Catalytic Behavior of Mono-N-Protected Amino Acid Ligands in Ligand-Accelerated C–H Activation by Palladium(II)

Abstract

Mono-N-protected amino acids (MPAAs) are increasingly common ligands in Pd-catalyzed C–H functionalization reactions. Previous studies have shown how these ligands accelerate catalytic turnover by facilitating the C–H activation step. Here, we show that MPAA ligands exhibit a second property commonly associated with “ligand-accelerated catalysis”: the ability to support catalytic turnover at substoichiometric ligand:metal ratios. This catalytic role of the MPAA ligand is characterized in stoichiometric C–H activation and catalytic C–H functionalization reactions. Palladacycle formation with substrates bearing carboxylate and pyridine directing groups exhibit a 50–100-fold increase in rate when only 0.05 equivalents of MPAA are present relative to Pd^II. These and other mechanistic data indicate that facile exchange between MPAAs and anionic ligands coordinated to Pd^II enables a single MPAA to support C–H activation at multiple Pd^II centers.

Graphical Abstract

Rapid exchange of mono-N-protected amino acid (MPAA) ligands with other carboxylate ligands plays a key role in the ligand-accelerated catalysis observed in Pd^II-catalyzed C–H functionalization reactions. The MPAA ligands are shown to play a catalytic role in Pd^II-mediated C–H activation.

“Ligand-accelerated catalysis” (LAC) is a term applied to many homogeneous catalytic reactions in which a specific ligand greatly enhances the rate of an existing catalytic transformation.^[1] Examples of LAC are often distinguished by dynamic ligand exchange processes that enable a single ligand to activate multiple catalyst species within an equilibrating mixture of metal complexes. A prominent example of this behavior is OsO₄-catalyzed dihydroxylation of alkenes,^{[ 2 ]} which uses dihydroquinidine ligands in a 1:20 ratio with respect to OsO4. LAC is especially important in asymmetric catalysis, where ligand-free background reactions erode enantioselectivity and diminish the utility of the reaction, but the principles of LAC are not limited to enantioselective reactions. Yu and others have demonstrated that mono-N-protected amino acid (MPAA) ligands promote Pd^II-mediated C–H activation (e.g., Scheme 1A), and this reactivity has led to dozens of synthetically useful reactions.^[3–6] The precise role of the MPAA continues to be the focus of debate and investigation,^{[ 7 ]} but experimental and computational studies clearly demonstrate that the MPAA ligand accelerates Pd^II-mediated C–H activation.^[8–16] Here, we complement these studies by showing that MPAA ligands exhibit a catalytic role that allows a single MPAA ligand to activate multiple Pd^II centers (Scheme 1B and 1C). This behavior, which arises from dynamic exchange of PD^II-bound carboxylate ligands (Scheme 1C),^[15–22] has important implications for catalytic reactivity and shows that MPAA/Pd-catalyzed C–H functionalization reactions incorporate each of the diagnostic features associated with LAC.

Scheme 1.

Mono-N-protected amino acid (MPAA) ligands in Pd^II-catalyzed C–H functionalization reactions.

The present study was initiated within a broader collaborative investigation of C–H functionalization reactions,^[23] with a focus on reactions capable of using O₂ as the oxidant.^[24,25] In 2011, Yu and coworkers reported that MPAA ligands support aerobic oxidative arylation of phenylacetic acid derivatives with aryltrifluoroborates, employing mono-N-Boc-protected L-valine (Boc-Val-OH) as the MPAA ligand.^[26] We made several minor modifications to the original conditions to facilitate mechanistic studies (see Supporting Information, Section 2 for details). The resulting conditions enabled oxidative coupling of the potassium salt of 2- CF₃-phenylacetic acid (1) and 4-fluorophenyl-Bpin (Ar^FBpin) (Scheme 2). In a preliminary assessment of ligand effects on the reaction, the MPAA ligand loading was varied from 0–4 equiv relative to [Pd]. The catalytic rate increases rapidly at low loadings of MPAA, maximizing at a MPAA:Pd ratio of 0.3–0.5, while inhibition occurs beyond 0.5 equiv (Figure 1). This unusual kinetic influence of MPAA, in particular, the observation that the optimal stoichiometry is substantially lower than 1:1 MPAA:Pd prompted us to probe the influence of the MPAA ligand on individual reaction steps, starting with C–H activation.

Scheme 2.

Conditions optimized for aerobic Pd^II-catalyzed C–H arylation.

Figure 1:

Kinetic influence of MPAA ligand (0–4 equiv with respect to Pd) on the catalytic arylation reaction in Scheme 2. Conditions: [1] = 100 mM, [Ar^FBpin] = 200 mM, [Pd]_t ([2] × 3) = 3 mM, [Boc-Val-OH] = 0–12 mM, [2,5-^tBu₂BQ] = 12 mM, ^tAmylOH (0.5 mL), 105 °C.

Palladium acetate was heated with 1 equiv of the substrate 1 in the absence of the MPAA ligand in ^tAmylOH at 80 °C for 14 h. Clean conversion of 1 into a new species was evident by ¹⁹F NMR spectroscopy (see Supporting Information, Section 4 for details). Cyclopalladation products of phenylacetic acid derivatives have not been characterized previously, but analogous reactivity has been documented with benzoic acid derivatives.^[27–29] Attempts to crystallize the product typically generating non-crystalline powders, but, in one case, a small single crystal was obtained. X-ray diffraction analysis revealed a dimeric cyclopalladation product with disorder arising from a mixture of acetates and substrate-derived carboxylates in the bridging positions (see Supporting Information, Sections 10c and 11b for details). To circumvent this problem, we prepared the substrate-derived Pd^II(O₂CR)₂ species 2 by addition of the phenylacetic acid analog of 1 to a solution of Pd(OAc)₂ in toluene. Facile exchange between the carboxylic acid and the acetate ligands (cf. Scheme 1C), and removal of AcOH under vacuum afforded complex 2. Crystallization of 2 and X-ray diffraction analysis revealed the trimeric Pd(O₂CR)₂ structure shown in Scheme 3. Heating a solution of 2 in the presence of a Brønsted base (e.g., K₂CO₃ or 1) results in formation of a new species with ¹⁹F NMR spectroscopic properties identical to that observed from the reaction of 1 with Pd(OAc)₂. In this case, crystallization led to a single compound corresponding to the dimeric palladacycle 3, which represents the first carboxylate-directed cyclopalladation product structurally characterized without requiring addition of an exogenous L-type donor ligand (e.g., phosphine, acetonitrile).^[27,30] This complex features a syn arrangement of the two aryl groups and two bridging carboxylates derived from substrate 1 (Scheme 3). Perhaps most importantly, this structure features carboxylate-coordinated potassium ions that balance the charge on the complex. Yu and coworkers have long postulated that alkali metal ions play a crucial role in carboxylate-directed C–H activation. Carboxylates often exhibit a κ² coordination mode that orients the C–H bond away from Pd^II center. The carboxylate/alkali metal ion interaction is proposed to support κ¹ carboxylate binding, which allows the C–H bond to orient favorably for activation at the Pd^II center.^[27,31] The importance of alkali metal coordination has been implicated in the literature, but without direct structural support.^[3,30,32,33]

Scheme 3.

Synthesis and structural characterization of trimeric Pd-carboxylate complex and dimeric palladacycle.

With this structural information established, we began probing the effect of MPAA on the rate of the cyclometalation step. It was possible to monitor the stoichiometric conversion of Pd-carboxylate complex 2 into palladacycle 3 by ¹⁹F NMR spectroscopy under catalytically relevant conditions (^tAmylOH, 10 equiv 1, 64 °C). In the absence of the MPAA ligand, 2 reacted slowly, achieving only 40% conversion into 3 after 14 h. In contrast, inclusion of 1 equiv of Boc-Val-OH as the MPAA ligand led to rapid conversion of 2 into palladacycle 3, resulting in complete formation of 3 within the time needed to acquire the first ¹⁹F NMR spectrum. When the experiment was repeated with only 5 mol% MPAA relative to [Pd], cyclopalladation proceeded with a 50-fold faster rate relative to that observed in the absence of the MPAA ligand (Figure 2A). Initial rate kinetic studies established that the reaction exhibits a linear dependence on [MPAA] (Figure 2B). A deuterium KIE, obtained from the independent rates of C–H activation of 1 and 1-d₁, exhibited a value of 4.0 at 1.25 mol% MPAA. An identical KIE was obtained at 1:1 MPAA:Pd, which corresponds the ligand:Pd ratio commonly used in catalytic C–H functionalization reactions (see Supporting Information, Section 5 for details), suggesting that C–H activation is the rate-limiting step under both conditions.

Figure 2:

Rate enhancement observed for the formation of palladacycle in the presence of 5 mol% of Boc-Val-OH (MPAA) with respect to Pd (A) and the [MPAA] dependence with a linear fit equation [rate = c₁x] (B) Conditions: (A) [Pd]_t ([2] × 3) = 10 mM, [1] = 100 mM, [Boc-Val-OH] = 0 or 0.5 mM, ^tAmylOH (0.55 mL), 64 °C. (B) [Pd]_t ([2] × 3) = 20 mM, [1] = 80 mM, [Boc-Val-OH] = 0–1 mM, ^tAmylOH (0.55 mL), 33 °C.

Ligand-directed C–H functionalization reactions catalyzed by Pd^II commonly feature nitrogen chelating groups, such as pyridines, imines, or amines.^{[15,16,34–36]} In light of the involvement of carboxylate ligand exchange in the reactions above, we decided to test whether similar MPAA catalysis also occurs with a substrate bearing a neutral nitrogen directing group. We employed the diarylmethane substrate 4 with an appended pyridine directing group.^[16,37] Cyclopalladation of 4 by Pd(OAc)₂ affords palladacycle 5, and this reaction was monitored by ¹⁹F NMR spectroscopy (Figure 3, see Supporting Information, Section 6 for details). A >100-fold rate enhancement was observed when the reaction was conducted in the presence of 5 mol% of Boc-Val-OH with respect to [Pd]. This result suggests that the ability of MPAA ligands to catalyze Pd^II-mediated C–H activation is general, and is not limited to substrates with carboxylate directing groups.

Figure 3:

Rate enhancement observed for the formation of pyridine directed palladacycle 5 in the presence of 5 mol% of Boc-Val-OH (MPAA) with respect to Pd.

The catalytic experiments in Figure 2A featured 10 equiv of substrate 1 with respect to [Pd] (added as Pd^II-carboxylate trimer 2). Analysis of this reaction mixture by ¹⁹F NMR spectroscopy indicates that Pd^II is present as a tetracarboxylate “-ate” complex, K₂[Pd(O₂CR)₄] (6), evident from integration of the bound and unbound carboxylate substrate relative to an internal standard (Figure 4A). Addition of the MPAA ligand Boc-Val-OH to this solution leads to several changes in the ¹⁹F NMR spectrum: (1) a change in the chemical shift of the unbound substrate 1, and (2) a decrease in the quantity of bound 1, and (3) appearance of multiple peaks in the region of the spectrum associated with bound 1 (i.e., complex 6). The first observation is rationalized by hydrogen bonding and/or proton-exchange equilibria between the MPAA carboxylic acid and unbound 1. The second observation is explained by substitution of bound 1 with the MPAA-derived carboxylate. The multiple peaks associated with bound 1 upon addition of excess MPAA (e.g., 10 equiv) may be rationalized by multiply ligated MPAA-Pd species, in addition to the possibility of dimeric or other carboxylate-bridged structures. The individual species were not independently characterized, but a binding curve derived from integration of unbound 1 with increasing [MPAA] shows that more than one MPAA can bind to Pd (Figure 4D). The NMR data show that only 40% of the Pd is coordinated by an MPAA ligand at a 1:1 MPAA:Pd ratio. Finally, under the conditions used in this ligand-exchange study, virtually no C–H activation in observed, indicating that carboxylate ligand exchange is rapid relative to C–H activation.^[38]

Figure 4:

Pd-carboxlate species in the presence of excess RCO₂K (1), in the absence (A) and presence (B–D) of MPAA ligands. Addition of Boc-Val-OH (MPAA) to a soluton of K₂[Pd(O₂CR)₄] (6) leads to changes in the Pd speciation, evident by ¹⁹F NMR spectroscopy (C). Quantitation of the displacement of 1 from 6 upon addition of MPAA reveals an equilibrium binding curve (D) [carboxylate displaced / Pd = c₁x/(c₂ + x)]. Conditions: [Pd]_t ([2] × 3) = 10 mM, [1] = 104 mM, [Boc-Val-OH] = 0–100 mM, ^tAmylOH (0.55 mL), 24 °C.

Having established the effect of the MPAA ligand on C–H activation, we evaluated whether the MPAA ligand could influence subsequent steps in the catalytic functionalization of 1 (cf. Scheme 4). Toward this end, stoichiometric reactions of palladacycle 3 with Ar^FBpin and butyl acrylate were analyzed under catalytically relevant conditions (Figure 5).^[26,39] When the reaction of 3 with Ar^FBpin was conducted in the absence of an MPAA ligand, quantitative biaryl product formation was observed in 1–2 h at 64 °C. Repeating this reaction in the presence of 1 equiv Boc-Val-OH (relative to [Pd]) led to more than a four-fold decrease in the reaction rate (Figure 5A), consistent with inhibition of transmetalation by the acidic MPAA ligand. On the other hand, the reaction of 3 with butyl acrylate proceeds to the expected olefination product 8 with nearly identical rates in the presence and absence of the Boc-Val-OH (Figure 5B). The data in Figure 5A show that deleterious effects of MPAA ligands arising from inhibition of certain steps in the catalytic reaction can (partially) offset the strongly favorable effect of MPAA ligands on Pd-mediated C–H activation. In such cases, the reactions may benefit from the use of substoichiometric quantities of the (catalytic) MPAA ligand, as illustrated in Figure 1.

Scheme 4.

Simplified Mechanism Highlighting the Catalytic Role of MPAA Ligand in Pd-Catalyzed C–H Arylation.

Figure 5:

Stoichiometric arylation and olefination of palladacycle 3 with and without Boc-Val-OH (MPAA). Conditions: (A) [Pd]_t ([3] × 2) = 10 mM, [1] = 100 mM, [Boc-Val-OH] = 0 or 10 mM, [Ar^FBpin] = 200 mM, ^tAmylOH, 64 °C. (B) [Pd]_t ([3] × 2) = 10 mM, [1] = 100 mM, [Boc-Val-OH] = 0 or 10 mM, [butyl acrylate] = 200 mM, ^tAmylOH, 24 °C.

The results described herein demonstrate a unique mechanistic property of MPAA ligands in Pd-catalyzed C–H functionalization reactions, whereby rapid dynamic exchange of the MPAA with Pd^II-bound carboxylate ligands enables catalytic quantities of the MPAA ligand to activate multiple Pd centers. This behavior demonstrates a diagnostic feature of ligand-accelerated catalysis and has important implications for the development of new catalysts and/or catalytic reactions. For example, it could be beneficial to use substoichiometric ligand:Pd ratios to take advantage of MPAA-accelerated C–H activation while minimizing MPAA inhibition of other steps in the catalytic mechanism. The results also provide a rational foundation for exploration of multi-ligand catalyst systems in which different ligands facilitate different steps in the catalytic cycle^[40] and/or play a synergistic role in C–H activation (e.g., in non-directed C–H functionalization methods).^[41–45]