Highly substituted benzofurans, synthesis

Friedel-Crafts reactions have also been employed in the synthesis of benzofurans. Ohishi and co-workers used a Friedel-Crafts acylation protocol to produce a highly substituted benzofuran with inhibitory activity for leukotriene B-4." Reaction of 3-(4-chlorophenyl)benzoftiran with 2-chloroacetyl chloride provided the corresponding benzofuran derivative in good yield with a handle for further functionalization. A Hantzsch thiazole synthesis was then used to produce the final amino-thiazole inhibitor. 

Phosphazene and its derivatives have been used as bases to catalyze the synthesis of highly substituted benzofurans. Krause and co-workers used phosphazenes in a key step of their total synthesis of amurensin H, an antiinflammatory compound. Treatment of a highly substituted benzophenone precursor with P4- Bu in benzene gave amuresin H after deprotection of the methyl esters with boron tribromide. 

The gold-catalysed synthesis of highly substituted arenes or benzofurans from furans has proved to be a powerful tool for organic synthesis.76 Experimental evidence has now been provided for the formation of (47) via (46). 

These annulations can be extended bqrond indole syntheses. For example, the analogous reaction with ortho-iodophenols can provide an effective method to build up benzofurans (Scheme 6.50) [67]. Presumably due to the lower nudeophilicity of the phenolic oxygen, these reactions generally require higher reaction temperatures. Nevertheless, similar regioselectivity was found here as with the indole synthesis, and, in particular, 2 -silyl-substituted benzofuran is often obtained with high selectivity. This same approach can be applied to the construction of pyrroles and furans [68]. 

As mentioned earlier (Chapter 9.2.1.1), a formal [3 + 2] approach toward the synthesis of benzofurans 57 and related compounds involving a coupling-cydization reaction between ortho-halophenol 54 and copper(I) acetylides 55 was first established by Castro and coworkers (Scheme 9.21) [75-77, 111]. It was proposed that the formation of the benzofuran 57 is a stepwise reaction involving formation of the ortho-alkynylphenol intermediate 56 [77]. The authors demonstrated that a variety of substituted benzofurans could be synthesized in generally high yields via this stoichiometric approach. 

High-yielding Suzuki substitutions of halogen in halo-boronates are also possible using Al-methylimino-diacetic acid (MIDA) to form the protected boronate, which resists coupling under anhydrous conditions. This approach has been applied to aryl and heteroaryl (only thiophene and benzofuran, shown below) systems, and also for polyene synthesis. ... 

The synthesis of saprisartan, reported by Judd and co-workers, used a Suzuki reaction as a key step to couple a benzofuran-based boronic acid with methyl 2-bromobenzoate in 30% yield. The resulting compound was then brominated and the methyl ester was hydrolyzed to produce the corresponding acid in 92% yield. Conversion of the acid to the Boc protected amine occurred with 18% yield. A second bromination, followed by substitution with a highly functionalized imidazole, gave the desired intermediate in 60% over two steps. Three additional steps were required to generate saprisartan in 1% overall yield. 

Despite high levels of efHciency and functional group compatibility achieved in the synthesis of the benzofuran framework via the cydoisomerization approach, utilization of alkynylphenols in this transformation dearly sets limits to the preparation of C3-unsubstituted cores only. This fact prompted development of alternative transition metal-catalyzed routes toward a straightforward assembly of far more valuable C3-functionalized benzofurans with a diverse substitution pattern. 

The authors applied this catalyst to a short and efficient synthesis of e t-corsi-furan A, the unnatural (-l-)-enantiomer of a metabolite derived from stilbenoid precursors (Scheme 3.11) [30]. They found that the hydrogenation of electron-deficient benzofurans was achieved under very mild conditions, while the presence of electron-donating groups in the benzofuran required harsher reaction conditions to achieve full conversion to the 2,3-dihydrobenzofuran. Furthermore, the study demonstrated that the oxygen atom of the benzofuran is crucial for getting high levels of enantioselectivity as the hydrogenation of 3-substituted indene leads to very low enantioselectivity (16% ee). 

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