Miyaura-Suzuki reaction

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 

The synthesis involved construction of a heteroaryl-aryl coupling, where the chloro-thiazole[5,4-i/]pyrimidine was coupled with p-fluorophenyl boronic acid in a Suzuki coupling. The reaction proceeded well even in the presence of a free amino group on the pyrimidine. 

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. 

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Scheme 36 Scaffold decoration via Stille and Suzuki-Miyaura reactions on solid support...

Sulfonamido-l,3,4-oxadiazoles 141 Sulfonyloximes 147 Supports, functional, ionic liquid 115 Suzuki couplings 21,122 Suzuki-Miyaura reaction 164... 

The Suzuki-Miyaura reaction, first reported by Suzuki and co-workers in 1979 [87], is the metal-mediated (often palladium) coupling of organic electrophiles such as alkenyl... 

The aforementioned PEPPSI-IPr pre-catalyst 16 has also been used in the Suzuki-Miyaura reaction. This pre-catalyst allowed the easy preparation of hindered biaryls and drug-like heteroaromatic compounds in good to excellent yields (Scheme 6.27). 

Cazin and co-workers recently reported on the use of the well-defined dimer complexes [Pd( a-C1)(C1)(NHC)]2 that are commercially available, and perform exceedingly well in the Suzuki-Miyaura reaction involving aryl chlorides [108]. The Cazin group has also recently disclosed well-defined mixed NHC/phosphite palladium systems of the type [PdCl2(NHC) P(OR)3j], enabling the Suzuki-Miyaura of aryl chlorides at 0.1 mol% Pd loading [109]. 

Inamoto and Doi have also worked on pincer-type biscarbene complexes of nickel(II). Pre-catalyst 20 was successfully applied to the Suzuki-Miyaura reaction... 

The Leznoff acetal linker 69 was used to anchor an aldehyde to the solid support and following a series of reactions, the aldehyde was released by acidic cleavage [78]. An application of this resin was demonstrated for a biaryl aldehyde library synthesis which incorporated a Suzuki-Miyaura reaction (Scheme 37) [79]. Cleavage was effected by a solution of 3 M HC1... 

Cross-coupling with organoboron compounds (the Suzuki-Miyaura reaction) is by far the most popular and versatile method of cross-coupling, and has been extensively reviewed.3-5... 

The scope of Suzuki-Miyaura reactions is extremely broad, covering practically all types of organic residues. The cross-coupling of arylboronic acids with aryl halides or triflates is the most... 

If the stannane bears substituents at the position geminal to tin, the reaction requires activation by Cu1 (Section 9.6.3.2.1). The cross-coupling of aryl (or heteroaryl) stannanes with aryl (or heteroaryl) halides or triflates is a general route to various biaryls and their analogues, particularly useful in those cases when the Suzuki-Miyaura reaction is less effective for... 

Anionic complexes of boron (boronates, borinates, etc.) have been introduced as convenient reagents in cross-coupling reactions of broad scope, particularly interesting for the transfer of alkynyl and primary alkyl residues, which cannot be accomplished using the standard protocols of the Suzuki-Miyaura reaction. Readily available Ph4BNa can be used as a convenient reagent for phenylation in place of the much more expensive PhB(OH)2, and all four phenyl groups can be utilized when the reaction is carried out with a phosphine-free catalyst in aqueous solutions.244... 

The pincer-type palladacycle (120) (R = 1Pr), which is actually a derivative of a dialkylphos-phinous acid (themselves excellent ligands see Section 9.6.3.4.6) was shown to allow the crosscoupling of aryl chlorides with terminal acetylenes ((120), ZnCl2, Cs2C03, dioxane, 160 °C). However the high reaction temperature may be prohibitive for the actual application of this catalytic system, as acetylenes are known to be thermally sensitive.433 The same palladacycle (R = Ph) is effective in the Suzuki-Miyaura reaction with aryl bromides and activated aryl chlorides (K2C03, toluene, 130 °C). 

A similarly high performance has been reported for oxime-derived (125) and benzylsulfide-derived (126) palladacycles.438 These precatalysts are effective in the cross-coupling of arylboronic acids,438,439 organotin compounds,440 and terminal acetylenes441 with aryl iodides and bromides, and of activated aryl chlorides. SC-palladacycles can effect the Suzuki-Miyaura reaction even at room temperature. 

Other successful examples of catalysts containing NHC ligands are found in palladium- and nickel-catalyzed carbon-carbon bond formations. The catalyst development with these metals has focused in particular on Heck-type reactions, especially the Mizoroki-Heck reaction itself [Eq. (42)] and various cross coupling reactions [Eq. (43)], e.g., the Suzuki-Miyaura reaction ([M] = and the Kumada-Corriu reaction ([M] = MgBr). " Related reactions like the Sonogashira coupling [Eq. (44)]326-329 Buchwald-... 

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)]. ... 

The Suzuki-Miyaura reactions with relatively inert arylchloride are known to require palladium complexes possessing highly electron-rich ligands which favor the oxidative addition of the arylchloride into Pd(0)-complex (Scheme 11) [67-69]. Herrmann et al. showed that the utilization of NHC ligands with bulky substituents... 

Reactions with Organoboron Reagents The Suzuki-Miyaura Reaction... 

Historically, one of the most important limitations of the Suzuki-Miyaura reaction was the poor reactivity of organic chlorides, attributed to the strength of the C-Cl bond. Aryl chlorides are very attractive halides due to their low cost and wider diversity of available compounds. Prior to 1998, reports of effective palladium-catalyzed Suzuki reactions of aryl chlorides were limited to activated substrates, and generally employing very high temperatures. In that year. 

A-heterocyclic carbenes (NHG) have become increasingly popular in the last few years as an attractive alternative to tertiary phosphines in homogeneous catalysis, due to their strong donating ability and thermal stability. Some examples are shown in Figure 4. For the Suzuki-Miyaura reaction, the first example was reported by Herrmann efa/. 

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