Fluorous systems, Heck reactions

Using a fluorous palladacycle catalyst 10 originating from the corresponding fluorous Schiff base and palladium acetate, a fluorous Mizoroki-Heck reaction was achieved with an excellent turnover number (Scheme 12). A homogeneous catalytic reaction system was obtained when DMF was used as the solvent. After the reaction, perfluorooctyl bromide was added to facilitate the separation of DMF (containing the products and amine salts) from the catalyst phase. The resulting lower fluorous layer was condensed under vacuum and the catalyst residue was used in a second run. In this reaction, the palladacycle catalyst appears to act as a source of palladium nanoparticles, which are thought to be the dominant active catalyst. 

In the last decade, a lot of attention has been paid to environmental aspects. As to the Mizoroki-Heck reaction, environmentally benign media currently involved in the design of catalytic systems encompass supercritical carbon dioxide (scCOa), fluorous systems, water and aqueous systems, solvent-free systems [66]. In this context, it should be noted that the so-called solvent-free reactions are actually not literally such, but are performed in media composed of substrates and often liquid amine. This was described as early as in 1972 by Heck himself [2, 8] (microwave heated version [53]). Amines are good coordinating solvents during the reaction, the amine is transformed into amine salt, which, being a major constituent or reaction mixture in the absence of a true solvent, adds to the net media polarity. 

There are only very few examples for Mizoroki-Heck reactions in fluorous systems. The catalyst systems, the fluorous or uoufluorous solvent and the additional base are listed in Table 15.1. There are detailed reviews on the Mizoroki-Heck reaction with nonconventional methods that also include fluorous media [12,63]. 

Most of the reported work on Mizoroki-Heck reactions in fluorous media applies palladium salts and free ligands. There are only five reports on the usage of preformed fluorous palladium complexes (Table 15.1, entries 1 ) [64-68]. They all used a biphasic system with an organic solvent and a fluorous catalyst that dissolved only at elevated temperatures. Gladysz and coworkers [64, 65] recovered the catalyst 22 in the only patent on Mizoroki-Heck reactions in fluorous media by simple filtration (Table 15.1, entries 1, 2). The first two runs with iodobenzene and methyl acrylate at 100 °C in DMF were almost quantitative after 2 h reaction time (TON 5251), but after the third run at 100 °C the activity decreased (TON 2500-2900) and the authors changed the reaction time in the fourth run to 10 h to receive again quantitative conversion and yield (TON 5251). 

The first time that a Mizoroki-Heck reaction was conducted in a flnorons system was in 1999 when Sinou and coworkers [71] applied Pd2(dba)3 (dba = dibenzylideneacetone) or Pd(OAc)2 and a perflnorinaled phosphine (e.g. 28-30) in a perflnorinated-nonflnorons solvent mixture in the Mizoroki-Heck reaction of aryl iodides (4h, 80 °C). In this system, the Mizoroki-Heck prodnct was soluble in acetonitrile and the catalyst was dissolved in the fluorous phase. However, some ligand was lost due to its partial solubility in acetonitrile and some of the palladinm was reduced to palladium black. Thus, after each run with the recovered catalyst, lower conversions were obtained. 

Ligand 29 (Table 15.1, entry 9) was also nsed in intramolecular Mizoroki-Heck reactions [72]. In combination with Pd(OAc)2, it catalysed a cascade ring-closing metathesis (RCM)/Mizoroki-Heck reaction. The RCM step was conducted at room temperature on (bromo or iodo) iV-alkenyl-A-allyl-2-halo-benzenesnlfonamides and the Mizoroki-Heck reaction was run at 110°C for 16 h in a perflnorons solvent system. The overall yield with fluorous conditions (0-67%) was significantly lower than a reference system with polymer-bound palladinm catalyst (58-80%). 

Grigg, R. and York, M. (2000) Bimetallic catalytic cascade ring-closing metathesis-intramolecular Heck reactions using a fluorous biphasic solvent system or a polymer-supported palladium catalyst. Tetrahedron Lett., 41, 7255-8. 

Examples of applying biphasic system to catalyzed reactions, such as phase-transfer catalysis, show the efficiency over stoichiometric reactions. In a typical catalytic biphasic system, one phase contains the catalyst while the substrate is in the second phase. In some systems, the catalyst and substrates are in the same phase while the product produced is transferred to the second phase. In a typical reaction, the two phases are mixed during the reaction and after completion, the catalyst remains in one phase ready for recycling while the product can be isolated from the second phase. The most common solvent combination consists of an organic solvent combined with another immiscible solvent, which, in most applications, is water. However, there are few examples of suitable water-soluble and stable catalysts, therefore various applications are limited to some extent [4]. Immiscible solvents other than water are recently becoming more applicable in biphasic catalysis due to the better solubility and stability of various catalysts in such solvents. For example, ionic liquids and fluorous solvents have many successful applications in liquid-liquid biphasic syntheses such as Heck reactions and hydroformylations using ionic liquid media, or Baeyer-Villiger reactions... 

Fluorous Systems Fluorous systems employ fluorinated compounds in perfluorinated solvents, which are immiscible with organic solvents. This allows the design of biphasic systems, where product is extracted from a reusable catalytic fluorous phase with organic solvents. Such systems have recently been applied to the Heck reaction with limited success. ... 

The Heck reaction is another Pdcarbon-carbon bond forming process that is widely employed in organic synthesis and can occur in water. A recent example reported by Cacchi and coworkers was applied to the chemoenzymatic synthesis of (f ) -Rhododendrol (34) and other chiral alcohols (Scheme 4.17) (67]. To aid this work, perfluoro-tagged palladium nanoparticles (Pd p) immobilized on fluorous silica gel or through covalent bonding to silica were used as the catalytic systems. The Heck coupled product could be further treated with (R)-selective LbADH and 2-propanol to address the synthesis of (R)-Rhododendrol in 90% conversion and with 99% ee. 

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