y J . Am . Chem . Soc . 136 : 6453 − 6462

Cross-dehydrogenative coupling reactions between -ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of -ketoesters and indoles. The mechanism of the reaction between a prototypical ketoester, ethyl 2-oxocyclopentanonecarboxylate and N-methylindole, has been studied experimentally by monitoring the temporal course of the reaction by 1 H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the -keto ester ligand from an O,O’-chelate to an C-bound Pd enolate. This ligand tautomerization event is assisted by the -bound indole ligand. Subsequent scission of the ’-C–H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step. INTRODUCTION– Dehydrogenative cross-couplings, or cross-dehydrogenative couplings between two partners with C–H bonds, constitute an attractive strategy in chemical synthesis. 1 In particular, when the reaction partners include sp 3 C– H bonds, the reactions can be used to generate molecular complexity in three dimensions, and at the same time allow functionalization in remote positions. Although there have been significant advances in this field in recent years, 2,3 dehydrogenative functionalization reactions involving remote sp 3 C–H groups are still rare. 4 In part, this might be due to the fact that the mechanisms of dehydrogenative cross-couplings are only partially understood. Herein, we present a full account on the mechanistic investigation and the scope of the selective Pd(II)-catalyzed dehydrogenative cross-coupling reaction between indoles and βketo esters. 5 This reaction is an example of a crossdehydrogenative coupling between sp 3 and sp 2 C−H bonds. Besides indoles, the reaction also accepts electron-rich aromatics and phenols as the coupling partner, 6 and also allows for a three-component coupling between arylboronates, indoles and β-keto esters (Scheme 1). Scheme 1. Development of Dehydrogenative β’−C(sp)−H C(sp 2 )−H Coupling Reaction Results and Discussion In our initial communication, we presented two possible mechanistic scenarios for this reaction (Scheme 2). The first, a “late indole”, scenario involves a Saegusa oxidation 8 of 1a to enone intermediate A followed by a Friedel-Crafts-type Pdcatalyzed conjugate addition of indole 2a. The second, an “early indole”, scenario starts with the well-established C3palladation of indole 9 in which a C3-palladated indole species B is involved in the dehydrogenation step, followed by reductive elimination. Our early mechanistic investigations 5 could not distinguish between these two mechanistic possibilities. The key initial observations were: 1) Isolated enone 4a also afforded the coupling product with indole 2a, at a rate that was comparable to the overall reaction rate, and 2) without indole 2a, only very slow formation of enone 4a was observed. These observations suggested that if enone 4a was an intermediate, its formation might be dependent on the assistance of indole. Scheme 2. Palladium-Catalyzed Dehydrogenative β′Functionalization of β-Keto Ester with Indole and Originally Proposed Reaction Mechanism In our early studies, the progress of the reaction was monitored by withdrawing aliquots from the reaction mixture. 5 In this work, we envisioned that the use of online NMR methods to monitor the temporal progress of the reaction would be most beneficial to reveal any fleeting intermediates, and to allow the simultaneous monitoring of several species, including the oxidant. 10 Kinetic Studies. Initially, the standard reaction of β-keto ester 1a with 1-methylindole (2a) was monitored by 1 H NMR spectroscopy (Figure 1). The results show that [4a] builds up and decays during the initial stage of the reaction, and product formation ([3a]) follows a sigmoidal curve. The consumption of indole 2a also plots a reverse sigmoidal curve. These results strongly suggested that enone 4a is an intermediate, and indeed the rate of formation of 3a peaks close to the concentration peak of 4a. 11 The sigmoidal shape of the curve for [4a] is characteristic of a delay caused by the buildup of the intermediate in a consecutive reaction. The initial rate for the consumption of β-keto ester 1a (-5.7 mM min -1 ) is also close to the initial rate of the consumption of the oxidizer tBuOOBz (5.1 mM min -1 ). Figure 1. Monitoring of the temporal progress of the coupling by H NMR spectroscopy. Reaction conditions: [1a]0= 0.476 M, [2a]0= 0.318 M, [tBuOOBz]0= 0.413 M, 10 mol% Pd(TFA)2, 4:1 [D8]-dioxane/AcOH, 300 K. The reported rates are averages of three experiments. Rate0 and rate53 refer to the initial rate and the rate at t = 53 min, respectively. Using separately prepared enone 4a, the reaction between enone 4a and indole 2a was investigated under two sets of conditions. The initial concentration of 4a was set to 0.12 M, close to the peak concentration of 4a obtained under the standard oxidative coupling conditions (Figure 1). With Pd(TFA)2 as the catalyst, the reaction between 2a and 4a (Scheme 3) progresses at a rate comparable to the peak rate obtained under the standard conditions (1.7 mM min –1 for both cases). In contrast, TFA alone as the catalyst allowed the reaction to proceed, but at a significantly slower rate (1.7 mM min -1 with Pd(TFA)2 vs. 0.26 min -1 with TFA, see Scheme 3). These results indicated that Pd(II) also plays a role in the second coupling step, with a possible acid-catalyzed background reaction. Scheme 3. Reactions of Indole 2a and Enone 4a Table 1. Effect of TFA on the Reaction Rate a Entry TFA Rate 3a (mM min) Rate 4a (mM min)