Biaryl synthesis Suzuki reactions

Qudguiner s group enlisted a combination of directed metalation and a Pd-catalyzed crosscoupling reaction for the construction of heteroaryl natural products [49]. One example was the total synthesis of bauerine B (64), a -carboline natural product [50], Or/fio-lithiation of 2,3-dichloro-A-pivaloylaminobenzene (61) was followed by reaction with trimethylborate to provide boronic acid 62 after hydrolysis. The Suzuki reaction between 62 and 3-fluoro-4-iodopyridine led to the desired biaryl product 63 contaminated with the primary amine (ca. 30%), both of which were utilized in the total synthesis of bauerine B (64). Another p-carboline natural product, the antibiotic eudistomin T (65), and a few other hydroxy p-carbolines have also been synthesized in the same fashion [3,51]. 

Solid-phase Suzuki reaction was first used in the preparation of biaryls [248]. One recent example is given by Baudoin et al. for the synthesis of biologically active biaryl compounds (Scheme 3.13) [249]. 

In the Suzuki reaction, an aryl iodide or synthetic equivalent thereof is coupled with an arylboronic acid or a borane, again using palladium(O) as the catalyst. This reaction is usually used to prepare biaryls, and few examples have been reported of the solid-phase synthesis of alkenes by means of a Suzuki coupling (Table 5.8). 

Trisphaeridine, [8]. The synthesis [9] of trisphaeridine (17) (Scheme 4) involved the known aryl boronic acid 18 and the sterically unencumbered o-bromophenylcaibamate 19 as coupling partners in the Suzuki reaction. The biaryl 20, thus obtained in customary good yield, underwent a Bischler-Napieralsky cyclisation with phosphorus oxychloride to afford the chlorophenanthridine 21. The latter on catalytic dechlorination furnished 17. 

Scheme 17 illustrates another fluorous sulfonate-based synthesis of library scaffolds. The tagged substrates were taken through aldol condensation and cycloaddition reactions to form the pyrimidine ring 18. The intermediates were then reacted with boronic acids for Suzuki reactions to form biaryl compounds 19 [31], reacted with HCO2H to give traceless detagged products 20 [34], or reacted with amine to form products 21 [33]. 

In 1996, workers at GlaxoWellcome disclosed the solution-phase preparation of 2-aminothiazole combinatorial libraries [99], Utilizing 20 glass vials and a DPC liquid dispensing robot, they prepared a library of 2500 compounds by this procedure. Also in 1996, Argonaut reported the use of their computer-controlled fluid delivery system for biaryl synthesis via a Suzuki coupling reaction [61],... 

The Suzuki reaction provides a versatile, general method for the stereo- and regiospe-cific synthesis of conjugated dienes, enynes, aryl substituted alkenes, and biaryl compounds via Pd-catalyzed cross-coupling of vinyl halides or aryl halides with... 

Carbonnelle, A.-C., Zhu, J. A Novel Synthesis of Biaryl-Containing Macrocycles by a Domino Miyaura Arylboronate Formation Intramolecular Suzuki Reaction. Org. Lett. 2000, 2, 3477-3480. 

The Suzuki reaction of j9-chlorobenzoyl chloride and thiophene-2-boronic acid was carried out under anhydrous conditions to furnish ketone 118 [81], providing an alternative synthesis of ketones. Behaving like simple aryl halides, iodothiophenes served as coupling partners with phenylboronic acid [82] and thienylboronic acid [83] to deliver biaryls 119 and 120, respectively. 

Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki reactions employing poly(ethylene glycol) (PEG)-bound aryl halides and sulfonates in palladium-catalyzed cross couplings [71]. It was shown that no additional phase-transfer catalyst (PTC) was needed when the PEG-bound electrophiles were coupled with aryl boronic acids in water under microwave irradiation conditions, in sealed vessels, in a domestic microwave oven (Scheme 16.49). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with ether. 

Beyond the Ullmann and Suzuki-Miyaura Reactions, Other Newer Approaches to Functional Biaryl Synthesis Pd, Fe, Co, and Other Metals... 

A recent example of the application of solid phase Suzuki reactions to the synthesis of pharmaceutically important biaryl compounds was shown by Nielsen et aL [115]. A range of aryl-substituted pyrroloisoquinolines were synthesized from biarylalanine precursors in high purity (Scheme 39). This involved a Suzuki coupling of sohd-supported iodophenylalanine derivatives containing a masked aldehyde to various boronic acids, followed by hberation of the aldehyde, TFA-mediated intramolecular Pictet-Spengler reaction, and cleavage. 

Another example is the synthesis of functionaUzed biaryl a-ketophospho-nic acids, a class of compound with a wide range of biological activity [116]. Initial solution phase Suzuki reactions showed that the a-ketophosphonic acid moiety was unaffected by the reaction conditions, which were then transferred to the solid phase synthesis. This involved the synthesis of several polymer-supported amide-arylboronic acids and their coupling to three different bromobenzyl a-ketophosphonates (Scheme 40). Microwave heating was utilized to produce functionalized biaryl a-ketophosphonic acids 58 in good yield. 

In Suzuki reaction, cross-coupling of aryl- or vinyl-boronic acid with an aryl or vinyl halide catalyzed by a palladium complex, is one of the most versatile reactions for the construction of carbon-carbon bonds, in particular for the formation of biaryls. Recent developments have expanded the possible applications of this reaction enormously. Microwave-assisted Suzuki reactions can now be performed in many different ways and have been incorporated into a variety of challenging synthesis. Under microwave-heated condition, the Suzuki coupling of aryl chlorides with bo-ronic acids was performed in an aqueous media using the air and moisture-stable palladium catalyst. A drastic reduction of the reaction time to 15 min and the formation of products in good yields were achieved (Miao et al, 2005). 

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