BQ and then characterized it by XPS. The deconvoluted Pd 3d XPS spectrum showed that there was a significant increase of the Pd(II)/Pd(0) ratio from about 5/95 to 25/75 on treatment of Pd 0 -AmP-MCF with BQ ( Figure 2a and b). 38 Additionally, compared to the untreated Pd 0 -AmP-MCF, the deconvoluted C 1s XPS spectrum of Pd 0 -AmP-MCF after treatment by BQ showed increased proportions of C−(C,H), C−O, and CO ( Figure 2c and d). Particularly, a new peak identified to be π−π* excitation was observed after the BQ treatment. 38 These results together indicate that the surface of the palladium clusters is partially oxidized by BQ and then BQ and the reduced hydroquinone (HQ) coordinate to Pd atoms on the surface. These generated Pd(II) atoms in the clusters could be the active sites required for oxidative cascade reactions (Figure 2e). The treatment of Pd II -AmP-MCF with BQ did not result in any obvious change of the Pd 3d XPS spectra, and Pd(II) was still dominant.
In the early 2010s, our group developed Pd-catalyzed oxidative functionalizations of allene compounds bearing an unsaturated moiety (Scheme 2a, X = olefin, alkyne, or allene). 31 In these transformations, the catalysts were homogeneous palladium salts such as Pd(OAc) 2 or Pd(TFA) 2 . To check the activity of the Pd-AmP-MCF prepared and discussed above, we designed an oxidative carbocyclization-borylation process (Scheme 2b). 38 With enallenol 1a and bis(pinacolato)diboron (B 2 pin 2 ) as the reaction partners, stoichiometric experiments were initially tried. The results showed that both Pd 0 -AmP-MCF and Pd II -AmP-MCF were active with BQ as the additive. However, control experiments demonstrated that the absence of BQ completely shut down the reaction (Scheme 2b). The catalytic experiments showed that both Pd 0 -AmP-MCF and Pd II -AmP-MCF catalyzed the reaction in the presence of BQ as the oxidant, giving the desired product cyclobutenol 2a in 59 and 71% yield, respectively. These results demonstrate that the heterogeneous palladium catalyst Pd-AmP-MCF is able to trigger the oxidative cascade process and complete the catalytic

Scheme 2. An Initial Attempt of Pd-AmP-MCF in an Oxidative Carbocyclization-Borylation Reaction
Accounts of Chemical Research pubs.acs.org/accounts Article cycle below (Scheme 2c). Meanwhile, BQ is essential in the reaction and plays an important role not only as an oxidant, but also as a ligand to promote the transformation. Deuterium kinetic isotope effect (KIE) studies indicate that C−H bond cleavage (from Int-1 to Int-2 in Scheme 2c) is the rate-limiting and first irreversible step in this heterogeneous process (Scheme 3). To rule out the possibility that the leached Pd species catalyze the reaction, we conducted inductively coupled plasma optical emission spectroscopy (ICP-OES, detection limit: 0.02 μg/mL) analysis of the liquid phase taken from the reaction mixture. The result showed that there was no detectable leaching of Pd in the reaction solution (<0.1 ppm). Hot filtration tests also confirmed this conclusion, which suggests a heterogeneous pathway. 39 Cyclobutenol is a versatile building block and key element in a large number of bioactive compounds and natural products. 40a The most straightforward route to cyclobutene derivatives via a [2 + 2]-cycloaddition of an alkyne and an olefin cannot be used for the construction of this skeleton. 40b Moreover, the diastereoselectivity control as seen in the current method for preparing cyclobutenol is challenging. 41 Under the optimized reaction conditions, enallenols 1 reacted with B 2 pin 2 , furnishing trans-cyclobutenols 2 with good substrate tolerance and high diastereoselectivity (Scheme 4). This heterogeneous method is a useful supplement to the synthetic route of cyclobutenols. It is noteworthy that an active hydrogen (OH or NH) is required in the substrate for controlling the diastereoselectivity, and the replacement of OH or NHTs by an acetyl group (OAc) or phthalimide group (NPhth) resulted in poor selectivity.
This initial try 38 gave us a positive indication that Pd-AmP-MCF with BQ is catalytically active in an oxidative cascade reaction of an allene via a heterogeneous pathway. Inspired by this work, in the following 2 years, we developed a series of heterogeneous palladium-catalyzed oxidative cascade processes toward the construction of complex compounds with high efficiency and selectivity.

High Palladium Efficiency
It is generally considered that heterogeneous palladium catalysts are less active and selective than their homogeneous counterparts as a result of the mass-transfer issue. 42 In our studies, we found the heterogeneous Pd II -AmP-MCF to be highly efficient in oxidative cascade reactions of allenes. In the oxidative alkynylation-cyclization reaction of enallenols with alkynes for the synthesis of furans (Scheme 5), the yields and TONs of Pd(OAc) 2 and Pd II -AmP-MCF are shown for comparison. 2  As shown in Scheme 5b, it is clear that a considerable amount of Pd black was generated from aggregation under the homogeneous reaction conditions, while this aggregation was not observed under the heterogeneous conditions with Pd II -AmP-MCF. 2 We conclude that the porous amino-functionalized support (AmP-MCF) protects the palladium species from aggregation, thus circumventing the Pd deactivation problem. This conclusion was further confirmed by XPS analysis of the heterogeneous catalyst in the oxidative carbocyclizationalkynylation reaction by using enallenol 6 as the starting material (Figure 3a): XPS spectra of Pd II -AmP-MCF before and after reaction showed a similar Pd(II) dominance (Figure 3b and c). 4 Pd II -AmP-MCF exhibits high palladium efficiency, on the one hand owing to its high TONs, and on the other hand due to its recyclability. It is recoverable and recyclable in the oxidative cascade reactions. Additionally, kinetic studies by using enallenol 6 as the starting material revealed that not only the yield, but also the reaction rate was essentially maintained between the first and the seventh runs, 4 which demonstrates that Pd II -AmP-MCF is robust and highly active under the heterogeneous reaction conditions (Figure 4). It should be pointed out that although the heterogeneous catalyst shows good recyclability during seven cycles, we cannot exclude the possibility that it might slowly lose the catalytic activity after a large number of runs. 43

Solvent-Controlled Chemoselectivity
Interestingly, the Pd II -AmP-MCF-catalyzed oxidative cascade reactions of enallenols (1 or 6) involving terminal alkynes as the reaction partner exhibited a solvent-controlled chemoselectivity. In the reaction of enallenol 1a with alkyne, 2 (Z)-tetrasubstituted olefin 3a, 2,5-dihydrofuran 4a, or tetrasubstituted furan 5a was isolated as the major product by using CH 3 CN, CH 3 OH, or CHCl 3 , respectively, as the solvent (Scheme 6). We speculated that 4 and 5 were generated from the Pd(II)-catalyzed intramolecular cyclization of 3 and isomerization of 4, respectively, which was confirmed by the further control experiments (Scheme 7). The solvent-controlled selectivity could be explained by (a) the interaction of CH 3 CN with Pd(II) inhibiting the subsequent Pd-catalyzed cyclization of 3, (b) the protic solvent (CH 3 OH) promoting transformation of 3 to 4, as a proton is essential during the process, and (c) the relatively acidic reaction conditions with the use of CHCl 3 (2CHCl 3 + O 2 → 2COCl 2 + 2HCl) favoring the isomerization from 4 to 5. 2 In the reaction of enallenol 6a with alkyne, 4 cyclopentenol 7a, (E)-tetrasubstituted olefin 8a, or 9a was the major product by using 1,2-dichloroethane (DCE), CH 3 CN, or CHCl 3 , respectively, as the solvent under the heterogeneous reaction conditions (Scheme 8). However, in CHCl 3 , there was still 32% yield of 7a in addition to the major product 9a. Based on the result that the addition of catalytic amounts of Et 3 N further improved the selectivity of the oxidative carbocyclizationalkynylation reaction to give 7a as the dominant product, we speculated that apart from the solvent, the amine additive also played an important role in altering the chemoselectivity of the   Accounts of Chemical Research pubs.acs.org/accounts Article reaction. Control experiments on using different amine additives confirmed our speculation (Scheme 9). These results demonstrate that the coordination of amine to Pd(II) improves the selectivity to give 7a, probably via suppressing the β-H elimination or promoting the alkyne ligand exchange of Int-6 ( Figure 3a). This could explain the result that 32% yield of 7a was still isolated in CHCl 3 by using Pd II -AmP-MCF as the catalyst, considering that the Pd(II) in Pd II -AmP-MCF is coordinated by amine (NH 2 ). Based on this conclusion, Pd(OAc) 2 was used in place of Pd II -AmP-MCF in CHCl 3 , and the selectivity of the reaction was completely switched to give 9a as the exclusive product in 90% yield under the homogeneous reaction conditions (Scheme 8). It is noteworthy that 5 mol % of Pd(OAc) 2 is required for full conversion of the starting material 6a, which demonstrates that Pd II -AmP-MCF is more efficient than the homogeneous palladium catalyst (Pd(OAc) 2 ). The solvent-controlled selectivity was utilized for the chemodivergent synthesis of highly substituted olefins, furans, and cyclopentenols (Scheme 10). Notably, the heterogeneous palladium-catalyzed oxidative cascade reactions not only displayed good chemoselectivity, but also showed excellent stereoselectivity. Cyclopentenols 7 were isolated as single cisdiastereomers in high yield in each case, and the olefins 3, 4, and 8 were obtained with stereodefined double bonds under the reaction conditions. 2,4

UNIQUE SELECTIVITY OF THE HETEROGENEOUS PALLADIUM CATALYSTS
Pd(II)-catalyzed oxidative carbonylation constitutes an efficient approach toward synthesis of organic molecules with carbonyl groups. 32,44,45 We designed an oxidative cascade route involving carbonylation 1,46 for the construction of ring fused γ-lactone 12, which is a core structure of many bioactive compounds, such as the strigolactone family members. 47 The envisioned cascade process (Scheme 11) for the construction of this skeleton involves four steps of bond formation including carbon monoxide (CO) insertions twice in the reaction sequence. 1 The possible side reactions of each palladium intermediate result in difficulties of controlling the chemoselectivity of the cascade reaction. Initial attempts to use 1a in the envisioned oxidative cascade reaction resulted in 10a as the major product under all homogeneous reaction conditions tried. Typically, in the presence of Pd(TFA) 2 , 10a and 12a were obtained in 65% and 28% yield, respectively (Scheme 12). However, when Pd II -AmP-MCF was used in place of the homogeneous palladium catalyst, the selectivity of the reaction was completely reversed, offering 12a in 68% yield. A slight modification of the oxidant under the heterogeneous reaction conditions improved the yield of 12a to 80%. The homogeneous Pd(TFA) 2 -catalyzed reaction, with 10 mol % of AcOH as an additive, gave 10a in 86% yield. The results of control experiments 1 suggest that the distinct chemoselectivity between Pd(TFA) 2 and Pd II -AmP-MCF originated from their different adsorption (coordination) capacity for CO. The high surface area of Pd II -AmP-MCF and presence of Pd(0) atoms favor adsorption and coordination of CO in the catalyst, which results in the aggregation of CO in Pd II -AmP-MCF. The local high CO concentration would promote the generation of Int-7 from Int-2 with subsequent carbocyclization to give Int-8. A second CO insertion of Int-8 would give 12. On the other hand, a low CO concentration would favor the formation of Int-7′ from Int-2 with subsequent reductive elimination to give 10. (Scheme 13).
The unique selectivity of Pd II -AmP-MCF-catalyzed oxidative carbocyclization-carbonylation reaction allows chemodivergent construction of γ-lactone 10 and fused γ-lactone 12. 1 It is noteworthy that 12 bearing two chiral centers were obtained with high diastereoselectivity as the cis-product (Scheme 14). Synthesis of optically pure fused γ-lactones 12 was realized by the use of (S)-enallenols 1 as starting materials in the stereoselective cascade reaction (Scheme 15). (S)-Enallenols 1 were readily obtained from kinetic resolution of enallenols 1 with C. antarctica lipase B (CalB).

SILVER-TRIGGERED HIGH ACTIVITY OF THE HETEROGENEOUS PALLADIUM CATALYSTS
Based on our previous reports, an unsaturated carbon−carbon bond is essential to trigger the allenic attack via coordination to Pd(II) in oxidative carbonylation reactions (Scheme 16a). 31,32,48 In 2019, we found that the sulfonamide group of α-tosylamide allenes could undergo anionic ligand exchange with ligands on the Pd(II) catalyst. The coordination of the sulfonamide group also triggered the allenic attack step and the subsequent alkynylation. 49 Inspired by this observation, we designed an oxidative carbonylation-cyclization process for the construction of pyrrolidones (Scheme 16b). 3 Initial attempts, however, gave very low yield of pyrrolidone 14a (<8%), and variation of solvent, oxidant, or temperature did not improve the Accounts of Chemical Research pubs.acs.org/accounts Article yield with the starting material 13a being almost completely recovered. After screening different additives, finally we found that the addition of catalytic amounts of AgOTf (10 mol %) in Pd II -AmP-MCF dramatically improved the yield of 14a to >90% ( Figure 5). Further optimization of the reaction conditions showed that the loading of Pd II -AmP-MCF and AgOTf could be reduced to 0.5 mol % and 1 mol %, respectively, furnishing 14a in satisfactory yield in 30 min. By using crystalline nanocellulose as the support, we prepared Pd II -AmP-CNC as a catalyst by using the same procedure as the synthetic method of Pd II -AmP-MCF (Figure 1a). Pd II -AmP-CNC also showed high catalytic activity with the addition of AgOTf in this oxidative cascade reaction. In contrast, homogeneous palladium catalysts such as Pd(TFA) 2 or Li 2 PdCl 4 did not give satisfactory yields with AgOTf ( Figure 5).
To reveal the origin of the high activity of this catalytic system (Pd II -AmP-CNC + AgOTf) in the oxidative carbonylationcyclization reaction, we conducted control experiments. 3 The results show that the Cl/Pd molar ratio of Pd II -AmP-CNC is 2.1/1 and 0.03/1 before and after treatment with AgOTf, respectively (Figure 6a). The analysis of XPS spectra indicates that the Pd 3d binding energy of Pd II -AmP-CNC treated by AgOTf is higher than that of untreated catalyst (Figure 6b). These results suggest that the chloride on the palladium clusters of Pd II -AmP-CNC has been completely removed by AgOTf, generating cationic palladium 50 with high activity in the oxidative carbonylation-cyclization reaction (Figure 6c). The addition of AgOTf to homogeneous palladium also results in an improvement of production of 14a ( Figure 5), which supports the generation of cationic palladium. However, the homogeneous catalytic system did not give satisfactory yield, probably due to the immediate deactivation of the palladium species under the reaction conditions. This heterogeneous method allows rapid access to pyrrolidones with high efficiency, and it has been utilized for the onepot construction of polycyclic compounds with a subsequent Diels−Alder reaction (Scheme 17). It is noteworthy that  To tap the potential of heterogeneous palladium catalysis in oxidative processes, rational design of efficient catalysts is of great importance and the following three proposed approaches could significantly stimulate further development of the field: (1) Robust heterogeneous nanopalladium catalysts with ultrasmall particle size would be able to overcome the mass-transfer issues and dramatically increase the catalytic activity. (2) Metal-doping in Pd nanoclusters would lead to a novel heterogeneous palladium catalysts, where the new metal introduced (e.g., Cu, Au) would cooperate with palladium and synergistically catalyze oxidative cascade reactions, realizing organic transformations that are hard to achieve by mononuclear homogeneous palladium catalysts.
(3) Design and synthesis of well-defined palladium nanoclusters with atomically precise structures, 51 and their applications in catalytic oxidations, will be helpful for in-depth understanding of structure−property correlations and catalytic mechanisms, promoting the recursive optimization of structure and catalytic performance of the heterogeneous palladium catalyst. The authors declare no competing financial interest.