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

Summary Small differences in the reactivity of weakly nucleophilic potassium aryltrifluoroborates are revealed in the silver-assisted Pd-catalyzed cross-coupling of K[4-RC6F4BF3] (R = H, Bu, MeO, EtO, PrO, iPrO, BuO, t-BuO, CH2=CHCH2O, PhCH2O, PhCH2CH2O, PhO, F, pyrazol-1-yl, pyrrol-1-yl, and indol-1-yl) with ArX (4-BrC6H4CH3, 4-IC6H4F and 3-IC6H4F). An assumed role of silver(I) compounds AgmY (Y = O, NO3, SO4, BF4, F) consists in polarization of the Pd–X bond in neutral complex ArPdLnX with the generation of the related transition state or formation of [ArPdLn][XAgmY] with a highly electrophilic cation and subsequent transmetallation with the weakly nucleophilic borate. Efficiency of AgmY as a polarizing agent decreases in order Ag2O > AgNO3 ≈ Ag2SO4 > Ag[BF4] > AgF. No clear correlation between the reactivity of K[4-RC6F4BF3] and substituent electron parameters, σI and σR°, of the aryl group 4-RC6F4 was found.


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][2][3]. Organoboron reagents containing an electron-poor organic moiety exhibit a low reactivity under the usual cross-coupling conditions [3][4][5][6][7][8][9] and the target products are formed in low yield and/or are contaminated with byproducts. Reactions of weakly nucleophilic organoboron reagents (alkyland cyclopropylboronic acids and esters [10][11][12][13][14], alken-1ylboronic acids and esters [15,16], some arylboronic acids [17][18][19], K[CF 2 =CFBF 3 ] [19]) often are accelerated by the addition of stoichiometric amounts of Ag 2 O. Initially this phenomenon was reported by Kishi et al. [16] for the cross-coupling of alkenylboronic acids with alkenyl iodides in the presence of Ag 2 O and elucidated by formation of AgOH which acts like aqueous KOH or TlOH. Korenaga et al. [20] have studied Pd-catalyzed cross-coupling of C 6 F 5 B(OH) 2 with aryl halides in the presence of Ag 2 O and assumed the generation of a hydroxy-palladium complex with higher ability to transmetallation under the action of the corresponding organoboron reagent than ArPdL 2 X. For example, complex trans-C 6 F 5 Pd(PEt 3 ) 2 OH is formed in the reaction of trans-C 6 F 5 Pd(PEt 3 ) 2 I with Ag 2 O in toluene-water and undergoes transmetallation with 4-MeOC 6 H 4 B(OH) 2 [21]. The subsequent reductive elimination leads to the corresponding polyfluorobiphenyl. In contrary, the reaction of trans-C 6 F 5 Pd(PEt 3 ) 2 I with 2,4,6-C 6 F 3 H 2 B(OH) 2 and Ag 2 O leads to an unsymmetrical diarylpalladium complex trans-(C 6 F 5 )Pd(PEt 3 ) 2 (2,4,6-C 6 F 3 H 2 ) 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 ArPdL 2 OH and subsequent transmetallation (Scheme 1).
The obtained results show a similar or slightly reduced reactivity of the majority of K[4-RC 6 F 4 BF 3 ] (R ≠ F) with respect to salt 1a. Exceptions are borates with R = H (1b), CH 2 =CHCH 2 O (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 Scheme 4: Synthesis of biphenyls 10a,c-f,h-p.
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[C 6 F 5 BF 3 ] (1a) and K[4-RC 6 F 4 BF 3 ] (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 19 F 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'-CH 3 C 6 H 4 )C 6 F 4 R from salts 1b-p and 4'-CH 3 C 6 H 4 C 6 F 5 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 AgNO 3 , Ag 2 SO 4 , Ag[BF 4 ], and AgF salts are less appropriate promotors for the palladium catalyzed cross-coupling than Ag 2 O. The significant contribution of the side reactions (hydrodeboration and homocoupling) 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-RC 6 F 4 BF 3 ] 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-RC 6 F 4 BF 3 ] 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 crosscoupling of K[ArBF 3 ] 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[C 6 F 5 BF 3 ] retards toward K 2 CO 3 [39] as well as K 2 CO 3 in a mixture with catalytic amounts of Scheme 5: Pd-catalyzed cross-coupling of 1a and salts 1b-p (1:1) with 11 (the results are presented in Table 3 and outlined in the Discussion section).  [19], while in the polar coordinating solvents (DME, DMF) the Ag 2 O-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[C 6 F 5 BF 3 ] (1a) and Ag m Y are insoluble in toluene and, very likely, the transmetallation proceeds on the surface of the silver(I) compounds. Both the aryltrifluoroborate anion and ArPdL n X can be adsorbed on the surface of solid Ag m Y 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 n X.
There is a popular notion that the transmetallation gives both cisand trans-ArPdL n Ar'. First of them is low stable and under-  goes easy reductive elimination to biphenyl. trans-ArPdL n Ar' can react only after transformation to the corresponding cisisomer [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-C 6 F 5 PdL 2 (2,4,6-C 6 F 3 H 2 ) (L = PEt 3 , PMe 2 Ph, PMePh 2 ) 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-RC 6 F 4 )PdL 2 Ar towards isomerisation to cis-isomer or the direct formation of reactive complex cis-(4-RC 6 F 4 )PdL 2 Ar during the transmetallation with closely related borates K[4-RC 6 F 4 BF 3 ] (Scheme 8).
At the next step, cis-(4-RC 6 F 4 )PdL 2 Ar undergoes reductive elimination which includes the carbon-palladium bond cleavage in both 4-RC 6 F 4 -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-RC 6 F 4 )PdL 2 Ar to 4-RC 6 F 4 Ar should depend on the specific property of the 4-RC 6 F 4 group. It may depend on the substituent electron parameters (SEP), σ I and σ R°, of substituent R or 4-RC 6 F 4 groups. We compared the relative rates of consumption C rel (Table 3) of K[4-RC 6 F 4 BF 3 ] with σ I (R) and σ R° (R) ( Table 5) and did not find any correlation between the obtained values.
SEP of the 4-RC 6 F 4 groups are not reported as yet except inductive constants σ I (C 6 F 5 ) [43,45,46] and σ I (2,3,5,6-C 6 F 4 H) [43], and resonance constants σ R° (C 6 F 5 ) [45]. We bridge this gap using a series of biphenyls 4a-r and 5a-r and determine SEP of 4-RC 6 F 4 groups using the Taft's method [42]. The 19 F NMR spectra were measured in CHCl 3 (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 CCl 3 F or benzene [45]. When R = H, Bu, or alkoxy group, inductive constants σ I (4-RC 6    and Ag m Y are insoluble in toluene). Neutral complex ArPdL n X is adsorbed on the acidic center (Ag + ) of the solid surface to form highly reactive complex [ArPdL n ···X···Ag m Y] which facilitates exchange of group BF 3 in K[4-RC 6 F 4 BF 3 ] by ArPdL n and thus accelerates the formation of (4-RC 6 F 4 )PdL n Ar.
3. Verification of the assumed correlation between reactivity (C rel ) of K[4-RC 6 F 4 BF 3 ] and the substituent electron parameters (SEP) (σ I and σ R°) as the measure of the electron-withdrawing properties of 4-RC 6 F 4 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-RC 6 F 4 with respect to C 6 F 5 group.

Supporting Information
Supporting Information File 1 Full experimental details and compound characterization data.