For the reaction of Pd(OAc)2 catalyzed C–H alkylation of indole with MesICH2CF3OTf, there are two major possibilities: C2-H alkylation and C4-H alkylation. Unexpectedly, the Pd(II)-catalyzed C4-H alkylation of indole with MesICH2CF3OTf was experimentally obtained. In order to explain the Pd(II)-catalyzed regioselective C-H alkylation of indole with MesICH2CF3OTf, the detailed reaction mechanism shown in Scheme 1 has been provided by us.6 Firstly, the mechanism of C4-H alkylation (Path 1A) occurs through the coordination of the indole substrate with active catalyst Pd(OAc)2 to form intermediate A. Then the C4-H bond activation gives a six-membered metallacycle intermediate B. Subsequently, the alkylation regent MesICH2CF3OTf comes in and take place an oxidative addition process to afford a Pd(IV) intermediate C, which was followed by a reductive elimination (RE) process to yield the intermediate D. Finally, the intermediate D yields C4-H alkylated products and recovers the Pd(II) catalyst through ligands substitution. The mechanism for C2-H alkylation of indole (Path 1B) is similar to that of C4-H alkylation.
Mechanism of C4-H alkylation
The free energy profile for C4-H alkylation of indole with MesICH2CF3OTf was calculated and shown in Fig. 1 (Path 1A). According to the previous studies on Pd(OAc)2 catalyzed C-H bond cleavage,15 the most common mechanism for C-H bond activation is concerted metalation-deprotonation(CMD). The reaction begins with the coordination of indole substrate with the active catalyst Pd(OAc)2 through the oxygen atom of directing group to form a 16-electron intermediate 2a, in which one acetate anion (-OAc) is bidentate and this step is endergonic by 6.1. kcal/mol. In order to retain a vacant coordination position for the CMD process, species 2a undergoes a facile isomerization to yield the precursor complex (2a´) for C-H bond activation. Subsequently, C4-H bond activation occurs at the C4 position of indole through the CMD process with the assistance of acetate anion, the transition state for this step is a six-membered ring TS2a and the activation barrier of the C-H bond cleavage is 21.0 kcal/mol. In TS2a, the C4-H bond cleavage and C-Pd bond formation occurs simultaneously. Meanwhile, in transition state TS2a the configuration of the metal center is square planer.
From species 3a, it extrudes an acetic acid into the reaction system to give a new 16-electron six-membered cyclic palladium species 4a, the energy released in the whole C-H activation step is 13.5 kcal/mol. Meanwhile, it’s worth noting that this step is irreversible, as the reverse reaction (34.5 kcal/mol) calls for much more energy than the forward reaction (21.0 kcal/mol). Subsequently, the oxidative reagent MesICH2CF3OTf comes in and undergoes an oxidative addition process to afford the intermediate 5a. After that the reductive elimination process takes place to give species 6a via the three-membered ring transition state TS5a by spanning a barrier of 13.0 kcal/mol (4a→TS5a). Especially, these two steps are energetically favorable and exergonic by 16.2 kcal/mol. Finally, the active catalyst Pd(OAc)2 and C4-H bond alkylated product are formed through ligands substitution with HOAc.
Overall, the energy released in C4-H bond alkylation of indole with MesICH2CF3OTf catalyzed by Pd(OAc)2 is 37.3 kcal/mol. And the C-H bond activation process is the rate-determining step of this reaction, which activation energy is 21.0 kcal/mol.
Mechanism of C2-H alkylation
As mentioned in the Introduction, another possible pathway to produce the hypothetical C2-H bond alkylated product was also been considered as shown in Fig. 2. Firstly, the coordination of directing group ketone in indole substrate with active catalyst Pd(OAc)2 affords a square planar 16-electron intermediate 2b, followed by C-H activation at the C2 position of indole, which undergoes a CMD process through the five-membered ring transition state TS2b to afford a five-membered ring intermediate 3b followed by dissociation of AcOH, the activation barrier for this step is 23.8 kcal/mol. Subsequently, one molecule of substrate MesICH2CF3OTf goes through an oxidative addition process attaching to the Pd2+ center to produce intermediate 5b. From intermediate 5b, the reductive elimination occurs to the Pd(IV) metal center via the transition state TS5b to give a square planar configuration intermediate 6b by overcoming an activation barrier of 20.1 kcal/mol(4b→TS5b). Finally, the intermediate 6b take place ligands substitution of AcOH with TfOH to give the C2-H bond alkylated product P2 (Fig. 2).
According to mechanism shown in Fig. 2, the rate-determining step for the C2-H alkylation of indole with MesICH2CF3OTf is the C2-H bond activation with an overall activation barrier of 23.8 kcal/mol. Meanwhile, the overall reaction is exergonic by 36.6 kcal/mol.
Comparison between C2-H and C4-H alkylation of indole with MesICH2CF3OTf
Based on the above calculated results (Fig. 1 and Fig. 2), It evidently reveal the fact that the C-H bond activation step is the rate-determining step for these two pathways and the overall activation barrier for C2-H alkylation of indole is 23.8 kcal/mol), which is higher than C4-H bond alkylation of indole (21.0 kcal/mol). Thus the C4-H bond alkylation of indole is kinetically more favorable than C2-H alkylation. The reason for this scenario can be explained by comparing the stabilities of the transition states in CMD process. The transition state (TS2a) for C4-H bond alkylation is a six-membered ring TS and the deprotonated hydrogen atom located on phenyl ring. In contrast, the transition state (TS2b) in C2-H bond alkylation is a five-membered ring structure and the departing proton located on pyrrole ring, the electron density of pyrrole ring is much greater than phenyl ring. Additionally, we also contend that the relative stabilities of deprotonated intermediates can affect this reaction selectivity through our computational data, the relative free energy of 3a in C4-H activation is -10.3 kcal/mol, which is much lower than 3b (-0.2 kcal/mol) in C2-H activation. Therefore, the overall activation barrier for C4-H bond alkylation is lower than C2-H bond alkylation. Meanwhile, the overall energy of C4-H bond alkylation of indole with MesICH2CF3OTf is exergonic by 37.3 kcal/mol, which is larger than C2-H bond alkylation (36.6 kcal/mol). Thus the C4-H bond alkylation of indole in Path 1A is clearly more favorable than the C2-H bond alkylation process in both kinetically and thermodynamically. These calculated results are in good consistent with experimental results.