Cross-coupling reactions biaryl synthesis

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

To demonstrate the applicability of this support in organic synthesis, the authors immobilized a (p-bromophenyl) acetic acid which was then transformed into the corresponding biaryl by means of the Suzuki cross-coupling reaction with p-methylphenylboronic acid. Quantitative NaOH cleavage of the ester linkage yielded the released biaryl, of which no purity was mentioned. 

Qudguiner s group enlisted a combination of directed metalation and a Pd-catalyzed cross-coupling reaction for the construction of heteroaryl natural products [49]. One example was the total synthesis of bauerine B (64), a fl-carboline natural product [50]. Ort/zo-lithiation of 2,3-dichloro-iV-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 fl-carboline natural product, the antibiotic eudistomin T (65), and a few other hydroxy 3-carbolines have also been synthesized in the same fashion [3, 51]. 

Three types of reaction systems have been designed and applied for the enantioposition-selective asymmetric cross-coupling reactions so far. First example is asymmetric induction of planar chirality on chromium-arene complexes [7,8]. T vo chloro-suhstituents in a tricarhonyl("n6-o-dichlorobenzene)chromium are prochiral with respect to the planar chirality of the 7t-arene-metal moiety, thus an enantioposition-selective substitution at one of the two chloro substituents takes place to give a planar chiral monosubstitution product with a minor amount of the disubstitution product. A similar methodology of monosuhstitution can be applicable to the synthesis of axially chiral biaryl molecules from an achiral ditriflate in which the two tri-fluoromethanesulfonyloxy groups are enantiotopic [9-11]. The last example is intramolecular alkylation of alkenyl triflate with one of the enantiotopic alkylboranes, which leads to a chiral cyclic system [12], The structures of the three representative substrates are illustrated in Figure 8F.1. 

The ferrocenylphosphine-nickel catalysts are also applied to asymmetric synthesis of axially chiral biaryl compounds through the cross-coupling reaction. Although initial attempts to this... 

Watanabe, T. Miyaura, N. Suzuki, A. Synthesis of sterically hindered biaryls via the Pd-cat-alyzed cross-coupling reaction of arylboronic acids or their esters with haloarenes. Synlett 1992, 207-210. 

Saito, S. Oh-tani, S. Miyaura, N. Synthesis of biaryls via a Ni(0)-catalyzed cross-coupling reaction of chloroarenes with arylboronic acids./. Org. Chem. 1997, 62, 8024-8030. 

N. Miyaura, Synthesis of Biaryls via the Cross-Coupling Reaction of Arylboronic Acids, in Advances in Metal-Organic Chemistry (L. S. Liebeskind, Ed.), JAI Press, Greenwich, 1998, 6, 187-243. 

S. P. Stanforth, Catalytic Cross-Coupling Reactions in Biaryl Synthesis, Tetrahedron 1998, 54, 263-303. 

The cross-coupling reaction currently provides the best and most versatile access to nonsymmetric biaryls [92-97]. Several transformations belong to the standard repertoire of organic synthesis and require mostly leaving functionalities on both reaction partners. Additionally, toxic transition metal catalysts based, e.g., on... 

Phase-switching strategy was applied to the multistep synthesis of isoxazolines 45-47. The approach exploits the boronic acid functionality as a phase-tag which can be easily immobilized on diethanolaminomethyl polystyrene (DEAM-PS) resin and then released by treatment with wet THF. Each reaction step was carried out in solution and the products were purified by addition of the scavenging resin, followed by filtration, washing of the supported material, hydrolytic release and evaporation. Finally, the boronic acid could be used to introduce additional substituents on the molecule. For example, 46 was converted into the biaryl-containing isoxazoline 47 by a Suzuki cross-coupling reaction <07JCO193>. 

The mixed Ullman reaction in which two haloarenes couple in the presence of copper powder is still commonplace in industrial process, but the catalyzed cross-coupling reactions appear to be more productive and provide reliable results in synthesis of unsymmetrical biaryls (Scheme 30). The isomeric michel-... 

The log, lath-like molecular structure of most liquid crystalline compounds makes the cross-coupling protocol very important in syntheses [178,179]. The method based on arylboronic acids simplifies the procedure for liquid crystal materials of more complex substitution patterns [64,180,181] (Scheme 32). The synthesis of arylboronic acids via ortho-metalation of fiuoroarenes and the successive cross-coupling reaction readily extended the aryl units. The Pd/C-cat-alyzed reaction was also reported as an economical alternative [64]. Several liquid crystals having a biaryl unit are now an industrial process of Merck in Germany (ca. 3 tons/year) [182]. 

Stanforth S. P. Catalytic Cross-coupling reactions in biaryl synthesis. Tetrahedron 1998 54 263-303. 

Of the various possible asymmetric cross-coupling reactions, (1) asymmetric alkylation with secondary alkylmetals, (2) asymmetric biaryl synthesis, and (3) asymmetric allylation with allylic electrophiles have been most extensively studied with chiral Ni and Pd complexes [166]. The initial study in this area was reported as early as 1974 by Kumada and his co-workers, but only a meager range of 8-15% ee was reported [167]. By the end of the 1970s, however, the cross-coupling reaction had been sufficiently developed so that its application to the asymmetric synthesis was already practically attractive, as indicated by an asymmetric total sythesis of (R)-(—)-a-curcumene in five steps in 66% ee and 34% overall yield shown in Scheme 1-47 [168]. 

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