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Synfacts 2014; 10(8): 0797
DOI: 10.1055/s-0034-1378442
Synthesis of Heterocycles
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Polysubstituted Benzofurans from 2-Alkynylphenols

Contributor(s):
Victor Snieckus
,
Benjamin N. Rocke (Pfizer)
Han Z, Zhang L, Li Z, * Fan R. * Fudan University, Shanghai, P. R. of China
Direct Assembly of 3,4-Difunctionalized Benzofurans and Polycyclic Benzofurans by Phenol Dearomatization and Palladium-Catalyzed Domino Reaction.

Angew. Chem. Int. Ed. 2014;
53: 6805-6809
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Publication History

Publication Date:
18 July 2014 (online)

 
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Key words

alkynylphenols - benzofurans - phenol oxidation - palladium catalysis

Significance

The synthesis of heterocycles bearing substituents at innately low active sites is a problem routinely encountered in the exploration of bioactive series. The reported transformation of 2-alkynylphenols 1 into benzofurans 4 allows the direct synthesis of difficult-to-access C-4-functionalized benzofurans. Yields reported are moderate to good, and the methodology was extended to cover polycyclic benzofurans via 2-alkynyl­phenols with tethered olefins. The transformation of one product into a dibenzazepine was also demonstrated.


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Comment

The investigation of the substrate scope revealed a number of requirements, including R2, R5 ≠ Ph and R3 = Ar. DFT calculations suggested a mechanism in which the reaction occurs by 1) phenol oxidation, 2) palladium-mediated cyclization, 3) nucleophilic addition to the benzofuran 4-position, 4) Heck reaction, and 5) re-aromatization. The selectivity in step 3, between the benzofuran 4- and 6-positions, was rationalized by a predicted electron-deficiency at the 4-position. When 3 contained strong electron-withdrawing groups, step 4 occurred instead as a conjugate addition, and the benzoquinone (BQ) was unnecessary.


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