Weakly nucleophilic potassium aryltrifluoroborates in palladium-catalyzed Suzuki–Miyaura reactions: relative reactivity of K[4-RC₆F₄BF₃] and the role of silver-assistance in acceleration of transmetallation

Introduction

The palladium-catalyzed reaction of organoboron compounds with C-electrophiles (Suzuki–Miyaura reaction) is one of the most intensively studied processes of the carbon–carbon bond formation. Organoboronic acids, their esters and organotrifluoroborates are partners in these reactions and the choice of the desired reagent depends on the specific requirements in each particular case [1-3]. Organoboron reagents containing an electron-poor organic moiety exhibit a low reactivity under the usual cross-coupling conditions [3-9] and the target products are formed in low yield and/or are contaminated with byproducts.

Reactions of weakly nucleophilic organoboron reagents (alkyl- and cyclopropylboronic acids and esters [10-14], alken-1-ylboronic acids and esters [15,16], some arylboronic acids [17-19], K[CF₂=CFBF₃] [19]) often are accelerated by the addition of stoichiometric amounts of Ag₂O. Initially this phenomenon was reported by Kishi et al. [16] for the cross-coupling of alkenylboronic acids with alkenyl iodides in the presence of Ag₂O and elucidated by formation of AgOH which acts like aqueous KOH or TlOH. Korenaga et al. [20] have studied Pd-catalyzed cross-coupling of C₆F₅B(OH)₂ with aryl halides in the presence of Ag₂O and assumed the generation of a hydroxy–palladium complex with higher ability to transmetallation under the action of the corresponding organoboron reagent than ArPdL₂X. For example, complex trans-C₆F₅Pd(PEt₃)₂OH is formed in the reaction of trans-C₆F₅Pd(PEt₃)₂I with Ag₂O in toluene–water and undergoes transmetallation with 4-MeOC₆H₄B(OH)₂ [21]. The subsequent reductive elimination leads to the corresponding polyfluorobiphenyl. In contrary, the reaction of trans-C₆F₅Pd(PEt₃)₂I with 2,4,6-C₆F₃H₂B(OH)₂ and Ag₂O leads to an unsymmetrical diarylpalladium complex trans-(C₆F₅)Pd(PEt₃)₂(2,4,6-C₆F₃H₂) in 92% yield. The latter is thermally stable and does not produce the cross-coupling product even upon heating in toluene at 100 °C for 24 h [21]. The authors suggested that acceleration of these reactions by silver(I) oxide results in the generation of a hydroxy–palladium complex with a higher ability to transmetallation, to coordinate to the organoboronic acid with the three-coordinated boron atom to ArPdL₂OH and subsequent transmetallation (Scheme 1).

However, some experimental facts indicate the multilateral role of silver(I) compounds Ag_mY in the acceleration of the Suzuki–Miyaura cross-coupling. Beside generation of ArPdL_nOH, Ag_mY may act as a Lewis acid producing complex [RPdL_n][XAg_mY] with a highly electrophilic cation. The reactions often are performed in polar aprotic solvents (MeCN, THF, acetone) and the complexes exist in solutions as solvates [RPdL_n(solv.)][XAg_mY]. Some complexes are much more stable and can be isolated [22,23], although for preparative aims they usually are generated in situ. This approach has been successfully used for arylation of alkenes, alkynes, insertion of CO species [23-31], polyfluoroarenes and thiophenes [32].

The effect of the counterion Y in silver(I) compounds Ag_mY on the rate of the cross-coupling was slightly investigated. For example, the rates of the CO insertion into cationic methylpalladium complex [MePd(PMe₃)₂][XAg_mY] generated from MePd(PMe₃)₂Cl, Ag[BF₄] or Ag[PF₆] in acetone are equal to 23 ∙ 10⁻⁵ and 24 ∙ 10⁻⁵ s⁻¹. The use of AgOTf (11 ∙ 10⁻⁵ s⁻¹) or AgNO₃ (5.9 ∙ 10⁻⁵ s^–1) causes a decrease in the reactivity towards the CO insertion [28,33]. The similar effect of anions Y = BF₄, OTf, PF₆ was observed in the formation of complexes [RPd(PMe₃)₂(solv.)][XAg_mY] and [RPd(PMe₃)(solv.)₂][XAg_mY] [34].

In continuation of systematic research of the Suzuki–Miyaura cross-coupling reaction of weakly nucleophilic organotrifluoroborates we report here the study of the relative reactivity of K[4-RC₆F₄BF₃] in the Pd-catalyzed reactions with some aryl bromides and iodides in the presence of Ag₂O. The borates were chosen as model organoboron reagents because of tuning electronic properties of 4-RC₆F₄ groups with varied R = H, Bu, MeO, EtO, PrO, iPrO, BuO, t-BuO, CH₂=CHCH₂O, PhCH₂O, Ph(CH₂)₂O, PhO, pyrazol-1-yl (Prz), pyrrol-1-yl (Pyr), indol-1-yl (Ind), imidazol-1-yl (Im), and benzamidazol-1-yl (Bim) and the equal steric requirements near reaction site C¹–BF₃. The relative reactivity was estimated (a) from the yield of biphenyl 4-RC₆F₄–Ar vs C₆F₅–Ar and (b) from the rate of consumption of K[4-RC₆F₄BF₃] and compared with the substituent electron parameters (SEP) of the 4-RC₆F₄ group. The efficiency of some other silver(I) compounds (AgNO₃, Ag₂SO₄, Ag[BF₄], and AgF) in the cross-coupling was examined too.

Results

All reactions were carried out under the previously elaborated optimal conditions [35]. The cross-coupling of K[4-RC₆F₄BF₃] (1a–r) with 1-fluoro-3-iodobenzene (2) produces pentafluorobiphenyls 4-(3'-FC₆H₄)C₆F₄R in 80–99% yield (Scheme 2 and Table 1). Pentafluorobiphenyls 4-(4'-FC₆H₄)C₆F₄R were obtained from K[4-RC₆F₄BF₃] and 1-fluoro-4-iodobenzene (3). Notably borates K[4-RC₆F₄BF₃] with R = H (1b), AllylO (1c) and azolides (1n–r) (see Table 1, entries 2, 3, 14–18) give much lower yields of the corresponding biphenyls than K[C₆F₅BF₃] (1a) (Table 1, entry 1) [19].

Potassium 2,3,5,6-tetrafluoropyridyltrifluoroborate (6) exhibits extremely low reactivity toward both 2 and 3 gives the corresponding 4-(3'-fluorophenyl)- (7) and 4-(4'-fluorophenyl)- (8) -2,3,5,6-tetrafluoropyridines with yields no more than 5% (¹⁹F NMR) (Scheme 3). It should be noted that 2,3,5,6-tetrafluoropyridine was not observed in the reaction mixtures in both cases.

The use of the electron-rich C-electrophile, 4-IC₆H₄CH₃ (9), instead of 3 leads to biphenyls 4-(4'-CH₃C₆H₄)C₆F₄R (10c–f,h–p) in 60–80% preparative yields (see Table 2, entries 2–14) while 4-CH₃C₆H₄C₆F₅ (10a) was isolated in 93% yield (see Table 2, entry 1) [19]. Although aryl bromides are less reactive than iodides, the substitution of 4-IC₆H₄CH₃ (9) for 4-BrC₆H₄CH₃ (11) does not affect the yields of the corresponding biphenyls (Scheme 4).

The obtained results show a similar or slightly reduced reactivity of the majority of K[4-RC₆F₄BF₃] (R ≠ F) with respect to salt 1a. Exceptions are borates with R = H (1b), CH₂=CHCH₂O (1c) and azolides (1n–r), which produce cross-coupling products in low to moderate yields because of the side reactions. Highly tolerant borate 6 also gives the product in a low yield, but its conversion is low too. Hence, the data based on an isolated yield of biphenyls 4a–r, 5a–r, or 10a,c–f,h–p are not a convenient measure for the quantitative estimation of the relative reactivity. We hoped to get more accurate data by the concurrent cross-coupling of equimolar mixtures of K[C₆F₅BF₃] (1a) and K[4-RC₆F₄BF₃] (1b–p) with 11. The reactions were carried out over a short period (5–15 min) and the product ratios were determined by analyzing the crude reaction mixtures with ¹⁹F NMR spectroscopy. The relative reactivity was determined as C^rel = C^R / C^F where C^R and C^F are the yield (in mmol) of 4-(4'-CH₃C₆H₄)C₆F₄R from salts 1b–p and 4'-CH₃C₆H₄C₆F₅ from 1a, respectively (Scheme 5, Table 3).

The above experiments were performed using silver(I) oxide. For better understanding the role of Ag⁺ we estimated the relative efficiency of some other silver(I) compounds under identical conditions (Scheme 6) (Table 4).

The presented data demonstrate clearly that AgNO₃, Ag₂SO₄, Ag[BF₄], and AgF salts are less appropriate promotors for the palladium catalyzed cross-coupling than Ag₂O. The significant contribution of the side reactions (hydrodeboration and homo-coupling) results in decreasing yields of 10a and hinders isolation of the desired product (see Table 4).

Discussion

The general concept of the Pd-catalyzed Suzuki–Miyaura (SM) reaction applied to the cross-coupling of K[4-RC₆F₄BF₃] with ArX is presented in Scheme 7.

The first step is the generation of neutral complex ArPdX by the oxidative addition of ArX to Pd(0) species. This step precedes the subsequent transformation of ArPdX and does not influence the reactivity of organoboron partner K[4-RC₆F₄BF₃] as well as its behavior in transmetallation and/or reductive elimination steps. For the further consideration we need to clarify the nature of the active organoboron partner. Despite of many publications [2,6,7,36,37] in this field it is not yet fully understood. For illustration, we refer to two examples. Molander argues for direct transmetallation of ArPdBr by aryltrifluoroborates in aprotic anhydrous THF in the presence of trialkylamine as a base or in alcohols [4]. Alternatively, the Pd-catalyzed cross-coupling of K[ArBF₃] in aqueous THF is proved to proceed through stepwise hydrolysis to produce more reactive [ArBF_n(OH)_3-n]⁻ or ArB(OH)₂ [35,38]. However, special experiments showed that K[C₆F₅BF₃] retards toward K₂CO₃ [39] as well as K₂CO₃ in a mixture with catalytic amounts of Pd(OAc)₂ in refluxing MeOH [19]. Resistance of K[C₆F₅BF₃] (1a) towards K₂CO₃ and Ag₂O in toluene (without palladium catalyst and phosphine ligand) is confirmed by stirring the corresponding suspensions at 100 °C for 10 min. These facts make it possible to reject any transformation of the [BF₃]⁻ moiety before the transmetallation of the palladium-containing intermediate generated in the previous step of the catalytic cycle by K[4-RC₆F₄BF₃]. Potassium carbonate scavenges toluene-soluble acidic impurities formed in the reaction and does not participate in the other steps [19,35].

The boron atom in K[4-RC₆F₄BF₃] is coordinately saturated and transmetallation via transition state A (Scheme 1) is impossible. An alternative pathway is the polarization of the palladium–X bond by Ag⁺ and the generation of complex [ArPdL_n][XAg_mY] with a highly electrophilic cation which is attacked by carbon atom C-1 of K[C₆F₅BF₃] (1a). In toluene salt 1a is consumed within 3 h to give 2,3,4,4’,5,6-hexafluorobiphenyl (5a) in 70–92% yield [19], while in the polar coordinating solvents (DME, DMF) the Ag₂O-assisted cross-coupling of 1a with 3 leads to formation of 5a at unsatisfactory conversions (22–38%) and low yields (10–22%). This indicates that the strong solvation of the Pd atom with DME or DMF reduces electrophilicity of [ArPdL_n][X] as compared with the electrophilicity in the case of weakly coordinating toluene.

K[C₆F₅BF₃] (1a) and Ag_mY are insoluble in toluene and, very likely, the transmetallation proceeds on the surface of the silver(I) compounds. Both the aryltrifluoroborate anion and ArPdL_nX can be adsorbed on the surface of solid Ag_mY due to the interaction with Ag atoms (acidic Lewis centers). This phenomenon causes an increase in the electrophilicity of the Pd atom and bond rearrangement through transition state B to give the diarylpalladium species (Scheme 8). Perhaps, transformations presented in Scheme 8 are parallel, i.e., the transmetallation proceeds simultaneously with polarization of ArPdL_nX.

There is a popular notion that the transmetallation gives both cis- and trans-ArPdL_nAr'. First of them is low stable and undergoes easy reductive elimination to biphenyl. trans-ArPdL_nAr' can react only after transformation to the corresponding cis-isomer [40,41]. Complexes with polyfluorinated aryl groups are highly stable and do not isomerize to the cis-isomer as well as do not form the cross-coupling products. Thus, independently prepared complexes trans-C₆F₅PdL₂(2,4,6-C₆F₃H₂) (L = PEt₃, PMe₂Ph, PMePh₂) do not undergo any changes even after heating in toluene at 100 °C for 24 h [21]. These facts lead to assume either instability of trans-(4-RC₆F₄)PdL₂Ar towards isomerisation to cis-isomer or the direct formation of reactive complex cis-(4-RC₆F₄)PdL₂Ar during the transmetallation with closely related borates K[4-RC₆F₄BF₃] (Scheme 8).

At the next step, cis-(4-RC₆F₄)PdL₂Ar undergoes reductive elimination which includes the carbon–palladium bond cleavage in both 4-RC₆F₄-Pd and Pd-Ar moieties. If the substituent Ar is the same for all cis-diarylpalladium, the rate of the intramolecular transformation from cis-(4-RC₆F₄)PdL₂Ar to 4-RC₆F₄Ar should depend on the specific property of the 4-RC₆F₄ group. It may depend on the substituent electron parameters (SEP), σ_I and σ_R°, of substituent R or 4-RC₆F₄ groups. We compared the relative rates of consumption C^rel (Table 3) of K[4-RC₆F₄BF₃] with σ_I (R) and σ_R° (R) (Table 5) and did not find any correlation between the obtained values.

SEP of the 4-RC₆F₄ groups are not reported as yet except inductive constants σ_I (C₆F₅) [43,45,46] and σ_I (2,3,5,6-C₆F₄H) [43], and resonance constants σ_R° (C₆F₅) [45]. We bridge this gap using a series of biphenyls 4a–r and 5a–r and determine SEP of 4-RC₆F₄ groups using the Taft's method [42]. The ¹⁹F NMR spectra were measured in CHCl₃ (non-polar weakly coordinating solvent) and in toluene (solvent for the present research). The calculated SEP values in both solvents are closely related to one another to indicate no specific intermolecular interaction biphenyl–solvent (Table 6) and obtained results are in agreement with the data by Sheppard for CCl₃F or benzene [45]. When R = H, Bu, or alkoxy group, inductive constants σ_I (4-RC₆F₄) consist of 0.16–0.18. The 4-RC₆F₄ groups with R = F, pyrazol-1-yl, pyrrol-1-yl, indol-1-yl, imidazol-1-yl and benzimidazol-1-yl possess a higher electron-withdrawing effect (σ_I = 0.21 − 0.27) which achieves maximum for the 2,3,5,6-tetrafluoropyridyl group (σ_I = 0.35). Resonance constants σ_R° of all tetrafluoroaryl groups are insignificant and reflect the substantial non-coplanarity of aryl moieties [45].

Unfortunately, the search for possible dependence between the relative rates of consumption of K[4-RC₆F₄BF₃] and SEP of the respective 4-RC₆F₄ group does not show certain correlation.

Conclusion

1. The relative reactivities of K[4-RC₆F₄BF₃] in the Ag(I)-assisted Pd-catalyzed cross-coupling reactions with 3-IC₆H₄F, 4-IC₆H₄F, 4-IC₆H₄CH₃ or 4-BrC₆H₄CH₃ in the presence of P(t-Bu)₃ or PPh₃ (toluene, 100 °C, 8 h) differ negligibly from each other. The same results show the competitive cross-coupling of mixtures of K[4-RC₆F₄BF₃] and K[C₆F₅BF₃] (1:1, mol) with 4-BrC₆H₄CH₃ at a low conversion of borates (<40%). K[2,3,5,6-C₅NF₄BF₃] is extremely weakly nucleophilic and conversion in the cross-coupling product is no more than 5% in 8 h.

2. It is very likely that transmetallation of ArPdL_nX with K[4-RC₆F₄BF₃] proceeds on the surface of the silver(I) compounds (K[4-RC₆F₄BF₃] and Ag_mY are insoluble in toluene). Neutral complex ArPdL_nX is adsorbed on the acidic center (Ag⁺) of the solid surface to form highly reactive complex [ArPdL_n···X···Ag_mY] which facilitates exchange of group BF₃ in K[4-RC₆F₄BF₃] by ArPdL_n and thus accelerates the formation of (4-RC₆F₄)PdL_nAr.

3. Verification of the assumed correlation between reactivity (C^rel) of K[4-RC₆F₄BF₃] and the substituent electron parameters (SEP) (σ_I and σ_R°) as the measure of the electron-withdrawing properties of 4-RC₆F₄ gives an unclear result. Intervals of change of both C^rel (0.6–1.0) and σ_I (0.16–0.27) are too narrow and small experimental errors of measurements may corrupt or mask electronic effect of 4-RC₆F₄ with respect to C₆F₅ group.