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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. 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), Cu^II, 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 (L1–L5) 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. 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. 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

entry	ligand	x	time (min)	yieldb (%)	TONc
1	none	5	15	9	2
2		1	30	7	7
3	p-(Me₂N)C₆H₄SEt (L7)	5	15	85	17
4		1	30	84	84
5		0.5	60	80	160
6		0.25	180	71	284
7d	(PMP)S(CH₂)₃SO₃^– (L14)	0.5	10	62	124
			60	95	190
8d		0.15	300	79	527

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.

Determined by GC versus an internal standard.

Mol 2 (mol Pd)⁻¹.

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., Cu^II) 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 (k_rel 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. 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 (k_H/k_D = 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. 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 L_nPd(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. 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 H_a, H_b, 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 H_b 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. 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. 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. 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

entry	additive(s)	yield of 4 (%)
1		18
2	L7	19
3b	L8	27
4b	L8 and CH₃(CH₂)₄SO₃^–Na⁺	7
5b	L14	98
6b	L15	79
7b	L16	73
8b	L17	71
9b	L18	28

Yields determined by ¹H NMR versus mesitylene as standard.

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 S_EAr 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 L8–L12 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

entry	ligand	9/10
1b	L14 (3 mol %)	>20:1
2b	L15 (3 mol %)	>20:1
3	4,5-diazafluorenone (3 mol %)	5.0:1
4	L7 (3 mol %)	1.9:1
5	pyridine (6 mol %)	0.9:1

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

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. 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).

Broad applicability of L14-Pd(OAc)₂ to the DHR with electron-rich N-heterocycles (Table 6) was also observed using Cu^II 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 Cu^II 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)

ja7b03887_si_001.pdf (14.61 MB)

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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
- Brad P. Carrow - Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States; http://orcid.org/0000-0003-4929-8074; Email: [email protected]
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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Towards ideal synthesis. Alkenylation of aryl C-H bonds by a Fujiwara-Moritani reaction
Zhou, Lihong; Lu, Wenjun
Chemistry - A European Journal (2014), 20 (3), 634-642CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. An overview of recent progress in the Fujiwara-Moritani reaction, which is the palladium-catalyzed oxidative coupling of arenes with olefins to afford alkenyl arenes, was described. It is emphasized that regioselectivity on aryl o- or m-C-H activation could be controlled very well in the presence of Pd, Rh, or Ru catalysts with the assistance of various chelation groups on arom. rings in this coupling reaction. Catalytic alkenylation of aryl C-H bonds from simple arenes was also discussed, esp. from electron-deficient arenes. These advanced protocols would not only make the Fujiwara-Moritani reaction more useful and applicable in org. synthesis but also light the way for the further development of the functionalization of normal C-H bonds.
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7
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137 DOI: 10.1021/ja105044s
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7
Ligand-Accelerated C-H Activation Reactions: Evidence for a Switch of Mechanism
Engle, Keary M.; Wang, Dong-Hui; Yu, Jin-Quan
Journal of the American Chemical Society (2010), 132 (40), 14137-14151CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Initial rate studies have revealed dramatic acceleration in aerobic Pd(II)-catalyzed C-H olefination reactions of phenylacetic acids when mono-N-protected amino acids are used as ligands. In light of these findings, systematic ligand tuning was undertaken, which has resulted in drastic improvements in substrate scope, reaction rate, and catalyst turnover. We present evidence from intermol. competition studies and kinetic isotope effect expts. that implies that the obsd. rate increases are a result of acceleration in the C-H cleavage step. Furthermore, these studies suggest that the origin of this phenomenon is a change in the mechanism of C-H cleavage from electrophilic palladation to proton abstraction.
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8
(a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578 DOI: 10.1021/ja035054y
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8a
Catalytic C-H Bond Functionalization with Palladium(II): Aerobic Oxidative Annulations of Indoles
Ferreira, Eric M.; Stoltz, Brian M.
Journal of the American Chemical Society (2003), 125 (32), 9578-9579CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A palladium-catalyzed aerobic oxidative annulation of alkenyl-substituted indoles, e.g. I (n = 1, R1 = Me, Et, PhCH2OCH2, R2 = H; n = 1, R1 = Me, R2 = 6-Cl, 5-PhCH2O; n = 2, R1 = Me, R2 = H), with formation of vinyl cyclopenta[b]indoles and tetrahydrocarbazoles, e.g. II, is described. A variety of factors influence these cyclizations, and in particular the electronic nature of the pyridine ligand is crucial. It is also remarkable that these oxidative cyclizations can proceed in good yield despite background oxidative decompn. pathways, testament to the facile nature with which mol. oxygen can serve as the direct oxidant for Pd(0). The mechanism most likely involves initial indole palladation (formal C-H bond activation) followed by migratory insertion and β-hydrogen elimination.
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(b) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254 DOI: 10.1021/ja8026295
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8b
Palladium-Catalyzed C-H Functionalization of Pyridine N-Oxides: Highly Selective Alkenylation and Direct Arylation with Unactivated Arenes
Cho, Seung Hwan; Hwang, Seung Jun; Chang, Sukbok
Journal of the American Chemical Society (2008), 130 (29), 9254-9256CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Two catalytic protocols of the oxidative C-C bond formation have been developed on the basis of the C-H bond activation of pyridine N-oxides. Pd-catalyzed alkenylation of the N-oxides proceeds with excellent regio-, stereo-, and chemoselectivity, and the corresponding ortho-alkenylated N-oxide derivs. are obtained in good to excellent yields. A direct cross-coupling reaction of pyridine N-oxides with unactivated arenes was also developed in the presence of a Pd catalyst and Ag oxidant, which affords ortho-arylated pyridine N-oxide products with high site-selectivity.
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(c) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072 DOI: 10.1021/ja900327e
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8c
Pd(II)-catalyzed olefination of electron-deficient arenes using 2,6-dialkylpyridine ligands
Zhang, Yang-Hui; Shi, Bing-Feng; Yu, Jin-Quan
Journal of the American Chemical Society (2009), 131 (14), 5072-5074CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Pd(II)-catalyzed meta-olefination of highly electron-deficient arenes is achieved through the use of a rationally designed mutually repulsive ligand. The combination of directed and nondirected C-H functionalization of arenes provides a versatile route for the synthesis of highly sought after 1,2,4-trisubstituted arenes.
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(d) Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012, 14, 1760 DOI: 10.1021/ol300281p
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8d
Pyridine Ligands as Promoters in PdII/0-Catalyzed C-H Olefination Reactions
Kubota, Asako; Emmert, Marion H.; Sanford, Melanie S.
Organic Letters (2012), 14 (7), 1760-1763CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
Com. available pyridine ligands, e.g., I and II, can significantly enhance the rate, yield, substrate scope, and site selectivity of arene C-H olefination (Fujiwara-Moritani) reactions. The use of a 1:1 ratio of Pd/pyridine proved crit. to maximize reaction rates and yields.
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(e) Zhao, J.; Huang, L.; Cheng, K.; Zhang, Y. Tetrahedron Lett. 2009, 50, 2758 DOI: 10.1016/j.tetlet.2009.03.124
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8e
Palladium-catalyzed alkenylation of thiophenes and furans by regioselective C-H bond functionalization
Zhao, Jinlong; Huang, Lehao; Cheng, Kai; Zhang, Yuhong
Tetrahedron Letters (2009), 50 (23), 2758-2761CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
A Pd-catalyzed direct alkenylation of thiophenes and furans was developed in the presence of AgOAc and pyridine. A variety of olefinic substrates such as acrylates, acrylamides, and acrylonitrile can perform the direct oxidative coupling reactions with various thiophenes and furans to give the mono-alkenylated products in good yields. In most cases, the (E)-isomers were isolated as the major products.
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9
(a) Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 15116 DOI: 10.1021/ja105829t
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9a
Allylic C-H acetoxylation with a 4,5-diazafluorenone-ligated palladium catalyst: a ligand-based strategy to achieve aerobic catalytic turnover
Campbell, Alison N.; White, Paul B.; Guzei, Ilia A.; Stahl, Shannon S.
Journal of the American Chemical Society (2010), 132 (43), 15116-15119CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Pd-catalyzed C-H oxidn. reactions often require the use of oxidants other than O2. Here we demonstrate a ligand-based strategy to replace benzoquinone with O2 as the stoichiometric oxidant in Pd-catalyzed allylic C-H acetoxylation. Use of 4,5-diazafluorenone as an ancillary ligand for Pd(OAc)2 enables terminal alkenes to be converted to linear allylic acetoxylation products in good yields and selectivity under 1 atm O2. Mechanistic studies have revealed that 4,5-diazafluorenone facilitates C-O reductive elimination from a π-allyl-PdII intermediate, thereby eliminating the requirement for benzoquinone in this key catalytic step.
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(b) Piotrowicz, M.; Zakrzewski, J. Organometallics 2013, 32, 5709 DOI: 10.1021/om400410u
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(c) Vasseur, A.; Laugel, C.; Harakat, D.; Muzart, J.; Le Bras, J. Eur. J. Org. Chem. 2015, 2015, 944 DOI: 10.1002/ejoc.201403475
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10
Zhang, C.; Santiago, C. B.; Crawford, J. M.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 15668 DOI: 10.1021/jacs.5b11335
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11
Vaughan, B. A.; Webster-Gardiner, M. S.; Cundari, T. R.; Gunnoe, T. B. Science 2015, 348, 421 DOI: 10.1126/science.aaa2260
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12
(a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125 DOI: 10.1002/anie.200500468
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12a
Palladium-catalyzed intermolecular alkenylation of indoles by solvent-controlled regioselective C-H functionalization
Grimster, Neil P.; Gauntlett, Carolyn; Godfrey, Christopher R. A.; Gaunt, Matthew J.
Angewandte Chemie, International Edition (2005), 44 (20), 3125-3129CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Either the C2- or the C3-substituted product can be obtained with the same palladium(II) catalyst in an oxidative intermol. alkenylation of indoles. A variety of conditions can be used for derivatization at the 3-position; however, the presence of acetic acid was required for the C2-selective process. Further elaboration of the products by a similar C-H functionalization process leads to the bisalkenylated indoles selectively.
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(b) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528 DOI: 10.1021/ja058141u
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(c) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004 DOI: 10.1002/anie.200705005
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(d) Su, Y.; Zhou, H.; Chen, J.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Org. Lett. 2014, 16, 4884 DOI: 10.1021/ol5023933
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(e) Su, Y.; Gao, S.; Huang, Y.; Lin, A.; Yao, H. Chem. - Eur. J. 2015, 21, 15820 DOI: 10.1002/chem.201502418
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12e
Solvent-Controlled C2/C5-Regiodivergent Alkenylation of Pyrroles
Su, Youla; Gao, Shang; Huang, Yue; Lin, Aijun; Yao, Hequan
Chemistry - A European Journal (2015), 21 (44), 15820-15825CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A solvent-controlled C2/C5-selective alkenylation of 3,4-disubstituted pyrroles has been developed. The C3 substituent of pyrroles proved crucial to the regioselectivity. Substrates bearing directing groups at the C3 position exhibited excellent C2-selectivities in chelation-assisted C-H activation in toluene or 1,4-dioxane. However, a DMSO/DMF solvent system could override the chelation effect of weak directing groups, such as carboxylate and carbonyl groups, favoring instead regioselectivity towards the more electron-rich C5 position. A series of 3-carboxylate and 3-carbonyl pyrroles were tested and showed moderate to good yields with good regioselectivities for both C2- and C5-alkenylation process.
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(f) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936 DOI: 10.1021/ar300014f
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12f
Controlling Site Selectivity in Palladium-Catalyzed C-H Bond Functionalization
Neufeldt, Sharon R.; Sanford, Melanie S.
Accounts of Chemical Research (2012), 45 (6), 936-946CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
A review. Effective methodol. to functionalize C-H bonds requires overcoming the key challenge of differentiating among the multitude of C-H bonds that are present in complex org. mols. This Account focuses on our work over the past decade toward the development of site-selective Pd-catalyzed C-H functionalization reactions using the following approaches: substrate-based control over selectivity through the use of directing groups (approach 1), substrate control through the use of electronically activated substrates (approach 2), or catalyst-based control (approach 3). In our extensive exploration of the first approach, a no. of selectivity trends have emerged for both sp2 and sp3 C-H functionalization reactions that hold true for a variety of transformations involving diverse directing groups. Functionalizations tend to occur at the less-hindered sp2 C-H bond ortho to a directing group, at primary sp3 C-H bonds that are β to a directing group, and, when multiple directing groups are present, at C-H sites proximal to the most basic directing group. Using approach 2, which exploits electronic biases within a substrate, our group has achieved C-2-selective arylation of indoles and pyrroles using diaryliodonium oxidants. The selectivity of these transformations is altered when the C-2 site of the heterocycle is blocked, leading to C-C bond formation at the C-3 position. While approach 3 (catalyst-based control) is still in its early stages of exploration, we have obtained exciting results demonstrating that site selectivity can be tuned by modifying the structure of the supporting ligands on the Pd catalyst. For example, by modulating the structure of N-N bidentate ligands, we have achieved exquisite levels of selectivity for arylation at the α site of naphthalene. Similarly, we have demonstrated that both the rate and site selectivity of arene acetoxylation depend on the ratio of pyridine (ligand) to Pd. Lastly, by switching the ligand on Pd from an acetate to a carbonate, we have reversed the site selectivity of a 1,3-dimethoxybenzene/benzo[h]quinoline coupling. In combination with a growing no. of reports in the literature, these studies highlight a frontier of catalyst-based control of site-selectivity in the development of new C-H bond functionalization methodol.
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13
(a) Yanagisawa, S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131, 14622 DOI: 10.1021/ja906215b
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(b) Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed. 2010, 49, 8946 DOI: 10.1002/anie.201005082
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13b
A General Catalyst for the β-Selective C-H Bond Arylation of Thiophenes with Iodoarenes
Ueda, Kirika; Yanagisawa, Shuichi; Yamaguchi, Junichiro; Itami, Kenichiro
Angewandte Chemie, International Edition (2010), 49 (47), 8946-8949, S8946/1-S8946/68CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The normally less-reactive β position of thiophenes was previously inaccessible to direct functionalization. However, the β selectivity obsd. with the catalytic system PdCl2/P{OCH(CF3)2}3/Ag2CO3 in the arylation of thiophenes with iodoarenes is a remarkably general phenomenon applicable to unsubstituted, monosubstituted, and disubstituted thiophene derivs., as well as thiophene-contg. fused arom. compds.
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(c) Ueda, K.; Amaike, K.; Maceiczyk, R. M.; Itami, K.; Yamaguchi, J. J. Am. Chem. Soc. 2014, 136, 13226 DOI: 10.1021/ja508449y
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14
Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew. Chem., Int. Ed. 2011, 50, 9409 DOI: 10.1002/anie.201103327
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Madesclaire, M. Tetrahedron 1986, 42, 5459 DOI: 10.1016/S0040-4020(01)88150-3
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(a) Fuchita, Y.; Hiraki, K.; Kamogawa, Y.; Suenaga, M. J. Chem. Soc., Chem. Commun. 1987, 941 DOI: 10.1039/C39870000941
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(a) Henderson, W. H.; Check, C. T.; Proust, N.; Stambuli, J. P. Org. Lett. 2010, 12, 824 DOI: 10.1021/ol902905w
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(b) Le, C. C.; Kunchithapatham, K.; Henderson, W. H.; Check, C. T.; Stambuli, J. P. Chem. - Eur. J. 2013, 19, 11153 DOI: 10.1002/chem.201301787
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17b
A Survey of Sulfide Ligands for Allylic C-H Oxidations of Terminal Olefins
Le, Chi; Kunchithapatham, Kamala; Henderson, William H.; Check, Christopher T.; Stambuli, James P.
Chemistry - A European Journal (2013), 19 (34), 11153-11157CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Allylic C-H oxidn. of terminal olefins catalyzed by Pd(OAc)2 in presence of sulfide ligands was investigated. Overall, dialkyl sulfides led to greater product formation than aryl alkyl sulfides and diaryl sulfides, which is presumed to emanate from increased basicity on sulfur. E.g., in presence of Pd(OAc)2, benzoquinone, and tetrahydrothiophene, oxidn. of 1-dodecene gave 95% conversion to Me(CH2)8CH:CHCH2OAc Me(CH2)8CH(OAc)CH:CH2, and Me(CH2)8CH2C(OAc):CH2 in a 20:1:1 ratio (E/Z = 10:1). Bidentate sulfide ligands favored formation of the linear allylic acetate, but required higher catalyst loadings and longer reaction times. Simple and inexpensive tetrahydrothiophene provided one of the most active and selective catalysts for allylic oxidn. of terminal olefins.
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18
Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346 DOI: 10.1021/ja039107n
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18
A sulfoxide-promoted, catalytic method for the regioselective synthesis of allylic acetates from monosubstituted olefins via C-H oxidation
Chen, Mark S.; White, M. Christina
Journal of the American Chemical Society (2004), 126 (5), 1346-1347CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Sulfoxide ligation to Pd(II) salts is shown to selectively promote C-H oxidn. vs. Wacker oxidn. chem. and to control the regioselectivity in the C-H oxidn. products. A catalytic method for the direct C-H oxidn. of monosubstituted olefins to linear (E)-allylic acetates, in high regio- and stereoselectivities as well as preparatively useful yields, is described. The method, using benzoquinone as the stoichiometric oxidant and a catalytic amt. of Pd(OAc)2 or Pd(O2CCF3)2, was found to be compatible with a wide range of functionalities. Addn. of DMSO was found to be crit. for promoting the C-H oxidn. pathway, with acetic acid alone, or in combination with a diverse range of dielec. media, leading to mixts. favoring Wacker-type oxidn. products. To explore the role of DMSO as a ligand, the bis-sulfoxide Pd(OAc)2 complex I was formed and found to be an effective C-H oxidn. catalyst in the absence of DMSO. I effected a reversal of regioselectivity, favoring the formation of branched allylic acetates.
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19
(a) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965 DOI: 10.1021/ja910900p
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19a
Auxiliary-Assisted Palladium-Catalyzed Arylation and Alkylation of sp2 and sp3 Carbon-Hydrogen Bonds
Shabashov, Dmitry; Daugulis, Olafs
Journal of the American Chemical Society (2010), 132 (11), 3965-3972CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
We have developed a method for auxiliary-directed, palladium-catalyzed β-arylation and alkylation of sp3 and sp2 C-H bonds in carboxylic acid derivs. The method employs a carboxylic acid 2-methylthioaniline- or 8-aminoquinoline amide substrate, aryl or alkyl iodide coupling partner, palladium acetate catalyst, and an inorg. base. By employing 2-methylthioaniline auxiliary, selective monoarylation of primary sp3 C-H bonds can be achieved. If arylation of secondary sp3 C-H bonds is desired, 8-aminoquinoline auxiliary may be used. For alkylation of sp3 and sp2 C-H bonds, 8-aminoquinoline auxiliary affords the best results. Some functional group tolerance is obsd. and amino- and hydroxy-acid derivs. can be functionalized. Preliminary mechanistic studies have been performed. A palladacycle intermediate has been isolated, characterized by X-ray crystallog., and its reactions have been studied.
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(b) Yu, M.; Xie, Y.; Xie, C.; Zhang, Y. Org. Lett. 2012, 14, 2164 DOI: 10.1021/ol3006997
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19b
Palladium-Catalyzed C-H Alkenylation of Arenes Using Thioethers as Directing Groups
Yu, Ming; Xie, Yongju; Xie, Chunsong; Zhang, Yuhong
Organic Letters (2012), 14 (8), 2164-2167CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
Thioethers have been proven to be reliable directing groups for palladium catalyzed alkenylation of arenes via C-H activation. Mechanistic investigation reveals that the C-H cleavage of arenes is the turnover-limiting step, and an acetate-bridged dinuclear cyclopalladation intermediate is involved. The alkenylated thioethers can be easily removed and transformed into a variety of useful groups.
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(c) Zhang, X.-S.; Zhu, Q.-L.; Zhang, Y.-F.; Li, Y.-B.; Shi, Z.-J. Chem. - Eur. J. 2013, 19, 11898 DOI: 10.1002/chem.201300829
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19c
Controllable Mono-/Dialkenylation of Benzyl Thioethers through Rh-Catalyzed Aryl C-H Activation
Zhang, Xi-Sha; Zhu, Qi-Lei; Zhang, Yun-Fei; Li, Yan-Bang; Shi, Zhang-Jie
Chemistry - A European Journal (2013), 19 (36), 11898-11903CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
Benzyl thioethers were alkenylated in excellent yields with broad substrate scope and the selectivity (mono- vs. disubstituted product) was controlled by the solvent and ratio of reactants. Sequential alkenylation with two different alkenes was also carried out in a 1-pot process. In addn., the thioether directing group was removed in a 1-pot process with simultaneous hydrogenation of the double bond to give the toluene derivs. Thus, e.g., Rh-catalyzed alkenylation of PhCH2SMe with Et acrylate afforded mono:di adduct ratio (I:II, %) of 79.7:28.3 in MeOH, whereas in tert-butanol the ratio was inverted to 15.1:58.8.
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20
Wu, C.-Z.; He, C.-Y.; Huang, Y.; Zhang, X. Org. Lett. 2013, 15, 5266 DOI: 10.1021/ol402492s
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Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097 DOI: 10.1021/ol991148u
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Highly Efficient Pd-Catalyzed Coupling of Arenes with Olefins in the Presence of tert-Butyl Hydroperoxide as Oxidant
Jia, Chengguo; Lu, Wenjun; Kitamura, Tsugio; Fujiwara, Yuzo
Organic Letters (1999), 1 (13), 2097-2100CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
The oxidative coupling of arenes with olefins has been performed efficiently in the presence of catalytic amts. of palladium acetate and benzoquinone with tert-Bu hydroperoxide as the oxidant in up to 280 turnover nos. The catalytic system is esp. active for the coupling of heterocycles such as furans and indole with activated olefins. The reaction is highly regio- and stereoselective, giving trans-olefins predominantly.
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22
Calculated from the yield of 2 (62%) at 10 min using 0.5 mol% of [Pd]/L14.
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23
(a) Dams, M.; De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew. Chem., Int. Ed. 2003, 42, 3512 DOI: 10.1002/anie.200351524
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Catalytic coupling of aromatics and olefins by homogeneous palladium(II) compounds under oxygen
Shue, Robert S.
Journal of the Chemical Society [Section] D: Chemical Communications (1971), (23), 1510-11CODEN: CCJDAO; ISSN:0577-6171.
Benzene and PhCl coupled to 5 olefins under mild O pressure in the presence of the homogenous catalysts Pd(OAc)2, Pd(OPr)2, or Pd(OBz)2; e.g. C2H4 reacted with benzene contg. Pd(OAc)2 and under O (300 psi) to give 648% (based on Pd) styrene in 51/2 hr.
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24
Zhang, H.-B.; Liu, L.; Chen, Y.-J.; Wang, D.; Li, C.-J. Eur. J. Org. Chem. 2006, 2006, 869 DOI: 10.1002/ejoc.200500863
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(a) Chen, W.-L.; Gao, Y.-R.; Mao, S.; Zhang, Y.-L.; Wang, Y.-F.; Wang, Y.-Q. Org. Lett. 2012, 14, 5920 DOI: 10.1021/ol302840b
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25a
Palladium-Catalyzed Intermolecular C3 Alkenylation of Indoles Using Oxygen as the Oxidant
Chen, Wen-Liang; Gao, Ya-Ru; Mao, Shuai; Zhang, Yan-Lei; Wang, Yu-Fei; Wang, Yong-Qiang
Organic Letters (2012), 14 (23), 5920-5923CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A general and efficient palladium-catalyzed intermol. direct C3 alkenylation of indoles using oxygen as the oxidant has been developed. The reaction is of complete regio- and stereoselectivity. All products are E-isomers at the C3-position, and no Z-isomers or 2-substituted product can be detected. For example, N-methylindole reacted with Et acrylate in the presence of Pd(OAc)2 and O2 in DMSO to give (E)-Et 3-(1-methyl-1H-indol-3-yl)acrylate in 85% yield.
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(b) Vasseur, A.; Muzart, J.; Le Bras, J. Chem. - Eur. J. 2011, 17, 12556 DOI: 10.1002/chem.201101992
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25b
Dehydrogenative Heck Reaction of Furans and Thiophenes with Styrenes under Mild Conditions and Influence of the Oxidizing Agent on the Reaction Rate
Vasseur, Alexandre; Muzart, Jacques; Le Bras, Jean
Chemistry - A European Journal (2011), 17 (45), 12556-12560, S12556/1-S12556/55CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The authors report dehydrogenative Heck reactions (DHRs) of furans and thiophenes with styrenes under mild conditions using Pd(OAc)2 as catalyst and benzoquinone as oxidizing reagent. The authors investigated the influence of solvent on DHR of heterocycles with styrene. The method is compatible with halogenated substances, including brominated thiophenes and styrenes. Compared with the previously reported Rh(III)-catalyzed reactions, this method is advantageous with a wider scope of substrates and cost-effective Pd(II) catalysts. DMSO and benzoquinone have an influence on the efficiency of the process.
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(c) Vasseur, A.; Harakat, D.; Muzart, J.; Le Bras, J. Adv. Synth. Catal. 2013, 355, 59 DOI: 10.1002/adsc.201200787
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(d) She, Z.; Shi, Y.; Huang, Y.; Cheng, Y.; Song, F.; You, J. Chem. Commun. 2014, 50, 13914 DOI: 10.1039/C4CC05827E
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26
The volatility of 1/1-5-d complicated the use of this substrate pair for the KIE experiment due to difficulty isolating the later isotopologue in pure form.
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27
Cook, A. K.; Sanford, M. S. J. Am. Chem. Soc. 2015, 137, 3109 DOI: 10.1021/jacs.5b00238
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Stromnova, T. A. Russ. J. Inorg. Chem. 2008, 53, 2019 DOI: 10.1134/S0036023608130032
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30
(a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586 DOI: 10.1021/ja0176907
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30a
Selective Pd-Catalyzed Oxidative Coupling of Anilides with Olefins through C-H Bond Activation at Room Temperature
Boele, Maarten D. K.; van Strijdonck, Gino P. F.; de Vries, Andre H. M.; Kamer, Paul C. J.; de Vries, Johannes G.; van Leeuwen, Piet W. N. M.
Journal of the American Chemical Society (2002), 124 (8), 1586-1587CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Using a high-throughput experimentation approach we found a selective and mild Pd-catalyzed oxidative coupling reaction between anilide derivs. and acrylates that occurs through ortho C-H bond activation. The reaction is carried out in an acidic environment and occurs even at room temp. with use of a cheap oxidant (benzoquinone) in yields up to 91%. The benzoquinone possibly also functions as a ligand, stabilizing the catalyst. From the electronic dependence of the reaction and the obsd. kinetic isotope effect (kH/kD = 3) the key step of the catalytic cycle is believed to be electrophilic attack by a [PdOAc]+ complex on the π-system of the arene.
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(b) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972 DOI: 10.1021/ol100331h
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31
(a) Ackerman, L. J.; Sadighi, J. P.; Kurtz, D. M.; Labinger, J. A.; Bercaw, J. E. Organometallics 2003, 22, 3884 DOI: 10.1021/om0303294
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(b) Zhong, H. A.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 2002, 124, 1378 DOI: 10.1021/ja011189x
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Wang, D.; Stahl, S. S. J. Am. Chem. Soc. 2017, 139, 5704 DOI: 10.1021/jacs.7b01970
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(a) Tunge, J. A.; Foresee, L. N. Organometallics 2005, 24, 6440 DOI: 10.1021/om0507225
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33a
Mechanistic Studies of Fujiwara Hydroarylation. C-H Activation versus Electrophilic Aromatic Substitution
Tunge, Jon A.; Foresee, Lindsay N.
Organometallics (2005), 24 (26), 6440-6444CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
The addn. of the C-H bonds of arenes across alkynes is catalyzed by Pd(OAc)2 in CF3CO2H (Fujiwara hydroarylation). Previously it has been suggested that this transformation proceeds by C-H activation of the arene followed by trans-addn. of a palladium-arene bond across an alkyne. We have investigated the kinetic isotope effects of intramol. hydroarylation with deuterated arene substrates and found that catalytic hydroarylation exhibits an inverse KIE. The obsd. inverse isotope effect is not consistent with known KIEs for C-H activation by electrophilic palladium; thus it suggests that the reaction proceeds by electrophilic arom. substitution.
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(b) Effenberger, F.; Maier, A. H. J. Am. Chem. Soc. 2001, 123, 3429 DOI: 10.1021/ja0022066
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(c) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166 DOI: 10.1021/ja01053a047
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33c
Aromatic substitution of olefins. VI. Arylation of olefins with palladium(II) acetate
Fujiwara, Yuzo; Noritani, Ichiro; Danno, Sadao; Asano, Ryuzo; Teranishi, Shiichiro
Journal of the American Chemical Society (1969), 91 (25), 7166-9CODEN: JACSAT; ISSN:0002-7863.
Olefins react with benzenes to produce aryl-substituted olefins via direct substitution of the aromatic compd. for H on the double bond of the olefin in the presence of Pd salts and reduced Pd metals. The reaction may be made catalytic with respect to the Pd salts by using Cu(OAc)2 or AgOAc and air as reoxidants. The reaction provides an extremely convenient method for the synthesis o f a wide variety of olefinic compds.
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34
Beck, E.; Gaunt, M. In C–H Activation; Yu, J.-Q.; Shi, Z., Eds.; Springer: Berlin, 2010; Vol. 292, p 85.
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35
Liégault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047 DOI: 10.1021/jo902515z
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36
Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848 DOI: 10.1021/ja802533u
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36
Analysis of the Concerted Metalation-Deprotonation Mechanism in Palladium-Catalyzed Direct Arylation Across a Broad Range of Aromatic Substrates
Gorelsky, Serge I.; Lapointe, David; Fagnou, Keith
Journal of the American Chemical Society (2008), 130 (33), 10848-10849CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The concerted metalation-deprotonation mechanism predicts relative reactivity and regioselectivity for a diverse set of arenes spanning the entire spectrum of known palladium-catalyzed direct arylation coupling partners. An anal. following an active strain model provides a more complete portrayal of the important arene/catalyst parameters leading to a successful coupling. The breadth of arenes whose reactivity can be predicted by the CMD mechanism indicates that it may be far more widespread than previously imagined.
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37
Pyridine or 4,5-diazafluorenone ligands still generated low 9/10 ratios using 1:1 L/Pd. See Table S5 for these data.
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38
(a) Cho, J.-Y.; Iverson, C. N.; Smith, M. R. J. Am. Chem. Soc. 2000, 122, 12868 DOI: 10.1021/ja0013069
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38a
Steric and Chelate Directing Effects in Aromatic Borylation
Cho, Jian-Yang; Iverson, Carl N.; Smith, Milton R., III
Journal of the American Chemical Society (2000), 122 (51), 12868-12869CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The title reaction is described. Thus, Cp*Ir(PMe3)(H)(BPin) (1) catalyzed borylation of benzene in the presence of HBPin (pinacolborane) at 120° gave 53% PhBPin. 1 Was generated in situ from the reaction of Cp*Ir(PMe3)(H)2 with HBPin.
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(b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390 DOI: 10.1021/ja0173019
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38b
Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate
Ishiyama, Tatsuo; Takagi, Jun; Ishida, Kousaku; Miyaura, Norio; Anastasi, Natia R.; Hartwig, John F.
Journal of the American Chemical Society (2002), 124 (3), 390-391CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The borylation of arenes leads to the formation of synthetically versatile products from unactivated arene reagents. It is reported that Ir(I) precursors in conjunction with bipyridine ligands catalyze in high yields the borylation of arenes under mild conditions. These reactions encompass arenes bearing both electron-withdrawing and electron-donating substituents. The temps. required for the transformation are much lower than those previously reported for direct arene borylation. The combination of [Ir(COE)2Cl]2 and (4,4-di-t-butyl)bipyridine even allows for reaction at room temp. The same catalyst system at 100° provides remarkably high turnover nos. for a hydrocarbon functionalization process. Mechanistic studies show that the reactions involve uncommon, Ir(II) tris-boryl complexes. An example of this type of complex ligated by di-t-butylbipyridine, [Ir(COE)(Bpin)3(4,4'-di-t-Bu-BPY)], was isolated and structurally characterized. It reacted rapidly at room temp. to produce aryl boronate esters in high yields.
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(c) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science 2002, 295, 305 DOI: 10.1126/science.1067074
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38c
Remarkably selective iridium catalysts for the elaboration of aromatic C-H bonds
Cho, Jian-Yang; Tse, Man Kin; Holmes, Daniel; Maleczka, Robert E., Jr.; Smith, Milton R., III
Science (Washington, DC, United States) (2002), 295 (5553), 305-308CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Arylboron compds. have intriguing properties and are important building blocks for chem. synthesis. A family of Ir catalysts (IndIr(COD), (η6-mesitylene)Ir(BPin)3 (4; HBPin = pinacolborane)) now enables the direct synthesis of arylboron compds. from arom. hydrocarbons and boranes under solventless conditions. For example, a 98% yield of PhBPin was obtained in 15 h at 150° from benzene and HBPin (16:1 ratio) in the presence of 4 and PMe3. The Ir catalysts are highly selective for C-H activation and do not interfere with subsequent in situ transformations, including Pd-mediated cross-couplings with aryl halides (e.g. 80% 3,5-dichloro-3'-methylbiphenyl). By virtue of their favorable activities and exceptional selectivities, these Ir catalysts impart the synthetic versatility of arylboron reagents to C-H bonds in arom. and heteroarom. hydrocarbons.
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(d) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890 DOI: 10.1021/cr900206p
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38d
C-H Activation for the Construction of C-B Bonds
Mkhalid, Ibraheem A. I.; Barnard, Jonathan H.; Marder, Todd B.; Murphy, Jaclyn M.; Hartwig, John F.
Chemical Reviews (Washington, DC, United States) (2010), 110 (2), 890-931CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review.
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39
(a) Cheng, C.; Hartwig, J. F. Science 2014, 343, 853 DOI: 10.1126/science.1248042
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39a
Rhodium-Catalyzed Intermolecular C-H Silylation of Arenes with High Steric Regiocontrol
Cheng, Chen; Hartwig, John F.
Science (Washington, DC, United States) (2014), 343 (6173), 853-857CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Regioselective C-H functionalization of arenes has widespread applications in synthetic chem. The regioselectivity of these reactions is often controlled by directing groups or steric hindrance ortho to a potential reaction site. Here, authors report a catalytic intermol. C-H silylation of unactivated arenes that manifests very high regioselectivity through steric effects of substituents meta to a potential site of reactivity. The silyl moiety can be further functionalized under mild conditions but is also inert toward many common org. transformations, rendering the silylarene products useful building blocks. The remote steric effect that we observe results from the steric properties of both the rhodium catalyst and the silane.
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(b) Cheng, C.; Hartwig, J. F. Chem. Rev. 2015, 115, 8946 DOI: 10.1021/cr5006414
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39b
Catalytic Silylation of Unactivated C-H Bonds
Cheng, Chen; Hartwig, John F.
Chemical Reviews (Washington, DC, United States) (2015), 115 (17), 8946-8975CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
A review. This Review will focus on the catalytic silylation of aryl and alkyl C-H bonds by C-H activation steps.
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40
(a) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072 DOI: 10.1021/ja0745862
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40a
Elements of Regiocontrol in Palladium-Catalyzed Oxidative Arene Cross-Coupling
Stuart, David R.; Villemure, Elisia; Fagnou, Keith
Journal of the American Chemical Society (2007), 129 (40), 12072-12073CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
By changing the stoichiometric oxidant and modifying the indole N-substituent in palladium-catalyzed oxidative arene cross-coupling reactions, both C2 and C3 oxidative indole arylation can be achieved in high yield. High regioselectivity can also be achieved with the benzene component, and the use of this methodol. with pyrrole substrates is illustrated. A mechanistic hypothesis for the change in C2/C3 selectivity is advanced.
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(b) Lapointe, D.; Markiewicz, T.; Whipp, C. J.; Toderian, A.; Fagnou, K. J. Org. Chem. 2011, 76, 749 DOI: 10.1021/jo102081a
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40b
Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis
Lapointe, David; Markiewicz, Thomas; Whipp, Christopher J.; Toderian, Amy; Fagnou, Keith
Journal of Organic Chemistry (2011), 76 (3), 749-759CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The challenge of achieving selective and predictable functionalizations at C-H bonds with complex poly(hetero)arom. substrates was addressed by two different approaches. Site-selectivity can be obtained by applying various reaction conditions that are (hetero)arene specific to substrates that contain indoles, pyridine N-oxide, and polyfluorinated benzenes. An exptl. classification of electron-rich heteroarenes based on their reactivity toward palladium-catalyzed C-H functionalization was established, the result of which correlated well with the order of reactivity predicted by the DFT-calcd. concerted metalation-deprotonation (CMD) pathway. Model substrates contg. two reactive heteroarenes were then reacted under general reaction conditions to demonstrate the applicability this reactivity chart in predicting the regioselectivity of the palladium-catalyzed direct arylation and benzylation reactions.
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41
(a) Zhang, H.; Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem. - Eur. J. 2011, 17, 9581 DOI: 10.1002/chem.201101300
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41a
Palladium-Catalyzed Regioselective Aerobic Oxidative C-H/N-H Carbonylation of Heteroarenes under Base-free Conditions
Zhang, Hua; Liu, Dong; Chen, Caiyou; Liu, Chao; Lei, Aiwen
Chemistry - A European Journal (2011), 17 (35), 9581-9585, S9581/1-S9581/50CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
An efficient protocol for palladium-catalyzed aerobic oxidative C-H carbonylation of heteroarenes to form a variety of heterocyclic esters using a balloon pressure of CO. was developed. High regioselectivity was obtained and an electrophilic palladation mechanism was proposed. In addn., this oxidative carbonylation catalytic system was also applied in the aerobic N-H carbonylation of N-free indoles to afford various indole carbamates.
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Organic Letters (2012), 14 (1), 226-229CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A direct Pd(II)-catalyzed olefination of furans and thiophenes with allyl esters is demonstrated. Under the typical conditions, the dehydrogenative Heck coupling reactions of heteroarenes with allylic esters proceeded via a β-H elimination rather than a β-OAc elimination to give the corresponding γ-substituted allylic esters.
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Science (Washington, DC, United States) (2010), 327 (5963), 315-319CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch together the carbogenic cores of numerous complex org. mols. Given that the position-selective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl carbon-hydrogen (C-H) bonds would obviate the inefficiencies assocd. with generating halide precursors or their equiv. However, methods for carrying out such a reaction have suffered from narrow substrate scope and low positional selectivity. We report an operationally simple, atom-economical, carboxylate-directed Pd(II)-catalyzed C-H olefination reaction with phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atm. pressure as the oxidant. The positional selectivity can be tuned by introducing amino acid derivs. as ligands. We demonstrate the versatility of the method through direct elaboration of com. drug scaffolds and efficient syntheses of 2-tetralone and naphthoic acid natural product cores.
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44a
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Lane, Benjamin S.; Brown, Meghann A.; Sames, Dalibor
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We have recently developed palladium-catalyzed methods for direct arylation of indoles (and other azoles) wherein high C-2 selectivity was obsd. for both free (NH)-indole and (NR)-indole. To provide a rationale for the obsd. selectivity ("nonelectrophilic" regioselectivity), mechanistic studies were conducted, using the phenylation of 1-methylindole as a model system. The reaction order was detd. for iodobenzene (zero order), indole (first order), and the catalyst (first order). These kinetic studies, together with the Hammett plot, provided a strong support for the electrophilic palladation pathway. In addn., the kinetic isotope effect (KIEH/D) was detd. for both C-2 and C-3 positions. A surprisingly large value of 1.6 was found for the C-3 position where the substitution does not occur (secondary KIE), while a smaller value of 1.2 was found at C-2 (apparent primary KIE). On the basis of these findings, a mechanistic interpretation is presented that features an electrophilic palladation of indole, accompanied by a 1,2-migration of an intermediate palladium species. This paradigm was used to design new catalytic conditions for the C-3 arylation of indole. In case of free (NH)-indole, regioselectivity of the arylation reaction (C-2 vs. C-3) was achieved by the choice of magnesium base.
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Phipps, Robert J.; Grimster, Neil P.; Gaunt, Matthew J.
Journal of the American Chemical Society (2008), 130 (26), 8172-8174CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
We have developed a new site-selective Cu(II)-catalyzed C-H bond functionalization process that can selectively arylate indoles at either the C3 or C2 position under mild conditions. The scope of the arylation process is broad and tolerates broad functionality on both the indole and aryl unit, which makes it amenable to further elaboration. The mechanism of the arylation reaction is proposed to proceed via a Cu(III)-aryl species that undergoes initial electrophilic addn. at the C3 position of the indole motif. We speculate that site of indole arylation arises through a migration of the Cu(III)-aryl group from C3 to C2, and this can be controlled by the nature of the group on the nitrogen atom; free (NH)- and N-alkylindoles deliver the C3-arylated product, whereas N-acetylindoles afford the C2 isomer, both with excellent yield and selectivity.
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45
Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. Beilstein J. Org. Chem. 2016, 12, 1040 DOI: 10.3762/bjoc.12.99
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Cationic Pd(II)-catalyzed C-H activation, cross-coupling reactions at room temperature: synthetic and mechanistic studies
Nishikata, Takashi; Abela, Alexander R.; Huang, Shenlin; Lipshutz, Bruce H.
Beilstein Journal of Organic Chemistry (2016), 12 (), 1040-1064CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
Cationic palladium(II) complexes have been found to be highly reactive towards arom. C-H activation of arylureas at room temp. A com. available catalyst [Pd(MeCN)4](BF4)2 or a nitrile-free cationic palladium(II) complex generated in situ from the reaction of Pd(OAc)2 and HBF4, effectively catalyzes C-H activation/cross-coupling reactions between aryl iodides, arylboronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to be crit. for achieving room temp. conditions, with the urea moiety the most effective in promoting facile coupling reactions at an ortho C-H position. This methodol. has been utilized in a streamlined and efficient synthesis of boscalid, an agent produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mechanistic investigations led to a proposed catalytic cycle involving three steps: (1) C-H activation to generate a cationic palladacycle; (2) reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3) regeneration of the active cationic palladium catalyst. The reaction between a cationic palladium(II) complex and arylurea allowed the formation and isolation of the corresponding palladacycle intermediate, characterized by X-ray anal. Roles of various additives in the stepwise process have also been studied.
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Abstract
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Scheme 1
Scheme 1. Examples of Switchable, Ligand-Controlled Site Selectivity in Undirected C–H Functionalization
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Figure 1
Figure 1. Identification of ancillary ligands that accelerate C–H alkenylation of 2-methylfuran (1) as a model reaction.
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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.
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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.
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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.
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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.
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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.
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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.
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Scheme 2
Scheme 2. Proposed Mechanism Using L7/Pd(OAc)₂ (1:1)
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Scheme 3
Scheme 3. Illustrative Examples of (a) Challenging Site Selectivity To Access (b) 2,3-Disubstituted Heteroarene Motifs
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Scheme 4
Scheme 4. Aerobic DHR Examples
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  8e
  Palladium-catalyzed alkenylation of thiophenes and furans by regioselective C-H bond functionalization
  Zhao, Jinlong; Huang, Lehao; Cheng, Kai; Zhang, Yuhong
  Tetrahedron Letters (2009), 50 (23), 2758-2761CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  A Pd-catalyzed direct alkenylation of thiophenes and furans was developed in the presence of AgOAc and pyridine. A variety of olefinic substrates such as acrylates, acrylamides, and acrylonitrile can perform the direct oxidative coupling reactions with various thiophenes and furans to give the mono-alkenylated products in good yields. In most cases, the (E)-isomers were isolated as the major products.
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9. 9
  (a) Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 15116 DOI: 10.1021/ja105829t
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  9a
  Allylic C-H acetoxylation with a 4,5-diazafluorenone-ligated palladium catalyst: a ligand-based strategy to achieve aerobic catalytic turnover
  Campbell, Alison N.; White, Paul B.; Guzei, Ilia A.; Stahl, Shannon S.
  Journal of the American Chemical Society (2010), 132 (43), 15116-15119CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Pd-catalyzed C-H oxidn. reactions often require the use of oxidants other than O2. Here we demonstrate a ligand-based strategy to replace benzoquinone with O2 as the stoichiometric oxidant in Pd-catalyzed allylic C-H acetoxylation. Use of 4,5-diazafluorenone as an ancillary ligand for Pd(OAc)2 enables terminal alkenes to be converted to linear allylic acetoxylation products in good yields and selectivity under 1 atm O2. Mechanistic studies have revealed that 4,5-diazafluorenone facilitates C-O reductive elimination from a π-allyl-PdII intermediate, thereby eliminating the requirement for benzoquinone in this key catalytic step.
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  (c) Vasseur, A.; Laugel, C.; Harakat, D.; Muzart, J.; Le Bras, J. Eur. J. Org. Chem. 2015, 2015, 944 DOI: 10.1002/ejoc.201403475
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10. 10
  Zhang, C.; Santiago, C. B.; Crawford, J. M.; Sigman, M. S. J. Am. Chem. Soc. 2015, 137, 15668 DOI: 10.1021/jacs.5b11335
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11. 11
  Vaughan, B. A.; Webster-Gardiner, M. S.; Cundari, T. R.; Gunnoe, T. B. Science 2015, 348, 421 DOI: 10.1126/science.aaa2260
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12. 12
  (a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125 DOI: 10.1002/anie.200500468
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  12a
  Palladium-catalyzed intermolecular alkenylation of indoles by solvent-controlled regioselective C-H functionalization
  Grimster, Neil P.; Gauntlett, Carolyn; Godfrey, Christopher R. A.; Gaunt, Matthew J.
  Angewandte Chemie, International Edition (2005), 44 (20), 3125-3129CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Either the C2- or the C3-substituted product can be obtained with the same palladium(II) catalyst in an oxidative intermol. alkenylation of indoles. A variety of conditions can be used for derivatization at the 3-position; however, the presence of acetic acid was required for the C2-selective process. Further elaboration of the products by a similar C-H functionalization process leads to the bisalkenylated indoles selectively.
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  (c) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004 DOI: 10.1002/anie.200705005
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  (e) Su, Y.; Gao, S.; Huang, Y.; Lin, A.; Yao, H. Chem. - Eur. J. 2015, 21, 15820 DOI: 10.1002/chem.201502418
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  12e
  Solvent-Controlled C2/C5-Regiodivergent Alkenylation of Pyrroles
  Su, Youla; Gao, Shang; Huang, Yue; Lin, Aijun; Yao, Hequan
  Chemistry - A European Journal (2015), 21 (44), 15820-15825CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A solvent-controlled C2/C5-selective alkenylation of 3,4-disubstituted pyrroles has been developed. The C3 substituent of pyrroles proved crucial to the regioselectivity. Substrates bearing directing groups at the C3 position exhibited excellent C2-selectivities in chelation-assisted C-H activation in toluene or 1,4-dioxane. However, a DMSO/DMF solvent system could override the chelation effect of weak directing groups, such as carboxylate and carbonyl groups, favoring instead regioselectivity towards the more electron-rich C5 position. A series of 3-carboxylate and 3-carbonyl pyrroles were tested and showed moderate to good yields with good regioselectivities for both C2- and C5-alkenylation process.
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  12f
  Controlling Site Selectivity in Palladium-Catalyzed C-H Bond Functionalization
  Neufeldt, Sharon R.; Sanford, Melanie S.
  Accounts of Chemical Research (2012), 45 (6), 936-946CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review. Effective methodol. to functionalize C-H bonds requires overcoming the key challenge of differentiating among the multitude of C-H bonds that are present in complex org. mols. This Account focuses on our work over the past decade toward the development of site-selective Pd-catalyzed C-H functionalization reactions using the following approaches: substrate-based control over selectivity through the use of directing groups (approach 1), substrate control through the use of electronically activated substrates (approach 2), or catalyst-based control (approach 3). In our extensive exploration of the first approach, a no. of selectivity trends have emerged for both sp2 and sp3 C-H functionalization reactions that hold true for a variety of transformations involving diverse directing groups. Functionalizations tend to occur at the less-hindered sp2 C-H bond ortho to a directing group, at primary sp3 C-H bonds that are β to a directing group, and, when multiple directing groups are present, at C-H sites proximal to the most basic directing group. Using approach 2, which exploits electronic biases within a substrate, our group has achieved C-2-selective arylation of indoles and pyrroles using diaryliodonium oxidants. The selectivity of these transformations is altered when the C-2 site of the heterocycle is blocked, leading to C-C bond formation at the C-3 position. While approach 3 (catalyst-based control) is still in its early stages of exploration, we have obtained exciting results demonstrating that site selectivity can be tuned by modifying the structure of the supporting ligands on the Pd catalyst. For example, by modulating the structure of N-N bidentate ligands, we have achieved exquisite levels of selectivity for arylation at the α site of naphthalene. Similarly, we have demonstrated that both the rate and site selectivity of arene acetoxylation depend on the ratio of pyridine (ligand) to Pd. Lastly, by switching the ligand on Pd from an acetate to a carbonate, we have reversed the site selectivity of a 1,3-dimethoxybenzene/benzo[h]quinoline coupling. In combination with a growing no. of reports in the literature, these studies highlight a frontier of catalyst-based control of site-selectivity in the development of new C-H bond functionalization methodol.
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13. 13
  (a) Yanagisawa, S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131, 14622 DOI: 10.1021/ja906215b
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  13b
  A General Catalyst for the β-Selective C-H Bond Arylation of Thiophenes with Iodoarenes
  Ueda, Kirika; Yanagisawa, Shuichi; Yamaguchi, Junichiro; Itami, Kenichiro
  Angewandte Chemie, International Edition (2010), 49 (47), 8946-8949, S8946/1-S8946/68CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The normally less-reactive β position of thiophenes was previously inaccessible to direct functionalization. However, the β selectivity obsd. with the catalytic system PdCl2/P{OCH(CF3)2}3/Ag2CO3 in the arylation of thiophenes with iodoarenes is a remarkably general phenomenon applicable to unsubstituted, monosubstituted, and disubstituted thiophene derivs., as well as thiophene-contg. fused arom. compds.
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  (c) Ueda, K.; Amaike, K.; Maceiczyk, R. M.; Itami, K.; Yamaguchi, J. J. Am. Chem. Soc. 2014, 136, 13226 DOI: 10.1021/ja508449y
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14. 14
  Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew. Chem., Int. Ed. 2011, 50, 9409 DOI: 10.1002/anie.201103327
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15. 15
  Madesclaire, M. Tetrahedron 1986, 42, 5459 DOI: 10.1016/S0040-4020(01)88150-3
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16. 16
  (a) Fuchita, Y.; Hiraki, K.; Kamogawa, Y.; Suenaga, M. J. Chem. Soc., Chem. Commun. 1987, 941 DOI: 10.1039/C39870000941
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17. 17
  (a) Henderson, W. H.; Check, C. T.; Proust, N.; Stambuli, J. P. Org. Lett. 2010, 12, 824 DOI: 10.1021/ol902905w
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  17b
  A Survey of Sulfide Ligands for Allylic C-H Oxidations of Terminal Olefins
  Le, Chi; Kunchithapatham, Kamala; Henderson, William H.; Check, Christopher T.; Stambuli, James P.
  Chemistry - A European Journal (2013), 19 (34), 11153-11157CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Allylic C-H oxidn. of terminal olefins catalyzed by Pd(OAc)2 in presence of sulfide ligands was investigated. Overall, dialkyl sulfides led to greater product formation than aryl alkyl sulfides and diaryl sulfides, which is presumed to emanate from increased basicity on sulfur. E.g., in presence of Pd(OAc)2, benzoquinone, and tetrahydrothiophene, oxidn. of 1-dodecene gave 95% conversion to Me(CH2)8CH:CHCH2OAc Me(CH2)8CH(OAc)CH:CH2, and Me(CH2)8CH2C(OAc):CH2 in a 20:1:1 ratio (E/Z = 10:1). Bidentate sulfide ligands favored formation of the linear allylic acetate, but required higher catalyst loadings and longer reaction times. Simple and inexpensive tetrahydrothiophene provided one of the most active and selective catalysts for allylic oxidn. of terminal olefins.
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18. 18
  Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346 DOI: 10.1021/ja039107n
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  18
  A sulfoxide-promoted, catalytic method for the regioselective synthesis of allylic acetates from monosubstituted olefins via C-H oxidation
  Chen, Mark S.; White, M. Christina
  Journal of the American Chemical Society (2004), 126 (5), 1346-1347CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Sulfoxide ligation to Pd(II) salts is shown to selectively promote C-H oxidn. vs. Wacker oxidn. chem. and to control the regioselectivity in the C-H oxidn. products. A catalytic method for the direct C-H oxidn. of monosubstituted olefins to linear (E)-allylic acetates, in high regio- and stereoselectivities as well as preparatively useful yields, is described. The method, using benzoquinone as the stoichiometric oxidant and a catalytic amt. of Pd(OAc)2 or Pd(O2CCF3)2, was found to be compatible with a wide range of functionalities. Addn. of DMSO was found to be crit. for promoting the C-H oxidn. pathway, with acetic acid alone, or in combination with a diverse range of dielec. media, leading to mixts. favoring Wacker-type oxidn. products. To explore the role of DMSO as a ligand, the bis-sulfoxide Pd(OAc)2 complex I was formed and found to be an effective C-H oxidn. catalyst in the absence of DMSO. I effected a reversal of regioselectivity, favoring the formation of branched allylic acetates.
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19. 19
  (a) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965 DOI: 10.1021/ja910900p
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  19a
  Auxiliary-Assisted Palladium-Catalyzed Arylation and Alkylation of sp2 and sp3 Carbon-Hydrogen Bonds
  Shabashov, Dmitry; Daugulis, Olafs
  Journal of the American Chemical Society (2010), 132 (11), 3965-3972CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  We have developed a method for auxiliary-directed, palladium-catalyzed β-arylation and alkylation of sp3 and sp2 C-H bonds in carboxylic acid derivs. The method employs a carboxylic acid 2-methylthioaniline- or 8-aminoquinoline amide substrate, aryl or alkyl iodide coupling partner, palladium acetate catalyst, and an inorg. base. By employing 2-methylthioaniline auxiliary, selective monoarylation of primary sp3 C-H bonds can be achieved. If arylation of secondary sp3 C-H bonds is desired, 8-aminoquinoline auxiliary may be used. For alkylation of sp3 and sp2 C-H bonds, 8-aminoquinoline auxiliary affords the best results. Some functional group tolerance is obsd. and amino- and hydroxy-acid derivs. can be functionalized. Preliminary mechanistic studies have been performed. A palladacycle intermediate has been isolated, characterized by X-ray crystallog., and its reactions have been studied.
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  (b) Yu, M.; Xie, Y.; Xie, C.; Zhang, Y. Org. Lett. 2012, 14, 2164 DOI: 10.1021/ol3006997
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  19b
  Palladium-Catalyzed C-H Alkenylation of Arenes Using Thioethers as Directing Groups
  Yu, Ming; Xie, Yongju; Xie, Chunsong; Zhang, Yuhong
  Organic Letters (2012), 14 (8), 2164-2167CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  Thioethers have been proven to be reliable directing groups for palladium catalyzed alkenylation of arenes via C-H activation. Mechanistic investigation reveals that the C-H cleavage of arenes is the turnover-limiting step, and an acetate-bridged dinuclear cyclopalladation intermediate is involved. The alkenylated thioethers can be easily removed and transformed into a variety of useful groups.
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  (c) Zhang, X.-S.; Zhu, Q.-L.; Zhang, Y.-F.; Li, Y.-B.; Shi, Z.-J. Chem. - Eur. J. 2013, 19, 11898 DOI: 10.1002/chem.201300829
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  19c
  Controllable Mono-/Dialkenylation of Benzyl Thioethers through Rh-Catalyzed Aryl C-H Activation
  Zhang, Xi-Sha; Zhu, Qi-Lei; Zhang, Yun-Fei; Li, Yan-Bang; Shi, Zhang-Jie
  Chemistry - A European Journal (2013), 19 (36), 11898-11903CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Benzyl thioethers were alkenylated in excellent yields with broad substrate scope and the selectivity (mono- vs. disubstituted product) was controlled by the solvent and ratio of reactants. Sequential alkenylation with two different alkenes was also carried out in a 1-pot process. In addn., the thioether directing group was removed in a 1-pot process with simultaneous hydrogenation of the double bond to give the toluene derivs. Thus, e.g., Rh-catalyzed alkenylation of PhCH2SMe with Et acrylate afforded mono:di adduct ratio (I:II, %) of 79.7:28.3 in MeOH, whereas in tert-butanol the ratio was inverted to 15.1:58.8.
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20. 20
  Wu, C.-Z.; He, C.-Y.; Huang, Y.; Zhang, X. Org. Lett. 2013, 15, 5266 DOI: 10.1021/ol402492s
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21. 21
  Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097 DOI: 10.1021/ol991148u
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  21
  Highly Efficient Pd-Catalyzed Coupling of Arenes with Olefins in the Presence of tert-Butyl Hydroperoxide as Oxidant
  Jia, Chengguo; Lu, Wenjun; Kitamura, Tsugio; Fujiwara, Yuzo
  Organic Letters (1999), 1 (13), 2097-2100CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
  The oxidative coupling of arenes with olefins has been performed efficiently in the presence of catalytic amts. of palladium acetate and benzoquinone with tert-Bu hydroperoxide as the oxidant in up to 280 turnover nos. The catalytic system is esp. active for the coupling of heterocycles such as furans and indole with activated olefins. The reaction is highly regio- and stereoselective, giving trans-olefins predominantly.
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22. 22
  Calculated from the yield of 2 (62%) at 10 min using 0.5 mol% of [Pd]/L14.
  There is no corresponding record for this reference.
23. 23
  (a) Dams, M.; De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew. Chem., Int. Ed. 2003, 42, 3512 DOI: 10.1002/anie.200351524
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  23b
  Catalytic coupling of aromatics and olefins by homogeneous palladium(II) compounds under oxygen
  Shue, Robert S.
  Journal of the Chemical Society [Section] D: Chemical Communications (1971), (23), 1510-11CODEN: CCJDAO; ISSN:0577-6171.
  Benzene and PhCl coupled to 5 olefins under mild O pressure in the presence of the homogenous catalysts Pd(OAc)2, Pd(OPr)2, or Pd(OBz)2; e.g. C2H4 reacted with benzene contg. Pd(OAc)2 and under O (300 psi) to give 648% (based on Pd) styrene in 51/2 hr.
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24. 24
  Zhang, H.-B.; Liu, L.; Chen, Y.-J.; Wang, D.; Li, C.-J. Eur. J. Org. Chem. 2006, 2006, 869 DOI: 10.1002/ejoc.200500863
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25. 25
  (a) Chen, W.-L.; Gao, Y.-R.; Mao, S.; Zhang, Y.-L.; Wang, Y.-F.; Wang, Y.-Q. Org. Lett. 2012, 14, 5920 DOI: 10.1021/ol302840b
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  25a
  Palladium-Catalyzed Intermolecular C3 Alkenylation of Indoles Using Oxygen as the Oxidant
  Chen, Wen-Liang; Gao, Ya-Ru; Mao, Shuai; Zhang, Yan-Lei; Wang, Yu-Fei; Wang, Yong-Qiang
  Organic Letters (2012), 14 (23), 5920-5923CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A general and efficient palladium-catalyzed intermol. direct C3 alkenylation of indoles using oxygen as the oxidant has been developed. The reaction is of complete regio- and stereoselectivity. All products are E-isomers at the C3-position, and no Z-isomers or 2-substituted product can be detected. For example, N-methylindole reacted with Et acrylate in the presence of Pd(OAc)2 and O2 in DMSO to give (E)-Et 3-(1-methyl-1H-indol-3-yl)acrylate in 85% yield.
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  25b
  Dehydrogenative Heck Reaction of Furans and Thiophenes with Styrenes under Mild Conditions and Influence of the Oxidizing Agent on the Reaction Rate
  Vasseur, Alexandre; Muzart, Jacques; Le Bras, Jean
  Chemistry - A European Journal (2011), 17 (45), 12556-12560, S12556/1-S12556/55CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The authors report dehydrogenative Heck reactions (DHRs) of furans and thiophenes with styrenes under mild conditions using Pd(OAc)2 as catalyst and benzoquinone as oxidizing reagent. The authors investigated the influence of solvent on DHR of heterocycles with styrene. The method is compatible with halogenated substances, including brominated thiophenes and styrenes. Compared with the previously reported Rh(III)-catalyzed reactions, this method is advantageous with a wider scope of substrates and cost-effective Pd(II) catalysts. DMSO and benzoquinone have an influence on the efficiency of the process.
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26. 26
  The volatility of 1/1-5-d complicated the use of this substrate pair for the KIE experiment due to difficulty isolating the later isotopologue in pure form.
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27. 27
  Cook, A. K.; Sanford, M. S. J. Am. Chem. Soc. 2015, 137, 3109 DOI: 10.1021/jacs.5b00238
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30. 30
  (a) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586 DOI: 10.1021/ja0176907
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  30a
  Selective Pd-Catalyzed Oxidative Coupling of Anilides with Olefins through C-H Bond Activation at Room Temperature
  Boele, Maarten D. K.; van Strijdonck, Gino P. F.; de Vries, Andre H. M.; Kamer, Paul C. J.; de Vries, Johannes G.; van Leeuwen, Piet W. N. M.
  Journal of the American Chemical Society (2002), 124 (8), 1586-1587CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Using a high-throughput experimentation approach we found a selective and mild Pd-catalyzed oxidative coupling reaction between anilide derivs. and acrylates that occurs through ortho C-H bond activation. The reaction is carried out in an acidic environment and occurs even at room temp. with use of a cheap oxidant (benzoquinone) in yields up to 91%. The benzoquinone possibly also functions as a ligand, stabilizing the catalyst. From the electronic dependence of the reaction and the obsd. kinetic isotope effect (kH/kD = 3) the key step of the catalytic cycle is believed to be electrophilic attack by a [PdOAc]+ complex on the π-system of the arene.
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  (a) Ackerman, L. J.; Sadighi, J. P.; Kurtz, D. M.; Labinger, J. A.; Bercaw, J. E. Organometallics 2003, 22, 3884 DOI: 10.1021/om0303294
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32. 32
  Wang, D.; Stahl, S. S. J. Am. Chem. Soc. 2017, 139, 5704 DOI: 10.1021/jacs.7b01970
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  (a) Tunge, J. A.; Foresee, L. N. Organometallics 2005, 24, 6440 DOI: 10.1021/om0507225
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  Mechanistic Studies of Fujiwara Hydroarylation. C-H Activation versus Electrophilic Aromatic Substitution
  Tunge, Jon A.; Foresee, Lindsay N.
  Organometallics (2005), 24 (26), 6440-6444CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)
  The addn. of the C-H bonds of arenes across alkynes is catalyzed by Pd(OAc)2 in CF3CO2H (Fujiwara hydroarylation). Previously it has been suggested that this transformation proceeds by C-H activation of the arene followed by trans-addn. of a palladium-arene bond across an alkyne. We have investigated the kinetic isotope effects of intramol. hydroarylation with deuterated arene substrates and found that catalytic hydroarylation exhibits an inverse KIE. The obsd. inverse isotope effect is not consistent with known KIEs for C-H activation by electrophilic palladium; thus it suggests that the reaction proceeds by electrophilic arom. substitution.
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  33c
  Aromatic substitution of olefins. VI. Arylation of olefins with palladium(II) acetate
  Fujiwara, Yuzo; Noritani, Ichiro; Danno, Sadao; Asano, Ryuzo; Teranishi, Shiichiro
  Journal of the American Chemical Society (1969), 91 (25), 7166-9CODEN: JACSAT; ISSN:0002-7863.
  Olefins react with benzenes to produce aryl-substituted olefins via direct substitution of the aromatic compd. for H on the double bond of the olefin in the presence of Pd salts and reduced Pd metals. The reaction may be made catalytic with respect to the Pd salts by using Cu(OAc)2 or AgOAc and air as reoxidants. The reaction provides an extremely convenient method for the synthesis o f a wide variety of olefinic compds.
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34. 34
  Beck, E.; Gaunt, M. In C–H Activation; Yu, J.-Q.; Shi, Z., Eds.; Springer: Berlin, 2010; Vol. 292, p 85.
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35. 35
  Liégault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047 DOI: 10.1021/jo902515z
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36. 36
  Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848 DOI: 10.1021/ja802533u
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  36
  Analysis of the Concerted Metalation-Deprotonation Mechanism in Palladium-Catalyzed Direct Arylation Across a Broad Range of Aromatic Substrates
  Gorelsky, Serge I.; Lapointe, David; Fagnou, Keith
  Journal of the American Chemical Society (2008), 130 (33), 10848-10849CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The concerted metalation-deprotonation mechanism predicts relative reactivity and regioselectivity for a diverse set of arenes spanning the entire spectrum of known palladium-catalyzed direct arylation coupling partners. An anal. following an active strain model provides a more complete portrayal of the important arene/catalyst parameters leading to a successful coupling. The breadth of arenes whose reactivity can be predicted by the CMD mechanism indicates that it may be far more widespread than previously imagined.
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37. 37
  Pyridine or 4,5-diazafluorenone ligands still generated low 9/10 ratios using 1:1 L/Pd. See Table S5 for these data.
  There is no corresponding record for this reference.
38. 38
  (a) Cho, J.-Y.; Iverson, C. N.; Smith, M. R. J. Am. Chem. Soc. 2000, 122, 12868 DOI: 10.1021/ja0013069
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  38a
  Steric and Chelate Directing Effects in Aromatic Borylation
  Cho, Jian-Yang; Iverson, Carl N.; Smith, Milton R., III
  Journal of the American Chemical Society (2000), 122 (51), 12868-12869CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The title reaction is described. Thus, Cp*Ir(PMe3)(H)(BPin) (1) catalyzed borylation of benzene in the presence of HBPin (pinacolborane) at 120° gave 53% PhBPin. 1 Was generated in situ from the reaction of Cp*Ir(PMe3)(H)2 with HBPin.
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  (b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390 DOI: 10.1021/ja0173019
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  38b
  Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate
  Ishiyama, Tatsuo; Takagi, Jun; Ishida, Kousaku; Miyaura, Norio; Anastasi, Natia R.; Hartwig, John F.
  Journal of the American Chemical Society (2002), 124 (3), 390-391CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The borylation of arenes leads to the formation of synthetically versatile products from unactivated arene reagents. It is reported that Ir(I) precursors in conjunction with bipyridine ligands catalyze in high yields the borylation of arenes under mild conditions. These reactions encompass arenes bearing both electron-withdrawing and electron-donating substituents. The temps. required for the transformation are much lower than those previously reported for direct arene borylation. The combination of [Ir(COE)2Cl]2 and (4,4-di-t-butyl)bipyridine even allows for reaction at room temp. The same catalyst system at 100° provides remarkably high turnover nos. for a hydrocarbon functionalization process. Mechanistic studies show that the reactions involve uncommon, Ir(II) tris-boryl complexes. An example of this type of complex ligated by di-t-butylbipyridine, [Ir(COE)(Bpin)3(4,4'-di-t-Bu-BPY)], was isolated and structurally characterized. It reacted rapidly at room temp. to produce aryl boronate esters in high yields.
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  (c) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R. Science 2002, 295, 305 DOI: 10.1126/science.1067074
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  38c
  Remarkably selective iridium catalysts for the elaboration of aromatic C-H bonds
  Cho, Jian-Yang; Tse, Man Kin; Holmes, Daniel; Maleczka, Robert E., Jr.; Smith, Milton R., III
  Science (Washington, DC, United States) (2002), 295 (5553), 305-308CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Arylboron compds. have intriguing properties and are important building blocks for chem. synthesis. A family of Ir catalysts (IndIr(COD), (η6-mesitylene)Ir(BPin)3 (4; HBPin = pinacolborane)) now enables the direct synthesis of arylboron compds. from arom. hydrocarbons and boranes under solventless conditions. For example, a 98% yield of PhBPin was obtained in 15 h at 150° from benzene and HBPin (16:1 ratio) in the presence of 4 and PMe3. The Ir catalysts are highly selective for C-H activation and do not interfere with subsequent in situ transformations, including Pd-mediated cross-couplings with aryl halides (e.g. 80% 3,5-dichloro-3'-methylbiphenyl). By virtue of their favorable activities and exceptional selectivities, these Ir catalysts impart the synthetic versatility of arylboron reagents to C-H bonds in arom. and heteroarom. hydrocarbons.
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  (d) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890 DOI: 10.1021/cr900206p
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  38d
  C-H Activation for the Construction of C-B Bonds
  Mkhalid, Ibraheem A. I.; Barnard, Jonathan H.; Marder, Todd B.; Murphy, Jaclyn M.; Hartwig, John F.
  Chemical Reviews (Washington, DC, United States) (2010), 110 (2), 890-931CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review.
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39. 39
  (a) Cheng, C.; Hartwig, J. F. Science 2014, 343, 853 DOI: 10.1126/science.1248042
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  39a
  Rhodium-Catalyzed Intermolecular C-H Silylation of Arenes with High Steric Regiocontrol
  Cheng, Chen; Hartwig, John F.
  Science (Washington, DC, United States) (2014), 343 (6173), 853-857CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Regioselective C-H functionalization of arenes has widespread applications in synthetic chem. The regioselectivity of these reactions is often controlled by directing groups or steric hindrance ortho to a potential reaction site. Here, authors report a catalytic intermol. C-H silylation of unactivated arenes that manifests very high regioselectivity through steric effects of substituents meta to a potential site of reactivity. The silyl moiety can be further functionalized under mild conditions but is also inert toward many common org. transformations, rendering the silylarene products useful building blocks. The remote steric effect that we observe results from the steric properties of both the rhodium catalyst and the silane.
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  (b) Cheng, C.; Hartwig, J. F. Chem. Rev. 2015, 115, 8946 DOI: 10.1021/cr5006414
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  39b
  Catalytic Silylation of Unactivated C-H Bonds
  Cheng, Chen; Hartwig, John F.
  Chemical Reviews (Washington, DC, United States) (2015), 115 (17), 8946-8975CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  A review. This Review will focus on the catalytic silylation of aryl and alkyl C-H bonds by C-H activation steps.
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40. 40
  (a) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072 DOI: 10.1021/ja0745862
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  40a
  Elements of Regiocontrol in Palladium-Catalyzed Oxidative Arene Cross-Coupling
  Stuart, David R.; Villemure, Elisia; Fagnou, Keith
  Journal of the American Chemical Society (2007), 129 (40), 12072-12073CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  By changing the stoichiometric oxidant and modifying the indole N-substituent in palladium-catalyzed oxidative arene cross-coupling reactions, both C2 and C3 oxidative indole arylation can be achieved in high yield. High regioselectivity can also be achieved with the benzene component, and the use of this methodol. with pyrrole substrates is illustrated. A mechanistic hypothesis for the change in C2/C3 selectivity is advanced.
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  (b) Lapointe, D.; Markiewicz, T.; Whipp, C. J.; Toderian, A.; Fagnou, K. J. Org. Chem. 2011, 76, 749 DOI: 10.1021/jo102081a
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  40b
  Predictable and Site-Selective Functionalization of Poly(hetero)arene Compounds by Palladium Catalysis
  Lapointe, David; Markiewicz, Thomas; Whipp, Christopher J.; Toderian, Amy; Fagnou, Keith
  Journal of Organic Chemistry (2011), 76 (3), 749-759CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The challenge of achieving selective and predictable functionalizations at C-H bonds with complex poly(hetero)arom. substrates was addressed by two different approaches. Site-selectivity can be obtained by applying various reaction conditions that are (hetero)arene specific to substrates that contain indoles, pyridine N-oxide, and polyfluorinated benzenes. An exptl. classification of electron-rich heteroarenes based on their reactivity toward palladium-catalyzed C-H functionalization was established, the result of which correlated well with the order of reactivity predicted by the DFT-calcd. concerted metalation-deprotonation (CMD) pathway. Model substrates contg. two reactive heteroarenes were then reacted under general reaction conditions to demonstrate the applicability this reactivity chart in predicting the regioselectivity of the palladium-catalyzed direct arylation and benzylation reactions.
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41. 41
  (a) Zhang, H.; Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem. - Eur. J. 2011, 17, 9581 DOI: 10.1002/chem.201101300
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  41a
  Palladium-Catalyzed Regioselective Aerobic Oxidative C-H/N-H Carbonylation of Heteroarenes under Base-free Conditions
  Zhang, Hua; Liu, Dong; Chen, Caiyou; Liu, Chao; Lei, Aiwen
  Chemistry - A European Journal (2011), 17 (35), 9581-9585, S9581/1-S9581/50CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An efficient protocol for palladium-catalyzed aerobic oxidative C-H carbonylation of heteroarenes to form a variety of heterocyclic esters using a balloon pressure of CO. was developed. High regioselectivity was obtained and an electrophilic palladation mechanism was proposed. In addn., this oxidative carbonylation catalytic system was also applied in the aerobic N-H carbonylation of N-free indoles to afford various indole carbamates.
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  (b) Jiang, Z.; Zhang, L.; Dong, C.; Cai, Z.; Tang, W.; Li, H.; Xu, L.; Xiao, J. Adv. Synth. Catal. 2012, 354, 3225 DOI: 10.1002/adsc.201200470
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  41c
  Pd-Catalyzed olefination of furans and thiophenes with allyl esters
  Zhang, Yuexia; Li, Zejiang; Liu, Zhong-Quan
  Organic Letters (2012), 14 (1), 226-229CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A direct Pd(II)-catalyzed olefination of furans and thiophenes with allyl esters is demonstrated. Under the typical conditions, the dehydrogenative Heck coupling reactions of heteroarenes with allylic esters proceeded via a β-H elimination rather than a β-OAc elimination to give the corresponding γ-substituted allylic esters.
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42. 42
  Gupta, R. R.; Kumar, M.; Gupta, V. In Heterocyclic Chemistry: Five-Membered Heterocycles; Springer: Berlin, 1999; Vol. II, p 3.
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43. 43
  Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315 DOI: 10.1126/science.1182512
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  43
  Ligand-Enabled Reactivity and Selectivity in a Synthetically Versatile Aryl C-H Olefination
  Wang, Dong-Hui; Engle, Keary M.; Shi, Bing-Feng; Yu, Jin-Quan
  Science (Washington, DC, United States) (2010), 327 (5963), 315-319CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch together the carbogenic cores of numerous complex org. mols. Given that the position-selective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl carbon-hydrogen (C-H) bonds would obviate the inefficiencies assocd. with generating halide precursors or their equiv. However, methods for carrying out such a reaction have suffered from narrow substrate scope and low positional selectivity. We report an operationally simple, atom-economical, carboxylate-directed Pd(II)-catalyzed C-H olefination reaction with phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atm. pressure as the oxidant. The positional selectivity can be tuned by introducing amino acid derivs. as ligands. We demonstrate the versatility of the method through direct elaboration of com. drug scaffolds and efficient syntheses of 2-tetralone and naphthoic acid natural product cores.
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44. 44
  (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050 DOI: 10.1021/ja043273t
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  44a
  Direct Palladium-Catalyzed C-2 and C-3 Arylation of Indoles: A Mechanistic Rationale for Regioselectivity
  Lane, Benjamin S.; Brown, Meghann A.; Sames, Dalibor
  Journal of the American Chemical Society (2005), 127 (22), 8050-8057CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  We have recently developed palladium-catalyzed methods for direct arylation of indoles (and other azoles) wherein high C-2 selectivity was obsd. for both free (NH)-indole and (NR)-indole. To provide a rationale for the obsd. selectivity ("nonelectrophilic" regioselectivity), mechanistic studies were conducted, using the phenylation of 1-methylindole as a model system. The reaction order was detd. for iodobenzene (zero order), indole (first order), and the catalyst (first order). These kinetic studies, together with the Hammett plot, provided a strong support for the electrophilic palladation pathway. In addn., the kinetic isotope effect (KIEH/D) was detd. for both C-2 and C-3 positions. A surprisingly large value of 1.6 was found for the C-3 position where the substitution does not occur (secondary KIE), while a smaller value of 1.2 was found at C-2 (apparent primary KIE). On the basis of these findings, a mechanistic interpretation is presented that features an electrophilic palladation of indole, accompanied by a 1,2-migration of an intermediate palladium species. This paradigm was used to design new catalytic conditions for the C-3 arylation of indole. In case of free (NH)-indole, regioselectivity of the arylation reaction (C-2 vs. C-3) was achieved by the choice of magnesium base.
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  (b) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172 DOI: 10.1021/ja801767s
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  44b
  Cu(II)-Catalyzed Direct and Site-Selective Arylation of Indoles Under Mild Conditions
  Phipps, Robert J.; Grimster, Neil P.; Gaunt, Matthew J.
  Journal of the American Chemical Society (2008), 130 (26), 8172-8174CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  We have developed a new site-selective Cu(II)-catalyzed C-H bond functionalization process that can selectively arylate indoles at either the C3 or C2 position under mild conditions. The scope of the arylation process is broad and tolerates broad functionality on both the indole and aryl unit, which makes it amenable to further elaboration. The mechanism of the arylation reaction is proposed to proceed via a Cu(III)-aryl species that undergoes initial electrophilic addn. at the C3 position of the indole motif. We speculate that site of indole arylation arises through a migration of the Cu(III)-aryl group from C3 to C2, and this can be controlled by the nature of the group on the nitrogen atom; free (NH)- and N-alkylindoles deliver the C3-arylated product, whereas N-acetylindoles afford the C2 isomer, both with excellent yield and selectivity.
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45. 45
  Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. Beilstein J. Org. Chem. 2016, 12, 1040 DOI: 10.3762/bjoc.12.99
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  45
  Cationic Pd(II)-catalyzed C-H activation, cross-coupling reactions at room temperature: synthetic and mechanistic studies
  Nishikata, Takashi; Abela, Alexander R.; Huang, Shenlin; Lipshutz, Bruce H.
  Beilstein Journal of Organic Chemistry (2016), 12 (), 1040-1064CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  Cationic palladium(II) complexes have been found to be highly reactive towards arom. C-H activation of arylureas at room temp. A com. available catalyst [Pd(MeCN)4](BF4)2 or a nitrile-free cationic palladium(II) complex generated in situ from the reaction of Pd(OAc)2 and HBF4, effectively catalyzes C-H activation/cross-coupling reactions between aryl iodides, arylboronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to be crit. for achieving room temp. conditions, with the urea moiety the most effective in promoting facile coupling reactions at an ortho C-H position. This methodol. has been utilized in a streamlined and efficient synthesis of boscalid, an agent produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mechanistic investigations led to a proposed catalytic cycle involving three steps: (1) C-H activation to generate a cationic palladacycle; (2) reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3) regeneration of the active cationic palladium catalyst. The reaction between a cationic palladium(II) complex and arylurea allowed the formation and isolation of the corresponding palladacycle intermediate, characterized by X-ray anal. Roles of various additives in the stepwise process have also been studied.
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C–H Alkenylation of Heteroarenes: Mechanism, Rate, and Selectivity Changes Enabled by Thioether Ligands

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Abstract

Introduction

Scheme 1

Results and Discussion

Identification of Active Thioether–Pd Catalysts

Figure 1

Figure 2

Figure 3

Mechanistic Experiments

Figure 4

Figure 5

Figure 6

Figure 7

Scheme 2

Anionic Thioether Ligands

Thioether Effects on Site Selectivity

Scheme 3

Scope of DHR Using Thioether–Pd Catalysts

Scheme 4

Conclusion

Supporting Information

Terms & Conditions

Author Information

Acknowledgment

References

Cited By

Abstract

Scheme 1

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Scheme 2

Scheme 3

Scheme 4

References

Supporting Information

Supporting Information

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STEP 1:

STEP 2:

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