Suzuki coupling example

To date a number of reactions have been carried out in ionic liquids [for examples, see Dell Anna et al. J Chem Soc, Chem Commun 434 2002 Nara, Harjani and Salunkhe Tetrahedron Lett 43 1127 2002 Semeril et al. J Chem Soc Chem Commun 146 2002 Buijsman, van Vuuren and Sterrenburg Org Lett 3 3785 2007]. These include Diels-Alder reactions, transition-metal mediated catalysis, e.g. Heck and Suzuki coupling reactions, and olefin metathesis reactions. An example of ionic liquid acceleration of reactions carried out on solid phase is given by Revell and Ganesan [Org Lett 4 3071 2002]. 

The first example of microwave-promoted solid-phase methodology in heterocyclic chemistry was the arylation of thiophene and indole via Suzuki couplings on TentaGel S RAM resin, as demonstrated by Hallberg and coworkers in 1996, before temperature- and pressure-controlled microwave instruments were even available [189]. Three years later Schotten and coworkers presented analogous but aqueous Suzuki couplings of 5-bromo-thiophene anchored to PEG soluble support via a carboxylic function at its C-2 position [116]. Unfortunately, this work was performed in a do-... 

Fig. 41 Representative example of microwave-assisted Suzuki couplings in fluorous phase. Reagents and conditions [Pd(dppf)Cl2], K2CO3, toluene/acetone/H20, MW 130°C, 10 min, closed system, 78%...

In a micro reactor, there is much more surface available than in standard reactors [18]. Thus, surface-chemistry routes may dominate bulk-chemistry routes. In this context, it was found sometimes micro-reactor routes can omit the addition of costly homogeneous catalysts, since the surface now undertakes the action of the catalyst. This was demonstrated both at the examples of the Suzuki coupling and the esterification of pyrenyl-alkyl acids. 

As it was shown before that conversions and selectivities can be increased, usually not at the expense of each other, it stand to reason that micro reactors provide high yields. For example, the Suzuki coupling of 4-bromobenzonitrile and phenylboronic acid gives a yield of 62% for micro-flow processing which is about six times higher than with batch processing (10%) at comparable process conditions [155]. 

C) [9, 10]. It is said to be the first example of a heated organic reaction performed in a glass chip reactor imder electroosmohc flow (EOF) control [10] (for EOF see [14]). The performance of this reactor for room-temperatare reactions such as the Wittig reaction and Suzuki coupling was demonstrated before. 

Another example of a one-pot indole synthesis, which proceeds through a Heck carbonylation and a Suzuki coupling, is shown below. The reaction conditions are similar to the previous example however microwave heating is employed [174] (Scheme 6.54). 

A closely related reaction that is currently receiving much attention is the palladium-catalysed Suzuki coupling of arylboronic acids with aryl halides (Fu and Littke, 1998). For example, this technology has recently been applied by Clariant workers for the production of o-tolyl-benzonitrile (Eqn. (13)), an intermediate to a series of so-called angiotensin-II antagonists, a new class of antihypertensive drugs (Bernhagen, 1998). 

Suzuki couplings have been used in the synthesis of complex molecules. For example, coupling of two large fragments of the epothilone A structure was accomplished in this way.229... 

Several microwave-assisted protocols for soluble polymer-supported syntheses have been described. Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki couplings. Schotten and coworkers presented the use of polyethylene glycol (PEG)-bound aryl halides and sulfonates in these palladium-catalyzed cross-couplings [70]. The authors demonstrated that no additional phase-transfer catalyst (PTC) is needed when the PEG-bound electrophiles are coupled with appropriate aryl boronic acids. The polymer-bound substrates were coupled with 1.2 equivalents of the boronic acids in water under short-term microwave irradiation in sealed vessels in a domestic microwave oven (Scheme 7.62). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with diethyl ether. Water and insoluble impurities need to be removed prior to precipitation in order to achieve high recoveries of the products. 

Equation (11.21) is an example of a single-mode microwave-promoted Suzuki coupling, delivering a cyclic H IV-protease inhibitor after a subsequent hydrolysis of the ketal group [35], Half a dozen compounds were synthesized with the help of micro-waves and some of the compounds had K, values in the nanomolar range. 

The first examples of microwave-assisted cross-couplings with organozinc compounds were recently reported [47]. In addition, the first high-speed synthesis of aryl boronates (Suzuki coupling reactants) has been performed under the action of single-mode irradiation with an in-situ-generated palladium carbene catalyst [48],... 

In the following, the reasons for the higher architectural demands are exemplified at two laboratory examples for liquid-liquid Suzuki coupling and imidazol-based ionic liquid synthesis and can only partly be shown in the example of liquid-liquid and gas-liquid processing scale-out. 

Two additional examples of the Suzuki coupling using diethyl (3-pyridyl)borane include the coupling with 4-chloro-2,3 -bipyridine l -oxide (40) to give terpyridine 41 [7] and the coupling with 1,8-dibromonaphthalene to afford a mixture of two atropisomers 42 and 43 of l,8-di(3 -pyridyl)naphthalene [33, 34], Interestingly, the N atoms in 42 and 43 provide enough steric and spectral differentiation to make the detection of atropisomers possible at room temperature. 

In contrast to 3- and (4-pyridyl)boranes, 2-pyridylborane is considered an unsuitable Suzuki coupling partner because it forms an unusually stable cyclic dimer resembling a dihydroanthracene. This obstacle can be circumvented by using 2-pyridylboronic ester in place of 2-pyridylborane. For example, Diederich s group synthesized 2-(2-pyridyl)-8-methylquinoline (49) via the Suzuki coupling of 2-pyridylboronic ester 47 and 2-bromo-8-methylquinoline (48) [36]. 

Figure 13.32. Example of industrially applied Suzuki coupling reaction...

Similar to the case of Suzuki couplings (6.1.2), ally lie alkylations can also be run in neat water as solvent in the presence of surfactants. In addition to the general solubihzation effect, the amphiphiles may also have a specific influence on the reaction rate. For example, the reaction of the P-ketoester substrate on Scheme 6.22 with allyl acetate, catalyzed by [Pd(PPh3)4] was only slightly accelerated by the anionic SDS (1.5 h, 18 % yield), however, the reaction rate dramatically increased in the presence of the cationic CTAB and the neutral Triton X-100 detergents, leading to 74 % and 92% yields in 1.5 h and 5 min ( ), respectively [51]. Several other carbonucleophiles were alkylated in such emulsions with excellent yields. 

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