A Highly Efficient and Reusable Palladium(II)/Cationic 2,2’-Bipyridyl-Catalyzed Stille Coupling in Water

A water-soluble PdCl2(NH3)2/cationic 2,2′-bipyridyl system was found to be a highly efficient catalyst for Stille coupling of aryl iodides and bromides with organostannanes. The coupling reaction was conducted at 110 °C in water, under aerobic conditions, in the presence of NaHCO3 as a base to afford corresponding Stille coupling products in good to high yields. When aryltributylstannanes were employed, the reactions proceeded smoothly under a very low catalyst loading (as little as 0.0001 mol %). After simple extraction, the residual aqueous phase could be reused in subsequent runs, making this Stille coupling economical. In the case of tetramethylstannane, however, a greater catalyst loading (1 mol %) and the use of tetraethylammonium iodide as a phase-transfer agent were required in order to obtain satisfactory yields.


Optimization of Stille Coupling Conditions
Water-soluble cationic 2,2 -bipyridyl ligand L was synthesized according to our previouslypublished method [58,59]. The catalytic system was prepared by mixing equimolar amounts of PdCl 2 (NH 3 ) 2 and L in water, and then it was stored under air. Stock solutions of this catalytic system were prepared at different concentrations to obtain various catalyst loadings. In order to discover the optimal conditions, the coupling of 4 -iodoacetophenone (1a, 1 mmol) and PhSnBu 3 (2a, 1.2 mmol) in the presence of PdCl 2 (NH 3 ) 2 /L (1 mol %) in water (3 mL), at 110 • C for 0.5 h, was first investigated, and the results are summarized in Table 1. Initially, several commonly-used bases were screened, and it was found that the use of NaHCO 3 provided the Stille coupling product in a 95% yield, which was higher than the yields obtained using other inorganic bases (Entries 1-6). Then, two additional experiments were performed to demonstrate the necessity of water-soluble ligand L. Under the same conditions as Entry 6, only a 32% yield of the cross-coupling product was obtained in the absence of the ligand (Entry 7), and a 35% yield was obtained when L was replaced with neutral 2,2 -bipydryl (Entry 8). These results clearly revealed that use of the water-soluble ligand was crucial in this Stille coupling reaction. When basic aqueous soluble 2,2 -bipyridine-4,4 -dicarboxylic acid was employed as ligand, however, Stille coupling did not occur, hence, 1a and 2a remained intact (Entry 9). Other phenylstannane sources, such as PhSnCl 3 and PhSnMe 3 , were also examined. Although these two reagents furnished 3aa in 90% and 95% yields, respectively (Entries 10 and 11), PhSnBu 3 can be synthesized from the much cheaper ClSnBu 3 ; hence, aryltributylstannanes were applied for the reactions.

Reuse Studies of the Residual Aqueous Solution
We then studied the reusability of the aqueous catalytic system for Stille coupling, which is important from the viewpoints of practical utilization and economics. Coupling of 1a and 2a under the conditions of Entry 6, in Table 1, was performed in order to test the feasibility of this approach (Scheme 2). After completion of the first run, the organic portion was easily separated from the aqueous phase by simple extraction with hexane (3 mL × 3), and 3aa was isolated in a 95% yield using a typical work-up procedure. The residual aqueous solution was then subjected to the next reaction run, charged with the same reactants, 1a and 2a, and NaHCO 3 . It was found that this residual aqueous solution could be reused at least four times, and a 78% isolated yield was reached in the fourth reuse run. In order to know the partitioning of the catalyst in the organic phase, the first run was performed again. After extracting the reaction mixture with hexane, the organic phase was then used for ICP-MASS analysis. It was found that there was no leaching of Pd into the organic phase. Thus, the slight decrease in activity was presumably due to a gradual decay of the catalytic activity. 35% yield was obtained when L was replaced with neutral 2,2′-bipydryl (Entry 8). These results clearly revealed that use of the water-soluble ligand was crucial in this Stille coupling reaction. When basic aqueous soluble 2,2′-bipyridine-4,4′-dicarboxylic acid was employed as ligand, however, Stille coupling did not occur, hence, 1a and 2a remained intact (Entry 9). Other phenylstannane sources, such as PhSnCl3 and PhSnMe3, were also examined. Although these two reagents furnished 3aa in 90% and 95% yields, respectively (Entries 10 and 11), PhSnBu3 can be synthesized from the much cheaper ClSnBu3; hence, aryltributylstannanes were applied for the reactions.

Reuse Studies of the Residual Aqueous Solution
We then studied the reusability of the aqueous catalytic system for Stille coupling, which is important from the viewpoints of practical utilization and economics. Coupling of 1a and 2a under the conditions of Entry 6, in Table 1, was performed in order to test the feasibility of this approach (Scheme 2). After completion of the first run, the organic portion was easily separated from the aqueous phase by simple extraction with hexane (3 mL × 3), and 3aa was isolated in a 95% yield using a typical work-up procedure. The residual aqueous solution was then subjected to the next reaction run, charged with the same reactants, 1a and 2a, and NaHCO3. It was found that this residual aqueous solution could be reused at least four times, and a 78% isolated yield was reached in the fourth reuse run. In order to know the partitioning of the catalyst in the organic phase, the first run was performed again. After extracting the reaction mixture with hexane, the organic phase was then used for ICP-MASS analysis. It was found that there was no leaching of Pd into the organic phase. Thus, the slight decrease in activity was presumably due to a gradual decay of the catalytic activity.

Scope of Substrates and Loading Amounts of Catalyst
Encouraged by the excellent results of the reuse studies of the residual aqueous solution, we then examined the scope of substrates, and attempted to reduce the catalyst loading required ( Table 2). Aryl iodides 1a and 1b with electron-withdrawing groups at the para-position coupled with various aryltributylstannanes 2a-2c under 0.01 mol % catalyst loading, giving the corresponding Stille coupling products at yields between 90% and 98%, in 3 h (Entries 1, 3 and 4, 6, and 8 and 9). Further reduction of the catalyst loading to 0.0001 mol % (1 ppm), and increase of the reaction scale to 10 mmol, resulted in the corresponding Stille coupling products being obtained at yields between 72% and 82%, in 48 h (Entries 2, 5, and 7), and the highest turnover number (TON) achieved was up to 820,000 (Entry 2). Iodobenzene (1c) showed only a slightly lower rate compared with electron-withdrawing 1a and 1b, but still resulted in excellent yields by prolonging the reaction time to 6 h (Entries 10-12). For aryl iodides bearing an electron-donating group at the para-position, 1d and 1e, high yields were isolated in 6 h, with a catalyst loading of 0.01 mol % (Entries 13, 15-17, and 19 and 20). Similarly, in the cases of entries 14 and 18, 59% and 66% yields were obtained, respectively, in 48 h, under 1 ppm catalyst loading, using a reaction scale of 10 mmol (Entries 14 and 18).

Scope of Substrates and Loading Amounts of Catalyst
Encouraged by the excellent results of the reuse studies of the residual aqueous solution, we then examined the scope of substrates, and attempted to reduce the catalyst loading required ( Table 2). Aryl iodides 1a and 1b with electron-withdrawing groups at the para-position coupled with various aryltributylstannanes 2a-2c under 0.01 mol % catalyst loading, giving the corresponding Stille coupling products at yields between 90% and 98%, in 3 h (Entries 1, 3 and 4, 6, and 8 and 9). Further reduction of the catalyst loading to 0.0001 mol % (1 ppm), and increase of the reaction scale to 10 mmol, resulted in the corresponding Stille coupling products being obtained at yields between 72% and 82%, in 48 h (Entries 2, 5, and 7), and the highest turnover number (TON) achieved was up to 820,000 (Entry 2). Iodobenzene (1c) showed only a slightly lower rate compared with electron-withdrawing 1a and 1b, but still resulted in excellent yields by prolonging the reaction time to 6 h (Entries 10-12). For aryl iodides bearing an electron-donating group at the para-position, 1d and 1e, high yields were isolated in 6 h, with a catalyst loading of 0.01 mol % (Entries 13, 15-17, and 19 and 20). Similarly, in the cases of entries 14 and 18, 59% and 66% yields were obtained, respectively, in 48 h, under 1 ppm catalyst loading, using a reaction scale of 10 mmol (Entries 14 and 18). Analogous reactions of cheaper aryl bromides were also investigated ( Table 3). Activated aryl bromides 4a and 4b, were efficiently coupled with 2a-c under conditions identical to those used for aryl iodides; however, a longer reaction time was required (Entries 1-9). A very low catalyst loading could also be applied when employing electron-withdrawing aryl bromides. For example, the coupling of 4a and 2a furnished 3aa in a 70% yield with a 1 ppm catalyst loading in 48 h (Entry 2). In the cases of 4c and electron-donating 4e, the reactions were much slower than those of the iodide analogs. Hence, conduction of the reaction using a 1 mol % catalyst loading and prolongation of the reaction time were necessary in order to obtain satisfactory yields (Entries 10-15). These results indicated that the oxidative addition of a carbon-bromine bond to palladium may be the rate-determining-step in this catalytic cycle. Surprisingly, the reaction rate was dramatically enhanced when deactivated 4-bromophenol (4f) was employed (Entries [16][17][18][19][20]. Compound 4f was soluble in basic aqueous solution, producing 4-bromophenoxide. This aryl bromide then underwent oxidative addition to palladium under homogeneous conditions, making this step much faster than for other water-insoluble aryl bromides. Taking advantage of this water-soluble property, 4f coupled with 2a very smoothly, providing a 56% yield (TON = 560,000) of 3fa under a catalyst loading of only 1 ppm at 110 • C for 48 h (Entry 18).
The utility of this reaction protocol for the formation of Csp 2 -Csp 3 carbon-carbon bonds was also evaluated. As illustrated in Table 4, the coupling of 1a and SnMe 4 , 5, using 1 mol % catalyst loading at 110 • C for 24 h, gave 6a in only a 51% yield (Entry 1). The use of two equivalents of 5 in the reaction was owing to its low boiling point (74-75 • C). In order to improve upon this outcome, a phase-transfer agent was added into the reaction [55][56][57]. The use of tetrabutylammonium bromide (TBAB) and tetrabutylammonium hydroxide (TBAOH) led to the formation of 6a in yields of 63% and 70%, respectively (Entries 2 and 3). It is worth noting that a 91% isolated yield of 6a could be achieved when tetraethylammonium iodide (TEAI) was applied in the reaction system (Entry 4). Thus, 1b coupled with 5 under such conditions afforded 6b in a 78% yield (Entry 5). However, a low product yield was obtained when electron-rich 1e was utilized (Entry 6). Activated aryl bromides 4a and 4b were also coupled with 5, furnishing 6a and 6b in 40% and 31% yields, respectively (Entries 7 and 8).

General Information
Chemicals were purchased from commercial suppliers and were used without further purification. Cationic 2,2 -bipyridyl ligand was prepared according to published procedures [58,59]. Aryltributylstannanes were prepared according to known procedures [64]. All 1 H-and 13 C-NMR spectra were recorded in CDCl 3 or DMSO-d 6 at 25 • C on a Bruker Biospin AG 300 NMR spectrometer (Bruker Co., Faellanden, Switzerland), in which chemical shifts (δ in ppm) were determined with respect to the non-deuterated solvent as a reference ( 1 H-NMR: CHCl 3 at 7.24, non-deuterated DMSO at 2.49 ppm; 13 C-NMR: CDCl 3 at 77.0, DMSO-d 6 at 39.5 ppm). Melting points were recorded using a melting point apparatus, and were uncorrected.

Typical Stille Coupling Procedure
A sealable tube, equipped with a magnetic stirring bar, was charged with aryl halide (1 mmol), organotin (1.2 mmol), NaHCO 3 (2 mmol), and H 2 O (2 mL). In the case of tetramethyltin, the addition of tetraethylammonium iodide (TEAI, 1 mmol) was required. After the addition of PdCl 2 (NH 3 ) 2 /L aqueous solution (1 mL H 2 O; different concentrations were required for various substrate/catalyst ratios), the tube was sealed under air using a Teflon-coated screw cap. The reaction vessel was then placed in an oil bath at 110 • C for the indicated reaction duration (see Tables 2-4). After cooling of the reaction mixture to room temperature, the aqueous solution was extracted with hexane or ethyl acetate; the organic phase was dried over MgSO 4 , and the solvent was then removed under vacuum. Column chromatography on silica gel afforded the desired product (see Supplementary Materials for the copies of NMR spectra). Table 2, Entries 1 and 2, and Table 3 4-(4-Fluorophenyl)benzonitrile (3bb, Table 2, Entry 8 and Table 3 (3cc, Table 2, Entries 12, 17 and 18, and Table 3 4-Fluoro-4 -methoxybiphenyl (3eb, Table 2, Entry 19 and Table 3 (3ec, Table 2, Entry 20 and Table 3

Procedure for Reuse of the Catalytic Aqueous Solution
The reaction was conducted following the procedure described in Section 3.2., and under the reaction conditions shown in Table 1, Entry 6. After the initial reaction, the aqueous reaction mixture was extracted with hexane (3 mL × 3) under vigorous stirring. The organic layer was separated from the aqueous phase by syringe, and the organic product was isolated from the combined organic phase according to a previously-described in Section 3.2. The residual aqueous solution was then charged with 1a, 2a, and NaHCO 3 for the next reaction.

Conclusions
In conclusion, we have proved that the PdCl 2 (NH 3 ) 2 /cationic 2,2 -bipyridyl system is highly efficient and provides a reusable catalyst for Stille couplings. This catalytic system exhibits a high efficiency for the coupling of aryl iodides and activated aryl bromides with various aryltributylstannanes under a very low catalyst loading (1 ppm). This water-compatible catalytic system enables the reaction to be conducted by a very simple procedure, allowing easy separation of the catalytic aqueous solution from the organic products, rendering it very suitable for practical applications.