Compatibility Score for Rational Electrophile Selection in Pd/NBE Cooperative Catalysis
A mechanistically guided approach is developed for predicting effective electrophiles in Pd/NBE cooperative catalysis. Computational and experimental mechanistic studies revealed an anionic aryl-norbornyl-palladacycle (ANP) as the catalytically active species. These insights are used to establish a computational procedure to rapidly predict compatibility between aryl halides and electrophiles by evaluating their orthogonal reactivity in the Pd(0)/(II) and Pd(II)/(IV) oxidative addition steps.
INTRODUCTION<!>RESULTS AND DISCUSSION<!>Experimental and Computational Validation of Anionic ANP as the Catalytically Active Species<!>Compatibility Score for Evaluating the Orthogonal Reactivity of Electrophiles and Aryl Halides<!>Article<!>ll<!>Conclusions<!>Article<!>EXPERIMENTAL PROCEDURES<!>Materials Availability<!>Data and Code Availability<!>Computational Methods<!>SUPPLEMENTAL INFORMATION
<p>A variety of multicomponent cross-coupling reactions and cross electrophile-electrophile coupling reactions have emerged over the past decade (Schemes 1B-1D). [1][2][3][4][5][6][7] These catalytic transformations often involve more than one electrophilic starting materials, and thus offer unique ways for bond formation that are complementary to traditional cross-coupling reactions between an electrophilic and a nucleophilic coupling partner. The central challenge in developing such reactions is the effective control of chemoselectivity. The electrophiles must react selectively with different transition-metal complexes at separate oxidative addition (OA) events in the catalytic cycle while not interfering with elementary steps involving other electrophiles (Scheme 1A). To achieve such orthogonal reactivity, it is imperative to utilize new paradigms of reactivity control that go beyond the classical understanding of steric and electronic effects on electrophile reactivity.</p><p>The complexity of the rational electrophile selection is exemplified in the palladium/ norbornene (Pd/NBE) cooperative catalysis, also known as Catellani-type reactions. [6][7][8][9][10][11][12] These reactions offer an effective approach for the synthesis of polysubstituted aromatics through selective functionalization of both ortho and ipso positions of aryl halides (Ar-X) with an electrophile and a nucleophile, respectively (Scheme 1D). [13][14][15][16] Because the catalytic cycle involves two different oxidation events between Ar-X and Pd(0) and between the electrophile (E-Y) and a putative aryl-norbornyl-palladacycle (ANP) species [17][18][19][20][21][22] (Scheme 1E), the choice of compatible electrophiles becomes an intricate process. The electrophile and the aryl halide must have orthogonal reactivities with Pd(0) and Pd(II) species (Scheme 1F): E-Y should</p><p>The Bigger Picture Developing catalytic methods for novel types of bond formation using readily available starting materials has been a long-term goal in organic synthesis. While traditional cross-coupling reactions take place between a nucleophile and an electrophile, various coupling reactions involving two different electrophiles have recently emerged. These reactions provide promising platforms for synthesizing functionalized molecules, considering the large variety of commercially available carbon and heteroatom electrophiles. However, it is not trivial to identify electrophiles that are compatible with each other because they must have orthogonal reactivity that allows them to react selectively with different organometallic species in different elementary steps of the catalytic cycle. Here, we describe a mechanistically guided approach to rationally predict electrophiles that meet these criteria and can be potentially used in multi-electrophile coupling reactions. be less reactive than Ar-X in the OA with Pd0; while E-Y must be more reactive than Ar-X when reacting with ANP. In addition, the reaction of electrophile with ANP to form intermediate III must outcompete several side reactions (e.g., formations of I and II, Scheme 1F). Despite the emergence of Pd/NBE cooperative catalysis as a powerful synthetic strategy, effective electrophiles that are known to meet these criteria are still rather limited. The lack of knowledge in discovering compatible electrophiles has hampered the development of new catalytic reactions with other electrophilic coupling partners and limited the application of Pd/NBE cooperative catalysis in natural product functionalization 23 and synthesis of pharmaceutical compounds. 24 The rational selection of compatible electrophiles must overcome several practical challenges. First, the crucial step involving the reaction of ANP with the electrophile is still mechanistically ambiguous. Although several ANP analogs have been synthesized using stoichiometric reactions and were found viable of generating the coupling product, [17][18][19] the actual form of the active ANP species under catalytic conditions may be different from the isolated complexes. In particular, phosphine and anionic ligands (e.g., I -) 25 may affect the reactivity and lead to a completely different chemoselectivity of the ANP species. Second, because a number of structurally distinct electrophiles have been employed in arene ortho alkylation, 9,[26][27][28][29][30] arylation, [31][32][33] amination, 14,34,35 acylation, [36][37][38][39] and thiolation [40][41][42] reactions (Scheme 1D), it is not clear whether the identity of the electrophile will affect the mechanisms of these reactions, in particular, the key step of reacting with the ANP intermediate. Last but not the least, there lacks a practical approach to tune the reactivity of the electrophile according to a given aryl halide starting material to achieve the orthogonal reactivity. Because most known Pd/NBE cooperative catalysis use aryl iodides as starting materials, electrophiles that are compatible with other aryl halides, such as aryl bromides 14 and triflates, are especially desirable.</p><p>We surmised that the rational selection of compatible electrophiles in the Pd/NBE cooperative catalysis and other multi-electrophile coupling reactions can be achieved via a two-step, mechanistically guided approach. This process would initiate via detailed computational and experimental mechanistic studies to elucidate the exact transition-metal complexes involved in reactions with different electrophiles. Then, the electrophile compatibility score (ECS) between two electrophilic starting materials is calculated based on the activation free energies of the possible reactions between the electrophiles and the catalytically active transition-metal complexes (Scheme 1A). In this manuscript, we demonstrate the application of this approach to predict the compatibilities between various electrophiles and aryl halide starting materials in Pd/NBE cooperative catalysis. We expect that this predictive approach can be extended to guide the electrophile design in other multielectrophile coupling reactions.</p><!><p>Experimental and Computational Mechanistic Studies to Identify the Catalytically Active ANP Species Before exploring the compatibility between aryl halides and various electrophiles in Pd/NBE cooperative catalysis, it is necessary to identify the catalytically active ANP species and to investigate the mechanisms of the reaction between ANP and electrophiles. We initiated our mechanistic investigations by a combined computational and experimental study on the Pd/NBE-catalyzed ortho-amination of aryl iodides using N-benzoyloxyamines as electrophilic coupling partners (Figure 1A). 14,34 The DFT-computed energy profile revealed that a bisphosphine-supported ANP complex (ANP-1) is generated through OA of aryl iodide (ArX-1) to bisphosphineligated Pd(0) species (TS-1), [43][44][45][46] exo-insertion of NBE (TS-2), 47 and concerted metallation deprotonation (CMD) of the ortho C-H bond (TS-3) (Figure 1B; see Figure S3 for an alternative CMD pathway and Figure S14 for alternative OA pathways). The relatively low barriers of these three steps indicate the ANP complex formation is facile under the experimental conditions ($100 C). A stoichiometric reaction of ANP-1 and morpholino benzoate EY-1 gave aryl amination product 5 in 66% yield (Figure 1C). These computational and experimental results suggest that ANP-1 is a potential intermediate of the catalytic amination reaction, consistent with the previous experimental mechanistic studies from Catellani and Lautens that indicated that ANPs can react with other electrophiles, including alkyl halides and aryl halides. [17][18][19] However, the stoichiometric reaction with ANP-1 yielded the C(sp 3 )-N reductive elimination side product 5b in 28% yield, which was not formed under catalytic conditions. This indicates that the subtle difference of reaction conditions (e.g., the relative concentrations of Pd, PPh 3 , and anionic ligands) significantly impacts the product selectivity. Because several three-and four-coordinated ANP species supported by phosphine or anionic ligands may exist in equilibrium under the catalytic conditions (Figure 2A), we surmised that the active ANP complex that reacts with the electrophile under catalytic conditions may not be the bisphosphine-bound ANP-1. 25 Therefore, we performed careful computational analysis on the possible ANP complexes formed under the experimental conditions and investigated the reactivity and chemoselectivity of these ANP complexes.</p><p>Our DFT calculations indicated that at least six ANP complexes could exist in equilibrium because their relative energies are within several kcal/mol (Figure 2A). We calculated the reaction pathways of these ANP intermediates with electrophile EY-1 via several possible mechanisms, [48][49][50] including the concerted OA via either a three-or five-membered cyclic transition state, 49 the S N 2-type OA, 22 and the aromatic electrophilic substitution (S E Ar) (Figure 2B). The S E Ar transition state has an extremely high energy barrier (DG z = 49.9 kcal/mol for the reaction between ANP-6 and EY-1), and thus, can be ruled out. Furthermore, the transmetalation mechanism, in which two independent Pd(0)/Pd(II) cycles activate the aryl halide and the electrophile, respectively, followed by transmetalation between the two Pd(II) complexes, 51 can also be ruled out because of the high barrier to OA of EY-1 to Pd(0). 52 The different OA pathways of EY-1 with the neutral ANP complexes (ANP-1 and ANP-2) and the iodide-bound anionic ANP complexes (ANP-3 and ANP-4) are summarized in Figures 3A and 3B, respectively. 53 The reaction pathways with the The reaction of the four-coordinated anionic complex ANP-3 with EY-1 occurs via an S N 2-type OA transition state (TS-9), with a relatively high barrier of 31.1 kcal/mol (Figure 3B). On the other hand, the three-coordinated anionic ANP complex ANP-4 is much more reactive. The S N 2-type transition state TS-11 has an activation free energy of 21.9 kcal/mol with respect to ANP-1, which is significantly lower than all other competing OA processes. 55 Similar to the reaction pathways with neutral ANP complexes, the subsequent steps, including C(sp 2 )-N reductive elimination (TS-12), b-carbon elimination, and hydride transfer are all relatively facile (see Figure S12).</p><p>Taken together, the DFT calculations revealed the catalytically active species in the amination is an anionic ANP complex ANP-4. Its reactivity is fundamentally different from that of the neutral ANP complex ANP-1, which was isolated from stoichiometric reactions. The anionic ANP not only reacts faster with the N-benzoyloxyamine  Article electrophile but also favors a different, S N 2-type OA mechanism. Natural population analysis (NPA) charge calculations indicated that this unique reactivity is due to the enhanced charge transfer from the anionic ANP complex to the electrophile in the S N 2-type OA transition state (0.70e in TS-11, see Figure 3B). The charge transfer promotes the reaction by facilitating the benzoate anion dissociation via the heterolytic cleavage of the N-O bond. 56 On the other hand, the S N 2-type OA with the neutral ANP complex has a much smaller amount of charge transfer (0.33e in TS-6, see Figure S19) and thus requires a much higher barrier.</p><!><p>Identifying the catalytically active species involved in reactions with electrophiles is a critical step in predicting the ECS. To confirm the computational prediction that the anionic ANP complex is catalytically active, we performed a series of experimental and computational validations. Because it is known experimentally that the reaction between the active ANP species and the N-benzoyloxyamine electrophile will suppress two undesired reaction pathways (Scheme 1F), the C-C reductive elimination from ANP 8,26 and the C(sp 3 )-E reductive elimination from the Pd(IV) OA intermediate, we then investigated the effects of anionic ligands (e.g., I À , OBz À ) on these competing pathways (Figure 4). Our DFT calculations indicated the C-C reductive elimination from the neutral ANP-1 requires a relatively low activation free energy of 20.2 kcal/mol, which is 7.6 kcal/mol lower than the reaction of the same ANP complex with EY-1 (via TS-7). The low barrier to the C-C reductive elimination suggests that ANP-1 cannot be the dominant form of ANP in an effective Pd/NBE catalysis system. On the other hand, the anionic ANP complex ANP-3 is predicted to be much less susceptible to C-C reductive elimination. 57 Because the C-C reductive elimination from ANP-3 requires a higher barrier than the reaction with EY-1 (via TS-11, Figure 3B), the undesired formation of benzocyclobutene derivative would be disfavored if the anionic ANP species, rather than the neutral ANP, dominates. These computational findings are corroborated by control experiments (Figure 4B) that suggest ANP-1 is converted to the C-C reductive elimination product 18 in 98% yield in 50 min at 60 C, which is at a lower temperature than that of typical Pd/NBE-catalyzed reactions. This result confirmed that the neutral ANP-1 cannot be the catalytically active species. When 110 mol % tetrabutylammonium benzoate (TBAOBz) or tetrabutylammonium iodide (TBAI) was added to the same reaction, the yield of 18 decreased dramatically to 16% and 25%, respectively, and a large amount of ANP-1 was recovered, indicating the presence of benzoate or iodide anions under catalytic conditions may prevent the formation of 18 by converting ANP-1 to anionic ANP species. On the other hand, the use of cesium carbonate had a negligible effect on inhibiting the C-C reductive elimination, potentially due to its low solubility. 58 Next, we investigated the effects of anionic ligands on the regioselectivity of the C-N reductive elimination from the Pd(IV) OA intermediate. In the stoichiometric reaction of ANP-1 with EY-1, products 5 and 5b were formed in a 2:1 ratio (Figure 1C) and the structure of the aryl Pd(II) intermediate leading to the undesired product 5b was confirmed by X-ray crystallography (Figure 4C). However, the C(sp 3 )-N reductive elimination product 5b was not observed under catalytic conditions (Figure 1). We surmised that under the catalytic conditions with higher concentrations of anions (e.g., I À , OBz À ), anionic ANP complexes are the active species reacting with the N-benzoyloxyamine electrophile to form an anionic Pd(IV) intermediate (IV, L = I -, Figure 4C). By contrast, under the stoichiometric conditions, neutral Pd(IV) species (IV, L = PPh 3 ) is formed. Our computational results revealed that the C(sp 2 )-N and C(sp 3 )-N reductive elimination transition states from the neutral IV (L = PPh 3 ) have comparable activation free energies, while the C(sp 2 )-N reductive elimination is favored by 7.5 kcal/mol from the ll 2816 Chem 6, 2810-2825, October 8, 2020 Article anionic IV (L = I -). These experimental and computational studies provided additional support to the hypothesis that the in situ formed anionic ANP complex is the catalytically active species because it can react efficiently with the N-benzoyloxyamine electrophile and suppress both the C-C reductive elimination from ANP and the C(sp 3 )-N reductive elimination from the Pd(IV) intermediate.</p><!><p>After identifying the catalytically active Pd(0) and Pd(II) species (Pd0 and ANP-4, respectively), we are now able to evaluate the compatibility between an aryl halide starting material and an electrophile using the ECS. The ECS is calculated based on the activation barriers of four competing OA events in the catalytic system: DG z (Pd0+ArX), DG z (Pd0+EY), DG z (ANP+ArX), and DG z (ANP+EY) (Scheme 2). A compatible system requires that Pd0 reacts faster with ArX than with EY (DG z (Pd0+EY) À DG z (Pd0+ArX) > 0) and ANP reacts faster with EY than with ArX (DG z (ANP+ArX) À DG z (ANP+EY) > 0). Therefore, a positive compatibility score indicates the electrophile EY meets both criteria and thus is compatible with ArX in Pd/NBE catalysis, and a negative score indicates the electrophile is incompatible because side reactions would outcompete the desired reaction pathways. For example, the computed ECS between ArX-1 and EY-1 is 3.3 kcal/mol, indicating these two starting materials are highly compatible, which is in agreement with the effective reactions involving these two compounds in the ortho-amination reactions.</p><!><p>We used this procedure to calculate the compatibility of nine representative electrophiles (EY-1$EY-9) when reacting with ArX-1 (Figure 5; Table S1). The computed ECS are in good agreement with previous experimental results: EY-1$EY-6 have positive compatibility scores with ArX-1 and have been successfully employed in Catellani-type amination, 34 alkylation, 26 arylation, 31 and acylation 36,38 reactions with ortho-alkyliodobenzenes 59 ; on the other hand, the low yield in the reaction of EY-8 with 2-iodotoluene 31 can be attributed to their low compatibility (ECS = À4.1 kcal/mol). In these reactions, the electrophile compatibility is determined in the second OA step, because all electrophiles investigated are less reactive than ArX-1 when reacting with Pd0, indicating that they will not interfere with the first OA step between ArX-1 and Pd0. In the second OA step, EY-1$EY-7 have comparable or lower barriers than ArX-1, indicating they can react effectively with ANP in the presence of the aryl iodide, while EY-8 and EY-9 are both incompatible because of the high barriers (DG z (ANP+EY) = 25.0 and 27.8 kcal/mol, respectively) when reacting with ANP-4.</p><p>To validate whether the compatibility scores can be used to identify effective electrophiles in reactions with other aryl halides, we computed the compatibility of EYs with 2-bromoanisole (ArX-4) and compared with previous experimental results (Figure 6). Because of the lower reactivity of the aryl bromide when reacting with ANP (DG z (ANP+ArX) = 27.9 kcal/mol), the four electrophiles all react faster with ANP than ArX-4. Therefore, the electrophile compatibility in these reactions are determined in the first OA step, where the electrophiles need to be less reactive with Pd(0) than ArX-4. The computed ECS values are in good agreement with experiment (Figure 6) 14 : n-butyliodide (EY-2) is incompatible with ArX-4 because it reacts faster with Pd(0) than ArX-4 and electrophiles EY-7, EY-1, and EY-10 are all Article compatible because they react slower with Pd(0) than ArX-4. The above computational predictions highlighted the importance of considering both criteria, DDG z (Pd0) and DDG z (ANP), when evaluating the electrophile compatibility.</p><p>Next, we further expanded the computational predictions to all nine electrophiles in reactions with five different aryl halides (Figure 7). The computed ECS not only provided a straightforward approach to rapidly predict compatible reactions but also revealed mechanistic insights that may be used in future electrophile design. Several factors leading to compatible and incompatible systems (indicated as C-1$C-3 and I-1$I-2 in Figure 7) can be generalized. 60 First, electrophiles with an sp 3 -hybridized electrophilic atom (e.g., N-benzyloxyamine EY-1, alkyl iodide EY-2, and alkyl bromide EY-7) are privileged coupling partners because of their high reactivity with the negatively charged ANP via the S N 2-type OA transition states [61][62][63][64] (see ''C-1'').</p><p>As discussed above, these reactions are promoted by the charge transfer from the anionic ANP to the electrophile which facilitates leaving group dissociation. Second, anhydrides (e.g., EY-3 and EY-6. See ''C-2'') are another type of effective electrophiles in Pd/NBE-catalyzed arene acylation and alkoxycarbonylation reactions [36][37][38][39] because they react more effectively with ANP via a five-centered OA transition state. 20 The five-centered OA is more favorable in the Pd(II) to Pd(IV) oxidation than in the Pd(0) to Pd(II) oxidation because of the chelation of the anhydride carbonyl group with the higher valent Pd. 65,66 On the other hand, carbonyl coordination with Pd(PPh 3 ) 2 is disfavored because the Pd(0) is more electron-rich and the large P-Pd-P angle prevents the more sterically encumbered five-centered transition state. 67 A similar chelation effect promotes the OA of EY-4 to ANP, in which d Experimental yields from Catellani and Cugini, 26 Faccini et al., 31 Dong and Dong, 34 Zhou et al., 38 Wang et al., 39 were from reactions with 2-iodotoluene unless otherwise noted. e Experimental yield was from the reaction with 2-bromoanisole.</p><!><p>Chem 6, 2810-2825, October 8, 2020 2819</p><p>Article the ortho-ester group coordinates to the Pd(II) center (see ''C-2'', Figure 7), 68 and thus makes EY-4 an effective coupling partner in arylation (Figure 5). 31 Third, electron-deficient aryl bromides (e.g., EY-5) are effective electrophiles in arylation reactions (see ''C-3'') because they have relatively low activation energies in the OA with ANP (see Figure S22 for details). 69 These reactions are promoted by the d(Pd)/ p*(Ar-Br) orbital interactions between the negatively charged ANP and the electron-deficient aryl bromide. 70,71 On the other hand, aryl bromides EY-8 and EY-9 are not effective electrophiles (see ''I-2'') 31 because of their low reactivity toward ANP resulting from steric effects 72  Comparisons of reactions with aryl iodide (ArX-1 $ ArX-3) and aryl bromide (ArX-4 and ArX-5) starting materials revealed the identity of halides as another key factor determining electrophile compatibility. Based on the computed ECS values, the amination and acylation reactions with EY-1, EY-3, and EY-6 are expected to proceed with either aryl iodides or aryl bromides. 14,34 However, the alkylation using alkyl iodide (EY-2) and arylation using aryl bromides EY-4 and EY-5 as electrophiles require the use of more reactive aryl iodides as the Ar-X substrate. Due to the lower reactivity of aryl bromides with Pd(0), the Pd(0) complex would react preferentially with the electrophile if aryl bromides (ArX-4 or ArX-5) were used in these reactions (labeled as ''I-1'' in Figure 7). This prediction is consistent with the experimental observations that the reaction of ArX-4 with EY-2 did not form the arene alkylation product (Figure 6). 14 It is noteworthy that the computational results predicted that Article n-butylbromide EY-7 is not an effective electrophile in the alkylation of aryl iodides (ArX-1 $ ArX-3) because of the low reactivity of EY-7 with ANP, while these reactions gave high yields experimentally. 73 These results suggest that the alkyl bromide electrophiles were converted to the more reactive alkyl iodides in situ via halogen substitution 74 prior to the OA to ANP.</p><!><p>We describe a mechanistically driven approach to predict compatible electrophiles in the Pd/NBE cooperative catalysis. This approach uses the ECS between two electrophilic starting materials to predict whether a reaction may proceed effectively. In the Pd/NBE cooperative catalysis, the Pd(0) catalyst needs to react selectively with the aryl halide starting material in the presence of the electrophile, while the Pd(II) ANP intermediate needs to react faster with the electrophile than with the aryl halide. The ECS evaluates whether such orthogonal reactivity can be achieved in the two OA events with the Pd(0) and Pd(II) species, respectively. We have demonstrated the application of this approach to predict whether an electrophile would be effective in a variety of Pd/NBE-catalyzed aryl halide functionalizations, including the amination, arylation, alkylation, and acylation of different aryl halide starting materials. We expect that this method can be extended to facilitate the rational design of electrophiles in other multi-electrophile coupling reactions.</p><p>The key to this mechanistically driven approach is to identify the organometallic species that react with electrophiles at different stages of the catalytic cycle. Through a combined computational and experimental mechanistic study, we revealed that, in Pd/NBE cooperative catalysis, the OA with electrophiles takes place with an anionic ANP intermediate with an iodide or a benzoate ligand bound to the Pd, rather than the previously proposed neutral ANP complexes. The anionic ANP is not only more reactive in the OA of electrophile but also suppresses two undesired side reaction pathways, the C-C reductive elimination from ANP and the C(sp 3 )-N reductive elimination from the Pd(IV) intermediate.</p><!><p>Based on these mechanistic insights, the compatibility scores of 45 pairs of aryl halide and electrophile starting materials were computed using their activation energies with Pd(0) and the anionic ANP species. The predicted ECS is in good agreement with experiments for those that have been previously investigated. This mechanistically driven approach also uncovered several general factors affecting the electrophile compatibility. Coupling partners with an sp 3 -hybridized electrophilic center and anhydrides are privileged electrophiles because they react with ANP via substrate-dependent mechanisms (S N 2-type OA and five-centered OA, respectively) that are often more favorable than the three-centered OA of aryl halide to ANP. In addition, the compatibility of the electrophiles may be altered electronically. For example, electron-deficient aryl bromides are good electrophiles in the arylation of aryl iodides because the anionic ANP reacts efficiently with electron-deficient aryl bromides, which are promoted by d/p* interactions. Moreover, electrophiles that may chelate with the Pd(II) during ANP oxidation, such as aryl bromides with an ortho-ester group, are also good coupling partners.</p><!><p>Resource Availability Lead Contact Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Peng Liu (pengliu@pitt.edu).</p><!><p>Full experimental details can be found in the Supplemental Information.</p><!><p>All data supporting this study are available in the Manuscript and Supplemental Information. The X-ray crystallographic data of VIII (L = PPh 3 ) reported in this article has been deposited in the Cambridge Crystallographic Data Centre under accession number CCDC: 2005718.</p><!><p>Geometry optimizations and single-point energy calculations were carried out using Gaussian 09. 75 All DFT calculations were performed on the University of Pittsburgh Center for Research Computing, XSEDE, 76 and Texas Advanced Computing Center (TACC) Frontera supercomputers. The geometries of intermediates and transition states were optimized using the B3LYP functional, 77,78 with a mixed basis set of LANL2DZ for Pd, Cs, I, and 6-31G(d) for other atoms in the gas phase. Vibrational frequency calculations were performed for all stationary points to confirm if each optimized structure is a local minimum or a transition state structure. Solvation energy corrections were calculated in a toluene solvent with the SMD continuum solvation model. 79 The M06 functional 80,81 with a mixed basis set of SDD for Pd, Cs, and I and 6-311+G(d,p) for other atoms were used for the single-point energy calculations in toluene. The stability of the DFT wavefunction was tested for all computed structures. Most of the intermediates and transition states are closed-shell singlets except for several OA transition states of EY-1 to ANP (TS-4, TS-6, TS-9, TS-11, and TS-13), which open-shell singlets. The comparison between open-shell and closed-shell singlet structures of these transition states is included in the Supplemental Information. Cartesian coordinates and energies of all computed structures are provided in Table S2.</p><!><p>Supplemental Information can be found online at https://doi.org/10.1016/j.chempr. 2020.09.004.</p>