Biarylic microwave Suzuki reactions

Scheme 40 Microwave Suzuki reactions to form biarylic compounds...

The first microwave-assisted Suzuki reactions involving heteroaromatic skeletons were reported in 1996 [35]. Hallberg et al. Hnked the substrates 4-iodo and 4-bromobenzoic acid to a TentaGel-Rink resin (Scheme 16). Suzuki reactions on these soUd-phase-Unked substrates were easily performed in less than 4 min using a constant microwave irradiation power (45 W) (no temperature control Standard acidic cleavage with TEA yielded the corresponding biaryls with an excellent yield. 

Fluorous phase modifications of the Stille reaction were shown by Curran et al. to be accelerated by microwave irradiation.10 Similarly, Hallberg et al. demonstrated that such irradiation gives remarkably fast solid-phase Suzuki reactions, in the generation of biaryl units.9 Their reaction involved the coupling of a tethered (Rink amide TentaGel) aryl iodide or bromide with several boronic acids under 45 W of irradiation at 2450 MHz in sealed... 

Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki reactions employing poly(ethylene glycol) (PEG)-bound aryl halides and sulfonates in palladium-catalyzed cross couplings [71]. It was shown that no additional phase-transfer catalyst (PTC) was needed when the PEG-bound electrophiles were coupled with aryl boronic acids in water under microwave irradiation conditions, in sealed vessels, in a domestic microwave oven (Scheme 16.49). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with ether. 

Another example is the synthesis of functionaUzed biaryl a-ketophospho-nic acids, a class of compound with a wide range of biological activity [116]. Initial solution phase Suzuki reactions showed that the a-ketophosphonic acid moiety was unaffected by the reaction conditions, which were then transferred to the solid phase synthesis. This involved the synthesis of several polymer-supported amide-arylboronic acids and their coupling to three different bromobenzyl a-ketophosphonates (Scheme 40). Microwave heating was utilized to produce functionalized biaryl a-ketophosphonic acids 58 in good yield. 

In Suzuki reaction, cross-coupling of aryl- or vinyl-boronic acid with an aryl or vinyl halide catalyzed by a palladium complex, is one of the most versatile reactions for the construction of carbon-carbon bonds, in particular for the formation of biaryls. Recent developments have expanded the possible applications of this reaction enormously. Microwave-assisted Suzuki reactions can now be performed in many different ways and have been incorporated into a variety of challenging synthesis. Under microwave-heated condition, the Suzuki coupling of aryl chlorides with bo-ronic acids was performed in an aqueous media using the air and moisture-stable palladium catalyst. A drastic reduction of the reaction time to 15 min and the formation of products in good yields were achieved (Miao et al, 2005). 

Early 2005, Leadbeater s team reported that the previously claimed tran-sition-metal-free Suzuki-type protocol was definitely palladium-catalyzed [ 53 ]. Palladium contaminants down to the level of 50 ppb found in commercially available sodium carbonate were responsible for the generation of the biaryl. For good product yields in a short reaction time under microwave irradiation, a loading of 1 ppm Pd was required. 

A rapid and efficient Suzuki-Miyaura coupling protocol utilising fibrous PS-based palladium catalysts (FibreCaF ) and microwave irradiation has been reported by Wang and Sauer (Scheme 8). The biaryl motif 26, formed in this reaction, is an important pharmacophore in many biologically active compounds. Each reaction... 

In most cases microwave reactions have been conducted in a batch system, but very recently the use of a microflow system for microwave reactions has been reported. For example, Suzuki-Miyaura coupling of aryl halides with phenylboronic acid to form biaryls is promoted by microwave irradiation of the supported Pd catalyst (Table 5.1). A thin, gold film patch located on the outside surface of the base of a glass microreactor is quite effective for absorbing microwaves. 

Coupling reactions. Microwave assists the Suzuki coupling in aqueous media. A route to biaryl-2-carboxylic acids is via coupling of l-hydroxy-l,2-benziodoxo-3(l//)-one."... 

Unprotected 4-heteroaryl phenylalanines have been prepared by microwave-assisted Suzuki-Miyaura reactions. Amino adds containing the biaryl motif have several interesting applications in medicinal chemistry and this method enabled their synthesis without protection of the amino acid. Optically pure boronic acids could be used without racemization (Scheme 15.16) [49]. 

---