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C–H Alkenylation of Heteroarenes: Mechanism, Rate, and Selectivity Changes Enabled by Thioether Ligands

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Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
Cite this: J. Am. Chem. Soc. 2017, 139, 28, 9605–9614
Publication Date (Web):June 16, 2017
https://doi.org/10.1021/jacs.7b03887
Copyright © 2017 American Chemical Society
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Abstract

Thioether ancillary ligands have been identified that can greatly accelerate the C–H alkenylation of O-, S-, and N-heteroarenes. Kinetic data suggest thioether–Pd-catalyzed reactions can be as much as 800× faster than classic ligandless systems. Furthermore, mechanistic studies revealed C–H bond cleavage as the turnover-limiting step, and that rate acceleration upon thioether coordination is correlated to a change from a neutral to a cationic pathway for this key step. The formation of a cationic, low-coordinate catalytic intermediate in these reactions may also account for unusual catalyst-controlled site selectivity wherein C–H alkenylation of five-atom heteroarenes can occur under electronic control with thioether ligands even when this necessarily involves reaction at a more hindered C–H bond. The thioether effect also enables short reaction times under mild conditions for many O-, S-, and N-heteroarenes (55 examples), including examples of late-stage drug derivatization.

Introduction

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Catalytic methods that directly functionalize the ubiquitous carbon–hydrogen bonds in organic molecules have been intensely pursued for their potential to construct and modify complex molecular structures in ways that compliment classic synthetic methods.(1) One of the most reliable strategies to date for the selective functionalization of unactivated C–H bonds relies on a native or temporary directing group that biases the reaction to a proximal site and accelerates the rate by facilitating substrate binding to the catalyst.(2) Undirected C–H functionalizations are therefore more challenging without such kinetic benefits and often require large substrate excesses to compensate for poorer rates and can occur with statistical selectivity.(3) Strategies to substantially increase catalyst activity and also to exert catalyst control over selectivity are therefore needed for undirected C–H functionalizations to be utilized more widely and on large scale. Ancillary ligands are a primary tool used to tune both reactivity and selectivity in homogeneous metal catalysis. In this context, the oxidative conditions and distinct reaction mechanisms of cross-dehydrogenative coupling (CDC) reactions,(4) a rapidly expanding field of C–H functionalization, present challenges toward the application of existing privileged ligand classes, such as phosphines and N-heterocyclic carbenes. Even today, examples of CDC reactions with ligand acceleration are considerably outnumbered by methods that use simple metal salts as catalysts (“ligandless” conditions). It is therefore desirable to identify new oxidatively stable ligand classes that can tune the catalytic efficiency and control selectivity in CDC chemistry.
An important CDC reaction that is a focus of the present study is the oxidative dehydrogenative Heck reaction (DHR), also known as the Fujiwara–Moritani reaction, that directly generates vinylarenes by the C–H alkenylation of arenes.(5, 6) Among examples of ligand-promoted DHR methods, nitrogen-based compounds such as amino acids,(7) pyridines,(8) 4,5-diazafluorenone,(9) pyridyl oxazolines,(10) and α-diimines(11) are most common. These N-ligands can give improved reaction rates and, in certain cases, enhance the inherent site selectivity of an undirected DHR versus classic “ligandless” catalysts. On the other hand, switchable, ligand-controlled site selectivity remains a major goal within the broad field of C–H functionalization because this approach is inherently more flexible and predictable than alternative approaches, such as relying on blocking groups or solvent effects.(12) Notable progress in this regard, such as Itami’s C–H arylation of heteroarenes (Scheme 1a)(13) or Sanford’s C–H acetoxylation of deactivated arenes (Scheme 1b),(14) demonstrates the feasibility of switchable, catalyst control in undirected reactions, yet this remains rare in the DHR. Intuitively, a significant change in the coordination sphere of the catalyst might give rise to distinct catalyst function (i.e., selectivity) that compliments existing catalysts. As a starting point to explore this possibility in the DHR, we considered a shift from typical hard ancillary ligands to soft elements, such as sulfur.

Scheme 1

Scheme 1. Examples of Switchable, Ligand-Controlled Site Selectivity in Undirected C–H Functionalization
Despite a historical reputation as catalyst poisons, sulfur compounds are nevertheless attractive for applications in oxidative CDC reactions because they have reasonable tolerance toward the mild oxidants used in these methods (e.g., benzoquinone (BQ), CuII, or O2)(15) and are widely available or easily synthesized. In fact, early work by Fujiwara demonstrated that a stable arylpalladium complex could be formed by the stoichiometric activation of benzene by dialkyl sulfide-coordinated Pd(OAc)2.(16) Stambuli and co-workers have also reported that Pd-catalyzed allylic C–H acetoxylation can give good linear selectivity using thioether ligands,(17) which compliments the branched products characteristic of analogous reactions using White’s catalyst.(18) Thioether directing groups and stoichiometric promoters have also been used in the DHR and other C–H functionalization reactions.(19, 20) Thioethers are, however, less often utilized as discrete ancillary ligands in catalytic arene C–H functionalization. Studies of their effects on the corresponding catalytic mechanisms are also lacking. We report here that simple thioethers can indeed give rise to unexpected changes in the rates and site selectivity (Scheme 1c) of Pd-catalyzed undirected C–H alkenylation of heteroarenes. Mechanistic data are presented that correlate these effects to a switch from a neutral to cationic mechanism for rate-determining C–H activation.

Results and Discussion

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Identification of Active Thioether–Pd Catalysts

Effective catalyst control of any type should be generally facilitated when the coordinated catalyst is kinetically superior to any ligand-free species to minimize the background process. With this in mind, we initially screened the potential of thioether ligands to significantly accelerate the DHR with five-atom heteroarenes that are compatible with ligandless Pd catalysts.(6a) The reaction of 2-methylfuran (1) with t-butyl acrylate (2 equiv) using BQ as oxidant (1.5 equiv) in acetic acid at 60 °C was chosen as the model reaction (Figure 1). Ligand effects on the yield of product 2 were assayed at a deliberately short reaction time (e.g., 30 min), which is atypical compared to other DHR methods with furans (e.g., 12 h),(8e, 21) to more easily differentiate highly active from poor catalysts. The yield of 2 was expectedly low (7%) under these conditions using Pd(OAc)2 (1 mol %) alone. The addition of catalytic quantities of ArS(CH2)nSAr ligands (L1L5) showed variable effects. Bis-thioether ligands that chelate strongly (e.g., n = 2 or 3) did not enhance the catalytic activity, but the yield of 2 did significantly increase for reactions with increasing ligand backbone flexibility (e.g., n = 4 or 5). Because chelation appeared counterproductive, monodentate thioethers were then tested, and several very active catalysts were subsequently identified. In particular, high yield (84%) was observed at 30 min using Pd(OAc)2 coordinated by the electron-rich alkyl aryl thioether L7. The yield of 2 from the DHR using sulfoxide L13 (6%) was similar to dative ligand-free conditions (7%), but the reaction using the analogous thioether L8 was much higher (70%). These observations suggest both that the more active catalytic species is a thioether–Pd complex rather than a sulfoxide–Pd complex and also that thioethers are persistent under the oxidizing reaction conditions. Representative examples of other important ligand classes for CDC reactions (e.g., pyridines, amino acids, bis-sulfoxide, and phosphine) were also tested, but none approached the accelerating effect of L7, L14, L15, or Ac-Met-OH.

Figure 1

Figure 1. Identification of ancillary ligands that accelerate C–H alkenylation of 2-methylfuran (1) as a model reaction.

Comparison of yields at a single time point was useful for catalyst screening, but these data cannot differentiate if the higher yields observed using the thioether–Pd catalysts occur because of changes in catalytic rate, catalyst initiation, and/or catalyst decomposition as compared to other systems. To gain some preliminary insight to this end, the yield of the model reaction was monitored over time using L7-Pd(OAc)2 and representative examples of other ligandless and ligated Pd catalysts (Figure 2). These data indicate that significant induction periods are not the primary origin of activity differences between catalysts. Furthermore, the other catalysts that were examined did not, even after 3 h, generate yields of 2 exceeding what L7-Pd(OAc)2 produced within 8 min (40%). Thus, the model DHR conducted with a thioether–Pd catalyst indeed occurs with much higher rates.

Figure 2

Figure 2. Kinetic profile of the DHR of 1 (0.25 mmol), t-butyl acrylate (0.5 mmol), BQ (0.5 mmol), Pd(OAc)2 (1 mol %), and the indicated ligand (1 mol %) in AcOH (1.5 mL) at 60 °C.

The capacity of thioether ligands to generate high yields in short reaction times at reduced catalyst loading was also examined (Table 1). Beginning at relatively high catalyst loading (5 mol %), ligandless Pd(OAc)2 generated only 9% yield of 2 at the point of high yield (85%) using L7-Pd(OAc)2 under otherwise identical conditions (entries 1 and 3). The yield of 2 remained good (71–84%) even as the L7-Pd(OAc)2 loading was progressively decreased to 0.25 mol %, which corresponds to a turnover number (TON) up to 284. Tethering an electron-releasing, noncoordinating anion (e.g., SO3) to the thioether scaffold such as in L14 exerts an additional accelerating effect that increases the turnover frequency up to 740 h–1 and allowed TON in excess of 500 at 0.15 mol % of Pd.(22) These values are among the highest reported for any DHR.(7, 21, 23) Note that the anionic thioethers represent a second generation of ligands inspired by the results of a mechanistic study (vide infra).
Table 1. Catalyst Loading Effectsa
entryligandxtime (min)yieldb (%)TONc
1none51592
2 13077
3p-(Me2N)C6H4SEt (L7)5158517
4 1308484
5 0.56080160
6 0.2518071284
7d(PMP)S(CH2)3SO3 (L14)0.51062124
   6095190
8d 0.1530079527
a

Conditions: 1 (0.25 mmol), t-butyl acrylate (0.5 mmol), BQ (0.38 mmol), Pd(OAc)2, ligand, and AcOH (1.5 mL) were stirred under air.

b

Determined by GC versus an internal standard.

c

Mol 2 (mol Pd)−1.

d

PMP = p-(MeO)C6H4.

Electron-rich N-heteroarenes can directly react with quinone oxidants,(24) thus a change in reaction conditions was needed to effect the DHR with these substrates using a milder oxidant (e.g., CuII) and DMF for solvent (eq 1).(12a) In the model reaction between indole and butyl acrylate under these conditions, we initially found that L7-Pd(OAc)2 was faster than ligandless conditions as indicated in Figure 3, yet only 50% conversion occurred after 3 h. Thus, the reaction is relatively slow compared to the analogous DHR with 2-methylfuran. Substitution of L14 for L7, however, led to a marked improvement in both yield and reaction time. Full conversion and 98% yield of 4 were observed within 1 h, as determined by 1H NMR versus mesitylene as internal standard. The initial rate was also dramatically faster than ligandless conditions (krel 800). It should be noted DHR methods have been reported that operate at milder temperatures (e.g., room temperature), albeit with higher catalyst loading (ca. 5–10 mol % of Pd) over longer times (ca. 24–48 h).(9c, 10, 12b, 25) We also found that a thioether–Pd catalyst can function at room temperature (Table 4, entry 8). Additionally, a head-to-head comparison at 70 °C using a (DMSO)nPd(OAc)2 catalyst, representative of another leading DHR method,(12a) led to a slower reaction and lower yield of 4 (24%) within 1 h (Figure 3). These data thus suggest thioether–Pd complexes are also very active catalysts for the DHR with N-heteroarenes.

Figure 3

Figure 3. Kinetic profile of the DHR in eq 1. aCosolvent with DMF (1:10); b1 mol %; c10 mol %; HOTs (10 mol %) added.

Mechanistic Experiments

A number of mechanistic experiments were conducted that have helped to clarify the origin of rate acceleration in the DHR using thioether-coordinated catalysts. Kinetics experiments using the method of initial rates were used to interrogate the molecularity of the active species in the DHR of 1 with t-butyl acrylate using L7-Pd(OAc)2. The effect of thioether loading was examined across the range of 0.42–3.3 mM (Figure 4a) with a maximum rate observed at [L7] = 1.7 mM, which corresponds to a 1:1 thioether/Pd ratio. Additionally, a Hg drop test did not alter the kinetic profile (Figure S12) as compared to a parallel control reaction. Together, these data are consistent with a homogeneous Pd active species coordinated by a single thioether. Furthermore, a primary kinetic isotope effect (kH/kD = 2.7 ± 0.2) was observed from independent reactions of 5 or 5-2-d with t-butyl acrylate (eq 2), indicating that cleavage of the arene C–H bond is the turnover-limiting step of catalysis.(26) Additionally, H/D scrambling experiments (Figures S2 and S3) also suggest C–H cleavage is irreversible under catalytic conditions.

Figure 4

Figure 4. Dependence of the observed rate constant on the concentration of (a) L7 (0.42–3.3 mM) during the DHR of 1 (0.17 M), t-butyl acrylate (0.33 M), BQ (0.25 M), and Pd(OAc)2 (1.7 mM) in AcOH at 50 °C; (b) 1 (0.083–1.0 M) during the DHR with t-butyl acrylate (0.33 M), BQ (0.25 M), Pd(OAc)2 (1.7 mM), and L7 (1.7 mM) in AcOH at 50 °C; (c) t-butyl acrylate (0.02–0.40 M) during the DHR of 1 (0.17 M), BQ (0.25 M), Pd(OAc)2 (1.7 mM), and L7 (1.7 mM) in AcOH at 50 °C; (d) BQ (0.083–0.33 M) during the DHR of 1 (0.17 M), t-butyl acrylate (0.33 M), Pd(OAc)2 (1.7 mM), and L7 (1.7 mM) in AcOH at 50 °C; (e) sodium acetate (0.0030–0.34 M) during the DHR of 1 (0.17 M), t-butyl acrylate (0.33 M), BQ (0.25 M), Pd(OAc)2 (1.7 mM), and L7 (1.7 mM) in AcOH at 50 °C; (f) L7-Pd(OAc)2 (0.40–15 mM) during the DHR of 1 (0.17 M), t-butyl acrylate (0.33 M), and BQ (0.25 M) in AcOH at 45 °C as determined by the methods of initial rates.

The dependence of the rate on [1] showed signs of saturation behavior (Figure 4b), suggesting that arene reversibly binds to the catalyst prior to activation of the C–H bond. The dependence of the rate on [alkene] (Figure 4c) or [BQ] (Figure 4d) was negligible in both cases, consistent with migratory insertion and oxidation of Pd0 occurring after the turnover-limiting step. An inverse first-order dependence of the rate on [OAc] was also observed (Figure 4e), which is unusual. This inhibition might arise by either of two effects: reversible dissociation of acetate from LnPd(OAc)2 to form a cationic species or association of acetate to form a stable, off-cycle [LPd(OAc)3] species. To distinguish between these possibilities, NaOAc was added to an equimolar solution of L7 and Pd(OAc)2 (8.4 mM) in AcOH-d4 at room temperature. Though several Pd species are present in solution prior to acetate addition (vide infra), only the relative populations of these were perturbed (Figure S20) upon addition of an excess of sodium acetate (0.17 M); no major new species was detected. This observation is inconsistent with the inverse order in acetate arising from diversion of the thioether–Pd catalyst to an off-cycle palladate species, and reversible ionization to generate a cationic Pd intermediate is therefore most likely.
A partial order dependence of the rate on the catalyst (0.8), generated in situ from L7 and Pd(OAc)2, was determined by nonlinear regression analysis of the kinetic data in Figure 4f. This observation hinted more than one aggregation state of Pd may be involved in the catalytic DHR. A mechanistic study by Sanford concluded that the half-order dependence of the rate on [Pd] observed during catalytic C–H acetoxylation of benzene, when conducted with a 1:1 mixture of pyridine and Pd(OAc)2 as catalyst, occurred as a consequence of an off-cycle dimer [Pd(py)(OAc)(μ-OAc)]2.(27) We thus considered the analogous potential for thioether-coordinated species of the type [Pd(L7)(OAc)2]n (n > 1) in this DHR. To provide insight to this end, we examined the 1H NMR of mixtures of L7 and Pd(OAc)2 in AcOH-d4 to probe catalyst speciation.
A titration experiment was performed in which the concentration of L7 (8.4–50 mM) was varied at constant [Pd(OAc)2] (8.4 mM) in AcOH-d4 at room temperature. Three distinct set of resonances were observed corresponding to coordinated thioether. The truncated spectra in Figure 5 correspond to 1H NMR data for these mixtures; full NMR spectra can be found in Figure S13. The major species present at higher L7/Pd ratios was assigned as the coordinatively saturated species Pd(L7)2(OAc)2 (L2[Pd]). This was corroborated by detection of a peak at m/z 527.1007 by high-resolution ESI-MS for a solution of L7 and Pd(OAc)2 (2:1) in AcOH, which corresponds to the exact mass of Pd(L7)2(OAc)2 minus acetate (527.1013).

Figure 5

Figure 5. Observation by 1H NMR of species formed from combinations of Pd(OAc)2 (8.4 mM) and L7 at (a) 50 mM, (b) 25 mM, (c) 17 mM, or (d) 8.4 mM concentrations in AcOH-d4 at rt; (e) L7 only.

The 1H NMR resonances of unknown species Y dissipated significantly at L7/Pd ≥ 2 while the unknown species X persisted. Additionally, the resonances corresponding to X and L2Pd increased concomitantly with increasing ligand to metal ratio, but their relative abundance was not constant. The ratio of L2Pd to X increased from 1.5:1 to 1.8:1 to 2.1:1 at L7/Pd ratios of 2, 3, and 6, respectively. Based on these observed fluctuations in [X], [Y], and [L2Pd] at varying [L7], we postulate that the relative ligand to metal ratio in these species is L2Pd > X > Y. Plausible structures of the unknown species X and Y could be dimeric and trinuclear complexes (eq 3) that have ligand to metal ratios of 1 and 2/3, respectively. These general structures are common among Pd(OAc)2 complexes coordinated by other ancillary ligands.(28) To interrogate these possibilities further, we conducted experiments to estimate the solution molecular weight of X and Y.
Diffusion-ordered spectroscopy (DOSY) NMR has proven useful for molecular weight determination of polymers, organic small molecules, and metal complexes in solution.(29) Sanford has employed this technique to estimate the aggregation state of [Pd(py)(OAc)2]n species present in AcOH solution.(27) To differentiate between the possible structures of unknown complexes X and Y, we conducted two internally calibrated DOSY NMR experiments at different ratios of L7 and Pd(OAc)2 in AcOH-d4 at room temperature (Figures S15 and S17). Using the linear regression analysis of the seven internal standards (Figure 6), a molecular weight of 1036 g/mol was calculated using the averaged diffusion coefficients (D) for Ha, Hb, and SCH2CH3 resonances corresponding to species Y. Among the potential structures for this unknown, illustrated in eq 3, the estimated molecular weight for Y is most consistent with that of trinuclear complex Pd3(L7)2(OAc)6 (1036 g/mol) but differs significantly from lower aggregation state complexes such as Pd(L7)2(OAc)2 (587 g/mol), Pd(L7)(AcOH)(OAc)2 (466 g/mol), or Pd2(L7)2(OAc)4 (812 g/mol). The concentration of Y can be suppressed at higher L7/Pd ratios, which then allowed clear analysis of the otherwise overlapping Hb resonance in X. The molecular weight for X (834 g/mol) calculated in an analogous manner (Figure 7) is similar to that of the dimeric complex Pd2(L7)2(OAc)4 (812 g/mol).

Figure 6

Figure 6. DOSY NMR data used to estimate the molecular weight of unknown species Y (triangle) generated in a 1:1 mixture of Pd(OAc)2 and L7 in AcOH-d4 at rt. The internal standards (diamonds) used were C6H6, cyclooctane, 1,3,5-(CF3)3C6H3, 18-crown-6, Me2Si(C6F5)2, Pd(L7)2(OAc)2, and Ir(4′-MeO-ppy)3.

Figure 7

Figure 7. DOSY NMR data used to estimate the molecular weight of unknown species X (circle) generated in a 2:1 mixture of L7 and Pd(OAc)2 in AcOH-d4 at rt. The internal standards (diamonds) used were C6H6, cyclooctane, 1,3,5-(CF3)3C6H3, 18-crown-6, Me2Si(C6F5)2, Pd(L7)2(OAc)2, and Ir(4′-MeO-ppy)3.

A catalytic mechanism illustrated in Scheme 2 is proposed based on our interpretations of the available mechanistic data. Beginning with a monoligated, monomeric thioether–Pd species, reversible arene coordination and dissociation of acetate generates an electrophilic, substrate-bound Pd cation. This cationic, arene-bound Pd complex differs from species typically proposed in other DHR reactions that begin from a neutral Pd catalyst.(30) Moreover, this electrophilic metal cation should be more reactive than the corresponding neutral species toward turnover-limiting C–H bond cleavage by any electrophilic-type mechanism.(30, 31) Currently, we cannot distinguish between C–H bond cleavage by a polarized yet concerted mechanism(32) versus a stepwise sequence of reversible electrophilic palladation followed by rate-limiting proton loss from a Wheland-type intermediate.(33) However, we believe another potential mechanism, outer-sphere attack on a π-alkene complex,(34) can be ruled out from the observed zeroth-order dependence of the catalytic rate on [alkene]. Subsequent to this rate-determining step, migratory insertion of alkene, β-H elimination, and then regeneration of the active species by the oxidant complete the cycle.

Scheme 2

Scheme 2. Proposed Mechanism Using L7/Pd(OAc)2 (1:1)

Anionic Thioether Ligands

The ligand survey and mechanistic studies revealed that (i) higher yields in the DHR were obtained using more electron-rich, neutral ArSEt ligands (Figure 1), and (ii) cationic and neutral Pd species are equilibrating prior to the rate-determining step. We considered that incorporating a weakly coordinating anion into the ligand framework might further enhance catalyst activity by making the thioether even more electron-rich and possibly by increasing the equilibrium population of cationic Pd through charge balance. To evaluate this idea, several new ligands (e.g., L14, L15, L17, and L18) containing a pendant sulfonate group were prepared in a single step by alkylation reactions with 1,3-propane sultone.
Screening these anionic ligands in the DHR of indole and butyl acrylate gave a range of behaviors (Table 2). Both ligandless and neutral thioether ligands, with and without added tosic acid, gave low yield after 1 h using 1 mol % of Pd (entries 1–3). On the other hand, L14 (entry 5) gave a near quantitative yield (98%) after 1 h. The negligible change in yield when using the chelating thioether L16 (entry 7) versus the strictly monodentate L17 (entry 8) suggests that ligand hapticity is not the primary reason the anionic thioethers are superior to neutral analogues. An analogue of L14 that lacks the thioether group (L18) was also ineffective (entry 9). Together, these results suggest a primary cause of the additional rate acceleration by the anion is electrostatic in nature.
Table 2. Anionic Thioether Effects on the DHRa
entryadditive(s)yield of 4 (%)
1 18
2L719
3bL827
4bL8 and CH3(CH2)4SO3Na+7
5bL1498
6bL1579
7bL1673
8bL1771
9bL1828

a

Yields determined by 1H NMR versus mesitylene as standard.

b

Tosic acid added (10 mol %).

The higher activity of Pd complexes with these anionic thioether ligands might occur because it coordinates more strongly to Pd, thereby decreasing the concentration of any less active ligandless Pd, or alternatively could generate a more electrophilic active species. For insight into the latter possibility, we turned to a competition experiment between 2-methylthiophene (7) and 2-chlorothiophene (8) that has previously been used as a mechanistic probe in this regard. For instance, an intermolecular competition between 7 and 8 during Vilsmeier–Haack formylation generates a 17:1 mixture of products favoring the more nucleophilic arene 7.(35) On the other hand, Fagnou reported that direct arylation, which occurs by a concerted metalation–deprotonation (CMD) mechanism that does not involve an arenium intermediate,(36) occurs with high but opposite selectivity favoring the arene with a more acidic C–H bond (Me/Cl = 1:11).(35) Competition between these two arenes therefore appears to be a sensitive reporter of the electronic nature of the selectivity-determining step.
We found that the choice of ligand has a significant impact on the product ratio formed from the competitive DHR between 7 and 8 (5 equiv each) with methyl acrylate (Table 3). The thioether-coordinated catalysts L14-Pd(OAc)2 or L15-Pd(OAc)2 (entries 1 and 2) were actually more selective for reaction with 2-methylthiophene (>20:1) than the Vilsmeier–Haack reaction, a classic SEAr reaction. This departure from selectivity typical of a (neutral) CMD mechanism,(36) and the lower reactivity of the DHR with a heteroarene easily activated by CMD (Figure S1), suggests a distinct mechanism in our system. On the other hand, a lower product ratio was observed for the same reaction conducted with neutral ligands (entries 3–5);(37) other neutral thioethers L8L12 with less electron-donating substituents also gave similar product ratios (Table S5).(9c) We interpret these observations as indicative of a more electrophilic catalyst in the DHR catalyzed by Pd complexes coordinated by a more electron-rich (anionic) thioether.
Table 3. Intermolecular Competition Experiments with 2-Substituted Thiophenesa
entryligand9/10
1bL14 (3 mol %)>20:1
2bL15 (3 mol %)>20:1
34,5-diazafluorenone (3 mol %)5.0:1
4L7 (3 mol %)1.9:1
5pyridine (6 mol %)0.9:1
a

Determined by 1H NMR versus 1,3,5-(CF3)3C6H3 as internal standard.

b

HBF4 (6 mol %) added.

Thioether Effects on Site Selectivity

A hallmark of current methods for undirected C–H functionalization, such as C–H borylation,(38) C–H silylation,(39) and the DHR, is steric control over site selectivity. Direct arylation reactions also generally occur at the most acidic C–H bond that is sterically accessible.(40) Reactions of 3-substituted thiophenes fall under this paradigm, and several examples highlighted in Scheme 3a emphasize the challenge of accessing selective C–H functionalization at the more hindered C(2) site.(8e, 35, 41) Direct generation of 2,3-disubstituted five-atom heteroarenes with such catalyst control would nevertheless provide a direct route to this motif that is common among natural products, pharmaceuticals, and optoelectronic materials, representative examples of which are highlighted in Scheme 3b.

Scheme 3

Scheme 3. Illustrative Examples of (a) Challenging Site Selectivity To Access (b) 2,3-Disubstituted Heteroarene Motifs
The C–H alkenylation of 3-methylthiophene has previously been reported to occur preferentially at C(2), but the selectivity in these examples was modest (C(2)/C(5) = 1.25:1–2.5:1).(8e, 41b, 41c) Other than by sterics, the two reactive sites in 3-methylthiophene are differentiated only by the inductive effect of the methyl group.(42) Thus, it seemed intuitive that a more electrophilic catalytic intermediate, which anionic thioether ligands provide, might enhance the reaction at the more electron-rich C(2) position. Indeed, the DHR between 3-methylthiophene and methyl acrylate using L15-Pd(OAc)2 (1 mol %) gave a high product isomer ratio (C(2)/C(5) > 20:1) in the crude mixture favoring the more hindered site, as determined by 1H NMR, and good isolated yield (80%) of the major product (Table 4). Larger thioethers (e.g., L14) generally gave the same major product but with decreased selectivity. Importantly, when pyridine-coordinated Pd(OAc)2 (5 mol %) was used (entry 2), the DHR occurred preferentially at the less hindered site (C(2)/C(5) = 1:3).
Table 4. Ligand Effects on Site Selectivity
Table a

Yield of major isomer as determined by 1H NMR versus internal standard; isolated yield in parentheses.

Table b

Crude reaction product isomer ratio.

Table c

Methyl acrylate, arene (2 equiv), Pd(OAc)2 (1 mol %), L15 (1 mol %), HBF4·Et2O (2 mol %), and BQ (1.5 equiv) in AcOH/THF (1:1) at 40 °C for 18 h.

Table d

Methyl acrylate, arene (5 equiv), Pd(OAc)2 (5 mol %), pyridine (10 mol %), and BQ (1.5 equiv) in AcOH at 60 °C for 3 h.

Table e

No ligand added.

Table f

Isolated as a mixture of isomers.

Table g

Pd(OAc)2 (6 mol %), L15 (6 mol %), and HBF4·Et2O (12 mol %) in AcOH/Ac2O (24:1) at rt for 24 h.

The good selectivity observed for C–H alkenylation at C(2) in 3-methylthiophene by L15-Pd(OAc)2 remained so even with other thiophenes and a pyrrole that possess a larger C(3) substituent. The DHR between 3-hexylthiophene and methyl acrylate using L15-Pd(OAc)2 (1 mol %) generated a C(2)/C(5) ratio of 12:1, and the major product was isolated in 80% yield (entry 3). A contrasting selectivity was again observed using 5 mol % of pyridine-coordinated Pd(OAc)2, and ligandless Pd also performed similarly (entries 4 and 5). The DHR using L15-Pd(OAc)2 still maintained good selectivity (C(2)/C(5) = 8:1) using a thiophene possessing a 3-aryl substituent (entry 6). In contrast, the pyridine-coordinated catalyst highly favored reaction at C(5) (entry 7), and Yu’s conditions with an amino acid ligand generated a third isomer (S3) corresponding to a carboxyl-directed DHR.(43)
Another challenging selectivity switch involved a 3-phenylpyrrole substrate (entries 8 and 9). A number of important methods have previously been developed that enable switchable site selectivity between C(2) and C(3) during the DHR(12a, 12b, 13b, 40a) or direct arylation(13a, 13c, 44) with indoles and pyrroles. On the other hand, catalyst control over reaction at C(2) versus C(5) in pyrroles remains challenging, as highlighted in Gaunt’s elegant synthesis of the pyrrole alkaloid rhazinicine. This synthesis involved the DHR as a key step, yet the inherent preference for reaction at C(5) in the 3-arylpyrrole using DMSO-coordinated Pd(OAc)2 could only be switched to the desired C(2) position by installing, then later removing, a C(5) blocking group.(12c) In contrast, we found L15-Pd(OAc)2 (6 mol %) promoted the DHR between a model 3-phenylpyrrole and methyl acrylate with 8:1 selectivity favoring C(2) over C(5) (entry 8).
The ligand-controlled (e.g., thioether or pyridine) site selectivity observed in these model reactions provides new support for the feasibility of tunable catalyst control in the undirected DHR. Preferential alkenylation at the less hindered C(5) position is observed for pyridine-coordinated or ligandless Pd(OAc)2 catalysts, which is accentuated by larger arene substituents. On the other hand, the thioether-coordinated catalyst L15-Pd(OAc)2 maintains a practical regioselectivity favoring the more hindered C(2) position (e.g., C(2)/C(5) = ≥ 8:1), even flanking substituents larger than methyl, which is rare. These ligand-dependent switches in site selectivity may reflect the mechanistic change from a neutral pathway of C–H activation, established by Sanford for (py)nPd(OAc)2 complexes,(27) to a cationic pathway uncovered here for thioether-coordinated Pd species.

Scope of DHR Using Thioether–Pd Catalysts

The capacity of L7-Pd(OAc)2 to enable short reaction times at relatively low catalyst loading was evaluated across a range of heteroarene and alkene combinations. High conversion within 3 h at 60 °C was generally observed across many combinations of furan or thiophene and an alkene (29 examples) using only 1 mol % of Pd in most cases (Table 5). Notable functional groups compatible with the thioether–Pd catalyst include free carboxylic acid, aldehyde, sulfonamide, aniline, azetidine, and the MIDA boronate group. Alkenylation at hindered sites occurred cleanly, as evidenced by the good isolated yields (65–86%) of the DHR with 2,4- or 2,5-dimethylthiophene, 3-methylbenzofuran, and 3-methylbenzothiophenes. Primary and secondary amines slowed the reactions, but high rates were restored by protection as a t-butyl carbamate. Derivatives of the drugs duloxetine and furosemide were prepared by C–H alkenylation in 86 and 56% isolated yield, respectively, after 3 h. The much lower NMR yield (14%) of the furosemide derivative using ligandless conditions highlights the advantages of the thioether–Pd catalyst.
Table 5. Scope of C–H Alkenylation of Furans and Thiophenes Using a Thioether–Pd Catalysta
Table a

Isolated yields. Conditions: arene (0.25 mmol), alkene (0.50 mmol), BQ (0.38 mmol), Pd(OAc)2, and L7 in AcOH under air.

Table b

5 mol % of L7/Pd(OAc)2, 6 h.

Table c

3 mol % of L7/Pd(OAc)2.

Table d

3 equiv of alkene and 3 equiv of BQ.

Table e

Yield determined by 1H NMR; 3 mol % of Pd(OAc).

Table f

L15 instead of L7.

Table g

HBF4 (2 mol %) added.

A wide selection of electron-poor alkenes commonly applied to the DHR, such as acrylates, acrylamide, acrolein, enone, and styrenes were also well-tolerated by thioether–Pd catalysts. Additionally, alkenes that are less common for the DHR such as acrylic acid and the unactivated olefin methyl 3,3-dimethyl-4-pentenoate also gave good isolated yields (79 and 85%, respectively). Lastly, the choice of BQ as oxidant in these reactions was convenient but not required; high yield of 2 (86%) within 6 h was also obtained using O2 (1 atm) as the sole oxidant and L7-Pd(OAc)2 as catalyst (Scheme 4).

Scheme 4

Scheme 4. Aerobic DHR Examples
Broad applicability of L14-Pd(OAc)2 to the DHR with electron-rich N-heterocycles (Table 6) was also observed using CuII as oxidant and DMF solvent. Isolated yields of 3-alkenylindole, alkenylpyrrole, and alkenylimidazo[1,2-a]pyridine compounds were good (40–89%) across 22 examples using only 1 mol % of L14-Pd(OAc)2. Lower Pd loading (0.3 mol %) still gave high yield of 4 (75%) after 4 h, which corresponds to a turnover number of 250. Improved yield was empirically observed when substoichiometric tosic acid was added, which we believe facilitates dissolution of the modestly soluble L14-Pd(OAc)2 adduct and might also promote formation of cationic Pd.(45) Additionally, a sulfur/Pd ratio of ca. 10:1 was superior in these cases, presumably by compensating for competitive ligation of the thioether to the soluble fraction of Cu(OAc)2. In absence of CuII under strictly aerobic conditions, however, a 1:1 L14/Pd ratio was sufficient to deliver a high yield of 6 (88%) within 4 h (Scheme 4). In total, the wide range and complexity of applicable furan, thiophene, pyrrole, indole, and imidazo[1,2-a]pyridine substrates (55 examples) are among the broadest demonstrated for the undirected DHR.
Table 6. C–H Alkenylation of N-Heteroarenesa
Table a

Isolated yields. Conditions: arene (0.50 mmol), alkene (1.0 mmol), Cu(OAc)2 (1.0 mmol), Pd(OAc)2, HOTs, and L14 in DMF were stirred under air.

Table b

1 h.

Table c

0.3 mol % of Pd(OAc)2, 4 h.

Table d

2 h.

Table e

18 h.

Table f

3 h.

Table g

24 h.

Table h

Methyl acrylate; 3 mol % of Pd(OAc)2.

Table i

Combined yield of a separable mixture of internal/exo-alkene isomers (1.3:1).

Conclusion

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A class of odorless thioethers has been identified that can greatly accelerate the undirected dehydrogenative Heck reaction and also enable ligand-switchable site selectivity in several cases. The rate of C–H alkenylation with indole by a thioether–Pd catalyst was ca. 800× faster than the analogous dative ligand-free catalyst. Similarly, catalyst turnover numbers can be very high for the DHR with a furan (>500) or indole (ca. 250) substrate even at short reaction times of 3–4 h. Additionally, an unusual pattern of selectivity was observed favoring the more hindered C(2) site in 3-substituted five-atom heteroarenes. Mechanistic studies provided several key insights to understand why thioether–Pd catalysts diverge from the behavior of dative ligand-free or pyridine-coordinated Pd catalysts. Kinetic and isotope effect studies suggest that reversible arene binding and reversible acetate dissociation generate a substrate-coordinated Pd cation as the key intermediate prior to rate-determining C–H bond cleavage. Existing catalysts for undirected reactions are generally proposed to operate through neutral mechanisms. We thus rationalize the observed changes in rate and selectivity as a consequence of the higher electrophilicity (increased electronic sensitivity) and coordinative unsaturation (decreased steric sensitivity) of the catalytic intermediate responsible for C–H bond cleavage when coordinated by a thioether.
Lastly, these thioether ligand effects translated to the Pd-catalyzed oxidative C–H alkenylation of many O-, S-, and N-heteroarenes (55 examples) with high rates, allowing for short reaction times under mild conditions. In particular, derivatization of the drugs duloxetine and furosemide highlights that these thioether–Pd catalysts can maintain activity even with increased substrate complexity. We are optimistic that thioether ligands have the potential for broad utility because the C–H bond activation in these reactions that is ligand-accelerated is a catalytic step conserved across a number of Pd-catalyzed cross-dehydrogenative coupling reactions.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b03887.

  • Experimental procedures and spectral data for new compounds; spectra and tabular data for kinetic experiments (PDF)

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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
  • Authors
    • Bradley J. Gorsline - Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
    • Long Wang - Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
    • Peng Ren - Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States
  • Author Contributions

    B.J.G. and L.W. contributed equally.

  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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Financial support was provided by Princeton University.

References

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  • Abstract

    Scheme 1

    Scheme 1. Examples of Switchable, Ligand-Controlled Site Selectivity in Undirected C–H Functionalization

    Figure 1

    Figure 1. Identification of ancillary ligands that accelerate C–H alkenylation of 2-methylfuran (1) as a model reaction.

    Figure 2

    Figure 2. Kinetic profile of the DHR of 1 (0.25 mmol), t-butyl acrylate (0.5 mmol), BQ (0.5 mmol), Pd(OAc)2 (1 mol %), and the indicated ligand (1 mol %) in AcOH (1.5 mL) at 60 °C.

    Figure 3

    Figure 3. Kinetic profile of the DHR in eq 1. aCosolvent with DMF (1:10); b1 mol %; c10 mol %; HOTs (10 mol %) added.

    Figure 4

    Figure 4. Dependence of the observed rate constant on the concentration of (a) L7 (0.42–3.3 mM) during the DHR of 1 (0.17 M), t-butyl acrylate (0.33 M), BQ (0.25 M), and Pd(OAc)2 (1.7 mM) in AcOH at 50 °C; (b) 1 (0.083–1.0 M) during the DHR with t-butyl acrylate (0.33 M), BQ (0.25 M), Pd(OAc)2 (1.7 mM), and L7 (1.7 mM) in AcOH at 50 °C; (c) t-butyl acrylate (0.02–0.40 M) during the DHR of 1 (0.17 M), BQ (0.25 M), Pd(OAc)2 (1.7 mM), and L7 (1.7 mM) in AcOH at 50 °C; (d) BQ (0.083–0.33 M) during the DHR of 1 (0.17 M), t-butyl acrylate (0.33 M), Pd(OAc)2 (1.7 mM), and L7 (1.7 mM) in AcOH at 50 °C; (e) sodium acetate (0.0030–0.34 M) during the DHR of 1 (0.17 M), t-butyl acrylate (0.33 M), BQ (0.25 M), Pd(OAc)2 (1.7 mM), and L7 (1.7 mM) in AcOH at 50 °C; (f) L7-Pd(OAc)2 (0.40–15 mM) during the DHR of 1 (0.17 M), t-butyl acrylate (0.33 M), and BQ (0.25 M) in AcOH at 45 °C as determined by the methods of initial rates.

    Figure 5

    Figure 5. Observation by 1H NMR of species formed from combinations of Pd(OAc)2 (8.4 mM) and L7 at (a) 50 mM, (b) 25 mM, (c) 17 mM, or (d) 8.4 mM concentrations in AcOH-d4 at rt; (e) L7 only.

    Figure 6

    Figure 6. DOSY NMR data used to estimate the molecular weight of unknown species Y (triangle) generated in a 1:1 mixture of Pd(OAc)2 and L7 in AcOH-d4 at rt. The internal standards (diamonds) used were C6H6, cyclooctane, 1,3,5-(CF3)3C6H3, 18-crown-6, Me2Si(C6F5)2, Pd(L7)2(OAc)2, and Ir(4′-MeO-ppy)3.

    Figure 7

    Figure 7. DOSY NMR data used to estimate the molecular weight of unknown species X (circle) generated in a 2:1 mixture of L7 and Pd(OAc)2 in AcOH-d4 at rt. The internal standards (diamonds) used were C6H6, cyclooctane, 1,3,5-(CF3)3C6H3, 18-crown-6, Me2Si(C6F5)2, Pd(L7)2(OAc)2, and Ir(4′-MeO-ppy)3.

    Scheme 2

    Scheme 2. Proposed Mechanism Using L7/Pd(OAc)2 (1:1)

    Scheme 3

    Scheme 3. Illustrative Examples of (a) Challenging Site Selectivity To Access (b) 2,3-Disubstituted Heteroarene Motifs

    Scheme 4

    Scheme 4. Aerobic DHR Examples
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