Suzuki reaction optimization

Ternary Pd-catalyzed coupling reactions of bicyclic olefins (most often norbor-nadiene is used) with aryl and vinyl halides and various nucleophiles have been investigated intensively over the past few years [44]. A new approach in this field is to combine Heck and Suzuki reactions using a mixture of phenyliodide, phenyl-boronic acid and the norbornadiene dicarboxylate. Optimizing the conditions led to 84% of the desired biphenylnorbornene dicarboxylate [45]. Substituted phenyl-iodides and phenylboronic acids can also be used, though the variation at the norbornadiene moiety is highly limited. 

The Suzuki coupling of arylboronic acids to the solid-supported arylha-lide 4 was initially performed by conventional heating methods, DMF at 85° in an oil bath for 16 h, to provide the desired products 6 after TFA cleavage. Due to the extended heating times necessary for the Suzuki reaction, full optimization of the reaction conditions were not investigated prior to compound library synthesis. Reaction conditions sufficient for the library synthesis were determined within a couple of weeks affording moderate yields of the desired oxazolidinones. Libraries of hundreds of... 

M. Palucki and co-workers synthesized 2-[3-aminopropyl]-5,6,7,8-tetrahydronaphthyridine in large quantities for clinical studies via a one-pot doubie Suzuki reaction followed by deprotection and a highly regioselective intramoiecuiar Chichibabin cyciization. This approach was amenable to scale-up unlike the traditional methods such as the Skraup and Friediander reactions that involve carbon-carbon bond forming steps. The Chichibabin reaction was optimized and afforded the desired product in high yield, excellent regioselectivity, and a significant reduction in reaction time compared to literature precedent. 

Application of the Suzuki reaction to the synthesis of cytisine 201 required optimization in order for completion [71]. The workers found that isolation of the boronic acid intermediate corresponding to 149 was problematic. The synthesis did proceed unevent-fully when the workers opted for using the in situ prepared boron-ate complex 199 for the cross-coupling to produce 200. 

Suryanarayana C. Mechanical alloying and miUing. Prog Mater Sci 2001 46 1-184. Schneider F, Szuppa T, Stolle A, Ondruschka B, Hopf H. Energetic assessment of the Suzuki-Miyaura reaction a curtate life cycle assessment as an easily understandable and applicable tool for reaction optimization. Green Chem 2009 11 1894-9. 

Recent developments aiming at highly active and versatile catalytic materials for Mizoroki-Heck and Suzuki reactions in various reaction media, including SCCO2, are exemplified by dendrimer-encapsulated metal (palladium) nanoparticles [121-123]. Although those systems are not yet fully developed and optimized, they have already delivered... 

Alkenylboronic acids and esters are also very useful substrates (Equation 71, Figure 1.38) [405], in particular to access substituted olefins and dienyl moieties commonly encountered in several classes of bioactive natural products [282, 406]. To this end, Kishi and co-workers examined the influence of the base, and developed an optimal variant using thallium hydroxide [281]. Recently, allylic alcohols were found to couple directly with alkyl and alkenyl boronic acids without the aid of a base [407]. In rare cases, the Suzuki reaction has been applied to the use of alkylboronic acids [296, 408], including cyclopropylboronic acids [409]. Hitherto notorious for their tendency to undergo [3-hydride elimination, alkyl bromides are now suitable as electrophiles under carefully optimized conditions that even allow Csp -Csp couplings with alkylboronic acids (Equation 72) [410]. The Suzuki reaction has also been applied very successfully in solid-phase chemistry and combinatorial library synthesis [411]. It has been applied industrially [412], especially in medicinal chemistry, e.g. in the production of the antihypertensive drug losartan [195]. 

Takemoto T, Tabata K, Teng Y, Yao S, Nakayama A, Suzuki E. Optimization of Ci-oxygenates for the selective oxidation of methane in a gas-phase reaction of CH4—O2—NO at atmospheric pressure. Energy Fuels 2001 15 44-51. 

Another industrial scale application of Pd/C in Suzuki reaction was explored by researchers at Merck for the preparation of 67, a PDE4 inhibitor with potential treatment for asthma and chronic obstructive pulmonary disease [27], Under the optimized Suzuki reaction, bromoquinoline 64 and bo-ronic acid 65 in the presence of Pd/C and K COj furnished drug intermediate 66 en route to 67 (Scheme 9.17). 

It should be noted that the success of soHd phase Suzuki reactions can be dependant on the linker. In a study by Fernandez et al., optimal conditions for the Suzuki coupling of solid-supported 5-bromonicotinic acid with various boronic acids were found to vary for three different resins [126]. For amide resins, i.e.. Rink and BAL, aqueous base in a toluene/EtOH solvent gave high yields and purities for a range of boronic acids. However, for ester-bound Wang resin, anhydrous conditions were required to achieve good conversion over a wide variation in the aryl boronic acid. 

Another way to produce biphenyl derivates using flow was described by Leeke et al. [34] where they performed a Pd catalyzed Suzuki-Miyaura synthesis in the presence of a base. First experiments were carried out in toluene/methanol solvent. A reaction mixture was passed through the encapsulated Pd filled column bed length 14.5 cm (some cases 10 cm) x 25.4 mm id. 45 g of PdEnCat. Base concentration, temperature and flow rate were optimized and at optimum parameters (0.05 M base concentration, 100°C and 9.9 mL/min) the conversion was 74%. Then the reaction was performed under supercritical conditions using supercritical CO2 at high pressure and temperature. After optimizing the concentration of base, flow rate, pressure and temperature, the highest conversion rate (81%) was observed at 166 bar and 100°C where the reactant mixture was monophasic in the supercritical state. This system is able to produce 0.06 g/min of the desired product. 

We have subsequently revisited this reaction and successfully optimized the Suzuki microwave-assisted coupling conditions using the Smith synthesizer. Several parameters were investigated, including the palladium catalysts, the reaction temperatures, and the reaction times (Table I). Optimization reactions were run in the Smith synthesizer using 50 mg of resin 7 and 6 equivalents of 4-methoxyphenylboronic acid to afford oxa-zolidinone 8. In just a few days, optimized conditions were identified that afforded the desired product in excellent yields and purities with reactions times of only 5-10 min.8... 

Gordon and Holmes32 used a supported triphenylphosphine-Pd(II) complex as an effective catalyst for Heck and Suzuki couplings in supercritical carbon dioxide (entry 27). After optimization of the amine base for the reaction, the final products have been isolated in good yields and high purity with no traces of metal. 

Table 4 Suzuki-Miyaura reaction used as a model to demonstrate the optimization of microwave induced continuous flow reactions...

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