Catalyst shuttling enabled by a thermoresponsive polymeric ligand: facilitating efficient cross-couplings with continuously recyclable ppm levels of palladium† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c9sc02171j

A thermoresponsive polymeric Pd-complex was synthesized, enabling highly efficient cross-couplings and continuous catalyst-recycling flow reactions with ultralow Pd usages.

In this research, a novel polymeric pre-catalyst was synthesized, which was composed of methoxy poly(ethylene glycol) (PEG) linked dicyclohexylphosphine ligand (WePhos) and Pd, which enables a general, efficient and low Pd loading SM coupling via a rapid catalyst transfer between aqueous and toluene phases (Scheme 1). This polymeric complex catalyzed reaction is tolerant of various functional groups as well as (hetero)aromatic rings, and is realized in tandem coupling with high chemoselectivity. Furthermore, taking advantage of the thermoresponsive catalyst shuttling, a continuous catalystrecycling approach based on ow chemistry was developed to streamline scalable SM couplings using down to 10 ppm of Pd.
The lower critical solution temperature (LCST) behaviour of PEG is known in polymer science, [47][48][49][50] with PEGylated materials exhibiting dramatically decreased solubility in water upon heating above the LCST. It was thought that by introducing a PEGylated phosphine ligand, the corresponding Pd complex would display a thermoresponsive solubility in a biphasic system, thereby promoting a reaction in the organic phase and facilitating catalyst recycling simply by phase separation.

Results and discussion
At the beginning of the investigation, to conrm and visualize the shuttling effect, a yellow polymeric compound 1 was synthesized with PEG 5000 (number average molecular weight, M n $ 5000 g mol À1 ) and carboxyferrocene (Fig. 1). When 1 is dissolved in a mixture of water and toluene at 25 C, only the water phase shows yellow coloration, however, upon heating to 90 C, the toluene phase turns yellow within 30 s. The whole process is rapid and completely reversible, clearly exhibiting the thermoresponsive shuttling of a PEG-supported compound between water and organic phases.
Subsequently, the new ligand WePhos 5000 5a was synthesized using a synthetic route illustrated in Scheme 2. Starting from 4-Scheme 1 Ligand design in transition-metal catalyzed cross-coupling. Fig. 1 Optical images of the migration behavior of compound 1 between water and toluene phases in response to temperature.
Scheme 2 Synthetic pathway of WePhos 5000 5a and pre-catalyst 6a; Cy ¼ cyclohexyl group, AcO ¼ acetate group. bromophenol 2, a high overall yield of 83% was obtained for ligand 5a. This compound was air stable, and was characterized using matrix-assisted laser desorption/ionization-time-of-ight (MALDI-TOF) mass spectrometry. As shown in Fig. 2a, a single set of peaks is observed in the MALDI-TOF mass spectrum, and each peak is separated by the molar mass of a single repeating unit in PEG (m/z ¼ 44.05, Fig. 2b). The absolute m/z value was consistent with the calculated molecular weight of 5a. The yintercept of the best-t trend line of m/z versus the number of repeating units indicated the molecular weight of the chain-end group of 5a (Fig. 2c), which was consistent with the expected value. The proton-nuclear magnetic resonance ( 1 H-NMR) analysis 51 also conrmed the chemical structure of WePhos 5000 . Mixing 5a with palladium(II) acetate [Pd(OAc) 2 ] in a 2 : 1 ratio, quantitatively generated pre-catalyst 6a. A peak shi from 1.24 to 45.21 ppm in the 31 P-NMR spectra revealed the successful coordination of phosphine to the Pd II center (Fig. 2d). 52,53 Using the same synthetic method, a series of WePhos ligands were prepared using PEGs of different molecular weights (M n $ 750 g mol À1 for 5b, M n $ 2000 g mol À1 for 5c, M n $ 10 000 g mol À1 for 5d). When these ligands were characterized using size-exclusion chromatography (SEC) (Fig. 3), the SEC proles showed clear shis from high to low retention times with no low molar mass tailing (molecular weight distribution, weight average molecular weight/number average molecular weight (M w /M n ) ¼ 1.05-1.09), which indicated the successful preparation of the polymeric ligands with a precise structure.
Next, Pd-complexes of ligands from 5a to 5d were used in the SM cross-coupling of bromobenzene and 4-methoxybenzeneboronic acid with potassium carbonate (K 2 CO 3 ) as the base in water/toluene (v/v ¼ 4/1) at 90 C. As summarized in Fig. 4a, when the pre-catalyst 6a was used, the reaction gave the highest yield, in a reaction time of 20 min, determined using gas chromatography (GC, yield > 99%). 54 Aer cooling down the reaction mixture with 6a to room temperature (RT), the metalcomplex catalyst was transferred to the aqueous layer and the 4-methoxybiphenyl product was le in the toluene. Using a simple phase separation, the aqueous layer was collected and reused in the next SM cross-coupling reaction. The water phase containing the catalyst was recycled 10 times in this way and there was no clear decrease in GC yields (Fig. 4b). The nal aqueous phase was analysed using inductively coupled plasmaatomic emission spectrometry (ICP-AES), which indicated that 97% of the Pd remained in the aqueous phase, which highlighted the robust catalyst shuttling facilitated by the thermoresponsive polymeric ligand.
Furthermore, the SM cross-coupling using pre-catalyst 6a was found to be applicable to (hetero)aryl chlorides with a wide substrate scope as shown in Scheme 4. Aryl chlorides with a substituent group at different positions could effectively react with aryl boronic acids (45)(46)(47)(48) to give biaryl compounds with yields of 94-98%. Functional groups [for example, acetyl (47), unprotected amino (48) and hydroxyl (49)] and heterocycles including pyridine (51)(52), pyrimidine (53), thiophene (54)(55)(56)(57)(58) and dibenzofuran (58) underwent a smooth reaction with a low (50-500 ppm) catalyst loading, and there were complete conversions in 2-5 h. Given the different reactivities of C-Br and C-Cl bonds demonstrated in Pd catalyzed cross-coupling with many small molecule catalysts, the chemical selectivity of polymeric catalyst 6a was next evaluated, as shown in Scheme 5. Excellent selectivity was observed in all the cases examined. A variety of functionalized bi(hetero)aryl were produced with intact aryl chlorides groups (59-65) at above 90% isolated yields, which could be useful in further metal-catalyzed transformations. It is important to note that the chemoselectivity was not affected by steric or electronic factors with use of the polymeric catalyst.
Tandem SM coupling based on chemoselective reaction facilitated modular and rapid synthesis of diversied molecules for applications such as material screening and drug discovery. [44][45][46][57][58][59] Next, the polymeric catalyst was used in tandem SM coupling based on the different reactivities of electrophiles (Scheme 6). In these reactions, aer the rst step arylation via C-Br bond cleavage, boronic acids were subsequently added into the reaction mixtures without additional catalyst and base. On the basis of the thermoresponsive catalyst migration, it was anticipated that a continuous-ow synthetic strategy 60-67 would be practical for scaling-up the SM couplings at ultralow Pd loadings by continuous recycling of catalyst. To realize this idea, a continuous-ow setup was assembled ( Fig. 5 and Scheme 7) to synthesize 73, a typical unit with aggregation-induced emission (AIE) behavior, which has been used in high-tech applications such as optoelectronic materials and biomedical sensors. 68 A solution of pre-catalyst and base in water was mixed with a solution of bromotriphenylethylene and 4-methylphenylboronic acid pinacol ester in toluene, and delivered into a packed bed reactor (packed with stainless steel beads) 51 submerged in  a preheated bath at 110 C with a 30 min residence time. Aer the reaction, the resulting mixture was collected in a ask under a nitrogen atmosphere at RT. The water layer containing the catalyst was continuously extracted using pump 1 and then reinjected into the ow line. In this way, aer 8.3 h of catalyst recycling, 4.15 g of 73 was isolated from the collected organic layer using only 1.3 mg of pre-catalyst 6a (13.8 mg Pd).
Once this ow technique was available, other bi(hetero)aryl compounds (74-78) and substituted styrene (79) were also successfully synthesized at the gram scale with 10-50 ppm of Pd. Based on the excellent behavior of the continuous catalystrecycling synthesis using ow chemistry, it is believed that a larger scale preparation could be realized by extending the collection time without adding extra catalyst.

Conclusions
In conclusion, a novel thermoresponsive polymeric catalyst was developed, which can rapidly shuttle between water and organic phases, facilitating a highly efficient SM cross-coupling and tandem reaction with good to excellent isolated yields at ppm levels of catalyst usage. This method allows the preparation of a broad scope of bi(hetero)aryls, and can tolerate various functional groups. Furthermore, in combination with ow chemistry, the catalyst shuttling enables continuous catalyst-recycling, further promoting the scalability and efficiency of cross-coupling using ultralow loadings of palladium. Given the signicant inuence of transition-metal-catalyzed cross-coupling and increasing interest in sustainable chemistry, it is believed that, based on the strategy presented here, new response modes can be developed by tuning the structures of the ligands using different polymeric species. Also, the compatibility of this method with other metal-catalyzed reactions is under investigation, which would show promise for facilitating other diverse applications.

Conflicts of interest
There are no conicts to declare.