Boronic acids Suzuki-Miyaura reaction

Application of the complexes 63 in the Mizoroki-Heck reaction did not reveal higher activity than the previously examined palladium(II) complexes. However, in the Suzuki-Miyaura reaction, a drastically increased activity was observed with complex 63. Catalysis starts without a measurable induction period at mild temperatures accompanied by an extraordinarily high turnover frequency (TOF) of 552 [mol product x mol Pd x h ] at the start of the reaction for the coupling of p-chlorotoluene and phenyl boronic acid [Eq. (48)]. ... 

An efficient aqueous phase Suzuki-Miyaura reaction of activated aryl chlorides with aryl boronic acids has been reported. The method uses a new D-glucosamine-based dicyclohexylarylphosphine ligand for the palladium catalyst and works well with nitro-and cyano-activated chlorides.32 The aryl fluoride bond has been considered inert to palladium-catalysed substitution reactions. However, a computational study, backed up by experiment, shows that the presence of a carboxylate group ortho to fluorine will allow reaction both with phenylboronic acids in a Suzuki-type reaction and with organotin reagents in a Stille-type reaction the presence of the adjacent oxyanion stabilizes the transition state.33... 

For the synthesis of a cavitand functionalized with terpyridyl groups via rigid linkages, transition metal catalyzed cross-coupling reactions are especially well suited. Starting with the boronic acid ester 48 [65], attachment of the terpyridyl groups to the cavitand was realized by Suzuki-Miyaura reaction with the tetraiodo-cavitand 47 (Fig. 15). 

The palladium-catalyzed Suzuki-Miyaura reaction of 3,5-dibromo-2-pyronc 100 with benzo[, ]furan-2-boronic acid 101 was applied to the synthesis of 3-(benzo[ ]furan-2-yl)-5-bromo-pyrone 102 in 50% yield (Equation 92) <2004SL2197>. 

The palladium-catalyzed coupling of boronic acids (as well as other boron derivatives) with aryl and vinyl halides and psendohalides is known as the Suzuki or Suzuki-Miyaura reaction. Because boron is nontoxic, this reaction has been used in pharmaceutical syntheses. In addition, hydroboration or borate substitution allows for the synthesis of virtually any desired coupling partner. For these reasons, as well as the high yields and functional group compatibility, the Suzuki reaction is the first reaction to consider for carrying out a cross coupling. Representative substrates and catalysts are shown in Scheme 17. The various bases are used to generate four-coordinate boron ate complexes that are more reactive in transmetalation. 

The PdCl2-EDTA complex is an efficient catalyst for the Suzuki-Miyaura reactions of aryl and heteroarylhalides with aryl-(heteroaryl)boronic acids in water. Aryl iodides and bromides provide coupled products with TON up to 97,000 (Table 14.3) [194]. 

The air-stable phosphine-borane la was evaluated in the Pd-catalyzed Suzuki-Miyaura reaction. Typically, 4-bromoanisole and phenyl boronic acid were efficiently coupled using 1 mol% of PdCOAc) and 2 mol% of ligand la (Scheme 6). The BMes moiety is compatible with the cross-coupling and it actually improves catalytic activity (under the same conditions, PPh gives a notably lower yield). Interestingly, a catalytically competent Pd(0) complex 39 was isolated and fully characterized. The phosphine-borane adopts a new coordination mode besides phosphorus, the Pd center is coordinated by one of the Mes groups at B interaction). 

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]. 

Several different transition metal-catalyzed reactions with the 2(li-f)pyrazinone template have been evaluated. The Suzuki-Miyaura coupling was efficient in introducing aryl groups to both the 3 and the 5-positions of the heterocycle. The 3-arylated product could be isolated in 75% yield by using 1.1 equivalents of boronic acid and sodium carbonate as base whereas use of 2.2 equivalents of boronic acid with cesium carbonate yielded the 3,5-disubstituted compound in 52% yield (Scheme 15.21) [56]. Efforts to widen the utility of this Suzuki-Miyaura reaction to include solid-phase reactions met with difficulties, because the reaction was problematic to drive to completion [57]. Other teams have also reported problems with Suzuki-Miyaura couplings on polymeric supports [44, 58]. 

C5-substituted 248 were synthesized through the Suzuki-Miyaura reaction of 5-halo derivatives 247 (X = Br, I), prepared from carboxylic acid 201 (R = H, = Me, X = O) through halodecarboxylation with Oxone and sodium halide in basic aqueous methanol (Scheme 95). Suzuki-Miyaura reaction of 247 with boronic acids afforded C-5 substituted derivatives, depending upon the nature of the boronic acid (10TL5103). 

The Suzuki-Miyaura reaction has proven useful for synthetic chemists in the formation of aryl-aiyl bonds. Benefits include generally mild reaction conditions, compatibility with most functional groups, and the use of readily available boronic acids known for their stability. In the reaction shown below, Meldal and co-workers reported a palladium-catalyzed Suzuki cross-coupling reaction of a bromothiophene using a solid-phase synthesis protocol. ... 

Suzuki-Miyaura reactions are perhaps the most widely employed palladium catalyzed cross-couplings in the realm of thiazole medicinal chemistry. They typically take place only when the thiazole is an electrophile in the transformation. The nucleophilic thiazole boronic acid or ester, especially at the 2-position, is relatively unstable and therefore difficult to prepare. The electrophiles namely the 2-, 4-, or 5-substituted halothiazoles are often readily accessible in terms of their synthetic ease or commercial availability. A remarkable application has been described by Jang et al. in the discovery... 

Romagnoli et al. have reported a convergent synthesis of a class of microtubule targeting agents where they aj lied the Suzuki-Miyaura reaction to highly substituted 5-bromothiazoles. With various aryl boronic acid, highly substituted thiazole derivatives were prepared and evaluated for their anti-proliferative activity against a panel of human tumor cell lines. 

Diastereoselective version of the Suzuki-Miyaura reaction was accomplished using planar chiral tricarbonylchromium-complexed aryl bromide with arylboronic acids to form the respective biaryls with very high diastereomeric excess (d.e.) For example, compound 582 underwent the Suzuki-Miyaura reaction with boronic acid 583 to give the biaryl 584 in 88% yield [20], Scheme 7. 

The three basic steps in the palladium-catalysed Suzuki-Miyaura reaction involve oxidative addition, transmetalation, and reductive elimination. A systematic study of the transmetalation step has found that the major process involves the reaction of a palladium hydroxo complex with boronic acid, path B in Scheme 3, rather than the reaction of a palladium halide complex with trihydroxyborate, path A. A kinetic study using electrochemical techniques of Suzuki—Miyaura reactions in DMF has also emphasized the important function of hydroxide ions. These ions favour reaction by forming the reactive palladium hydroxo complex and also by promoting reductive elimination. However, their role is a compromise as they disfavour reaction by forming of unreactive anionic trihydroxyborate. A method for coupling arylboronic acids with aryl sulfonates or halides has been developed using a nickel-naphthyl complex as a pre-catalyst. It works at room temperature in toluene solvent in the presence of water and potassium carbonate. ... 

A detailed study of the transmetaUation in the Suzuki-Miyaura reaction by the group of Amatore and Jutand shows that hydroxide [261] and fluoride anions [262] form the key trans-[ArPdX(L)2] complexes that react with the boronic acid in a rate-determining transmetaUation. In addition, the anions promote the reductive elimination. Conversely, the anions disfavor the reaction by formation of nonreactive anionic [Ar B(OH)3 X ] (7t=l-3). Countercations M" " (Na" ", K" ", and Cs+) of anionic bases in the palladium-catalyzed Suzuki-Miyaura reactions decelerate the transmetaUation step in the following decreasing reactivity order nBu4NOH > KOH > CsOH > NaOH this is due to the complexation of the hydroxy ligand in [ArPd(OH)(PPh3)2] by M+[263]. 

In its original format, the Suzuki-Miyaura reaction involves the cross-coupling of an aryl or alkenyl haHde with a boronic acid or boronate ester in the presence of a base under Pd catalysis. 

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