Industry perspective FELIX SPINDLER*, PATRICK FURER AND JÜRGEN ROTZLER *Corresponding author Solvias AG, Roemerpark 2, CH-4303 Kaiseraugst, Switzerland Felix Spindler Ligands for Pd catalysed cross-coupling reactions A comparison of commercially accessible ligands KEYWORDS: cross-coupling reaction, palladium, phosphine ligands, Suzuki-Miyaura cross-coupling, Buchwald-Hartwig amination. In a comparative study, a large variety of commercially available phosphine ligands and types of Pd Abstractcatalysts was evaluated for Suzuki-Miyaura cross-coupling, the Buchwald-Hartwig amination and Buchwald amidation reactions. Electron rich and sterically demanding phosphine ligands such as Buchwald or cataCXium ligands were found to frequently exhibit improved catalyst performance in those cross-coupling reactions compared to generic ligands. In general the use of catalysts of the type PR3-Pd G3 was found advantageous, particularly with respect to low catalyst loadings and high chemoselectivities. Despite the fact, that exceptions from this tendency could be found, as generic diphosphines matched or even outperformed such ligands, it was demonstrated that these modular and in bulk amounts available ligands are a valuable starting point for rapid and efficient development of C-X cross coupling reactions. INTRODUCTION coupling reactions. While the evaluation of all commercially available ligands is a rather time consuming task, the Over the last two decades the field of Pd catalysed C-C practitioner under time pressure prefers to work with only a and C-X cross coupling reactions has wit nessed re mark able limited number of potentially active ligands, which are progress, which eventually led to the development of modular, easy to handle (including easily implementable numerous pro ces ses on pilot plant or production scale (1). catalytic protocols) and readily available. With respect to Such advancement came true be cause of the availability such restrictions and the fact that no comprehensive of suitable ligands, the broad evaluation of the scope of the systematic comparison of the performance of such ligands metho do logy and the evolution of new ligands and catalyst in cross coupling reactions has been published until today, precursors (2). The dedication of industrial groups to we anticipated that the evaluation of a series of generic implement such procedures on commercial scale was an and advanced ligands for cross coupling reactions might additional driving force for further improvement of the state- be useful as preliminary study that in turn allows for further of-the-art. While a “one-catalyst-fits-all” solution still has to in-depth substrate specific reaction development. In this be identified, the fast and efficient evaluation of the most article, we report a comparison of dif ferent types of ligands suited ligand/catalyst system is still a major task in the course being used in selected Pd catalysed C-X cou p ling reactions, of process development. From an industrial perspective, such as Suzuki-Miyaura cross-coupling, Buchwald-Hartwig factors such as com mercial availability, cost of goods, amination and Buch wald ami dation re actions. According to supply assurance and intellectual property associated with the above mentioned criteria for considerable ligands, this ligands and catalysts are equally important as the catalyst study was focused on identifying a limited number of performance. ligands, which are deemed promising for an in-depth optimization of the various cross-coupling reactions and not The evolution of various types of ligands, in particular of the to optimize one catalyst for a specific reaction. Buchwald ligand family is the result of a sophisticated fine tuning of steric and electronic properties of phosphine ligands, which have resulted in the development of very EXPERIMENTAL SETUP OF STUDY effective Pd catalysts for cross-coupling reactions. Nowadays, the practitioner is faced with an overwhelming Totally, 20 different phosphine and diphosphine ligands number of ligands that are considered useful for such cross have been evaluated in this study, which were selected not 26 Monographic special issue: Biocatalysis & Catalysis - Chimica Oggi - Chemistry Today - vol. 33(4) July/August 2015 generic monophosphines (PPh3, PtBu3, Pcy3, P(2-furyl)3) have been tested in five Pd catalysed cross- coupling reactions (see Scheme 1). As depicted in Scheme 2, two Suzuki-Miyaura coupling reactions (3), two Buchwald- Hartwig amina tion reactions (4) and a Buchwald amidation reaction (5) were selected for this ligand evaluation study. Scheme 1. Structures of ligands. The catalysts were generated in situ using either [Pd(OAc)2], [Pd2(dba)3] or precursor Pd-G3. For four ligands, the in situ formation of the corresponding PR3- Pd G3 catalysts (see Scheme 3) (6) was monitored by means of 31P-NMR. In the past, the generation of the catalytically active “LnPd(0)” species Scheme 2. Cross-coupling reactions. was a critical issue. The Pd precursors Pd(OAc)2 and Pd2(dba)3 were typically used for such procedures; the drawbacks of this methodology are well documented in the literature (7). Recently, significant progress was achieved in the formation of “L-Pd(0)” species. The introduction of Scheme 3. In situ formation of PR3-Pd G3 catalysts. 2-aminobiphenyl based palladacycles only because of their differences in cone angle, bite angle, with both mono- and diphosphine ligands allows an efficient steric demand and electronic properties, but also because and fast activation of PR3-Pd G3 pre-catalyst, yielding the of their modularity and availability in bulk. Five biphenyl “LnPd(0)” species at room temperature. These pre-catalysts based phosphine ligands (JohnPhos, tBu-XPhos, RuPhos, are easily prepared and can be handled on the benchtop. BrettPhos and tBu-BrettPhos), which were developed by S. Furthermore, the ratio Pd/ligand (PR3) can be critical with Buchwald and co-workers, cataCXium A, seven ligands of respect to maximum catalyst productivity (turnover numbers). the cataCXium P family (K104-0, K105-0, K106-0, K107-0, Typically 2 eq. PR3 are used in combination with the K108-0, K109-0 and K118-0), dppf, XantPhos, cBRIDP and four precursors Pd(OAc)2 and Pd2(dba)3. In contrast, for maximum Monographic special issue: Biocatalysis & Catalysis - Chimica Oggi - Chemistry Today - vol. 33(4) July/August 2015 27 catalyst productivity only 1 eq. of the ligand/eq. Pd (plus 2-methyltetrahydrofurane/water and DMF/water, were approx. 20% excess in order to supress catalyst superior in comparison to biphasic anhydrous conditions. deactivation) is required with the palladacycles Pd G3. The best chemoselectivities (up to 80 – 90%) with 2 mol% However, a standard value of 2 eq. PR3/eq. Pd has been catalyst were obtained with the ligands K118-0, K106-0, tested in this study, which represents the initial part of a K107-0, RuPhos and BrettPhos. process optimization. By taking these results into account, both coupling reactions were reevaluated using 0.5 mol% catalyst, aqueous sol vents, and both catalyst precursors Pd-G3 and RESULTS AND DISCUSSION Pd(OAc)2, respectively (Table 1). In both coupling reactions, the precur sor Pd-G3 outperformed Pd(OAc)2. The evaluation of the various ligands was carried out in a Specifically, using the catalyst K106-0 – Pd G3 in semi-systematic manner using Solvias’ High Throughput­­ combination with aqueous DMF (5.1 vol% H2O) and K3PO4 Experi men tation (HTE) platform. In a first series Buchwald at 80°C gave complete conversion to the cross-coupling and cataCXium ligands were tested in all five coupling product 3 after 12 hrs. (86% conv. after 4 hrs.). Basically, reactions applying eight different reaction conditions with 2 the use of Pd(OAc)2 instead of the precursor Pd-G3 mol% catalyst (s/c: 50). In a second experimental series 16 of resulted in lower catalyst activity and/or chemoselecti vity. the most promi sing ligands (in clu ding commercially The catalyst RuPhos – Pd G3 at s/c 200 had the best available generic ligands) were evaluated systematically overall performance in the coupling of 4 with 5 in the under three different reaction condi tions at 0.5 mol% solvent mixture 2-methyltetrahydrofuran/water (95:5). After catalyst loading. In these series the conversions and yields 4 hrs. the conver sion was 97% and the yield >99.5%. After were deter mined after 4 and 12 hrs. reaction time, 12 hrs. complete conversion together with an almost respectively. perfect chemoselectivity was observed for this coupling reaction (yield >99.5%). The same excellent chemoselec ­­ tivities were observed with the catalysts K106-0 – Pd G3 and K107-0 – Pd G3, but both were found slightly less active than the RuPhos – Pd G3 catalyst (95% conv. after 12 hrs.). On the other hand, the catalysts K118-0 – Pd G3 and BrettPhos – Pd G3 showed also high activities (complete conversion after 12 hrs.), but slightly lower chemoselectivities (96 – 98%). The activity of the catalysts generated in situ from Pd(OAc)2 and the correspon ding phos phine was improved in DMF/water compared to 2-MeTHF/water, as these results revealed. In both reactions high levels of chemoselectivity (>85%) were observed with basically the same set of ligands. In contrast to literature precedence (9), generic ligands such as triphenylphosphine were less efficient in these two Suzuki-Miyaura coupling reactions compared to the best Buchwald or cataCXium ligands. With many catalysts a fast reaction rate over the initial 4 hrs. was observed, Table 1. Evaluation of catalysts for Suzuki-Miyaura coupling reactions. which quite often ended up in a stalling of the reaction. The conversion and the chemoselectivity were determined by HPLC The Buchwald-Hartwig amination reactions 7 + 8 → 9 and (220 nm). Uncorrected integrals were used for the calculation of the 1 + 10 → 11 have been studied in a similar manner as the conversion, the chemoselectivity and the yield. Suzuki-Miyaura coupling reactions. In an initial series Reaction Conditions (RC): twelve Buchwald and cataCXium ligands were evaluated A: 1: 50 µmol; 2: 60 µmol; Pd catalyst: 0.5 mol%; PR3/Pd: 2.4; K3PO4: applying eight ‘stan dard conditions’ with 2 mol% catalyst 62.5 µmol; DMF/water (95:5): 316 µl; T: 80°C, Time 12 hrs.