Study of the Individual Steps in the Catalytic Cycle

The independent synthesis of the proposed transmetalation precursor began with the preparation of the oxidative addition complex.113 The oxidative addition of aryl halides employing t-Bu3P has been studied extensively by Hartwig and co-workers.42b The three-

coordinate palladium(II) bromide can be prepared by treating (t-Bu3P)2Pd 58 with an excess of

40v at elevated temperatures. Although this method produces the T-shaped, monomeric complex (t-Bu3P)(4-FC6H4)PdBr (68), the isolated yield is often lower than desired (avg. 30%). The yield

of 58 can be improved by addition of catalytic quantities of t-Bu3P•HBr 69, which has been

butanone at 70 °C in the presence of 3 mol % of 69 results in the formation of 68 which could be isolated in 40-50% yield (Scheme 26).

Scheme 26 (t-Bu3P)2Pd + F Br t-Bu3P.HBr 69 (3 mol %) 2-butanone, 70 °C 45 min Pd Br t-Bu3P 40-50% 58 40v 68 F

4.4.2.2. Displacement of Palladium(II) Bromide Intermediate By Silanolate

Next, the displacement step was simulated by adding an equimolar quantity of K+39– to a solution of 68 in toluene. Inspection of both the 31_{P and} 19_{F NMR spectra of the mixture}

revealed no observable changes of the diagnostic resonances in the spectra. Even after 30 min, only a single species was present that appeared to be the starting complex 68. To establish if, in fact, no reaction had taken place, or if the resonance position of the educt and product are coincident, a systematic titration study was undertaken (Scheme 27).

Scheme 27 Pd Br t-Bu3P + Si O-Cs+ Me Me MeO Cs+39– x equiv. toluene, rt F _Pd O t-Bu3P F Si Me Me OMe 68 70

Accordingly, complex 68 was treated with 0.2 equiv of Cs+39– and immediately upon addition of the silanolate, a new 31_{P NMR resonance was generated (77.0 ppm) in addition to that}

for 68 (-64.5 ppm) (Figure 17). An additional 0.3 equiv of Cs+39– was added to the reaction solution and 68 was completely consumed leaving a single species (77.0 ppm) in the 31P NMR.

The stoichiometry of these experiments suggested that displacement occurs rapidly and the mutual coexistence of the bromide complex 68 and silanolate product resulted in a dimerization. Subsequent addition of 0.5 equiv of Cs+₃₉– _{caused disappearance of the signal at 77.0 ppm with}

concomitant formation of a new signal at 65.4 ppm. This new species was spectroscopically identified as the proposed aryl palladium(II)silanolate complex 70.

Figure 17. 31P NMR of Displacement Step for Cross-Coupling of Arylsilanolates

Ultimately, the structure of adduct 70 was confirmed by isolation and single crystal X-ray analysis (Figure 18).114,115 As hypothesized, compound 70 contains the Pd-O-Si linkage that was proposed for the transmetalation precursor. The bulkiness of the tert-butyl phosphine allows for only one ligand to bind to palladium resulting in a three-coordinate complex with an empty coordination site. The Pd(1)-O(1) bond length (2.02 Å) is similar to those previously observed for palladium(II) silanolates.116 Furthermore, the Si(1)-O(1) bond length is typical for silanolates which suggests that the ligand effect at the palladium center is not as substantial compared to other bisphosphine palladium(II)silanolate complexes (Chapter 6). A weak agostic interaction

Cs+₃₉–

Cs+₃₉–

between one of the H atoms of a t-Bu methyl group and the palladium is noted. In addition, the Pd(1)-O(1)-Si(1) angle of 128.5˚ is considerably more acute compared to other known palladium(II)116 _{and platinum(II)}109 _{silanolates and the nonbonded distance between the silicon-}

bearing ipso carbon and the palladium atom (3.70 Å) hints to a weak interaction that anticipates the transmetalation event.

Pd1 O1 Si1 O2 P1 F1 Pd _O P Si H₃C CH₃ H3C CH3 CH₃ H₃C CH3 H3C H₃C H₃C CH₃ 70 O H3C F

Figure 18. X-ray crystal structure of complex 70. Hydrogens removed for clarity.

4.4.2.3. Transmetalation of Arylsilanolates from an Arylpalladium(II) Silanolate

With the desired arylpalladium(II) silanolate complex in hand, a study of the transmetalation process was initiated. Simply heating complex 70 in toluene at 50 °C resulted in the formation of the biaryl product in 80-90% yields with concomitant formation of PdL2

(Scheme 28).117,118 The thermal transmetalation process followed a first-order decay at 5.0 x 10-4 s-1. Because the starting palladium catalyst has a 2:1 ligand/palladium ratio, the stoichiometric transmetalation was performed in the presence of t-Bu3P to establish if a partial order in ligand

presence of 2 and 5 equiv of t-Bu3P led to a clean reaction with rate constants of 4.7 x 10-4 s-1

and 4.9 x 10-4 s-1, respectively. Thus, the similar rates of thermal reaction at varying concentrations of free phosphine clearly indicate a zeroth order concentration dependence for the ligand. These data suggest that phosphine dissociation is not required for transmetalation and that the arene simply transfers to the open coordination site on palladium directly. These experiments provide further evidence of an unactivated, thermal transmetalation pathway for silicon-based, cross-coupling reactions.

Scheme 28 in situ conditions MeO F 80-90% 70 41v K+39– (25 mM) / toluene / 50 ˚C; kobs = 5.0 x 10-3 s-1 Pd P(t-Bu)3 O F Si Me Me MeO toluene / 50 ˚C; kobs = 5.0 x 10-4 s-1 Pd P(t-Bu)3 Br F 68 K+₃₉–

For these kinetic studies described above, the palladium(II)silanolate complex 70 was generated in situ for ease of manipulation. Because the arylpalladium(II) arylsilanolate complex was generated in situ together with cesium or potassium bromide, the ability for the inorganic salt to serve an activating role could not be discounted. First, to determine if any appreciable amount of the inorganic salt was present in toluene, the solubility of these inorganic salts was determined independently.119 Both CsBr and KBr (> 3 g each separately) were added to boiling toluene (20 mL) and vigorously stirred for ca. 5 min. The mixture was cooled to room temperature and the solids were allowed to settle to the bottom. The supernatant solution was removed (6 mL) using a 22G needle to ensure no solids transferred and added to a oven dried vial. The volatiles were removed in vacuo and no detectable quantity of either CsBr or KBr was found even in 6 mL of a saturated toluene solution. Nonetheless, to ensure that similar rate

constants could be obtained in the absence of the alkali-metal bromide, the reactions were repeated with careful separation of the reaction solution from the inorganic precipitate. The rate constant for the thermal transmetalation removing the inorganic salts was similar to that previously determined, thereby suggesting the effect by the inorganic salt is negligible. However, in a few instances the rapid formation of biaryl products was observed at room temperature. To elucidate the origin of these anomalously fast reactions, complex 70 was treated with K+39– (1.0 equiv) and 41v was formed in excellent yield (>90%) at room temperature! Because the catalytic reaction is necessarily performed with a large excess of silanolate with respect to palladium, a kinetic study was undertaken to compare the rates of transmetalation of these different processes. Therefore, treating 70 with 1.0 equiv of K+39– at 50 °C afforded the biaryl product with a kobs of 5.0 x 10-3 s-1. This observed rate constant corresponds to a 10-fold

increase compared to the thermal process established above. These data suggest that an activation-type pathway via a 10-Si-5 complex may also be operative.

If, in fact, the silanolate is opening a pathway for activated transmetalation, then modulating the nucleophilicity of the arylsilanolate should manifest in an observable change in rate. Thus, when the cesium salt of 39 was employed in combination with 70 at 50 °C, product formation was so fast that the rate could not be measured. To compare the rates of transmetalation using different silanolates, the reaction was instead performed at room temperature (21 °C). Scheme 29 clearly shows that Cs+39– leads to a more rapid consumption of 70 compared to K+39– to afford the unsymmetrical biaryl product. In fact, the rate constant for the Cs+39– induced reaction was 4.5 times larger than that for K+39–. These data suggest that the increased nucleophilicity of the arylsilanolate plays a role in the formation of the 10-Si-5 siliconate intermediate.

Scheme 29 in situ toluene, 21° MeO F MeO Si Me O-M+ Me when M = Cs; kobs = 1.4 x 10-3 s-1 _{M = K; k} obs = 3.1 x 10-4 s-1 70 _41v Pd P(t-Bu)₃ O F Si Me Me MeO

Furthermore, the kinetic dependence on [Cs+₃₉–_{] was determined by comparing the rate}

constants for the reaction in Scheme 29 at 6.6, 12.5 and 25 mM (Figure 19). A positive slope of 1.00 obtained from a log plot of the kobs versus concentration clearly shows a first order

dependence and provides additional support for the activated pathway. Once the palladium(II) silanolate is formed from a fast displacement step, a second molecule of Cs+39– is required to activate the silicon atom toward transmetalation.

Figure 19. First-order decays for the activated transmetalation of 70 at varying concentrations of Cs+39–

4.5. Discussion