Solid-phase organic synthesis in the presence of compressed carbon dioxide.

Solid-phase organic synthesis (SPOS) has been established as an important tool for preparative chemistry with a broad range of applications in modern organic synthesis. In very few reaction steps, libraries of molecularly diverse compounds can be synthesized by taking advantage of the efficient removal of excess or unconsumed reagents by extraction and filtration as simple workup operations. However, solid-supported reactions are often characterized by slow reaction kinetics as a result of severe mass-transfer limitations. In particular, this effect is observed for reactions that occur under triphasic (g/l/s) conditions with gaseous reagents under elevated pressure (Figure 1a). In most cases, standard methods for agitation under elevated pressure can not be applied owing to the mechanical instability of the solid supports and/or the typically small scales of parallel synthesis. Consequently, the use of SPOS has been limited for many synthetically useful catalytic processes that involve medium to high pressures of gaseous building blocks, such as hydrogenation or carbonylation reactions. To overcome this limitation, Marchetti and co-workers used a special reactor setup, whereby the solid support was incorporated in a stirrer device and thus agitated through the solution. Breinbauer and co-workers addressed the problem at a molecular level by using soluble polymers as supports to remove one masstransfer barrier. The reaction products were separated after cleavage by dialysis over a period of 12–36 h. We report herein an alternative approach, whereby the use of compressed carbon dioxide either as a supercritical fluid or with expanded liquids (XPLs) leads to an efficient enhancement in the mass-transfer properties in catalytic SPOS. The concept is readily applicable to small-scale and parallel synthesis, as demonstrated for two types of carbonylation reaction. Under conventional SPOS conditions (Figure 1a), mass transfer and the availability of the gaseous reagents are very low, whereas the catalyst concentration is high in the organic solvent. In contrast, supercritical conditions (Figure 1c) result in a maximized gas availability and mass transfer, but at the same time in a decrease in catalyst concentration because of the larger volume of the supercritical phase. The situation in the expanded liquid (Figure 1b) is intermediate, with significantly increased gas availability relative to the gas availability under conventional conditions and a higher catalyst concentration relative to supercritical conditions. The best operating conditions are difficult to predict and depend on the reaction system. As a first benchmark reaction, the hydroformylation of polymer-supported 1-hexen-5-ol (1) was investigated. Trityl polystyrene resin was chosen as the support, as it enables the use of straightforward coupling and cleavage conditions. [Rh(CO)2(acac)] (2), which is known to exhibit high solubility and activity in hydroformylation reactions in conventional solvents and in scCO2, [7] was used as an unmodified Rh catalyst for the carbonylation reaction. To prevent the formation of aldol condensation products under these conditions, the aldehyde 3 was reduced to the corresponding diol 4 with NaBH4 prior to cleavage. [2a] The product 4 was cleaved from the resin with trifluoroacetic acid (TFA) in CH2Cl2. Representative results are summarized in Table 1. First, the reaction was carried out using conventional conditions with toluene as the solvent under synthesis gas (40 bar) in a high-pressure view cell (10 mL stainless-steel reactor). No significant conversion occurred without agitation (Table 1, entry 1). The use of a magnetic stir bar was not possible, since grinding of the substrate beads resulted, as Figure 1. Catalytic carbonylation of solid-supported substrates a) under conventional conditions, b) in an expanded liquid, and c) in scCO2 (g=gas phase, l= liquid phase, s=solid phase).