The Suzuki-Miyaura Reaction

MW irradiation. The same reaction had previously been conducted with conventional heating with a reported reaction time of 4 h [18]. 

Another topic often encountered in the literature on microwave-promoted reactions is the lower consumption of energy associated with the use of MW technology in small-scale chemistry. For the palladium-catalyzed Suzuki reaction there have been attempts to investigate this matter in more detail. Clark et al. have performed a comparative study of the energy efficiency of the different reaction techniques. The Suzuki reaction was analyzed and under the reaction conditions used the MW-assisted reaction was 85 times more energy-efficient than the corresponding oil-bath-heated reaction. As there are a multitude of reaction conditions for the Suzuki coupling, this value should be seen as an example, rather than a definite value [20]. 

The development of MW-assisted reactions using aryl chlorides has attracted the interest of several research groups. Transition metal-catalyzed reactions with aryl chlorides were elusive for a long time and were generally only successful with very high reaction temperatures and special reaction conditions. Lately, new catalytic systems, most notably those presented by Fu [21], have spurred the development of several schemes for MW-assisted activation of aryl chlorides. 

N-Heterocyclic carbene ligands were used with good results in the sluggish coupling of electron-rich aryl chlorides with phenylboronic acid. These ligands enabled 

Some reactions gave increased yields on addition of tetrabutylammonium bromide (TBAB) [27]. 

Excellent first results have shown the general efficiency in the cross-coupling reactions of arylboronic acids with aryl iodides and bromides, while the reactions with apparently less reactive chlorides failed under this conditions. Further, the SM reaction was significantly developed through a great number of contributions regarding improvements in all above mentioned factors which have strong influence on the reaction efficacy and wide applicability. 

Although the use of triethylamine and other trialkylamines has been reported, these compounds are generally far less efficient bases in the SM reactions [21], The main point concerning the base effect is not only the basicity of an anion, but also the cation contribution is very important. To understand this, briefly discussion on the SM reaction mechanism is essential. Once again, the oxidative addition / reductive 

The nickel-catalysed SM reactions follow closely related reaction pathway. Although the SM reaction mechanism is not completely clear, several experimental evidences indicate the following facts  

The negatively charged base reacts with the arylpalladium(II) halide to give the arylpalladium hydroxide or alkoxide complex, which is able to form the dimeric palladium-boron complex XXIII what is crucial for the transmetallation process [2-6]. It is apparent that the metal cation (from the base) accelerates the formation of the latter, as clearly showed by Zhang and coworkers [15]. They have developed the SM coupling procedure for sterically bulky arylboronic acids when the clear influence of the anion basicity and the cation effect were discovered. The cationic radius is presumably an important parameter which influences the formation of dimeric 

The catalyst plays the most important role in the SM reaction as the reaction actually proceeds within the palladium or nickel coordinative sphere. Since only Pd(0) and Ni(0) complexes possess the catalytic activity, they can be used by  

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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... 

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... 

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/. 

Heterogeneous Pd catalysts can activate the C-Cl bond in aryl chlorides for the Suzuki-Miyaura reaction, presumably due to a synergistic anchimeric and electronic effect that occurs between the Pd surface and the aryl chlorides. Pd on carbon has been found to be a very effective pre-catalyst for a variety of substrates even under very mild reaction conditions and aqueous solvent mixtures.In 2001, Kabalka and co-workers described that Pd powder and KF as base were useful to couple aryl iodides with arylboronic acids in methanol." At the conclusion of the reaction, Pd metal could be recovered by simple decantation. The use of microwave irradiation accelerates the reaction by... 

Along with palladium, several metal-based catalysts have been used for the Suzuki-Miyaura reaction. Zhou and Fu have reported on the use of Ni(COD)2 and bathophenanthroline for the coupling of unactivated secondary bromides... 

Besides photochromism of aziridinyl anils, possible radiochromic properties are mentioned in the literature [110, 124, 125]. In the opinion of Chebanov et al. [110, 124, 125], the most representative radiochromic compounds are the bi- and tricyclic aziridines containing polyarene fragments. To synthesize polyarene derivatives of aziridinyl anils, a modification of the Suzuki-Miyaura reaction was used (Scheme 1.47). 

The Suzuki—Miyaura reaction of protected 6-chloropurine and 2-amino-6-chloropurine bases and nucleosides with substituted phenylboronic acids led to the corresponding protected 6-(substituted phenyl)purine derivatives 6—9. Their deprotection yielded a series of substituted 6-phenylpurine bases and nucleosides 10—13. Significant cytostatic activity (IC50 0.25—20 /tmol/ L) in CCRF-CEM, HeLa, and L1210 cell lines was found for several 6-(4-X-substituted phenyl-purine ribonucleosides 12 (X = H, F, Cl, and OR), while the 6-phenylpurine and 2-amino-6-phenylpurine bases 10 and 11, as well as 2-amino-6-phenylpurine ribosides 13, were entirely inactive against these cell lines. 

In conclusion, the application of the Suzuki—Miyaura reaction of 6-chloropurine derivatives with substituted phenylboronic acids is a facile and effective approach for the synthesis of a series of specifically substituted 6-phenylpurine bases and nucleosides. In comparison with the previously known methods25-30 using other types of organometallic reagents or photochemistry, this method is more effective and selective, and therefore, further applications in the synthesis of 6 C-substituted purine derivatives may be expected. 

Scheme 11 Schematic illustrating the Suzuki-Miyaura reaction, using microwave heating.

In addition to the Suzuki-Miyaura reaction, the authors also found the catalyst 136 to be active toward the arylation of olefins with aryl halides as illustrated in Table 20. Again to conduct a reaction, the authors circulated a solution containing 4-iodoacetophenone 138 (1.00 mmol), the alkene (3.00 mmol) under investigation, and tributylamine 139 (3.00 mmol) in anhydrous DMF (3 ml), through the heated reactor (120 °C) at a flow rate of 2 ml min After 24h, the flow reactor was rinsed with DMF and the... 

The development of catalytic systems using neat water as solvent is of high importance to industrial and environmentally friendly applications. In this respect, water is perhaps the ultimate solvent because of its lack of toxicity and ready availability. Leadbeater has published several papers where the Suzuki-Miyaura reaction has been optimized for aqueous conditions [9,120]. Aryl bromides and iodides were coupled and the corresponding products isolated in good yields with an attractive ligandless protocol. Some reactions gave increased yields with the addition of tetrabutylammonium bromide (TBAB) [121], Recently, an application for a scaled-up Suzuki-Miyaura synthesis in water using an automated batch stop-flow apparatus was also published (Scheme 46) [89]. 

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