The scope and limitations of Pd(0)-mediated coupling reactions between aromatic halides linked to a polystyrene resin and boronic acid derivatives (Suzuki coupling), aromatic and vinylic tin compounds (Stille coupling), as well as thiols are reported. For all reactions, conditions were optimized and evaluated with various reagents. In many cases, upon cleavage from the solid support, products were obtained in excellent yields. In most cases, the optimized reaction conditions are superior to those previously reported in the literature.The emergence of combinatorial chemistry stimulated intensive efforts in the application of reactions broadly used in solution to the solid phase synthesis. 1 Among the versatile reactions already investigated on solid support, the Pd-mediated C-C bond formation received much attention due to its enormous potential for the derivatization of functionalized structures. 2 A major feature of the Pd-catalyzed coupling reactions between aromatic (or vinylic) iodides and various nucleophilic reagents is their compatibility with most functional groups, which, consequently, do not require to be protected. Although several recent reports encouraged the use of Pd-mediated C-C bond-forming reactions on solid support, generally applicable procedures leading to single products of defined structures in high purity and high overall yield were not yet available. 3 We describe here improved procedures resulting from our scope and limitation studies which allow, in many cases, high conversion of the starting material into the desired products. The improved procedures described here were identified using polystyrene bound aryl iodides. Later on, these procedures were successfully translated with only marginal changes to various highly functionalized core structures. 4For the work described, we used three linkers for the connection of aromatic iodides to polystyrene. 5 Aromatic aryl halides attached through a base labile linker were readily obtained as outlined in Scheme 1. The p-alkoxybenzoate esters 5, 6 and 7 were resistant to basic conditions required for the Suzuki coupling, but were found to be sufficiently labile for transesterification with NaOMe at RT, allowing efficient recovery of reaction products from the solid phase. The acid labile Rink linker 9 was also used in this study (Scheme 2). 6 In many instances, we observed that products obtained from the base labile linker 5 had higher purity compared with those obtained from the Rink-resin 9. It must be stressed, that all reactions reported here were performed on a scale (typically 150-200 mg beads; 0.7 mmol/g) allowing the isolation of at least 20 mg crude product. Yields, therefore, refer to the weight of the crude products corrected by the purity evaluated by 1 H NMR (400 MHz). In some cases, weight of products purified by flash chromatography are reported in parentheses. The structure of all compounds were established by 1 H-NMR and mass spectroscopy. The use of HPLC for yield-and purity determination was avoided, thus allowing a fair compa...