Immobilized aryl halides

C-C bond formation using the Heck reaction allows the introduction of functional groups to obtain new organic structures on solid supports. This reaction between an alkene with an alkenyl or an aryl halide has been widely employed in various in-tra- and inter-molecular versions on solid-phase because of the readily accessibility of starting materials. The Heck reaction was performed on immobilized aryl or alkenyl halides with soluble alkenes and vice versa (Scheme 3.11). 

One of the first cross-coupling reactions performed on solid supports was the Stille reaction [250] which is a paUadium-catalyzed reaction of a trialkylaryl or trialkylalkenyl stannane with an aromatic iodide, bromide or triflate. In contrast to the process in liquid-phase, the organotin reagent is easily removed from the solid-phase because of the subsequent washing processes. Immobilized aryl halides have been frequently coupled with aryl and alkenylstannanes, whereas stan-nanes attached to the solid support have been used less frequently for the StiUe reaction. An example is the synthesis of a benzodiazepine library by EUman et al. Recently, a Stille cross-couphng reaction has been employed in the synthesis of al-kenyldiarylmethanes (ADAM) series of non-nucleoside HlV-1 Reverse Transcriptase Inhibitors (Scheme 3.14) [251]. 

In a similar way, Guiles and co-workers immobilized an aryl pinacol boronate on resin via an ester linkage, and then a small number of aryl halides were coupled to this (Scheme 31). The products were cleaved and immediately transformed into their methyl esters, presumably for ease of analysis and separation from unreacted boronate. The reaction was found to be slower than that of the opposite polarity (i.e., with the resin-bound iodide), and only moderate yields were obtained after as much as 48 h. Yields could be considerably improved upon a second round of coupling, but only one example was given of this. The aryl bromides were found to react only upon heating. 

Intermolecular Stille reaction of aryl halides with immobilized stannanes (Scheme 6.1.21) provided the coupling products in good yield [45], In addition, the stanny-... 

This may imply that the intermolecular coupling of various aryl halides with other heteroaromatic compounds may proceed. Indeed, it is now known that not only the special heteroaromatic halides but also usual aryl halides can react with a variety of five-membered aromatic heterocycles, including furans, thiophenes, and azole compounds such as M-substituted imidazoles, oxazoles, and thiazoles [133-137]. The arylation of azoles can be carried out using iodobenzoate immobilized on an insoluble polymer support [138]. Related intermolecular reactions of indole [139] and imidazole [140] derivatives have also been reported. 

Application of immobilized palladium catalyst under the action of MW, with phase-transfer agents, has also been reported to promote the Suzuki reactions of a range of aryl halides and triflates in solvents such as water and ethanol under MW conditions [120, 121]. Similar results were obtained when aryl halides were attached to a PEG matrix as para-substituted benzoates [122]. It was found that conventional thermal conditions induced up to 45% cleavage of the benzoates whereas this side reaction was suppressed when MW conditions were employed. 

Highly active immobilized palladium catalysts modified with a rigid C,N,C-pincer carbene ligand were successfully applied in the coupling of aryl halides to terminal acetylenes. The homogeneous catalyst was immobilized on three types of solids - montmorillonite K-10, bentonite A, and bentonite B - by the solvent-impregnation method. No significant differences were observed in the catalytic efficiency between the various supports. The reactivity of the system is relatively constant after as many as five cycles [68]. 

A non-covalent immobilization of Heck catalyst on silica (SILP concept) has been realized by Hagiwara et al. [217]. They used a silica surface, supported with Pd(OAc)2 dissolved in [BMIM][PFe]. This catalyst was appUed to the Mizoroki-Heck reaction of aryl halides with acrylate without a ligand in n-dodecane as solvent. It was six times reused and the overall TON reached 68 400 (for more details see Section 5.6). 

Investigations of a variety of zeoHtes by Djakovitch et al. showed that the shuc-ture or the Si/Al ratio had little influence on the activity of the catalyst. All catalysts achieved complete conversions of bromobenzenes in 20 h with 0.2 mol% Pd at 140 °C [147]. However, kinetic experiments showed that monomeric Pd complexes (in particular [Pd(NH3)4] ) incorporated into the zeolite cages have reaction rates orders of magnitude higher than Pd particles. The immobilized complex converts the aryl halides within a few minutes. Recycling experiments showed that the... 

The carbonylation of aryl halides was performed with [diiodobis(3-methyl-2(3H)-benzothiazolylidene)palladium] immobilized in tetrabutylammonium bromide (melt), [G4GiIm]BF4, [G4CiIm]Cl, [G4CiIm]Br, and tricaprylmethyl-ammonium chloride (aliquat). Palladium acetate associated with phosphines immobilized in [C4GiIm][PF6] or [G4CiIm]BF4 catalyze hydroxycarbonylation of aryl halides and benzyl chloride derivatives (Scheme 19), and the acids are separated by extraction with water. ... 

The Mizoroki-Heck reaction can either be performed on immobilized aryl halides with soluble alkenes [13] or alkynes or with the latter being attached to solid phase and free aryl halides. When performed on the same type of resin and using identical catalyst cocktails, however, it generally seems preferable to use immobilized aryl halides with soluble alkenes rather than doing it the other way around [14]. Both possibilities have been reported and will be discussed below [11]. 

Mizoroki-Heck Reaction Using Immobilized Aryl Halides... 

In general, intermolecular Mizoroki-Heck reactions using immobilized alkenes are not as common as the variant that deals with solid-supported aryl halides, but we will come across another example in Section 14.2,3 on multicomponent Mizoroki-Heck reactions. 

The beneficial application of ultrasound was also demonstrated in the application of immobilized aryl halides. The air- and water-stable Merryfield-type resins could be reused without loss of activity [ 193]. A variety of olefins (e.g. styrene) were reacted to the expected products after cleavage from the resin in yields of up to 81% (purity >90%). 

Acetylene black-immobilized CuO hollow nanospheres (CuO/AB) can be used for the N-arylation of heterocycles (Kim et al 2009). This novel catalytic system was suitable for a variety of substrates, including the electron-rich aryl halides and A-heterocycles. Heteroarylamines such as pyridine-2-amine, pyridine-3-amine, and pyrimidin-2-amine also afforded the desired A-aryl heterocyclic amines. However, a high temperature (180°C) was required to achieve good conversions. 

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