Biaryls solid-phase synthesis

Combs and coworkers have presented a study on the solid-phase synthesis of oxa-zolidinone antimicrobials by microwave-mediated Suzuki coupling [38], A valuable oxazolidinone scaffold was coupled to Bal resin (PS-PEG resin with a 4-formyl-3,5-dimethoxyphenoxy linker) to afford the corresponding resin-bound secondary amine (Scheme 7.18). After subsequent acylation, the resulting intermediate was transformed to the corresponding biaryl compound by microwave-assisted Suzuki coupling. Cleavage with trifluoroacetic acid/dichloromethane yielded the desired target structures. 

Forman, F. W. Sucholeiki, I. Solid-Phase Synthesis of Biaryls via the Stille Reaction, J. Org. Chem. 1995, 60, 523-528. 

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). 

Forman FW, Sucholeiki I, Solid-phase synthesis of biaryls via the Stille reaction, J. Org. Chem., 60 523-528, 1995. 

A solid-phase synthesis of biaryls has been described by Forman and Sucholeiki [133] they used both phenyltrialkyltins with polymer-supported aryl iodides or the reverse technique involving polymer-supported aryltributyltins and aryl iodides or triflates. The fonmer approach was preferred, even though overall yields were poor. Related chemistry has been reported by Plunkett and Ellmann [134], who prepared 1,4-benzodiazepine derivatives via an initial solid-phase reaction between an aryltin moiety and acid chlorides (Scheme 4-38). 

The reaction was exploited very recently in a solid phase synthesis of biaryls. Aryl zinc bromides undergo palladium catalyzed coupling reactions with aryl bromides bound to a polystyrene resin. The product can be released from the resin by transesterification [44]. Ni(0) catalysed homocoupling of arylzinc reagents could also be realised using aryl triflates [45], as well as aryl tosylates and mesylates [46]. 

In an alternative synthesis, a two-step sequence involved an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution to provide rapid access to biaryl-ether-containing macrocycles in solution phase and solid phase (Figure 11.34). 55 Using isonitriles, aldehydes, amines, and carboxylic acids as inputs for the Ugi reaction, dipeptides 70 were formed. Upon cyclization of 70 with K2CO3 in DMF, macrocycles 71 with four points of diversity were obtained. Moreover, the presence of the nitro group allowed the introduction of further structural variation. In the solid-phase synthesis, the Ugi condensation used isonitriles attached to a Wang resin. 

During their evalnations, plugs were used as supports for solid-phase synthesis of small libraries of biaryl compounds, sulfonamides, tertiary amines, ureas, and amides. Althongh yields and purities were similar to the loose beads counterpart, the reaction times were slightly increased. Becanse of their mechanical stability and limited swelling, plugs are much easier to handle than the corresponding... 

F. Brucoli, P. W. Howard, D. E. Thurston, Efficient solid-phase synthesis of a library of distamycin analogs containing novel biaryl motifs on SynPhase lanterns. J. Comb. Chem. 2009, 77, 576-586. 

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. 

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. 

The protocol offers a direct and efficient method for the synthesis of the boronic ester in the solid phase, which hitherto met with little success using classical methodology (Scheme 1-42). A solid-phase boronate (113 [155], 114 [156]) is quantitatively obtained by treating a polymer-bound iodoarene with the diboron (82). The subsequent coupling with haloarenes furnishes various biaryls. The robot synthesis or the parallel synthesis on the surface of resin is the topic of further accounts of the research. 

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]. 

Finally, by introducing the aryl halide into the isocyanide component, as in 96, various macrocyclic peptidomimetics containing a nonsymmetrical endo biaryl ether bridge have been synthesized [89-91]. Aryl nucleophilic substitution also takes place in this case under standard base-promoted conditions. The synthesis was also carried out on solid phase. Selected examples are shown in Fig. 19, but also a... 

Palladium-catalyzed carbon-carbon bond formation has emerged as one of the most powerful methods in organic synthesis. Consequently, it is unsurprising that adaptation of such methods to the solid phase is an important initiative. Many pharmacophores and scaffolds are directly accessible with simple palladium-catalyzed chemistry, for example, the biaryl subunit,1 which has also been used as the template for a universal library. 2... 

Organ MG, Dixon CE, The preparation of amino-substituted biaryl libraries the application of solid-supported reagents to streamline solution-phase synthesis, Biotechnol. Bioeng., 71 71-77, 2000. 

A 9-phenylfluoren-9-yl polystyrene-based resin has been described for the attachment of nitrogen and oxygen nucleophiles. Greater acid stability compared to the standard trityl resins that are widely used in solid-phase peptide synthesis make this solid support an interesting alternative in solid-phase organic synthesis. This resin can be used in Suzuki coupling reactions to furnish biaryls in good yields [100]. 

B Chenera, JA Finkelstein, DF Veber. Protodetachable arylsilane polymer linkages for use in solid phase organic synthesis. J Am Chem Soc 117 11999-12000, 1995. Y Han, SD Walker, RN Young. Silicon directed ipso-substitution of polymer bound arylsilanes preparation of biaryls via the Suzuki cross-coupling reaction. Tetrahedron Lett 37 2703-2706, 1996. 

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. 

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