Metal–ligand cooperation and synergistic palladium catalysis for the dual ligand system [2,2′-bipyridin]-6(1H)–one/PCy₃: milder conditions for the undirected C–H arylation of arenes

Abstract

The use of Pd(OAc)₂ and a mixture of the cooperating ligand [2,2′-bipyridin]-6(1H)–one (bipy-6-OH) and PCy₃ in an optimal mol ratio of Pd/bipy-6-OH/PCy₃ = 1 : 0.5 : 1 leads to a more active system for the non-chelate-assisted direct arylation of simple arenes. The system operates at a temperature 30 °C lower than that for the Pd/bipy-6-OH system, and it is active for aryl chlorides as arylating partners. Mechanistic experiments support the operation of a bimetallic pathway via two connected catalytic cycles: a Pd/PCy₃ system responsible for the oxidative addition and reductive elimination steps and a Pd/bipy-6-OH system that enables C–H activation. Both cycles are connected by a transmetalation step. The phosphine ligand is not directly involved in the C–H activation, but compared to the monoligand system, the occurrence of the bimetallic route changes the nature of the key intermediate species in the C–H activation, favoring this turnover limiting step and the overall reaction rate.

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Introduction

The direct use of arenes as coupling partners in metal-catalyzed C–C bond-forming reactions is a sustainable alternative to the conventional cross-coupling processes.¹ These reactions eliminate the need to use either the main group organometallic reactant or the organic halide (sulfonate)—or even both reagents, saving the previous reaction steps required for their preparation. The direct arylation of arenes is a straightforward example, where the organometallic reactant is substituted by an arene that is converted in a biaryl derivative with an aryl halide as a reaction partner.² However, strong reaction conditions are generally required because a C–H activation step is needed, and it involves the coordination of the arene to the metal and the cleavage of the sluggish C–H bond. This difficulty is more pronounced for non-chelate-assisted (undirected) functionalization of simple arenes,³ where the interaction of the arene with the metal is not facilitated by the presence of a coordinating functional group, the directing group, that anchors the substrate and allows an easier approach of the C–H bond to the metal center. The introduction of directing groups has many advantages in terms of increased reactivity and selectivity.⁴ However, the prefunctionalization of the substrate arene with these groups erodes the step economy and the sustainability of the whole reaction. Recent advances in the use of transient directing groups that can be installed and detached in situ can alleviate this drawback.⁵ In any case, more active catalytic systems that functionalize simple arenes are needed to bring the undirected C–H functionalization closer to the mild conditions of the conventional cross couplings.⁶

The functionalization of simple arenes often relies on the use of metal–ligand cooperation to enable the C–H activation step.^7,8 Ligands containing a basic group that can participate in the concerted metalation deprotonation mechanism have proved useful: N-monoprotected amino acids (MPPA)⁹ and pyridone derivatives, both mono-¹⁰ and bidentate,¹¹ are the most important, and a few examples are presented in Scheme 1. Even with the use of some of these ligands, the palladium-catalyzed direct arylation of simple arenes requires long reaction times and temperatures above 120 °C,¹² except for some specific activated substrates, such as highly fluorinated arenes¹³ or pyridine oxide,¹⁴ which have been carried out at about 110 °C.

Scheme 1 Some examples of cooperating ligands in C–H activation.

The use of a palladium precursor and two different ligands, a so-called dual ligand system, has been used in C–H functionalization reactions, leading to more efficient catalytic systems in some cases.¹⁵ In addition to the cooperating ligand, i.e., a MPAA or a pyridone derivative that enables C–H activation, a second monodentate ligand is added to the mixture. In all the reported cases, the C–H activation step has been proposed to occur in an intermediate complex with both ligands coordinated to the metal (Scheme 2). Thus, van Gemmeren et al. used a combination of an N-monoprotected amino acid and an N-donor heterocyclic ligand, usually a pyridine (Scheme 2a), for more efficient C–H functionalization reactions of simple arenes,¹⁶ such as olefination,¹⁷ cyanation,¹⁸ and alkynylation processes.¹⁹ Yu et al. used a similar approach in directed C(sp³)–H functionalization reactions,²⁰ and a mixture of a chelating pyridone and a monodentate pyridine was employed for the olefination of pyridine (Scheme 2a).²¹ The olefination of arenes using a mixture of a MPAA and a thioether as ligands,²² and the chalcogenation of arenes or the arylation of fluoroolefins with a MPAAs/monodentate pyridine, have also been reported.²³ De Vos's group developed the arylation of heterocycles using a mixture of a pyridone and a phosphine (Scheme 2a). As in all the above-mentioned examples, the authors proposed that both ligands are coordinated to the metal in the key steps of the reaction, and they provided experimental MS evidence of the occurrence of palladium species with both ligands attached to the metal.²⁴

Scheme 2 Dual-ligand approach in C–H functionalization: (a) two ligands/one complex in the C–H activation step; (b) two ligands/two complexes working synergistically (this work).

We report here a palladium catalytic system that uses a combination of a bipyridone and a phosphine ligand and shows higher activity than the cooperating monoligand system (bipyridone). At variance with the examples reported in the literature, the system requires a specific metal-to-ligand ratio that points to a synergistic bimetallic palladium route with two connected catalytic cycles. Each ligand is involved in one catalytic cycle, and they are not simultaneously coordinated to the metal (Scheme 2b).

In contrast to other heterometal combinations, synergistic Pd–Pd catalysis is rare, and only a few examples have been reported,²⁵ even fewer in the realm of C–H activation. Studying the direct arylation of pyridine oxide with the mixture of Pd(OAc)₂ and P^tBu₃ as catalyst system, Hartwig et al. reported a bimetallic mechanism where the metalation of P^tBu₃ led to a palladacycle responsible for the C–H activation step, whereas the oxidative addition of the aryl halide takes place in a palladium–phosphino complex (Scheme 3a).²⁶ Hong et al. observed a similar process using a diimine palladium complex, where the chelating nitrogen-donor ligand is not involved in the C–H activation step; this occurs in the absence of ligand via a CMD mechanism assisted by the carboxylate used as a base (Scheme 3b).²⁷ A bimetallic pathway has also been observed by Stahl et al. in the oxidative coupling of two arenes to give biaryl derivatives.²⁸ The direct arylation reactions in Scheme 3 still required high temperatures and long reaction times. The combination of a cooperating chelating bypiridone and a phosphine shown here affords, by optimization of each ligand role, a more active catalyst system that allows a shift to milder reaction conditions.

Scheme 3 Catalysts for the direct arylation of arenes that operate by a bimetallic mechanism.

Results and discussion

Reaction optimization and arylation examples

The direct arylation of toluene with aryl iodides can be carried out using a Pd-catalyst with [2,2′-bipyridin]-6(1H)–one (bipy-6-OH) as the only ligand at 130 °C, as has been shown previously.^11a,29 The effect of the addition of a phosphine ligand was tested using the coupling between toluene and p-CF₃C₆H₄X (an aryl that allows the easy monitoring of the reaction by ¹⁹F NMR) as a model reaction (eqn (1)). With toluene as a reactant and solvent at 130 °C and using bipy-6-OH as the only ligand, the biaryl derivative is formed in 20% yield after 6 h (Table 1, entry 1; 91% after 24 h, see the ESI†). The use of a combination of the bipyridone ligand and tricyclohexylphosphine has a beneficial effect on the reaction, and the mixture of Pd(OAc)₂ (5 mol%)/bipy-6-OH (2.5 mol%)/PCy₃ (5 mol%) accelerated the reaction, which was complete in 6 h (90% yield vs. 22% in the absence of PCy₃, Table 1, entries 1 and 2). This effect is also observed for the corresponding and less expensive bromoaryl, and a respectable 59% of the coupling product was obtained after 6 h, vs. 16% in absence of PCy₃ (entries 3 and 4, Table 1).

Table 1 Arylation of toluene with p-CF₃C₆H₄X according to eqn (1) using different reaction conditions^a

Entry	L1 ^b (mol %)	L2 ^b (mol %)	X	Solvent	T (°C)	Crude yield, %, (Conv., %), 6 h^c
a Reaction conditions: p-CF3C6H4X (0.34 mmol), Cs2CO3 (0.68 mmol), total volume 3 mL. b L1 = bipy-6-OH; L2 = PCy3. c Crude yields determined by ^19F NMR of the reaction mixture. The reduction of the arylbromide (ArH) and the homocoupling (Ar–Ar) are the observed byproducts. d Data from the literature (ref. 29). e 1/1 volume ratio (mol ratio toluene/ArX = 40 : 1). f Reaction time 3 h. g 96% yield after 24 h. h 33% yield after 24 h.
1^d	5	—	I	Toluene	130	20 (22)
2	2.5	5	I	Toluene	130	90 (100)
3	5	—	Br	Toluene	130	16 (16)
4	2.5	5	Br	Toluene	130	59 (65)
5	2.5	5	Br	Toluene	100	25 (28)
6	2.5	5	Br	Toluene/DMA^e	100	90 (94)^f
7	2.5	5	Br	Toluene/DMA^e	90	42 (44)^g
8	2.5	5	Br	Toluene/DMA^e	80	15 (15)^h

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Other phosphines such as PPh₃ and P^tBu₃ were also tested under these conditions, as well as other Pd precursors, but PCy₃ and Pd(OAc)₂ gave the best results (see Table S1, ESI†). The use of a cosolvent such as DMA or pinacolone accelerates this type of reaction, and this has been shown and studied before.²⁹

Thus, the use of a toluene/DMA mixture allowed the lowering of temperature to 100 °C and the reaction to complete in 3 h (entry 6, Table 1). Excellent yields were obtained at 90 °C after 24 h, (96% yield), but the conversion is too low at 80 °C (entries 7 and 8, Table 1). A lower excess of toluene (mol ratio toluene/ArX = 10 : 1) led to a strong decrease in the yield (29% after 24 h). The rate of the reaction and yield are not affected by the way the precatalyst mixture is prepared. The reactions in Table 1 were carried out by mixing Pd(OAc)₂ and both ligands in the reaction flask. Under the same conditions, the previous independent mixtures (in separate flasks of Pd(OAc)₂/PCy₃ on the one hand and Pd(OAc)₂/bipy-6-OH on the other hand), before addition to the solution of the reactants, gave the same results shown in entry 6, Table 1.

Under the optimum conditions of solvent and temperature (dry DMA as co-solvent and 100 °C, eqn (2)), other ligands and ligand ratios were tested, and the results are presented in Table 2. The absence of PCy₃ or bipy-6-OH results in no C–C cross-coupling product, and aryl bromide is mainly converted into the dehalogenated ArH derivative, so both ligands are necessary under those conditions (entries 1–3, Table 2). The C–H functionalization was not observed for analogous ligands to bipy-6-OH that cannot be involved in metal–ligand cooperation because of the lack of a cooperating pyridone moiety (i.e. bipy) or because, upon coordination, the pyridone oxygen is far from the metal (i.e. bipy-4-OH, eqn (2)) (entries 4 and 5, Table 2).

Table 2 Catalyst screening for the arylation of toluene with p-CF₃C₆H₄Br according to eqn (2) ^a

Entry	Pd(OAc)2 (mol %)	L1 (mol %)	L2 (mol %)	Crude yield, %, (Conv., %), 6 h^b
a Reaction conditions: p-CF3C6H4Br (0.34 mmol), Cs2CO3 (0.68 mmol), dry toluene (1.5 mL), dry DMA (1.5 mL), 100 °C. b Crude yields determined by ^19F NMR of the reaction mixture. The reduction of the arylbromide (ArH) and the homocoupling (Ar–Ar) are the observed byproducts. c After 3 h. d 80–90% yield after 24 h (see ESI†).
1	5	Bipy-6-OH (2.5)	PCy 3 (5)	90 (94)
2	5	Bipy-6-OH (5)	—	0 (100)
3	5	—	PCy3 (10)	0 (100)
4	5	Bipy (2.5)	PCy3 (5)	0 (22)
5	5	Bipy-4-OH (2.5)	PCy3 (5)	0 (0)
6	5	BipyCH2-6-OH (2.5)	PCy3 (5)	3 (10)
7	5	N-Ac-Gly (2.5)	PCy3 (5)	0 (5)
8	5	2-Pyridone (2.5)	PCy3 (5)	3 (12)
9	5	Bipy-6-OH (2.5)	PPh3 (5)	38 (45)
10	5	Bipy-6-OH (2.5)	P^tBu3 (5)	4 (9)
11	5	Bipy-6-OH (2.5)	XPhos (5)	80 (85)
12	5	Bipy-6-OH (2.5)	(PCy 3 H)BF 4 (5)	93 (97)
13	5	Bipy-6-OH (5)	PCy3 (5)	78 (84)^c
14	5	Bipy-6-OH (5)	PCy3 (10)	31 (40)^d
15	5	Bipy-6-OH (2.5)	PCy3 (7.5)	46 (54)^d
16	5	Bipy-6-OH (2.5)	PCy3 (2.5)	35 (38)^d
17	2.5	Bipy-6-OH (2.5)	[Pd(PCy3)2] (2.5)	92 (95)
18	2.5	Bipy-6-OH (2.5)	1 (2.5)	72 (75)
19	2.5	Bipy-6-OH (2.5)	2 (1.25)	27 (35)^d
20	2.5	Bipy-6-OH (2.5)	2 (1.25) (PCy3H)BF4 (1.25)	98 (98)^c

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Modifications in the bipy scaffold resulted in a loss of activity (entry 6, Table 2). MPAA-type ligands and the monodentate 2-pyridone were also tried, but they gave no coupling product (entries 7 and 8, Table 2). Different phosphines were tested: PPh₃ and P^tBu₃ led to moderate or low yields; however, XPhos produced similar results to PCy₃ but in longer reaction times (entries 9–11, Table 2). Thus, bulky and electron-donating phosphines are adequate for this dual system; the inability of P^tBu₃ to accelerate the reaction might be related to its known ability to form P–C palladacycles, which are not active under the reaction conditions used here.²⁶ Tricyclohexylphosphonium tetrafluoroborate, less sensitive than PCy₃ and easily deprotonated under the reaction conditions, also gave excellent yields (entry 12, Table 2). Different ligand concentrations were also tested: a 5 mol% of bipy-6-OH has a small effect on the reaction rate and yield; however, increasing or decreasing the molar ratio of PCy₃ results in lower rates (entries 13–16, Table 2). In these cases, the reactions need longer times for completion, but good yields (80–90%) were obtained after 24 h.

We decided to test the reaction using preformed palladium complexes with coordinated PCy₃. Thus, the mixture Pd(OAc)₂ + bipy-6-OH was combined with the corresponding palladium phosphino complex. These complexes could be formed under catalytic conditions and even be involved as reaction intermediates. The Pd(0) derivative [Pd(PCy₃)], as well as the Pd(II) complex 1, led to excellent yields of the arylated toluene but in longer reaction times than the analogous experiment using the free phosphine (6 h, entries 17 and 18 vs. 3 h for entry 1, Table 2). The dimeric palladium complex 2 was also tested. In this case, only one PCy₃ is coordinated to each palladium, and the effective amount of phosphine added is half that in the experiments above (entry 19, Table 2). Longer reaction times (24 h) are needed to get full conversion and good yield (87%). A fine tuning of the amount of phosphine present along with the preformed complex 2 to a final effective ratio Pd/bipy-6-OH/PCy₃ = 1 : 0.5 : 0.75, as shown in entry 20, Table 2, restored the rate and yield observed under the best conditions of entry 1, Table 2.

The direct arylation of toluene using this catalyst system can be extended to other aryl bromides as coupling partners (Scheme 4). Electron-donating or electron-withdrawing functional groups can be present in the aryl halide (3aa–3ae, Scheme 4). Longer reaction times were used to ensure the complete conversion of the reactants when the reaction could not be followed by NMR of the crude mixture. The arylation of toluene is not regioselective, and a mixture of three isomers (ortho, meta and para) was obtained in all cases, with no strong preference for any position after considering the statistical factor. p-Bromobenzonitrile and p-bromobenzoic acid were also tested, but they did not lead to the cross-coupling product. Although electronically similar to other aryl bromides tested, the coordination ability of the substituent, specially the carboxylate moiety expected under catalytic conditions, may influence the reaction outcome. The ortho substitution in aryl bromide disfavored the reaction, and only 25% of a mixture of isomeric coupling products was obtained when o-CF₃C₆H₄Br was reacted with toluene.

Scheme 4 Direct arylation of different arenes with the Pd(OAc)₂/bipy-6-OH/PCy₃ catalyst system.

Interestingly, the reaction also works for aryl chlorides, which bear both electron-donating and electron-withdrawing groups (Scheme 4). This is remarkable since aryl chlorides are rarely active in direct arylation reactions of simple arenes with no directing groups.^12a,30 As a result, the reaction of p-bromochlorobenzene with toluene as arene gave a mixture of mono- and ditolyl products.

Different arenes were also tested. Ethyl benzoate, trifluorotoluene, and N,N-dimethylaniline gave moderate to good yields of the biaryl, the meta isomer being the major product (3ca, 3ef, 3ha, Scheme 4). The reaction is completely meta regioselective for pyridine (3ka). On the other hand, when anisole and fluorobenzene were reacted, the ortho biaryl product was preferred (3da, 3ga). There is no clear correlation between the electronic properties of the arene and the regioselectivity of the reaction. The preference of pyridine for arylation in the meta position has been observed before,^11a,31 as well as the ortho substitution for fluorinated arenes.³² In a few cases, good results were obtained using just 10 equivalents of the arene (anisole, pyridine).

The C–H arylation did not take place with aniline as the arene, and the competitive C–N coupling product was obtained as the only product (amination reaction), in sharp contrast with the catalytic system with bipy-6-OH as the only ligand, which is capable of selectively producing ortho-arylated unprotected anilines.³³

Mechanistic experiments

In order to shed light into the reaction mechanism, several experiments were carried out. First of all, we studied the species formed from the mixture of Pd(OAc)₂ and PCy₃. We observed the coordination of two phosphines to palladium acetate resulting in the complex [Pd(OAc)₂(PCy₃)₂] as well as [Pd(PCy₃)₂] with the concomitant oxidation of one phosphine (eqn (3) and Fig. S1, ESI†).³⁴ Therefore, Pd(0) species can be easily formed from the precatalytic mixture, consuming some of the phosphine added, which acts as a reducing agent. This is consistent with the preformed complex [Pd(PCy₃)₂] also being efficient in the catalytic reaction (entry 17, Table 2).

Kinetic experiments were carried out using the reaction between toluene and p-CF₃-C₆H₄Br as a model (eqn (4)). Using the variable time normalization analysis (VTNA) reported by Burés,³⁵ the results showed a first-order dependence on palladium in a concentration range of 2.8–5.6 mM (Fig. 1). The use of much lower catalyst concentrations led to a very slow reaction, so the hypothetical change in catalyst order from one to two, sometimes observed in some bimetallic processes at very low catalyst concentrations,^27,28 was not found. A zero-order dependence on the concentration of the aryl bromide or aryl chloride was observed (see ESI, section 1.5.2†). The kinetic isotope effect was determined, and large values were found for both p-CF₃-C₆H₄Br (KIE = 4.0 ± 0.5) and p-CF₃-C₆H₄Cl (KIE = 3.5 ± 0.3) when two separate experiments were carried out using toluene and toluene-d₈, consistent with C–H activation being the turnover limiting step (eqn (4) and section 1.5.1, ESI†).

Fig. 1 Plots derived from the variable time normalization analysis (VTNA). Overlay of plots gives the order in the catalyst (power value in abscissa axis). [Cat] = Pd(OAc)₂/0.5 bipy-6-OH/PCy₃; the given concentration corresponds to the Pd precursor. See the ESI for details (section 1.5.2).†

The mechanistic scheme for this dual system has to explain the advantage of both ligands and account for the fact that the optimal metal-to-ligand mol ratio is Pd/bipy-6-OH/PCy₃ = 1 : 0.5 : 1. Moreover, considering the reduction to Pd(0) mentioned above, the actual phosphine amount present under catalytic conditions can be smaller. Also, the kinetic experiments show that the C–H activation step is turnover limiting and that the C–H cleavage is assisted by the cooperating bipy-6-O (cf. entries 1 and 3–5, Table 2). The dual system is active for aryl chlorides, whereas the monoligand (bipy-6-OH) system is not, even at the higher temperature used for the reaction (130 °C). This points to the involvement of PCy₃ in the oxidative addition step.

The plausible mechanistic pathway is represented in Scheme 5. It shows a bimetallic process through two different palladium complexes acting in a synergistic way: on one cycle, PCy₃ is coordinated to half of the palladium centers and on the other, a bipy-6-OH-containing complex. The oxidative addition of aryl bromide occurs on the phosphine complex. Meanwhile, the coordination and C–H activation of toluene takes place in the bipy-6-OH complex. After deprotonation of the ligand, which easily occurs in the presence of Cs₂CO₃, a transmetalation step between both metal centers places the organic groups coordinated to a phosphine complex that would undergo the reductive elimination step, leading to the final product and the Pd(0) complex that reenters the catalytic cycle.

Scheme 5 Reaction pathway for the Pd/bipy-6-OH/PCy₃ dual ligand system.

We performed some independent stoichiometric experiments in order to probe this proposal. Ligand exchange experiments were carried out first, as shown in Scheme 6. We used isolable, well-defined model derivatives that show analogies to the complexes formed after the C–H activation process (complexes 4 and 6) or as a result of the oxidative addition of the aryl halide (complex 1). Complex 4, as a model complex with a coordinated neutral ligand bipy-6-OH, was reacted with 2 equivalents of PCy₃ in the solvent mixture used in the catalytic experiments (toluene/DMA, 1 : 1 v/v). A complex with two coordinated PCy₃ (5) and free bipy-6-OH was formed after a few minutes at room temperature (Scheme 6a and Fig. S3–S7, ESI†).

Scheme 6 Ligand exchange experiments.

The same experiment was carried out using the preformed complex 6, where the coordinating ligand is deprotonated and monoanionic (bipy-6-O). It has been shown previously that the coordination ability of the ligand is better when it is deprotonated.^11a One hour after the addition of phosphine at room temperature, the formation of a new complex was observed, which we tentatively assigned to complex 7 (Scheme 6b). The reaction evolved to the formation of complex 5 after heating the mixture at 100 °C for 30 min (Fig. S8–S10, ESI†). This shows that the substitution of the bipy-6-O by PCy₃ is more difficult than in the case of bipy-6-OH; however, it is occurring under the catalytic conditions. The reverse reaction, the substitution of a coordinated PCy₃ by the bipyridone ligand, was also tested. Bipy-6-OH was added to complex 1 in toluene/DMA (1 : 1), and no changes in the reaction mixture were observed. The addition of cesium carbonate to deprotonate the ligand led to the same results both at room temperature and at 100 °C (Scheme 6c and Fig. S11, ESI†). These experiments clearly show that the coordination ability of the ligands present in the catalysis follows the trend PCy₃ > bipy-6-O > bipy-6-OH. Thus, an excess of phosphine will have a detrimental effect in the reaction by coordinating to palladium preferentially and decreasing the concentration of the bipy-6-O complexes, responsible for the turnover limiting step. This is observed in the catalytic experiments (cf. entries 1, 15 and 13, 14 in Table 2). When an excess of bipy-6-OH is added, the relative concentration of both types of complexes is not altered significantly, and the effect on the reaction rate is not important (cf. entries 1 and 13, Table 2).

Both synergistic catalytic cycles in Scheme 5 are connected by a transmetalation step, and the feasibility of the aryl exchange between palladium centers was tested by using two model complexes for both interconnecting cycles. The bipy-6-O complex 8 was prepared in situ by bromide abstraction and deprotonation of 4 using silver carbonate. After filtration of the insoluble silver byproducts, complex 1 was added to the solution of 8 and heated at 100 °C. The coupling product C₆F₅-C₆H₄-p-CF₃ was clearly observed by ¹⁹F NMR (14%, referring to the total amount of pentafluorophenyl species) along with [PdBr(C₆F₅)(PCy₃)₂] (5) as a result of the substitution of the bipy-6-O ligand by the free phosphine generated in the decomposition reaction (Scheme 7a and Fig. S12 in the ESI†).

Scheme 7 Transmetalation experiments.

A fraction of the added phosphine in the catalysis is consumed in the reduction of Pd(OAc)₂ to Pd(0), as shown in the experiment in eqn (3); because of this, the actual amount of PCy₃ under catalytic conditions would lead to a phosphine complex with a ratio of PCy₃/Pd < 2. Therefore, the palladium complex with only one coordinated PCy₃ (2) was tested as the transmetalation partner of 8. The experiment was done in the same way as mentioned above, and complex 2 was added to the in situ generated 8, then the mixture was heated at 100 °C. After 3 h, 48% of the coupling product was formed (Scheme 7b and Fig. S13, ESI†). The addition of cesium carbonate (also present in the catalytic reactions) has no influence in the amount of C₆F₅-C₆H₄-p-CF₃ obtained (45%). These experiments show that a transmetalation step between a bipy-6-O palladium complex and a phosphine-containing Pd-derivative is possible, and it is a plausible elementary step in the catalytic cycle. An excess of phosphine disfavors this process, which is more efficient for monophosphine derivative 2, and this contributes to the slow rate observed for the catalytic reactions upon the addition of higher amounts of phosphine (cf. entries 1, 15 and 13, 14 in Table 2). The inverse dependence of the transmetalation rate on the concentration of the ligand has been studied for other metal combinations such as Au/Pd or Sn/Pd in the context of Stille couplings.^36–38

The nature of the intermediates in the C–H activation

When this dual bipy-6-OH/PCy₃ catalytic system is compared to that enabled by the cooperating bipy-6-OH only, there are some differences that are worth mentioning. The bipy-6-OH-only system shows no significant differences in reactivity for arenes with electron-withdrawing or electron-donating groups, and the regioselectivity observed favors the meta isomer in all cases.²⁹ In contrast, the dual system showed an effect of the electronic properties of the arene in the reaction rate as determined by the monitoring of the initial rate of the direct arylation of toluene, ethyl benzoate and anisole with p-CF₃-C₆H₄Br. The k_obs for each experiment are presented in Table 3; they show that the reaction is faster for arenes with electron-donating groups (anisole) than for arenes with electron-withdrawing groups (ethyl benzoate). In the former case, the ortho/para selectivity is favored. These data point to more electrophilic palladium intermediates involved in the C–H activation step for the dual system.

Table 3 Rate constants for the arylation of arenes with different electronic properties with p-CF₃-C₆H₄Br ^a

Arene	Product	k obs (M min^−1)
a Reaction conditions shown in entry 1, Table 2.
Anisole	p-CF3-C6H4-C6H4(OMe)	3.6 ± 0.3 × 10^−4
Toluene	p-CF3-C6H4-C6H4Me	2.7 ± 0.1 × 10^−4
Ethyl benzoate	p-CF3-C6H4-C6H4CO2Et	7.3 ± 0.7 × 10^−5

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When bipy-6-OH is used as the only ligand, the oxidative addition of the aryl halide leads to aryl palladium intermediates such as c4–c5 in Fig. 2, where the C–H activation takes place as has been tested experimentally in model complexes.^11a,29 In the dual system, this elementary step would happen in a palladium complex with the bipy-6-O coordinated, which is responsible for the C–H bond activation, and for example, an acetate (c2, Fig. 2a) instead of the more electron-rich complex c5 with an aryl group that is involved in the monoligand catalytic cycle (Fig. 2b). DFT calculations of the C–H activation step on a simple model were carried out using the M06 functional and including solvation in the optimizations through the SMD implicit solvent method (DMA) at the experimental temperature (100 °C, see computational details in the ESI†). A total ΔΔG^‡ of 26.9 kcal mol⁻¹ was found viac2 (Fig. 2a). The calculated ΔΔG^‡ for the C–H activation via intermediate c5 was found to be higher (28.4 kcal mol⁻¹, Fig. 2b). This accounts for the difference in activity of both systems.³⁹ The intermediate complex c2 with a coordinated acetate is the most plausible intermediate vs. a bromide-ligated derivative [Pd(bipy-6-O)Br(toluene)] since, given the higher solubility of cesium acetate vs. cesium bromide in the solvent used, the equilibrium c1–c2 is expected to be less disfavored when CsBr is formed. A hypothetical C–H activation in a cationic complex with both bipy-6-O and PCy₃ coordinated to palladium was also calculated, but the total ΔΔG^‡ found rises to 37.2 kcal mol⁻¹, which makes the involvement of such species unlikely (Fig. 2c).

Fig. 2 DFT profiles for the C–H activation in: (a) the dual bipy-6-OH/PCy₃ catalytic system; (b) the catalytic system that uses bipy-6-OH only; (c) a complex with both bipy-6-O and phosphine ligands coordinated to palladium. Energies in kcal mol⁻¹.

Comparing both transition states in Fig. 2a and b, it can be seen that the C–H and C–Pd bond distances for TS c2–c3 are slightly shorter than those in TS c4–c5, indicating that the mechanism for C–H activation has an electrophilic CMD character (eCMD, also known as BIES, base-assisted internal electrophilic substitution),^40,41 where the transition state is characterized by more advanced metal–carbon bonding and less C–H bond cleavage, as discussed by Wang and Carrow.⁴¹ This is in agreement with the higher rate observed for electron-rich arenes.

Thus, because the oxidative addition step is happening in a phosphine complex and not in the bipy-6-O complex (Scheme 5), the nature of the intermediates in the turnover limiting C–H activation step is modified, lowering the overall barrier of the reaction and making the whole system more active.

Conclusions

The mixture of a cooperating bipyridone ligand, capable of assisting the C–H activation step (bipy-6-OH), and a phosphine (PCy₃) in combination with Pd(OAc)₂ in a suitable mol ratio forms a very active catalyst for the challenging direct arylation of simple arenes. The dual ligand combination is more active than the monoligand Pd/bipy-6-OH catalyst, and the reactions can be carried out under milder conditions (short reaction times and a decrease in temperature by 30 °C). Besides the common aryl iodides or bromides, the system is also capable of arylating simple arenes using aryl chlorides. This expands the utility of this reaction to a wider range of reactants.

The increase in activity of the dual system occurs by a novel combined metal–ligand cooperation (MLC) for C–H activation and a synergistic Pd–Pd mechanism. Two catalytic cycles operate: (a) a Pd/PCy₃ system where the ArX oxidative addition and the biaryl reductive elimination take place, and (b) a Pd/bipy-6-OH system where the C–H activation occurs via MLC with no involvement of the phosphine ligand. Both cycles are connected by transmetalation of an aryl group from one Pd to another Pd center (Scheme 5). The presence of the phosphino palladium species acts in fact as a Pd-aryl reservoir and, as a result, a change in the nature of the species responsible for the C–H activation of the arene occurs. This species bears a more electrophilic metal center and leads to a lower barrier for C–H activation, the turnover limiting step, producing an overall acceleration effect. Thus, the beneficial effect of the additional ligand is not a direct involvement in the turnover limiting step of the reaction via coordination to the key intermediate, but the opening of a different pathway which indirectly influences the nature of the intermediate where the C–H cleavage takes place.

Experimental

General considerations

¹H, ¹³C{¹H}, ³¹P{¹H} and ¹⁹F NMR spectra were recorded on Agilent MR-500, Agilent MR-400 or Bruker AV-400 spectrometers at the LTI/UVa. Chemical shifts (in δ units, ppm) were referenced to SiMe₄ (¹H and ¹³C), CFCl₃ (¹⁹F) and H₃PO₄ (85%, ³¹P). The spectral data were recorded at 298 K unless otherwise noted. HRMS analyses were carried out on a Bruker Maxis Impact mass spectrometer at the LTI/UVa. Elemental analyses were carried out in a Thermo Scientific FLASH 2000 microanalyzer (at the Parque Científico Tecnológico/UBU).

Solvents were distilled from appropriate drying agents under nitrogen and stored over 3 Å or 4 Å molecular sieves (toluene) or used directly from storage with the drying agent (anisole, ethyl benzoate, α,α,α-trifluorotoluene, fluorobenzene and N,N-dimethylaniline). DMA, pinacolone, toluene-d₈ and pyridine were purchased as anhydrous and stored under nitrogen over 3 Å or 4 Å molecular sieves. In the case of DMA, used as co-solvent in the catalytic reactions, the drying procedure was as follows: it was stored over molecular sieves for a week and then transferred to a flask with freshly activated molecular sieves and kept for another week prior to use.

The haloaryl derivatives, cesium carbonate, palladium acetate, PR₃ (R = Cy, Ph, ^tBu), (PCy₃H)BF₄, X-Phos, 2,2′-bipyridine, N-acetylglycine, and 2-pyridone are commercially available and were purchased and used as received unless otherwise noted. [2,2′-Bipyridin]-6(1H)-one (bipy-6-OH),^11a [2,2′-bipyridin]-4(1H)-one (bipy-4-OH),^11a [Pd(bipy-6-OH)Br(C₆F₅)] (4),^11a (NBu₄)[Pd(bipy-6-O)Br(C₆F₅)] (6),^11a [Pd(C₆H₄-p-CF₃)I(TMEDA)],⁴² and [Pd₂dba₃].CHCl₃,⁴³ were prepared according to the procedures in the literature.

Catalytic reactions

General procedure for the direct arylation of arenes. Pd(OAc)₂ (3.8 mg, 0.017 mmol), bipy-6-OH (1.5 mg, 0.0085 mmol) and cesium carbonate (222 mg, 0.68 mmol) were introduced in a Schlenk flask under a nitrogen atmosphere. The corresponding aryl halide (0.34 mmol), PCy₃ (4.7 mg, 0.017 mmol) dissolved in the corresponding arene (1.5 mL) and DMA (1.5 mL) were added to the flask. The mixture was stirred at 100 °C and checked by ¹⁹F NMR at the indicated time. When total conversion was observed, the solvent was evaporated in vacuo, and the organic product was extracted with a mixture of n-hexane (8 mL) and ethyl acetate (2 mL). The extract was filtered through kieselgur and evaporated to dryness. The products were checked by NMR and GC-MS. Crude yields and isomer ratios were determined by ¹⁹F NMR of the crude mixture or ¹H NMR for samples without fluorine.

Synthesis of palladium complexes

[PdBr(C₆H₄-p-CF₃)(PCy₃)₂] (1). [PdBr(C₆H₄-p-CF₃), TMEDA] (76.1 mg, 0.17 mmol) and dry dichloromethane (2 mL) were introduced into a N₂-flushed flask. PCy₃ (95.3 mg, 0.34 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed, and cold Et₂O was added to the residue. A yellow solid appeared. The solid was filtered, washed with cold Et₂O and air dried. Yield: 115.7 mg (76%). ¹H NMR (500.13 MHz, δ, CDCl₃): 7.55 (d, J = 8.3 Hz, 2H, H^meta), 7.16 (d, J = 8.3 Hz, 2H, H^ortho), 2.10–0.96 (m, 66H, H^PCy3). ¹³C{¹H} NMR (125.78 MHz, δ, CDCl₃): 161.9 (C^ipso), 138.2 (C^meta), 124.9 (C^CF3)*, 124.5 (C^para), 122.5 (C^ortho), 34.2 (pseudo-t, ¹J_P–C = 9.6 Hz, CH PCy₃), 30.1 (s, CH₂ PCy₃), 27.6 (pseudo-t, ²J_P–C = 5.2 Hz, CH₂ PCy₃), 26.5 (s, CH₂ PCy₃).¹⁹F NMR (470.168 MHz, δ, CDCl₃): −62.06 (s, CF₃). ³¹P{¹H} NMR (202.31 MHz, δ, CDCl₃): 19.8. *The chemical shift was determined by ¹³C–¹⁹F HSQC. HRMS (ESI-TOF): calcd for C₄₃H₇₀F₃P₂Pd (M − Br)⁺ 811.395, found 811.3946.

[Pd(μ-Br)(C₆H₄-p-CF₃)(PCy₃)]₂ (2). Following a similar synthesis described in the literature,⁴⁴ [Pd(C₆H₄-p-CF₃)(μ-OAc)(PCy₃)]₂ (100 mg, 0.08 mmol) was dissolved in CH₂Cl₂ (1 mL), and NBu₄Br (69 mg, 0.21 mmol) was added to the mixture while stirring. Acetone (10 mL) and water (0.2 mL) were added to the solution. A white solid appeared. The mixture was stirred at room temperature for 3 h. The suspension was filtered, and the solid was washed with water and acetone and air-dried. Yield: 70 mg (67%). ¹H NMR (500.13 MHz, δ, CDCl₃): 7.55 (d, J = 7.6 Hz, 2H, H^ortho), 7.18 (d, J = 7.6 Hz, 2H, H^meta), 2.0–0.93 (m, 33H, H^PCy3). ¹³C{¹H} NMR (125.78 MHz, δ, CDCl₃): 157.4 (C^ipso), 136.3 (C^ortho), 125.2 (C^para)*, 124.8 (C^CF3)*, 122.9 (C^meta), 35.1 (d, J_P–C = 22 Hz, C^ipso, PCy₃), 30 (s, C^meta, PCy₃), 27.4 (d, J_P–C = 11 Hz, C^ortho, PCy₃), 26.3 (s, C^para, PCy₃). ¹⁹F NMR (470.168 MHz, δ, CDCl₃): −61.95 (s, CF₃). ³¹P{¹H} NMR (202.31 MHz, δ, CDCl₃): 37.74. *The chemical shift was determined by ¹³C–¹⁹F HSQC and HMBC. Anal. calc. for C₅₀H₇₄Br₂F₆P₂Pd₂: C, 49.08%; H, 6.10%; found: C, 49.07%; H, 6.11%.

Additional experimental information, characterization and kinetic data, spectra for the compounds and computational details (pdf), as well as cartesian coordinates for the calculated species (xyz file) can be found in the ESI.†

Author contributions

C. P. and M. G. Z. conducted the investigation under A. C. A.'s supervision. A. C. A. wrote the manuscript, and C. P. prepared the ESI.† All authors contributed to the conceptualization of the project and the review and editing of the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the financial support of the Spanish MICIU (AEI, PID2022-142100NB-I00) and the Junta de Castilla y León- FEDER (VA087-18 fellowship to CP), as well as the joint support of the EU/MICINN/JCyL (C17.I01.P01.S21, H₂MetAmo).

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, characterization and kinetic data, selected spectra, computational details and absolute energies of all the optimized structures (PDF). Cartesian coordinates (xyz file). See DOI: https://doi.org/10.1039/d4qo01877j

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