Benzofuran 2-methyl-, ring synthesis

A synthesis of the [l]benzothieno[3,2- ][l]benzofuran 63 based on the formation of the furan ring in the key step was elaborated. Alkylation of methyl 2-sulfanylbenzoate 349 with 2-hydroxybenzylalcohol 348 was effected with freshly prepared Znl2 in CH2CI2 and 350 was obtained. Cyclization with lithium diisopropylamide (LDA) in THF afforded 351, which on subsequent cyclodehydration with polyphosphoric acid (PPA) gave 63 in moderate yield (Scheme 36) <2000CCC1939>. 

Intramolecular aldol/Perkin type condensation of orf/to-formylaryloxyacetic acids and arylthioacetic esters produces benzofuran- and benzothiophene-2-esters respectively, as illustrated below. The synthesis can be performed in one pot, thus ortfto-hydroxyaryl-aldehydes or -ketones, are 0-alkylated with a-halo-ketones, then intramolecular aldol condensation in situ produces 2-acyl or 2-aroyl-benzofurans. ° For benzothiophenes, the ring-closure substrates can also be obtained via methyl thioacetate displacement of fluoride from orf/to-fluoro-araldehydes. ... 

Further, we cyclized the methyl group on the nitrogen with the CH2 of the ethoxy linker to form a hve- or six-membered ring (Scheme 19.4) to obtain compounds that showed activity superior to that of their parent molecules. The synthesis of these molecules is outlined in Scheme 19.5. The activity of these compounds to reduce blood glucose and triglyceride in db/db mice is shown in Table 19.2. It is observed that the cyclic linker moiety improved the antidiabetic activity of the compounds compared to the N— Me ethoxy linker. The unsaturated analogs showed better activity than that of their saturated counterparts. Benzyl-protected compounds have been found to be better than free OH compounds, despite losing antioxidant activity. Further, the benzopyran moiety in these molecules were shrunk to dihydrobenzofuran and benzofuran derivatives, which showed modest antidiabetic activities. 

An important plant protection agent based on catechol is carbofuran, manufactured by Bayer diViA FMC, It is obtained by the reaction of catechol with methallyl chloride, followed by Claisen rearrangement at around 200 °C and ring closure to the respective benzofuran, with subsequent reaction of the hydroxyl group with methyl isocyanate in the presence of triethanolamine. (An alternative method of synthesis is based on o-nitrophenol). 

The Pechmann condensation also played a key role in the Biichi group s efforts toward the total synthesis of aflatoxin Bi (44). In this work, the central coumarinic ring system of aflatoxin was prepared by condensing the racemic tricyclic phenol 40 with ethyl methyl-3-oxoadipate (41) in methanolic HCl at 5 °C to provide tricycle 42 in 57% yield. The use of methanol as a solvent was crucial to the success of this reaction, as attempts to perform this reaction in sulfuric acid led to the rapid isomerization of 40 to the corresponding benzofuran-3-acetic acid, which could be converted to the analogous coumarin product only in very poor yield. Subsequent cyclization of the pendant ester moieties of 42 afforded pentacyclic lactone 43. Treatment of 43 with disiamylborane resulted in selective reduction of the dihydrofuranone to the corresponding hemiaminal, which was then acetylated and pyrolyzed (240 °C) to provide ( )-aflatoxin Bi (44). 

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